Abstract
Substance use disorders are increasingly being conceptualized as behavioral misallocation disorders; however, the neurobiological determinants of this behavioral misallocation are poorly understood. Cocaine use disorder (CUD) develops as a result of behavior being disproportionally directed towards the procurement and use of cocaine at the expense of behaviors maintained by more adaptive, nondrug reinforcers (i.e., job, family). Preclinical cocaine-vs-nondrug reinforcer choice procedures are uniquely positioned to 1) elucidate the biological mechanisms of drug and nondrug reinforcement and 2) inform the development of effective pharmacological and behavioral CUD therapies. Accordingly, this review addresses the existing preclinical literature regarding the economic substitutability and mesolimbic dopaminergic mechanisms underlying cocaine self-administration in the context of three different concurrently available nondrug reinforcers: food, social interaction, and electric foot shock (a negative reinforcer). The manuscript focuses on how the existing cocaine-vs-nondrug reinforcer choice literature guides future research directions to facilitate advances in understanding of CUD from both a neuroscience and translational research perspective.
Keywords: Substance use disorder, cocaine, drug choice, behavioral economics, social interaction, negative reinforcement, dopamine
1. Introduction
Cocaine is an illicit substance that continues to impose significant public health issues. Over 50 million individuals over the age of 12 have used cocaine within their lifetime and 1.4 million people met DSM-5 criteria for cocaine use disorder (CUD) in 2021 (National Survey on Drug Use and Health, 2021). Furthermore, cocaine-related deaths have increased every year since 2010 (Jones et al., 2017; Kampman, 2019; Lipari and Park-Lee, 2020) and have exponentially risen from 2016 to 2021 (National Institute on Drug Abuse, 2023), earning stimulant use disorder the title of the “twin” or “silent” epidemic related to the current opioid crisis (Fischer et al., 2021). Unlike opioid use disorder, for which there are currently three Food and Drug Administration-approved pharmacotherapies (i.e., naltrexone, buprenorphine, and methadone), there are currently zero widespread treatment options for CUD.
The overarching goal of this review is to examine how the existing cocaine-vs-nondrug reinforcer choice literature informs future CUD treatment efforts from both a neuroscience and translational research perspective. We begin by describing the existing cocaine-vs-nondrug reinforcer choice literature focusing on the degree of economic substitutability of cocaine and three different nondrug reinforcers: food, social interaction, and foot shock (as a negative reinforcer). The current knowledge on the temporal dynamics of mesolimbic dopamine (DA) signaling that may underlie the behavioral economic relationship between cocaine and each nondrug reinforcer will be discussed, as these temporal dynamics may provide mechanistic insights regarding how subjects choose between drug and nondrug reinforcement options when concurrently available. We will focus on outlining the additional information gleaned by integrating in vivo neurochemical biosensor technology with the sophisticated cocaine-vs-nondrug self-administration procedures. Finally, each section will discuss how investigating these neurobiological and behavioral mechanisms of cocaine choice provide new research directions in the development of pharmacological and behavioral treatments for individuals with CUD.
2. Background
a. Substance use disorder is a behavioral allocation disorder
Over half of the DSM-5 diagnostic criteria are associated with a distinct behavioral pattern in which an individual with SUD will allocate the majority of their behavior towards procuring and using the drug and consequently, engagement with more adaptive, nondrug reinforcers may be reciprocally reduced. As such, SUD is increasingly being conceptualized as a behavioral allocation disorder (Acuff et al., 2024b; Banks and Negus, 2017a; Heyman, 2009; Lamb and Ginsburg, 2018). Figure 1 illustrates this conceptual framework. An individual without SUD allocates most of their behavior amongst nondrug reinforcers (e.g., social interaction, money, health) and therefore allocates little to no behavior towards commonly misused drugs (Panel A). On the other hand, an individual with SUD may fail to engage or reduce engagement with family or employment and reallocate a maladaptive amount of their behavior towards drug use (Panel B). One contemporary theory suggests this behavioral misallocation in individuals with SUD is driven by decision-making processes focused on maximizing local or immediate satisfaction, as opposed to global or long-term satisfaction (Heyman, 2009; Rachlin, 1997). In alignment with this conceptual framework, an effective SUD treatment would encourage individuals to consider and make decisions that resulted in maximizing global satisfaction. This shift in perspective would result in individuals reducing drug-taking behavior and increasing engagement with nondrug reinforcers.
Figure 1.
In the natural environment, there are several non-drug positive reinforcers available. Examples are social interaction, money, food, sleep, or exercise. An individual without SUD (Panel A) will allocate their behavior amongst these reinforcers (wide arrows) and consequently engage in little to no drug-taking behavior (dashed arrow). In contrast, an individual with SUD (Panel B) exhibits a maladaptive allocation of behavior in which most behavior is allocated towards taking and procuring commonly misused drugs (wide arrow). Consequently, less behavior is allocated towards engaging with non-drug reinforcers (dashed arrows). An effective treatment for SUD would shift behavioral allocation to non-drug reinforcers (Panel A). Adapted from Banks and Negus 2017. Created with BioRender.
b. Drug-vs-nondrug reinforcer choice procedures
Preclinical drug-vs-nondrug reinforcer choice procedures provide a simplified model of this concurrent reinforcer availability clinical context. In a typical preclinical drug choice procedure, monkeys or rats have concurrent access to a drug reinforcer (e.g., cocaine) and a nondrug positive reinforcer (e.g., food). Presentation of either reinforcer follows the three-term contingency (Skinner, 1953) that forms the basis of all operant conditioning (Box 1). For instance, in the rodent cocaine-vs-food choice procedure illustrated in Figure 2, the illumination of a tricolor stimulus light (the ) indicates that pressing the cocaine-associated response lever () will result in the delivery of an intravenous (IV) cocaine injection (the ). A second, food-associated, yellow stimulus light () is also presented, indicating that completing the response requirement on the food-associated response lever () will result in presentation of a food reinforcer (the ). Thus, the rat is given the opportunity to allocate its behavior or “choose” between these two available reinforcers of cocaine and food. The primary dependent measures are 1) behavior maintained by the cocaine reinforcer 2) behavior maintained by the food reinforcer, and 3) the proportion of behavior allocated towards cocaine choice.
Box 1. Operant conditioning theory, established by Skinner (1953), explains how behaviors are learned and influenced by their consequences according to a three-term contingency:
A discriminative stimulus () is an aspect of an organism’s environment that signals an operant contingency is in place and a consequent stimulus () is available. Reinforcement contingencies increase the likelihood of a subject emitting the response () through either presentation (positive reinforcement) or removal (negative reinforcement) of . Punishment contingencies on the other hand decrease the likelihood of a subject emitting the response through either presentation (positive punishment) or removal (negative punishment) of the .
Commonly misused drugs function as positive reinforcers. Individuals learn discriminative stimuli () associated with drug availability (e.g., drug paraphernalia), engage in drug-taking behavior (R), and consequently experience drug intoxication (). If drug intoxication is reinforcing, then intoxication increases the likelihood that they will engage in drug-taking behavior again. Human and preclinical drug self-administration experiments utilize the three-term contingency with the drug delivery as the and therefore can be readily used to study the function of commonly misused drugs as reinforcing stimuli. Humans, monkeys, and rats will self-administer commonly misused drugs, indicating the translational utility of preclinical self-administration procedures (see Table 1).
One contemporary theory is that drug-taking behavior is motivated not by the positive reinforcing effects of the drug, but by the removal of an endogenous aversive withdrawal state (negative reinforcement) (Koob, 2020). In this interpretation, the withdrawal state would be the negative reinforcer whose removal by the self-administered drug infusion increases drug-taking behavior. However, the empirical evidence does not support a robust role for cocaine withdrawal as a negative reinforcer driving cocaine self-administration (Negus and Banks, 2018) and recent studies suggest that opioid withdrawal may also function as a relatively weak negative reinforcer (Marcus et al., 2024).]
Figure 2.
Identification of stimuli and response options in a rodent concurrent cocaine-vs-food choice procedure. The rat is free to allocate behavior between these two concurrently available reinforcers, depending upon the programmed experimental parameters. : discriminative stimulus; R: Response; : consequent stimulus. Created with BioRender.
Two fundamental independent variables that have been manipulated to assess the behavioral economics of commodities within drug-vs-alternative nondrug reinforcer choice procedures are reinforcer magnitude and response requirement. The reinforcer magnitude or “strength” of a reinforcer can be altered by changing reinforcer size, amount, duration, or intensity. For example, increasing the magnitude of a drug reinforcer is conventionally done by increasing the intravenous drug dose that the rat receives (). Methods to alter the reinforcing magnitude of various nondrug reinforcers (food, social interaction, and a negative reinforcer) will be discussed in the following sections. Another set of independent variables that can be manipulated in an experimental choice context is response requirement or “cost.” In laboratory studies, altering response requirement often refers to changing the number of operant responses () the subject is required to emit to be presented with the consequent stimulus (). When a fixed number of operant responses are required for reinforcer presentation, this is called a fixed-ratio (FR) schedule of reinforcement (Skinner, 1938). Increasing the response requirement for a reinforcer could be achieved by changing the schedule of reinforcement from FR1 (i.e., one lever press results in a cocaine infusion) to FR30 (i.e., 30 lever presses result in a cocaine infusion).
Historically, preclinical drug self-administration research has been conducted under single operant experimental conditions, such that only the commonly misused drug was available as a in the environment. As discussed in published reviews (Banks et al., 2019; Banks and Negus, 2012; Negus and Banks, 2021), the use of drug choice procedures to study the mechanisms of and treatments for drug self-administration offers many advantages over the use of traditional single operant drug self-administration procedures. Briefly, preclinical choice procedures have been shown to facilitate translation of animal-to-human results (Ahmed et al., 2013; Foltin et al., 2015; Johnson et al., 2016; Lile et al., 2016; Negus and Banks, 2020, 2021). Additionally, substance use disorder treatment should not only reduce drug-taking behavior but also promote a reallocation of behavior to nondrug reinforcers. Preclinical choice procedures provide a simplified context to measure this desired therapeutic-like effect.
c. Effective behavioral treatments for CUD are founded on scientific principles of operant conditioning and behavioral economics
Contingency management is a behavior-focused treatment strategy for CUD that facilitates the therapeutic outcome of behavioral reallocation to nondrug reinforcers using the scientific principles of operant conditioning and behavioral economics. In fact, a 2021 meta-analysis found contingency management to be the only treatment significantly associated with an increased likelihood of cocaine abstinence in individuals with CUD (Bentzley et al., 2021). Contingency management programs focus on reducing engagement with the three-term drug reinforcement contingency (Box 1) by introducing a competing nondrug reinforcement contingency. In conventional contingency management programs, individuals are presented a monetary nondrug positive reinforcer in exchange for a drug-free urine sample. Thus, contingency management programs establish conditions where there are two mutually exclusive reinforcement contingencies concurrently available to the individual: use the drug and experience intoxication or remain drug abstinent and receive a monetary reinforcer.
Contingency management programs are founded in the economic principles of demand, which state that two available commodities or reinforcers can interact as substitutes, complements, or independents. Economic substitutes are two commodities (e.g., Coca-Cola and Pepsi) where only one or the other is chosen. Changes in the price or availability of Coca-Cola affects consumption of both Coca-Cola and Pepsi, but in opposite directions. Alternatively, commodities could function as economic complements if they are consumed together, where the changes in the price or availability of hotdog buns affects consumption of both hotdog buns and hotdogs in the same direction. Finally, independent commodities are two commodities that are not related. Changes in the price or availability of textbooks does not change consumption of baby diapers. Economic independents, complements, and substitutes are not three discrete categories. Rather, these terms exist along a continuum with perfect substitutes at one end, perfect complements at the other, and independents in the middle.
An important requirement of contingency management is that the nondrug reinforcer functions as an economic substitute for the commonly misused drug reinforcer. Therefore, increases in availability or accessibility of the nondrug reinforcer should decrease engagement with the drug reinforcer. For example, traditional contingency management programs utilize money as the nondrug reinforcer. Money is a token that can be exchanged for any number of commodities, making it a good economic substitute for almost any positive reinforcer, including commonly misused substances. Although money is effective in reducing drug-taking behavior in this contingency management context, adoption of monetary-based contingency management remains limited (Petry et al., 2017), and this highlights an opportunity to identify other nondrug reinforcers that function as economic substitutes for drug-taking. Identification of other economic substitutes could improve contingency management and inform the development of novel, effective behavioral therapies for individuals with SUD. Further, if two commodities function as economic substitutes, this may suggest a more similar biological mechanism of reinforcement than two commodities that function as economic independents or complements.
d. Studying the temporal dynamics of mesolimbic DA signaling may reveal mechanistic insights on cocaine and nondrug reinforcement processes
The primary pharmacological mechanism of cocaine reinforcement is NAc dopamine transporter inhibition, resulting in increased synaptic NAc DA levels. Thus, studies have begun to examine the temporal dynamics of NAc DA during cocaine self-administration. One FSCV study found that when rats self-administer cocaine IV, NAc DA rises prior to the lever press (R), reaching peak concentration between 1 and 2 s post-lever press, and then declines over the next 10 s (Cameron et al., 2014). Similarly, a mouse fiber photometry study indicated that NAc DA peaked within 5 s of the operant response (R) for cocaine (Luján et al., 2023). However, studies have yet to determine precise changes in the NAc DA signal relative to the presentation of the cocaine discriminative stimulus (SD), and during the cocaine infusion (SC). One future direction would be to combine FSCV or fiber photometry with operant cocaine self-administration to improve our fundamental knowledge regarding how the mesolimbic DA system is activated during each one of these key steps in the three-term contingency.
Similar to cocaine, there is evidence to suggest that the underlying neurobiological mechanism of reinforcement for each of the three nondrug reinforcers described in the following sections (food, social interaction, and negative reinforcement) also involves mesolimbic DA pathway activation. However, the temporal dynamics of this mesolimbic DA signaling may slightly differ between cocaine and these nondrug reinforcers. Each of the following sections will describe the current knowledge on the temporal dynamics of DA signaling in food, social, and negative reinforcement. This discussion will emphasize areas for future research towards understanding neurobiological underpinnings to predict if two reinforcers will function as economic substitutes, independents, or complements. Our knowledge of how mesolimbic DA signaling is altered when two reinforcers are available remains unknown as literature has focused on the role of DA neurotransmission during either single reinforcer availability or non-operant procedures. Thus, there are critical gaps in our knowledge as to how mesolimbic DA signaling functions when two reinforcers are concurrently available.
3. Cocaine-vs-food choice
The rich literature on cocaine-vs-food choice provides insight on the economic substitutability of cocaine and food reinforcers. Cocaine-vs-food choice studies in both rats and monkeys (Table 1) have shown that cocaine-vs-food choice is related to the magnitude of the cocaine reinforcer (i.e., cocaine dose), whereby there is a dose-dependent increase in cocaine choice (although see Lenoir et al., 2007). As an example, when the choice is between a small cocaine dose and a food reinforcer, subjects allocate their behavior towards food. When given the choice between a large cocaine dose and a food reinforcer, subjects allocate their behavior towards cocaine (Figure 3, black line).
Table 1.
Summary of papers contributing to the current cocaine-vs-non-drug reinforcer choice literature. Studies included in this table were identified based on an extensive PubMed search for nonhuman and human studies that systematically manipulated one of the independent variables in the first column in a cocaine-vs-non-drug reinforcer (money, food, social interaction, negative reinforcer) choice procedure and reported the effects of these manipulations on cocaine choice.
↑ increase in cocaine choice
↓ decrease in cocaine choice
– no change in choice behavior
? no published data
n/a not applicable
when combined with increasing money reinforcer magnitude
only in subjects with high addiction score
when combined with increasing cocaine response requirement
only in rats who fail to acquire avoidance-maintained responding
when combined with decreasing cocaine response requirement
only tested in males
only tested in females
Figure 3.
Prototypical preclinical cocaine-vs-food choice dose-response curve under different environmental conditions. Based on rat and monkey literature cited in Table 1. (A) Increasing the available dose of cocaine leads to a dose-dependent increase in cocaine-vs-food choice (black line). Increasing the magnitude of the food reinforcer (blue line) shifts the dose-response curve to the right. Increasing the response requirement for cocaine (green line) or food (red line) shifts the curve down or up, respectively. (B) Increasing cocaine dose leads to decreases in the total number of reinforcers earned (black line). Increasing the magnitude of the food reinforcer has been reported to result in a slight upward shift (blue line). Increasing the food response requirement (red line) decreases the total number of reinforcers earned at low to moderate cocaine doses.
Numerous studies in rats, monkeys, and humans have altered the reinforcing magnitude of food within the choice procedure (Table 1). In preclinical drug-vs-food choice studies, subjects may or may not be food-restricted and have unlimited access to standard food in their home cage outside of the operant session. During the operant session, subjects typically have access to a non-standard food “treat” that is highly palatable and may or may not have nutritional value. In rats, the food reinforcer available during the choice session could be either a liquid such as a saccharin solution or Ensure™, or a solid such as a flavored pellet. In monkeys, the food reinforcer is conventionally a fruit-flavored pellet or liquid milk. In the studies cited in Table 1, the magnitude of the food reinforcer was altered by changing the concentration (in rats) or amount (in monkeys) of food concurrently available to cocaine. In both rats and monkeys, increasing the magnitude of the food reinforcer decreased cocaine choice. This effect can be shown graphically as a rightward shift of the cocaine choice dose-effect function (Figure 3, blue line). These reinforcer magnitude studies suggest large alternative food reinforcers will shift behavioral allocation away from cocaine, consistent with food and cocaine functioning as economic substitutes.
In cocaine-vs-food choice studies in both rats and monkeys, increasing the FR response requirement for cocaine decreases cocaine choice and shifts behavioral allocation towards food (Table 1). This effect is represented as a rightward and downward shift in the cocaine choice dose-effect function (Figure 3, green line). Inversely, increasing the FR response requirement for the food reinforcer increases cocaine choice and this effect is depicted as an upward and leftward shift of the cocaine dose-effect function (Figure 3, red line). These response requirement manipulation studies provide further empirical evidence for a high degree of economic substitutability between cocaine and food reinforcers.
Extended access conditions (i.e., 6-12h cocaine self-administration sessions) are another environmental manipulation hypothesized to impact cocaine reinforcement and underlying neurobiological mechanisms (Ahmed, 2011; Ahmed et al., 2003). For example, single-operant cocaine self-administration studies show that extended access cocaine self-administration sessions in rats results in higher progressive-ratio (PR) breakpoints suggesting that extended cocaine access increases cocaine’s reinforcing strength (Paterson and Markou, 2003). Based on these results, extended cocaine access should shift the cocaine-vs-food choice dose-effect function leftward. One monkey study tested this hypothesis and found that extended cocaine access resulted in a 10-fold increase in single operant cocaine intake but did not significantly alter cocaine-vs-food choice (Banks and Negus, 2010). Another monkey study found extended cocaine access resulted in a rightward shift in the cocaine-vs-food choice dose-effect function (Banks et al., 2013a). Consistent with these nonhuman primate data, a history of extended cocaine access failed to enhance cocaine-vs-saccharin choice in rats (Lenoir et al., 2007). Furthermore, Sedighim and colleagues (2021) showed that extended cocaine access increased PR cocaine breakpoints and decreased sensitivity to electric foot shock punishment of cocaine self-administration in a subset of rats. In addition, these subset of rats with a high “addiction score” (defined by Sedighim and colleagues as rats exhibiting escalated cocaine intake, high progressive ratio breakpoints, and responding despite adverse consequences) showed a greater preference for cocaine over food following extended cocaine access compared to rats with a low “addiction score.” One interpretative complication of this rat study is that only a single cocaine dose was tested in the choice procedure, so the full cocaine choice dose-effect function remains unknown. Overall, there is inconsistent evidence that extended cocaine access robustly alters cocaine-vs-food choice and the relative economic substitutability of cocaine and food in nonhumans.
a. Temporal dynamics of DA signaling for food reinforcement
There is ample evidence to suggest the involvement of the mesolimbic DA pathway in food reinforcement. Briefly, early microdialysis studies demonstrated nucleus accumbens (NAc) DA increased following food consumption (Doyon et al., 2004; Hajnal et al., 2004; Hernandez and Hoebel, 1988; Rada et al., 2005), and that DA antagonists impair feeding behavior (Rolls et al., 1974; Wise and Raptis, 1986; Wise and Schwartz, 1981). For full review, see (Baik, 2021; Wise, 2006). However, the literature investigating the precise temporal dynamics of mesolimbic DA signaling in food reinforcement is less robust.
There is evidence that the timing of mesolimbic DA signaling might subtly differ between cocaine and food reinforcement. In fact, some researchers theorize that DA kinetics is one of the main factors driving choice between cocaine and food such that cocaine increases DA to a larger magnitude than food, but also is more delayed temporally than food (Canchy et al., 2021). For instance, the peak NAc DA concentration was observed slightly prior to food reinforcer presentation using fast scan cyclic voltammetry (FSCV) (Cameron et al., 2014). The timing of this peak DA response differed from cocaine reinforcer presentation, in which the peak NAc DA concentration was after the drug infusion (Cameron et al., 2014). Similarly, another FSCV study found that DA release was increased in the NAc core during an audiovisual food (Brown et al., 2011). However, DA response during food consumption was not recorded in this study so the timing of peak DA response was not determined. In opposition of these studies which reported a DA response to the , an early in vivo microdialysis study found no change in NAc DA response to a food (Hernandez and Hoebel, 1988); however, this might be due to the poor temporal resolution of the microdialysis technique. A more temporally precise study by Kutlu and colleagues (2021) using DA fiber photometry in mice demonstrated that following operant training, NAc DA peaked in response to the instead of a sucrose reinforcer. Currently, there is no study that elucidates the precise timing of DA signaling in response to the three terms of the food reinforcement contingency (, R, and ). Improved understanding of temporal DA neurotransmission to food reinforcement may reveal neurobiological insights into how food functions as an economic substitute for cocaine despite resulting in dramatically smaller DA increases.
b. Pharmacological treatment implications
Recently, pharmacological agents initially developed for weight loss/diabetes, such as GLP-1 agonists (e.g., semaglutide) and 5-HT2C agonists (e.g., lorcaserin), have been evaluated as candidate SUD treatments. In preclinical studies, GLP-1 and 5-HT2C agonists have been shown to decrease rates of food-maintained responding (Bernosky-Smith et al., 2016; Collins et al., 2016), likely via suppression of the mesolimbic DA system (Alhadeff et al., 2012; Matteo et al., 2002; Merkel et al., 2025). The rationale for studies investigating application of appetite-suppressant drugs as SUD treatment is founded on the hypothesis that these medications are clinically effective in part by dampening the mesolimbic DA response to food reinforcers and this effect would extend to drug reinforcers, similar to amphetamine maintenance effects on cocaine self-administration (Johnson et al., 2018). Thus, treatment with GLP-1 agonists or 5-HT2C agonists may also reduce drug self-administration towards an effective CUD treatment (for review see Jerlhag, 2023).
In line with this hypothesis, both peripheral (Sørensen et al., 2015) and central (Schmidt et al., 2016) GLP-1 agonist administration attenuated cocaine self-administration in mice and cocaine-induced reinstatement (Merkel et al., 2025). Similarly, the 5-HT2C agonist lorcaserin decreased cocaine self-administration in rats (Harvey-Lewis et al., 2016) and monkeys (Collins et al., 2016). However, in a cocaine-vs-food choice context, GLP-1 agonists and lorcaserin would fail to produce the therapeutic profile of behavioral reallocation away from cocaine and towards food within a cocaine-vs-food choice context. Treatment with either GLP-1 or 5-HT2C agonists should attenuate the reinforcing magnitude of both reinforcers through the shared reduction in mesolimbic DA signaling. The net result of GLP-1 or 5-HT2C agonist treatments on cocaine-vs-food choice would depend upon the relative sensitivity of food and cocaine to the GLP-1 or 5HT2C agonist treatment. The most likely treatment effect would be a generalized depression of operant behavior. This lack of therapeutic effect in a cocaine-vs-food choice procedure would suggest that GLP-1 or 5-HT2C agonists would be ineffective clinically.
In line with this hypothesis, repeated lorcaserin treatment failed to attenuate cocaine-vs-food choice, but decreased operant responding in monkeys (Banks and Negus, 2017b). This preclinical cocaine-vs-food choice result predicted lorcaserin’s ineffectiveness to attenuate cocaine self-administration in humans in both a human laboratory study and clinical trial (Johns et al., 2021; McCann et al., 2024). In fact, lorcaserin increased cocaine-vs-money choice (Johns et al., 2021). There are currently no preclinical or human laboratory cocaine self-administration studies determining GLP-1 agonist effects under a cocaine-choice context. Thus, even if cocaine and food function as economic substitutes in nonhumans, consideration of how pharmacological manipulations might alter behavioral allocation within an economy of multiple reinforcers will be essential to ensuring translational predictive validity of preclinical results towards the evaluation of candidate pharmacotherapies.
c. Behavioral treatment implications
Cocaine-vs-food choice procedures have not been as widely utilized in human laboratory studies as they have in preclinical studies. One study that did examine cocaine-vs-food choice in a population of non-treatment seeking individuals with CUD (Stoops et al., 2010) had participants identify food items worth various dollar amounts ($0.01 - $1.00) that they found palatable. Stoops and colleagues (2010) found that despite increasing food reinforcer magnitude (operationalized as a palatable food of a higher dollar value), participants self-administered cocaine in nearly 100% of the choice trials. This finding suggests that in humans, food may not function as an economic substitute for cocaine. These discordant results in clinical vs. preclinical food choice procedures may be due to the maximum magnitude of food reinforcers offered. Perhaps higher value foods would be chosen over cocaine. Overall, the small human cocaine-vs-food choice literature suggests that food may not be an effective means of decreasing cocaine-taking behavior in humans in a simplified choice context because cocaine and food may not function as economic substitutes.
However, preclinical cocaine-vs-food choice studies are congruent with cocaine-vs-money choice studies in humans with CUD (Table 1). For example, cocaine-vs-money choice increases with cocaine dose (Hart et al., 2000; Lile et al., 2020) where money is chosen over small cocaine doses, but not over large cocaine doses. Similarly, increasing the amount of money available as an alternative to cocaine decreased cocaine choice (Hart et al., 2000; Higgins et al., 1994; Lile et al., 2016). Additionally, cocaine choice decreased when both the cocaine response requirement and the magnitude of the alternative monetary reinforcer were high (Foltin et al., 2016, 2015). Finally, increasing the response requirement for the alternative, monetary reinforcer resulted in increased cocaine choice (Stoops et al., 2012). These results suggest that money functions as an economic substitute for cocaine in humans, and the presence of an alternative monetary reinforcer can reduce cocaine-taking behavior. These results further support the success of money-based contingency management programs in treating individuals with CUD. As previously discussed, money is a token that functions as a universal economic substitute for multiple reinforcers.
The alignment of preclinical cocaine-vs-food choice studies with human cocaine-vs-money choice studies, along with the success of contingency management programs highlights how information gleaned from preclinical studies can be used to inform clinical studies and ultimately have therapeutic applications. However, due to criticisms of monetary-based contingency management, preclinical researchers have begun to identify additional nondrug stimuli that may function as reinforcers in both preclinical and clinical procedures and act as an economic substitute for cocaine. Identifying these nondrug reinforcers can have translational implications as well as elucidate the similarities and differences in biological processes underlying reinforcement.
4. Cocaine-vs-social interaction choice
Social interaction has been established as a reinforcer in a rat preclinical drug-vs-social choice procedures (Venniro et al., 2018). In these procedures, rats lever-press for either an intravenous drug infusion or social interaction with a same-sex peer through a perforated metal barrier. The results of cocaine-vs-social interaction choice studies have shown a similar pattern of results to cocaine-vs-food choice studies (Table 1). Notably, studies report a dose-dependent increase in cocaine-vs-social interaction choice such that a same-sex peer was chosen over small cocaine doses (0.1mg/kg/inf), but as the cocaine dose increased to larger doses (1.0 mg/kg/inf) subjects allocated most of their behavior towards cocaine (Marcus et al., 2022). Additionally, increasing the cocaine response requirement promoted a behavioral reallocation to social interaction-maintained responding in both a mutually exclusive (Bird et al., 2024; Marcus et al., 2022) and non-mutually exclusive (Smith et al., 2023b) cocaine-vs-social interaction choice procedure. Inversely, increasing the response requirement (FR 8-16) for social interaction prompted rats to reallocate their behavior to cocaine (Bird et al., 2024; Venniro et al., 2021). However, increasing the response requirement for social interaction in a rat non-discrete-trial cocaine-vs-social choice procedure did not increase cocaine self-administration (Smith et al., 2023b). This is likely due to the consistently high rates of cocaine self-administration maintained by rats in this procedure. Overall, behavioral allocation between cocaine and social interaction is sensitive to both reinforcer magnitude and response requirement manipulations, indicating that cocaine and social interaction function as economic substitutes.
Given this observed economic substitutability, one would hypothesize that within a choice context, increasing the reinforcing magnitude of social interaction would promote a behavioral reallocation away from cocaine and towards the social reinforcer. One study attempted to increase the reinforcing magnitude of social interaction in a cocaine-vs-social interaction choice procedure by increasing the duration of the social interaction period (Marcus et al., 2022). However, cocaine-vs-social interaction choice behavior was unchanged. This result indicates that duration of the social interaction period is not an effective means of increasing the reinforcing magnitude of social interaction. This conclusion is further supported by evidence that increasing the duration of the social interaction period from 30 to 60 s does not affect social interaction-maintained operant responding (Baldwin et al., 2022; Chow et al., 2022).
One means of increasing social interaction reinforcer magnitude in rats may be by increasing the level of physical contact between the social pair. An early study found that the success rate of learning to emit a lever-press response for social interaction was higher when there was full physical contact between the two rat subjects (Angermeier, 1960). Additional conditioned place preference (CPP) studies have indicated that beyond just physical contact, specifically the ability to engage in play behavior with the partner rat is critical to the rewarding aspect of social interaction (Calcagnetti and Schechter 1992; Trezza et al. 2009). Thus, the removal of the metal barrier in the operant cocaine-vs-social interaction choice procedure may prompt a more robust behavioral reallocation towards social interaction. However, as rough and tumble play is more apparent during adolescence (Pellis and Pellis, 1997; Thor et al., 1985) and males initiate more play fights than females (Pellis and Pellis, 1990) increasing the level of physical contact between adult and/or female rats may have a minimal effect. Additionally, social interaction may overall have stronger rewarding properties during adolescence, as suggested by the higher social CPP scores in adolescent vs adult rats (Douglas et al., 2004). Future studies could compare cocaine-vs-social interaction choice in adolescent vs adult rats.
Other independent variables have also been manipulated to alter social interaction reinforcer magnitude in rodents. For example, one study manipulated both housing condition and familiarity with the social partner and found that rats who are single-housed and responding for a familiar partner displayed the highest rates of operant responding for social interaction (Chow et al., 2022). This result aligns with previous studies indicating that social isolation promotes social interaction (Latane and Steele, 1975). Other potential manipulations of reinforcer magnitude include attempts to alter the internal state of the animal. For instance, studies have found that rats exhibit decreased levels of social interaction in putatively anxiogenic novel testing environments (File and Seth, 2003; Varlinskaya and Spear, 2008) or while in an acute pain state (Baldwin et al., 2022). The sex of the test subject and/or the sex of the social partner may also change the magnitude of social interaction as a reinforcer. A recent study found that male rats show higher rates of social interaction-maintained responding for a female, compared to a male social partner (Chow et al., 2024). In contrast, female rats showed consistent rates of social interaction-maintained responding regardless of the sex of the social partner (Chow et al., 2024). Other studies have not reported robust sex differences with regards to operant responding for social interaction in rats (Chow et al., 2022; Sharp and Smith, 2022). Nevertheless, recent studies have suggested potential sex differences in the neural processing of social interaction (Borland et al., 2019; Li et al., 2020; Poceviciute et al., 2023).
The studies described above report independent variable manipulations that may alter reinforcing magnitude of social interaction in rodents. The extent to which the preclinical manipulations described (duration, physical closeness, age, level of familiarity, time since last social interaction, stress, pain state, or sex as a biological variable) also alter the reinforcing magnitude of social interaction in monkeys and/or humans remain outstanding research questions. This complexity of social interaction as a reinforcer highlights both future research opportunities and the difficultly in isolating what component(s) of social interaction are key to its reinforcing effects. In addition, future studies of cocaine-vs-social interaction choice in monkeys and humans could have profound translational implications for the development of effective behavioral interventions for individuals with CUD.
Drug history has been hypothesized as an independent variable that may alter cocaine-vs-social choice. In one study, rats with a limited cocaine history were evaluated in a cocaine-vs-social choice procedure. Then, rats self-administered cocaine under extended access conditions and were tested again in the choice procedure (Venniro et al., 2021). Although the study did not directly compare the effects of different access conditions on cocaine-vs-social choice, behavioral allocation appeared unchanged following extended access, suggesting that different cocaine access conditions may have a minimal effect on cocaine-vs-social choice. However, one limitation was only a single dose of cocaine (0.75 mg/kg/inf) was examined and the degree to which drug self-administration history might alter choice behavior across a range of self-administered drug doses would be a future direction towards enhancing the rigor of the literature. These future experiments could have important translational implications, as individuals with CUD have an extensive drug history. Perhaps individuals with CUD engage with social reinforcers differently or have a different neurobiological response to social reinforcement than individuals without an extensive cocaine history. This hypothesis is supported by a study in which recent cocaine exposure enhanced social interaction-maintained responding (Sharp and Smith, 2022).
a. Temporal dynamics of DA signaling in social reinforcement
Previous studies have shown that positively-valanced social interactions involve activation of the mesolimbic DA reward pathway (Chow et al., 2024; Gunaydin et al., 2014; Hu et al., 2021; Hung et al., 2017; Solié et al., 2022), suggesting a common mechanism of reinforcement between both cocaine and social interaction. In particular, a mouse study by Gunaydin and colleagues (2014) used fiber photometry to study the precise temporal dynamics of VTA-NAc signaling during interaction with a same-sex partner. Interestingly, peak VTA activity occurred during approach to a same-sex social peer. The timing of this peak activity differed from when mice were exploring a novel object, in which peak VTA activity occurred during novel object withdrawal. Similarly, Dai and colleagues (2022) found that extracellular NAc DA increased in both male and female mice during approach to an opposite sex social partner, and that this approach-induced DA increase was greater than the DA response to approaching a novel object. Furthermore, an in vivo electrophysiology study found that the majority of VTA DA neurons were active when the subject mouse was nose-to-nose with the partner (“reciprocal interaction”) or nose-to-tail with the partner (“unilateral interaction”), and very few neurons were active when the subject rat was tail-to-tail with the partner (“passive interaction”; Solié et al., 2022) during non-operant social interaction. These results provide biological evidence that social interaction might be most rewarding or reinforcing when both subjects are actively engaged.
Other studies have measured mesolimbic DA activity during operant social interaction tasks like the ones used in cocaine-vs-social interaction choice procedures. Using fluorescent biosensors, Hu and colleagues (2021) found that extracellular NAc DA increased following the performance of the operant response (nose poke), and then reached peak levels when the dividing gate started to open, signaling the onset of social interaction. During early training, DA levels remained elevated throughout the social interaction period and then decreased as the gate started to close (offset of social interaction). However, after several training days, DA levels began to decline to baseline levels during the social interaction period and decreased below baseline as the gate closed (Hu et al., 2021). Similarly, another study also found a decline in the NAc DA signal throughout the social interaction operant session (Chow et al., 2024). This is an interesting result which suggests there may be some satiety to operant responding for social interaction that may not be observed with cocaine self-administration. Further, the greater magnitude of NAc DA response to an unfamiliar vs a familiar social partner (Dai et al., 2022) combined with the lack of a correlation between NAc DA and operant demand for a social partner (Chow et al., 2024) suggests that mesolimbic DA response may be driven primarily by the novelty of the social partner rather than the magnitude of the social interaction. A future cocaine-vs-social interaction choice study using a fluorescent biosensor to monitor DA levels in the NAc could determine whether an attenuated DA signal to social interaction corresponds to a behavioral reallocation to cocaine choice.
Additionally, Solié and colleagues (2022) found that over the course of social operant training, mouse VTA DA activity measured using in vivo electrophysiology transitioned from peaking during the social interaction period to peaking during the operant lever-press response. This result is in alignment with reward prediction error theory and suggests that the timing of DA signaling may be similar across different positive reinforcement contingencies, underlying the substitutability of positive reinforcers in a concurrent choice context.
b. Pharmacological treatment implications
Social interaction may have unique reinforcing effects due to the involvement of social-specific biological mechanisms. For instance, there may be critical involvement of the “pro-social” peptide hormone oxytocin within the mesolimbic DA system during social reinforcement (Rappeneau and Castillo Díaz, 2024; Rigney et al., 2022).
Virus-based tracing studies have shown that oxytocin neurons in the paraventricular nucleus (PVN) of the hypothalamus project to VTA dopaminergic neurons (Beier et al., 2015; Hung et al., 2017). In addition, oxytocin release enhances VTA DA neuron activity (Xiao et al., 2017). One pharmacological study used a selective oxytocin receptor antagonist in adult male hamsters to demonstrate that activation of oxytocin receptors in the VTA was necessary for establishing social interaction CPP (Song et al., 2016). Similarly, Hung and colleagues (2017) showed that knocking out the oxytocin receptor selectively in the VTA prevented the development of social CPP whereas cocaine CPP remained intact, suggesting that VTA oxytocin activity was both necessary and specific to social vs drug reward. Additionally, microdialysis studies show that oxytocin administration in the VTA enhances NAc shell DA release (Melis et al., 2007; Sanna et al., 2012) and intracerebroventricular oxytocin increases medial NAc shell neuron firing rate (Moaddab et al., 2015). Interestingly, optogenetic stimulation of PVN oxytocin neurons was insufficient to produce CPP but did facilitate social CPP (Hung et al., 2017), suggesting that activation of PVN oxytocin signaling does not produce a rewarding effect alone, but may enhance social reward learning.
These CPP results suggest that determining the role of oxytocin in future cocaine-vs-social choice studies could be an interesting research direction. Studying oxytocin involvement in an operant social interaction paradigm may facilitate our understanding of the neurobiological mechanism of social interaction as a reinforcer alone or in the context of cocaine-social choice studies. For example, oxytocin administration may produce behavioral reallocation towards social interaction, while an oxytocin receptor antagonist may decrease social interaction-maintained responding and produce behavioral reallocation towards cocaine. Given the growing interest in the oxytocin system as a potential therapeutic target for substance use disorders (Bowen and Neumann, 2017; Edinoff et al., 2023; King et al., 2020; Proskynitopoulos et al., 2024; Rastogi et al., 2024; Souza et al., 2023), preclinical investigation of the influence of oxytocin receptor agonists on drug-vs-social choice may reveal a therapeutic effect, indicating the potential success of oxytocin agonists in CUD clinical trials.
c. Behavioral treatment implications
Preclinical cocaine-vs-social interaction choice studies indicate that social interaction is an economic substitute for cocaine self-administration in rats. Although there are no human laboratory studies of cocaine-vs-social interaction choice, the economic substitutability of drug and social reinforcement does appear to be maintained in a human population, as evidenced by the effectiveness of the community reinforcement approach for treating individuals with SUD. In the community reinforcement approach, individuals with SUD are encouraged to build and strengthen social relationships with nondrug-associated family members and friends (Meyers et al., 2011; Miller et al., 1999). The scientific premise is that through increasing the reinforcing magnitude of social interaction, individuals would reduce drug use and potentially achieve abstinence. Results of cocaine-vs-social interaction choice studies in rats offer preclinical evidence in support of the further development and implementation of community reinforcement programs.
Using social interaction as an alternative nondrug reinforcer in a behavioral treatment program rather than a monetary reinforcer could have several advantages. For instance, after completion of a money-based contingency management program, reductions in drug-taking behavior may not be maintained upon removal of the nondrug reinforcement contingency. In contrast, by encouraging patients to make meaningful connections with drug-abstinent or nondrug-associated family and friends, a community reinforcement-based contingency management program would facilitate sustained reductions in drug-taking behavior. This may help prevent a return to drug use after leaving the treatment program. In fact, a study in individuals receiving opioid use disorder medications found that higher loneliness scores predicted positive urine screenings at a six month-follow-up (McDonagh et al., 2020), suggesting that ameliorating feelings of social isolation may reduce drug-taking and could be used in combination with pharmacological treatment for SUD to improve treatment outcomes.
Additionally, programs that encourage social interaction as an alternative reinforcer might mitigate the current financial and practical burden of money-based contingency management programs. Recently, a randomized clinical trial of telehealth-delivered cognitive-behavioral therapy for perceived social isolation among individuals with opioid use disorder found that participants described the program as both helpful and useful (Ashrafioun et al., 2024). Further, participants who received this cognitive-behavioral therapy showed greater reductions in opioid and overall substance use compared to controls (Ashrafioun et al., 2024). These programs may represent a cost-effective and practical means of increasing engagement with social reinforcers among individuals with SUD as a means of treatment.
Additionally, cocaine is often used in social settings such that the individual is choosing to engage with cocaine and social interaction simultaneously. In this type of non-exclusive choice situation, the reinforcing properties of cocaine and social interaction may interact such that presentation of one reinforcer enhances the magnitude of the other reinforcer in an additive or synergistic fashion. In support of this hypothesis, Thiel and colleagues (2008) showed that neither peer social interaction nor a small dose of cocaine produced CPP in rats, but a combination of social interaction and the small cocaine dose did produce CPP (Thiel et al., 2008). Furthermore, studies have shown that acute cocaine pre-treatment increased operant responding for social interaction (Sharp and Smith, 2022) and that prior training on operant responding for cocaine + social interaction maintained higher PR breakpoints for social interaction than a history of responding for social interaction alone (Smith et al., 2023a). These studies would suggest that behavioral treatments attempting to implement social interaction as a mutually exclusive alternative reinforcer to cocaine may find patients reporting that social interaction has a weak reinforcing magnitude when they are not under the influence of cocaine. Thus, behavioral treatment programs would need to find ways to enhance the reinforcing magnitude of these social interactions while also decreasing drug-taking behavior. This could be achieved through engagement of fun and novel experiences with a drug-abstinent or nondrug-associated social partner. For instance, instead of having a friend over to your home to talk (familiar environment, minimally engaging activity), you and the friend could explore a museum, take a cooking class, or paint pottery (new environments with nondrug-reinforced activities).
Similarly, studies by Smith and colleagues have demonstrated that although cocaine self-administration was inhibited by concurrent access to a non-drug-taking peer, cocaine self-administration was facilitated by the presence of a co-self-administering peer. In these studies, male and female rats who were housed with a cocaine self-administering same-sex peer showed greater cocaine-maintained responding across a range of doses (0.1 – 1.0 mg/kg/inf, FR1) compared to their counterparts who were housed with a drug-abstinent same-sex peer (Robinson et al., 2017; Smith, 2012). Also, in a free-operant choice procedure, male rats exhibited higher demand for cocaine (0.5 mg/kg/inf) when social interaction with a cocaine-treated same-sex peer was available on an alternative lever, compared to when social interaction with a non-intoxicated same-sex peer was concurrently available (Smith et al., 2023b). Several additional studies from this group support the conclusion that there is a bidirectional impact of social contact on drug self-administration according to intoxication state of the peer (Peitz et al., 2013; Robinson et al., 2017; Strickland and Smith, 2014). As is true in epidemiological studies, social relationships with non-drug-using individuals exert a protective effect against the development of drug use, while relationships with drug-using individuals is a risk factor for drug use (Bahr et al., 2005; Nawi et al., 2021; Simons-Morton, 2007). Thus, behavioral treatment programs for CUD should encourage individuals in early recovery to establish social relationships with drug-abstinent peers and discourage social relationships with drug-using peers.
Group therapy and social living houses are excellent examples of effective behavioral interventions that encourage social relationships with drug-abstinent peers. A systematic review and meta-analysis found that group therapy is more effective at promoting drug abstinence, relative to individual therapy (Lo Coco et al., 2019). Additionally, sober living houses promote a host of positive recovery outcomes including sustained improvements in abstinence, frequency of substance use, legal system involvement, mental health, and employment (Polcin et al., 2010a, 2010b).Overall, this literature demonstrates how mutually exclusive vs. non-mutually exclusive choice contexts of cocaine and social interaction influence behavioral allocation. In addition, whether a social partner is drug intoxicated or not, may be important independent variables in developing behavioral or pharmacological treatment programs for people with CUD and the preclinical evaluation of candidate CUD medications.
5. Cocaine-vs-negative reinforcer choice
In addition to positive reinforcers, negative reinforcers are also available in our natural environment and may also compete with behavior maintained by commonly misused drugs. A negative reinforcer is a consequent stimulus whose removal increases the likelihood of responding (see Box 1). For example, brushing your teeth is a negatively reinforced behavior because the absence of a cavity (the negative reinforcer) increases the likelihood that you will continue to brush your teeth. In preclinical studies, foot shock is often used as a negative reinforcer, where subjects are trained to emit a response to avoid or escape the electric foot shock (Babbini et al., 1979; Berger and Brush, 1975; Sidman, 1953). In contrast to the extensive literature on cocaine-vs-positive reinforcer choice procedures described above, behavioral allocation between cocaine and a negative reinforcer has only recently been explored.
Two studies have examined behavioral allocation between cocaine and a negative reinforcer. One study utilized a discrete-trial cocaine-vs-shock avoidance/escape procedure in which rats made a mutually exclusive choice between a cocaine infusion and avoiding or escaping an electric foot shock (i.e., negative reinforcement) (Marcus and Banks, 2023). In contrast to the cocaine-vs-positive reinforcer choice procedures described above, cocaine-vs-negative reinforcer choice was insensitive to manipulations of cocaine dose such that even at large cocaine doses that were chosen over food or social interaction (1-1.8 mg/kg/inf), rats allocated the majority of their behavior to the negative reinforcement contingency. Manipulating the negative reinforcer magnitude by decreasing shock amplitude did shift behavioral allocation away from shock and towards cocaine in a sub-set of rats who failed to learn a shock avoidance response (i.e., pressing prior to the shock presentation to cancel an upcoming shock) and therefore only emitted escape responses (i.e., pressing during the shock presentation to immediately terminate the shock). This result aligns with cocaine-vs-positive reinforcer choice studies regarding cocaine choice sensitivity to nondrug reinforcer magnitude manipulations (Table 1). However, rats that learned the avoidance response were insensitive to shock amplitude manipulations because they rarely experienced the shock stimulus (Marcus and Banks, 2023).
Another study used a non-discrete trial, independent concurrent schedule of cocaine-vs-timeout from shock avoidance choice in rats to assess behavioral allocation between cocaine and a negative reinforcer and determine the effects of response requirement manipulations (Beasley et al., 2023). Similar to Marcus and Banks (2023), increasing the response requirement for the cocaine reinforcer failed to significantly attenuate cocaine choice (Beasley et al., 2023). Manipulating the response requirement for a negative reinforcer in a discrete-trial procedure is experimentally difficult because of the short, limited hold for the animal to respond before presentation of the negative reinforcer (i.e., emit an avoidance response), or emit an escape response. Due to these time constraints, the subjects failed to complete the negative reinforcer response requirement at high response requirements and did not promote a reallocation of behavior to the cocaine-associated lever (Marcus and Banks, 2023). However, Beasley and colleagues (2023) found that simultaneously increasing the response requirement for the negative reinforcer and decreasing the response requirement for the cocaine reinforcer produced an increase in cocaine choice in male rats using their independent, non-discrete trial procedure. The different results found in these two studies are likely due to the discrete-trial vs non-discrete-trial differences in the choice procedures.
Overall, there is a paucity of evidence to suggest that cocaine and electric shock as a negative reinforcer are economic substitutes. Instead, the evidence overall suggests that cocaine and negative reinforcers function as economic independents. One limitation to this conclusion is that thus far, the only negative reinforcer tested in cocaine choice procedures has been electric foot shock and the degree to which other negative reinforcers might compete with cocaine remains to be empirically determined. Additional stimuli that could be used as negative reinforcers in future choice procedures are removal of histamine infusions or removal of access to an aggressive social partner.
Cocaine self-administration under extended access conditions is hypothesized to be critical to the development of “compulsive” cocaine-taking behavior, or cocaine-taking despite adverse consequences (Ahmed, 2011; Vanderschuren and Everitt, 2004). Indeed, some rats exposed to extended access cocaine demonstrate a decreased sensitivity to shock-associated punishment of cocaine reinforcement (Belin et al., 2009; Deroche-Gamonet et al., 2004; Pelloux et al., 2007). Accordingly, one might hypothesize that extended cocaine access would lead to a reallocation of behavior away from the negative reinforcer of shock avoidance/escape and towards cocaine self-administration. However, the existing evidence demonstrates no effect of extended access cocaine on cocaine-vs-negative reinforcer choice (Marcus and Banks, 2023). These results are consistent with other studies (Ahmed et al., 2013; Pelloux et al., 2015) suggesting that persistent cocaine self-administration despite adverse consequences may be driven by a lack of alternative reinforcers available in the environment rather than reduced sensitivity to positive punishment or because of some hypothesized internal state of the subject.
a. Temporal dynamics of DA signaling in negative reinforcement
The literature regarding changes in DA signaling to aversive stimuli and the role of DA signaling in negative reinforcement learning is more nuanced. However, the extant literature does suggest a critical role for mesolimbic DA signaling in negative reinforcement (although see Fiorillo 2013) and that there may be subtle differences in mesolimbic signaling underlying positive and negative reinforcement, that may contribute to their economic non-substitutability.
Numerous studies show that aversive stimulus presentation, such as foot shocks, do elicit changes in extracellular NAc DA levels. However, there is conflicting evidence regarding the directionality of this change and thereby whether NAc DA signaling tracks the valence or the salience of the stimulus. Several studies show extracellular NAc DA decreases during foot shock using both FSCV (Oleson et al., 2012; Stelly et al., 2019) and fiber photometry (Patriarchi et al., 2018). A recent study found that aversive white noise significantly attenuated NAc DA in male and female rats (Grafelman et al., 2025). Combined with the previously discussed evidence that positive reinforcement increases mesolimbic DA signaling, these results suggest that mesolimbic DA signaling increases in response to reward (positive valence) and decreases in response to aversive stimuli (negative valence). However, other studies have shown opposite results, reporting that NAc DA increases in response to a foot shock (Kutlu et al., 2021, 2022) and tail pinch (Budygin et al., 2012), and that extracellular NAc DA increases with increasing shock intensity (Kutlu et al., 2021). These data suggest that DA signal tracks stimulus salience, regardless of valence. Often, these conflicting results are attributed to the presence of distinct cell types within various brain regions of the mesolimbic DA pathway such as the NAc (Budygin et al., 2012; de Jong et al., 2019), dorsal striatum (Hikida et al., 2010; Shin et al., 2018; Xiao et al., 2020), VTA (Brischoux et al., 2009), or amygdala (Yang et al., 2023) that respond differently to aversive stimuli. In summary, the lack of consensus in the literature regarding whether mesolimbic DA signaling (a) is associated with stimulus valence or salience, and (b) is specific to certain cell types within certain brain regions, complicates interpretation of mesolimbic DA signaling during complex behavioral contingencies such as negative reinforcement.
A study using fast-scan cyclic voltammetry (FSCV) (Stelly et al., 2019) and a study using dLight fiber photometry (Kutlu et al., 2021) trained subjects to engage in an operant response to avoid or escape a foot shock and measured extracellular NAc DA. Both studies reported an increase from baseline DA levels during the shock safety signal. This result suggests a common directionality and temporal pattern of NAc DA signaling between positive and negative reinforcement. A recent publication by Grafelman and colleagues (2025) similarly found that lever-pressing to terminate an aversive white noise resulted in increased NAc DA in male and female rats. Additionally, both Stelly (2019) and Kutlu (2021) reported that the magnitude of the NAc DA increase during the safety signal was attenuated over the course of learning the escape/avoidance response. This suggests that extracellular NAc DA response in negative reinforcement might follow the same reward prediction error theory often used to explain positive reinforcement learning in which the safety signal “reinforcer” becomes expected following extensive training of the avoidance/escape response (Schultz, 2016, 1988). However, Stelly (2019) and Kutlu (2021) reported opposite directionalities of the DA signal in response to the negative reinforcement-associated . To fully align with positive reinforcement DA dynamics and prediction error theory, the NAc DA signal should increase in response to the negative reinforcement-associated as presentation of the becomes associated with predicted safety signal presentation. While increases in NAc DA in response to the negative reinforcement-associated were found by Kutlu (2021), the studies referenced have not differentiated between avoidance and escape responses in data analysis. There are likely meaningful differences in the time course of DA response between avoidance and escape responses that could influence the economic substitutability with commonly misused drugs.
A study by Oleson and colleagues (2012) used FSCV to compare NAc DA signal between avoidance and escape responses in a discrete-trial foot shock avoidance/escape procedure. They found that the temporal pattern of DA signaling differed between the escape and avoidance responses (Oleson et al., 2012). When an escape response was emitted, rats did not show a response to the negative reinforcement-associated but did show a decrease in NAc DA during the shock. This was followed by an increase in DA signal upon completion of the operant response. During an avoidance response, there was an increase in DA following presentation of the negative reinforcer . Then, there was a further increase in DA signal after completing the operant response. These temporal dynamics (especially for escape responses) differ from the early stages of cocaine self-administration, where NAc DA remains stable until peaking seconds after the cocaine infusion (Cameron et al., 2014; Luján et al., 2023). In the Oleson (2012) study, DA response during early training was not reported, so changes over the course of training in response to the are unknown. Overall, the current literature suggests that negative and positive reinforcer-associated discriminative and consequent stimuli may evoke different mesolimbic DA responses. Potential differences in DA signaling could underlie the non-substitutability of positive and negative reinforcement in a concurrent choice context. Future studies of cocaine-vs-negative reinforcer choice studies combined with fiber photometry could address some outstanding questions about the similarities and differences in mesolimbic DA signaling between positive and negative reinforcement, and between avoidance and escape responses.
b. Pharmacological treatment implications
The use of cocaine-vs-negative reinforcer choice procedures to identify potential pharmacological treatments for CUD may be difficult for several reasons. First, the couple preclinical studies discussed suggest that negative reinforcement contingencies maintain high (if not near maximal) rates of responding, even when an alternative cocaine reinforcer is available. Thus, from a practical perspective, there may not be sufficient behavioral allocation towards cocaine to detect an effect of a candidate medication. Second, pharmacological manipulations that increase attentiveness to negative reinforcement contingencies may have undesirable side-effects associated with symptoms of neuropsychiatric disorders such as anxiety or obsessive-compulsive disorders, in which a harmful drive to avoid dreaded outcomes is a defining diagnostic feature.
However, drug-vs-negative reinforcer choice procedures may have utility in addressing fundamental questions about the underlying neurobiological circuitry associated with operant escape and avoidance responding. Targeting brain regions and circuits implicated in avoidance behavior, such as glutamatergic prefrontal cortex → basolateral amygdala projections (Diehl et al., 2020; Kajs et al., 2022), may selectively alter negative reinforcement-maintained responding in a cocaine-vs-negative reinforcer choice procedure. In addition, the discrete-trial negative reinforcement procedure used by Marcus and Banks (2023) produced both “Escaper” and “Avoider” rat phenotypes, resulting in the opportunity to study potential individual differences in the neural mechanisms underlying each of these negative reinforcement-maintained behaviors.
c. Behavioral treatment implications
The findings from cocaine-vs-negative reinforcer choice procedures offer an interesting perspective on methods employed in behavioral drug treatment programs. Importantly, these findings do not support the use of additional aversive stimuli to punish drug-taking behavior. Instead, these studies begin to provide some preliminary evidence in support of drug treatment programs scheduling aversive stimuli already associated with drug use (such as legal and financial repercussions) as negative reinforcers, rather than positive punishers.
Several preclinical studies have shown that punishment is not an effective means of producing drug abstinence (McNally et al., 2023; Monroe and Radke, 2021). This is in part because punishers are most effective in shaping behavior when administered immediately and consistently after every positive reinforcer. The immediacy and consistency of punishment requires constant monitoring of drug-taking behavior (Negus, 2005; Woolverton et al., 2012), which poses significant practical and financial challenge to implementation in the clinical environment by both law enforcement and healthcare providers. Instead of using punishment contingencies, negative reinforcement contingencies could be implemented to promote patient engagement in alternative behaviors that would compete with drug use. Both Beasley and colleagues (2023) and Marcus and Banks (2023) indicate that concurrently available negative reinforcement contingencies are an effective means of decreasing drug-taking behavior, and thus negative reinforcement may have clinical therapeutic potential.
A real-world example of re-scheduling punishers as negative reinforcers is the expansion of drug treatment courts (DTC). Ideally, DTCs replace drug-related incarceration (a punisher) with involvement in a local substance abuse treatment program, with legal contingencies in place. Thus, the patient can avoid incarceration by completing an operant task (e.g., community service, clinician appointments) consistent with the treatment goals and exclusive of drug use. While current DTC programs employ extensive drug-testing, these programs may not require as much costly, time-consuming, and precise monitoring of drug use because the goal is not to punish drug use, but to displace it with an alternative nondrug reinforced behavior. Additionally, once learned, avoidance contingencies are very resilient to extinction in humans (Vervliet and Indekeu, 2015), meaning that even inconsistent presentation of the aversive stimulus could maintain high rates of engagement with the negative reinforcement contingency. Negative reinforcers of lesser magnitude (i.e., monetary fines rather than incarceration) could also be used to maintain a reallocation of behavior away from drug-taking.
While scientifically sound in theory, one issue with implementing DTC is the inconsistent quality of care amongst local substance use disorder treatment clinics (Fisher, 2014). Additionally, although DTC is overall successful at reducing rates of recidivism and return to substance use (Marchand et al., 2006; Mitchell et al., 2012; Rossman et al., 2011), these outcomes are strongly influenced by social determinants of health such as race and ethnicity, education, and employment status (Wilson et al., 2018). Maintaining a consistent level of high-quality SUD care across states and counties in addition to individualizing treatment programs to account for different social determinants of health are two ways to improve the acceptability and efficacy of these behavioral treatment programs.
6. Conclusion
Studies conducted with cocaine-vs-nondrug reinforcer choice procedures have enhanced our fundamental knowledge of the behavioral and neurobiological mechanisms of CUD and have offered valuable insights on the development of behavioral and pharmacological treatments for individuals with CUD. However, there are still many opportunities to expand upon existing cocaine-vs-alternative reinforcer choice studies to have even greater neuroscience and translational implications for CUD. Three potential future directions are proposed.
One future direction for drug choice studies would be to incorporate in vivo biosensors to monitor neurotransmission simultaneously during behavioral studies to allow for a greater mechanistic understanding of neurobiological processes underlying drug and nondrug positive and negative reinforcement. Advances in this area of research may help reveal novel drug targets for CUD pharmacotherapies that may selectively block cocaine reinforcement while leaving non-dug reinforcement intact. Additionally, studies determining whether there is a reinforcer magnitude-dependent increase in NAc DA response to cocaine and nondrug reinforcers in a choice context are an important future direction to understand behavioral allocation between commonly misused drug and nondrug reinforcers. Moreover, these studies could improve our understanding of how candidate CUD medications promote behavioral reallocation away from cocaine and towards nondrug alternative reinforcers. For example, combining repeated treatment with the muscarinic agonist xanomeline with in vivo biosensors monitoring NAc DA could improve our mechanistic understanding of how xanomeline treatment attenuates cocaine-vs-food choice in rats (Thomsen et al., 2014). Completion of these studies might provide researchers with a neurobiological correlate of reinforcer magnitude which may allow for predictions of choice behavior in preclinical and ultimately clinical studies.
Second, the substitutability of cocaine and positive reinforcers in a preclinical context supports the further investigation of additional nondrug positive reinforcers that could be used to decrease drug-taking behavior. New preclinical behavioral procedures where the subject chooses between cocaine and concurrently available exercise or environmental enrichment, for example could help propel the development of additional behavioral interventions to help treat individuals with CUD. Exercise and environmental enrichment have been shown to alter cocaine conditioned place preference (Smith et al., 2008; Solinas et al., 2008; Thanos et al., 2010), and adolescent female rats with concurrent access to wheel running self-administered less cocaine than their counterparts without access to a wheel (Zlebnik et al., 2012). However, these positive reinforcers have yet to be investigated as economic commodities to cocaine in an operant choice procedure and represent a future direction for preclinical research. These proposed studies would help probe the environmental determinants of economic substitutability of different nondrug reinforcers with cocaine and develop new research areas for both mechanistic and medication development directions. Moreover, data collection in CUD clinical trials on nondrug reinforced behaviors both at baseline and following evaluation of a candidate CUD treatment would facilitate reverse translation. Currently, the primary dependent measure in clinical trials evaluating candidate pharmacotherapies is cocaine-positive urines, but an interesting and informative endpoint would be whether the candidate pharmacotherapy increased nondrug reinforced behaviors (see Acuff et al., 2024a; González-Roz et al., 2025).
Finally, sex as a biological variable has not been rigorously studied within cocaine-vs-nondrug reinforcer choice procedures (Table 1). Preclinical non-choice studies have generally found that high estradiol/low progesterone is associated with increased levels of cocaine reward and reinforcement (for reviews see Anker Justin J. and Carroll, 2011; Carroll & Anker, 2010; Moran-Santa Maria et al., 2014). Observational studies examining the subjective effects of cocaine in human participants have found similar results (Evans et al., 2002; Sofuoglu et al., 1999). However, to our knowledge very few studies have examined the effect of estrous cycle on cocaine-vs-alternative reinforcer choice. These studies report conflicting results, with one study showing that cocaine-vs-food choice does not vary across the female rat reproductive cycle (Kerstetter et al., 2012), others reporting that female rats’ food self-administration declines while cocaine self-administration remains stable (i.e., cocaine choice increases) during the proestrus/diestrus phase (Perry et al., 2015, 2013), and another reporting that the magnitude of reduction in cocaine-vs-food choice was the greatest during the monkey’s follicular phase (high estrogen) (Carroll et al., 2016). Additional studies of cocaine-vs-food choice and novel studies of cocaine-vs-social interaction or cocaine-vs-negative reinforcer choice that investigate sex as a biological variable could further our understanding of sex differences in cocaine choice behavior, how mesolimbic DA neurotransmission might be similar or different between males and females during cocaine choice behavior, and the potential influence of sex hormones. Ultimately, these studies could aid in the development of sex and gender-informed treatment methods for people with CUD.
Highlights.
Preclinical drug-choice studies inform pharmacological/behavioral cocaine use disorder treatments
Cocaine and food function as behavioral economic substitutes
Cocaine and social interaction also function as behavioral economic substitutes
Cocaine and foot shock as a negative reinforcer function as behavioral economic independents
Incorporating in vivo biosensors with drug-choice should improve mechanistic understanding
Funding:
Funding for this project was provided by the National Institute on Drug Abuse (F31DA059209 to MMM, R21DA053820 and R01DA055825 to MLB). Dr. Marcus also received support from T32DA007027, R34DA058494, and R01DA059483. The funding sources had no role in the interpretation, writing, or decision to submit this review for publication.
Footnotes
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