Place conditioning in humans: opportunities for translational research

Abstract

Rationale

Translational research, especially research that bridges studies with humans and nonhuman species, is critical to advancing our understanding of human disorders such as addiction. This advancement requires reliable and rigorous models to study the underlying constructs contributing to the maladaptive behavior.

Objective

In this commentary, we address some of the challenges of conducting translational research by examining a single procedure, place conditioning. Place conditioning is commonly used with laboratory animals to study the conditioned rewarding effects of drugs, and recent studies indicate that a similar procedure can be used in humans.

Results

We discuss the opportunities and challenges of making the procedure comparable across species, as well as discuss the benefits of more systematically applying the procedure to humans.

Conclusion

We argue that the capacity of humans to report verbally on their internal experiences (perceptions, affective states, likes and dislikes) add an important dimension to the understanding of the procedures used in laboratory animals.

Introduction

Addiction is an acquired psychiatric condition characterized by the compulsive use of drugs despite their negative consequence on self and society. To understand the behavioral and biological machinery underlying compulsive drug seeking and to develop pharmacological interventions, animal models of addiction are necessary. Animal models such as intravenous drug self-administration or place conditioning (often called conditioned place preference) have been used to study many constructs related to drug use and misuse such as initiation, escalation, and relapse (Carr et al. 1989; Lynch et al. 2010; Tzschentke 1998, 2007; Vanderschuren and Ahmed 2013; Venniro et al. 2020). While these models have advanced our understanding of drug use, they depend on assumptions about shared processes between human and nonhuman animals. Thus, it is critical to establish behavioral procedures in human and nonhuman animals that are more directly comparable (Stephens et al. 2013). In this commentary, we illustrate some of the challenges along with the opportunities involved in generalizing across species using a single yet widely used behavioral procedure, place conditioning.

Place conditioning has been used to assess the conditioned rewarding (or aversive) effects of drugs in nonhuman animals for almost 80 years (Bardo and Bevins 2000; Carr et al. 1989; Rossi and Reid 1976; Spragg 1940; Tzschentke 2007). Despite this long history, it has only recently been translated to humans (Linhardt et al. 2022). Place conditioning is based on the idea that a context (i.e., distinct environment) repeatedly paired with a drug can acquire the hedonic effects of the drug through Pavlovian conditioning (Fig. 1). If rewarding effects predominate, then the drug-paired context will control approach behaviors that result in what is often termed a conditioned place preference or CPP. Evidence for these conditioned rewarding effects of a drug-associated context can persist long after withdrawal and is presumed to reflect such constructs as drug craving, seeking, and relapse. Conversely, aversive or negative effects of a drug associated with a context may lead to avoidance of the context (i.e., conditioned place aversion).

Fig. 1.

Place conditioning in laboratory animals and humans. Example apparatus used to test place conditioning in (A) rats (Bevins unpublished) and (B) humans (de Wit unpublished). Each chamber/room has distinct characteristics and is paired with either a drug or a vehicle in a counter-balanced manner

Despite the widespread use of this procedure to study the rewarding effects of drugs in animals, little is known about place conditioning in humans. This paucity is especially surprising as there is good face validity for place conditioning in humans. Anecdotally, people develop preferences for places associated with pleasurable drug experiences (e.g., bars, co-users’ houses). Conversely, they develop aversions for places associated with unpleasant drug experiences, such as a hospital associated with blood tests or chemotherapy. The scarcity of human drug place conditioning studies leaves a translational void in our understanding of one of the most common animal models of drug reward. Examination of the methods and findings in human and nonhuman animals highlights some of the opportunities and challenges in generalizing across species.

In this commentary, we focus on the limited number of published place conditioning studies with humans. We elaborate on why place conditioning can be useful to study addiction in humans and identify commonalities and differences between the procedures used in humans and nonhuman animals. On the surface, the procedures across species appear similar. In both cases, subjects receive either a drug paired with one environment (context) and on separate occasions a vehicle in a second distinct unpaired environment. Following this conditioning, they are permitted to choose between the two distinct environments. More time spent in the drug-paired environment is taken to indicate that the drug has conditioned rewarding effects (i.e., place preference); less time spent in the drug-paired environment is taken as evidence that the drug has aversive effects. Despite these commonalities, there are critical differences in the approach that may affect interpretation of the findings. Herein we discuss these differences along with the challenges and benefits of cross-species comparisons, gaps in our knowledge, and potential directions for future studies. Given the nescient state of the research with humans, we focus on behavioral and pharmacological factors.

Why study place conditioning in humans?

One may argue that a complex place conditioning procedure is not necessary to assess drug reward in humans because the pleasurable effects of drugs can be ascertained through a simple self-report (e.g., “Do you like the drug?”). This argument contrasts to the need for a behavioral measure of reward like place conditioning in non-verbal animals (Bardo and Bevins 2000). We hold that conducting parallel place conditioning studies in humans is necessary for several reasons. First, studies in humans provide validation for the cross-species assumptions involved in investigating a complex human problem such as drug use/misuse in animal models (Stephens et al. 2013). For instance, in studies with rodents, researchers have sometimes questioned whether the measure of time spent in the previously drug-paired environment solely reflects the conditioned rewarding or aversive effects of the drug, or whether it results, at least in part, from some other process such as approach to novelty or differential habituation to the test environments (Bardo and Bevins 2000; Bevins and Cunningham 2006). Human studies can validate this assumption by examining the relation between self-report measures of drug liking and the outcome of parallel place conditioning studies. At present, place conditioning studies with humans generally support this assumption. Namely, self-reported liking of the drug effect during the conditioning phase of the experiment was a good predictor of the subsequent time spent in the drug-paired context on the test session (Childs and de Wit 2016; Lutz and Childs 2021).

A second reason the human studies are important is that conditioned responses controlled by places associated with drug effects likely contribute to addictive behaviors in drug users’ natural environments. For example, habitual drinking contexts such as bars or parties may evoke conditioned incentive responses that attract the individual to approach the location and other alcohol-associated contextual stimuli leading to greater alcohol consumption. In this way, processes related to place conditioning may contribute to the risk for greater use and relapse. Surprisingly, this conditioning phenomenon has received little attention in clinical studies of addiction treatment despite the fact that it may offer a valuable tool for understanding relapse and developing relapse prevention strategies (Napier et al. 2013).

Third, the place conditioning procedure in humans may provide key information about the relationships between subjective reports of positive drug effects in humans and behavioral measures of drug preference or aversion. Typically, self-reports of feelings of euphoria and drug liking are used by researchers and regulators to assess the abuse liability of drugs (Jasinski 1991). That is, drugs that produce feelings of euphoria and liking are considered to have a higher liability for misuse or dependence. Most drugs that produce positive subjective effects are self-administered by humans and laboratory animals (Griffiths and Balster 1979). Further, behavioral measures of drug-taking in humans are usually, but not always (Lamb et al. 1991), associated with positive subjective effects (de Wit et al. 1987; Li et al. 2020). Thus, a drug may have conditioned rewarding effects as measured by place conditioning without producing reports of positive subjective effects. Partial support for this dissociation has been seen with alcohol. In a study by Childs and de Wit (2016), they found that the sedative effects of alcohol were more predictive of a conditioned place preference than its stimulating effects. This outcome is paradoxical because the stimulant effects of alcohol are usually described as more pleasant in subjective reports and associated with alcohol self-administration in humans in and outside the laboratory (A. King et al. 2021). Much remains to be learned about the relationships between subjective reports of drug liking and behavioral indices of drug preference or self-administration. Whether other classes of drugs, especially those that do not typically show strong reinforcing effects like nicotine or diazepam, also display this characteristic is a possibility that requires further empirical investigation. For all these reasons, human place preference studies and cross-species comparisons are necessary to validate the assumptions made in studies with both humans and nonhuman animals.

Commonalities in place conditioning between human and rodent studies

Human and rodent place conditioning studies are similar in the sequence of events in the procedure itself, and in the specific drug rewards that are effective in establishing place conditioning. The procedures typically include a baseline pre-test of pre-existing preference for the to-be-conditioned places, followed by repeated pairings of the drug in one environment and an inactive substance in a separate environment (i.e., conditioning), and then a choice test of preference for the two environments. The procedures share the components of Pavlovian conditioning, with the conditioning context as the conditioned stimulus (CS) and the drug effect(s) as the unconditioned stimulus (US). The conditioned response (CR) is the approach to the CS. USs include the effects of drug and non-drug rewards. In humans, a conditioned place preference has been demonstrated with drugs like amphetamine (Childs and de Wit 2009, 2013) and alcohol (Childs and de Wit 2016; Lutz and Childs 2021) as well as in a preliminary study with cocaine (Shipman et al. 2006). In laboratory animals, these same drugs can establish conditioned place preferences (Bardo et al. 1995; Cunningham et al. 2000; Tzschentke 2007).

As for non-drug rewards, humans exhibit conditioned place preference with USs such as food, music, money, toys, points, and social interaction (Astur et al. 2015; Baron et al. 2020; Childs et al. 2017; Molet et al. 2013; Radell et al. 2016; van den Akker et al. 2013). In rodents, conditioned place preferences have been reported with non-drug rewards such as food, novel objects, access to rat pups, copulatory opportunity, and social interaction (Bevins and Besheer 2005; Fleming et al. 1994; Spyraki et al. 1982; Tenk et al. 2009; Thiel et al. 2008). In a recent meta-analysis on 17 human place conditioning studies by Linhardt et al., (2022), they concluded that humans, like animals, show a preference for places associated with either drug or non-drug rewards. Such convergence suggests that the procedure is robust and generalizable across species (cf. Linhardt et al. 2022). With these commonalities come key differences in place conditioning procedures between humans and laboratory animals that also need to be highlighted.

How are human studies different from animal studies?

The studies with humans differ from studies with rodents in several important ways. One difference, as mentioned earlier, is the additional outcome measure of subjective responses to the drug. Whereas studies with animals use time spent in the paired context (or some variant such as percent time), human studies often use a measure of ‘room liking’ as an alternative to time spent in the room. In addition, studies with humans also obtain subjective ratings of drug liking during the conditioning sessions. Humans also differ from rodents in the amount of prior knowledge and experience they have with the to-be-conditioned drugs, as well as various parameters of the procedure (e.g., doses, routes of administration, number of conditioning trials). The extent to which these variables contribute to findings with nonhuman and human animals is yet to be determined because of the small number of studies in humans. We elaborate on these issues below.

1. Outcome measures: In nonhuman animal studies, the primary measure of place conditioning is time spent in the drug paired vs. unpaired environment. While some human studies have used ‘time spent’ in the drug-paired environment as the outcome measure (Childs and de Wit 2016; Lutz and Childs 2021; Shipman et al. 2006), others use self-reported ratings of ‘liking’ the drug-paired environment as the main outcome measure to assess place preference (Childs and de Wit 2009, 2013). Whether ‘room liking’ and ‘time spent’ measure the same underlying construct remains unclear. The measures are suited to the different species. Room ‘liking’ ratings are interpretable and easy to obtain in humans, whereas time spent may be more suited in rodents because exploratory and locomotor behavior can be more prepotent. Future studies utilizing both outcome variables in humans will help to determine the relative sensitivity of the two measures and how they vary with key parametric variables (e.g., dose, duration of context pairing, number of conditioning sessions, etc.).

2. Prior drug experience: Another difference between animal and human studies is that human participants often have some prior history with the to-be-conditioned drug and/or with other drugs. Laboratory animals, in contrast, are naive to the drug unless explicitly manipulated by the experimenter. For example, studies with alcohol place conditioning in humans typically enroll social drinkers (Childs and de Wit 2016), and one study with cocaine used participants experienced with cocaine (Shipman et al. 2006). There are at least three reasons why prior experience with the drug may influence place conditioning. First, with Pavlovian conditioning, prior experience with the unconditioned stimulus (i.e., drug) is known to interfere with acquisition of a conditioned association—the so-called US preexposure effect (e.g., Ayres et al. 1992; Pavlov 1927). Second, previous experience with a drug may drive expectations or biases that can influence outcomes. For example, humans with previous experience with a specific drug may be more accurate in identifying its effects, even in a double-blind procedure. Third, experienced individuals may have developed either tolerance or sensitization for the effects of the drug. In animals, several studies have shown that pre-exposure to the to-be-conditioned drug in rodents dampens conditioning, either through tolerance or the US preexposure effect (Biénkowski et al. 1995; Koek 2016; Zarrindast et al. 2007). How exactly the participants’ prior experience with the to-be-conditioned drug affects place conditioning remains to be determined. However, it is important to consider the drug history of the participants when comparing results from animal and human studies. Notably, to enhance translation across species, research with rodents could consider the history of the human participants of interest and design studies to simulate that history.

3. Route and timing of drug administration. The mode of drug intake is typically different in humans vs animals. Humans typically ingest a drug in capsule or beverage form, which may be considered an active form of ingestion, even if it is at the behest of the researcher. In most rodent studies, the conditioning drug is administered by the experimenter via intraperitoneal or subcutaneous injection (Cunningham et al. 2006), which may be considered passive because the animal does not voluntarily consume it. Many studies have shown that passive administration effectively conditions a place preference in laboratory animals (Bardo and Bevins 2000). Interestingly, some studies with rats have investigated place conditioning with voluntary oral self-administration of the drug during conditioning sessions and found a conditioned place preference for the context where the drug was previously self-administered (McKendrick et al. 2020; Seidman et al. 1992). Such paradigms are considered active as the animal must respond to consume the drug. In most human studies, subjects voluntarily ingest the drug orally (capsule, gum, beverage) and are informed that they might receive a certain drug (or placebo). In an interesting exception to this, one human study demonstrated place preference using experimenter-administered intravenous cocaine or saline (Shipman et al. 2006).

The timing of drug administration also varies across studies in both laboratory animals and humans. In most studies with animals, drugs are injected just before the animal is placed in the chamber, so that blood and brain drug concentrations are rising during the conditioning trial. Yet, in a minority of studies, animals consume drugs in the environment (e.g., through a bottle placed in the environment). In some of the human studies, the drug was ingested before exposure to the environment (e.g., Childs and de Wit 2009, 2013), while in others it was ingested when the participants were in the environment (Childs and de Wit 2016; Lutz and Childs 2021). These variations in the time of drug administration, relative to the onset of the CS (i.e., placement in context) may influence the development of conditioning in both humans and nonhuman species. We propose that advances in understanding the commonalities in processes between humans and nonhuman animals would be accelerated with greater empirical attention on place conditioning protocols that require self-administration of the drug in animals.

Thus, despite the similarities in conditioning outcomes, there are several notable methodological differences that exist between animal and human place conditioning studies. A better understanding of how these factors may or may not play a role in the nature of the place conditioning effect and individual differences need further investigation to enable better cross-species comparisons.

What can we learn from human studies that we do not know in animal studies?

One key feature of studies with humans is the ability to correlate the behavioral measure of place preference to the quality and magnitude of subjective experiences using verbal reports. Verbal self-reports can be used to determine the subjective experiences that lead to, or limit, the acquisition of place preference. That is, humans can report on the wide range of interoceptive effects they experience after administration of a drug, including both pleasurable and aversive effects. Studies with humans are needed to support the assumption made implicitly in animal studies that the “pleasurable” or rewarding interoceptive effects of drugs are related to behavioral place preference. In general, the evidence from research with humans supports this idea. For instance, a study with amphetamine [20 mg oral; Childs and de Wit 2009] found that liking of the room was positively correlated to liking the subjective effects of amphetamine during conditioning. In a separate study with alcohol [0.8 g/kg; Lutz and Childs 2021], subjects who exhibited stronger place preference for the alcohol-paired room as measured by time spent in that room also reported greater feelings of euphoria and stimulation in the alcohol conditioned room during conditioning. However, another study with alcohol (0.8 g/kg) found that the sedative, rather than stimulating effects of alcohol, were correlated with greater place preference (Childs and de Wit 2016). These apparently divergent findings raise interesting questions about the quality or magnitude of subjective drug effects that may form the basis of drug reward in different individuals. There is also evidence that individual variations in subjective liking or disliking of a drug can influence the degree of place conditioning. In studies with rodents, while it is recognized that there are wide individual differences in the acquisition of place conditioning, whether these are related to differences in acute internal responses to the drugs is uncertain (Erb and Parker 1994; Klebaur and Bardo 1999; Seymour and Wagner 2008; Shimosato and Watanabe 2003; Takahashi et al. 2020). Although it is beyond the scope of this commentary to provide a comprehensive review of how individual differences affect place conditioning in rodents, we believe that parallel investigation of individual predictors in humans and rodents will be informative and help to establish the utility of the model to understand determinants of drug preferences.

Future studies

Given the small number of place conditioning studies with humans, there are still many unknowns. In this section, we describe potential future studies that would build on the existing foundation and further the needed validation across species. For example, little is known about conditioned place aversions. While it seems intuitively likely that humans would avoid and express dislike for a context associated with an emotionally negative experience, this has yet to be demonstrated in the laboratory. Further, many procedural variables have yet to be studied in humans, such as whether conditioning is dependent on the duration of drug exposure or the number of conditioning trials, whether it is sensitive to the dose of the drug, and how long preferences endure. Another potentially interesting question is whether competing alternative rewards, such as concurrently available non-drug rewards, can compete for preference against a drug reward. These gaps in knowledge are not surprising considering the small literature on place conditioning in humans (Linhardt et al. 2022)—compare this to the thousands of place conditioning studies in rodents (Tzschentke 2007). Moreover, as pointed out by Linhardt et al. (2022), the designs used in human studies are heterogeneous and lack a common structure, making interpretation across studies more difficult. Indeed, the same problem holds true to a lesser extent in studies with rodents, which vary in procedures and designs. These issues will need to be considered for future human place conditioning studies and their links to parallel work in nonhuman animals.

1. Aversive stimuli or relief from aversive states: Studies with humans are yet to examine if drugs known to produce aversive, unpleasant or dissociative subjective effects (such as nicotine, morphine, or psilocybin) can produce conditioned place aversion. Anecdotally, conditioned place aversion has been reported in patients receiving chemotherapy in hospital settings (Aapro et al. 2005; Rock et al. 2016). One controlled laboratory study with humans used ipecac to produce nausea but failed to detect conditioned aversion to the room where the drug was administered (Van Hedger et al. 2018). In animals, a place that is associated with relief of a negative state may produce preference. For example, in rats with chronic pain, a pain-relieving drug administered in a distinct environment produced a later conditioned place preference (Cahill et al. 2013; T. King et al. 2009; Navratilova et al. 2013). Researchers have yet to explore this possibility in humans.

2. Optimal duration: In human studies, many questions remain about the optional parameters for place conditioning. What is the optimal duration of exposure to a drug-paired environment? How does conditioning vary across different drugs, different doses of drugs, or in relation to past exposure to drugs? Nonhuman animal studies have clearly established that the time spent in the chamber (context) or its overlap with context exposure can affect the outcome. For example, rats that were left in the conditioning chamber for 5 min after cocaine administration exhibited place preference, while animals retained in the conditioning context for 15 min displayed place aversion (Ettenberg et al. 1999; Ikemoto and Donahue 2005). This difference may be due to the purported biphasic rewarding effects of cocaine, with earlier more positive and later more negative effects. Similar effects of trial duration have been found in rats with alcohol (Cunningham and Prather 1992). On the other hand, with opioid drugs, the strength of conditioning increases with longer trial durations (Bardo et al. 1995). Therefore, in animals, the duration of conditioning depends on the drug and the route of drug administration (Cunningham et al. 2006; McKendrick and Graziane 2020). In humans, thus far, trial durations have ranged from as long as four hours with alcohol (Childs and de Wit 2013) to as little as 25 min with cocaine (Shipman et al. 2006). A more systematic investigation is required to understand the relationship between the drug, the trial duration, and the drug overlap with environment on place conditioning in humans.

3. Number of conditioning trials: Another variable that needs investigation is the number of conditioning trials required to induce place preferences. In most studies with rodents several conditioning sessions are conducted on consecutive days, alternating between the drug or vehicle. Although in general more conditioning trials lead to stronger conditioning (e.g., Cunningham et al. 2006; Wilkinson and Bevins 2008), under the right conditions a conditioned place preference has been observed following a single conditioning trial (Bardo and Neisewander 1986; Nentwig et al. 2017). In humans, the number of conditioning trials (i.e., place-drug pairings) have varied between 4 and 6, usually separated by 2 to 7 days.

4. Biased vs unbiased design: Little is known about the relative utility of the two commonly used place conditioning study designs in humans. The biased design includes a baseline exploration of inherent preferences for one environment and then pairs the drug with the non-preferred environment for all subjects (i.e., conditioning against a preference). In the unbiased design, the drug is paired with either a distinct environment without regard to initial baseline preference or counterbalanced for initial preference. Animal studies indicate that there are advantages and disadvantages of both approaches (Cunningham et al. 2006). Studies with humans on the relative sensitivity of biased and unbiased designs may help to interpret issues in animal studies. The human studies add value through concurrent self-report measures of liking the contexts both before and after conditioning, as well as liking the effects of the drugs. Thus far, two studies with humans have used both unbiased (Childs and de Wit 2009) and biased (Childs and de Wit 2013) designs with amphetamine, and seen similar place preference for amphetamine-paired rooms.

5. Persistence of conditioned responses: Another question for future studies is to determine how long conditioned responses (approach or avoidance) last in humans and how this may help us understand the effects of these conditioned contexts in withdrawal and relapse. Extinction and reinstatement paradigms are often conducted in animals to investigate the persistence of the conditioned association between the paired context and the drug. For extinction in these studies, animals are placed repeatedly in the place conditioning apparatus without the drug and allowed to explore the two chambers (i.e., drug paired and unpaired). The outcome measure is the time or number of trials needed to return the animals’ place preference to pre-conditioning levels. In reinstatement procedures, animals first undergo extinction, and then receive a priming injection of the drug just before a preference test. These priming doses reinstate the extinguished preference to the drug-paired chamber (Lee et al. 2020; Scherma et al. 2021). To date, no studies have examined extinction or reinstatement of place conditioning in humans.

6. Different drug types: Many questions remain about which drugs effectively establish either conditioned place preference or aversion in humans. Thus far, only amphetamine, cocaine, and alcohol have been tested in humans, whereas place preference in rodents has been tested with a wide variety of drug classes including opiates, cannabinoids, cholinergic, GABAergic, glutamatergic, serotonergic, dopaminergic drugs, and their various antagonists (Tzschentke 1998, 2007). Interestingly, the studies in nonhuman animals indicate that place preferences are more robust with certain drug classes like opiates, amphetamine, and cocaine, but with other drugs, such as alcohol, nicotine, or cannabinoids, there is considerable inter-animal variability (Murray and Bevins 2010; Tzschentke 1998). These between-drug differences could be studied in humans, and the human studies may shed light on the reasons for the variability prompting new studies in animals. For example, some drugs may be associated with greater inter-individual variability in place conditioning, and a portion of this variability may be related to subjectively reported drug liking.

7. Competition between drug and non-drug rewards: Laboratory animal studies suggest that sometimes non-drug rewards can compete for the rewarding effects produced by the drug and alter preference for the drug-paired environment (Mattson et al. 2001; Reichel and Bevins 2008, 2010). For instance, following initial place conditioning with cocaine, rats had access to a novel object in the previously unpaired environment (i.e., the saline-paired side). This access to a novel object shifted their preference away from the environment previously paired with cocaine (Reichel and Bevins 2008). This competition between rewards needs to be tested with human studies. Such studies may provide empirical evidence for the idea that alternative non-drug rewards compete with conditioned drug effects and may be developed as an intervention method to prevent relapse.

8. Virtual Reality: Virtual reality (VR) contexts present an attractive means to study conditioned place preference in humans because of their ease of use for testing, and potential reproducibility in and across laboratories. They eliminate the need for physical rooms and enable creation of environments that are matched in geometry and visual features. One preliminary study thus far has used a VR context to condition a VR place preference with intravenously administered cocaine in humans (Shipman et al. 2006). Other studies have used aspects of VR to study conditioning with drugs. One series of studies used simple two-dimensional visual images depicting physical scenes (beach or mountain) as the CS paired with oral administration of amphetamine (Mayo et al. 2013) or alcohol (Mayo and de Wit 2016). Another study used VR stimuli to examine the combined effects of nicotine and a food reward (Palmisano et al. 2018). They found that nicotine enhanced preference for a food conditioned VR context, but only in subjects who had higher levels of nicotine dependence. Several studies have used VR to study place conditioning using non-drug rewards, like food (Astur et al. 2014), money (Childs et al. 2017), secondary reinforcers (Astur et al. 2016) and music (Molet et al. 2013).

   One major advantage of VR stimuli is that they can be studied using brain imaging to investigate neural activity during or after conditioning (Banz et al. 2019; Folley et al. 2010; Shipman and Astur 2008). Interestingly, VR may also have potential for use in nonhuman animals. For example, Williams et al. (2019) used a VR environment with mice that were head-fixed and could run freely on a Styrofoam ball. Mice viewed the VR environment on large monitors and their movement on the ball was used to update the visual display. Thus, the mouse’s movement on the ball controlled the VR display and served as a proxy for exploration of the VR context. The study found that mice spent more time in a VR context paired with morphine administration than one paired with saline. Thus, preliminary work suggests VR environments could be used as an alternative to real-world contexts in both humans and laboratory animals. More studies in both species are needed to enable parallel comparisons.

9. Neurobiological mechanisms: The neurobiology underlying place conditioning is complex. It depends on the drug used as the unconditioned stimulus and on features of the stimuli used during conditioning. It is likely that the mesolimbic reward circuit is involved in acquisition of conditioned place preference, and other regions likely to be involved include the amygdala and prefrontal cortex (emotional and cognitive control) and the hippocampus (learning and memory) (for detailed review on the neural mechanisms see, Prus et al. 2009; Tzschentke 1998, 2007). Different drugs, acting on different neurotransmitter systems, activate different circuits during the conditioning phase and during the retrieval phase of place conditioning. Further, place conditioning is likely to involve conditioning of both contextual cues and discrete localizable cues such as lights or environmental features, and there is evidence that different processes mediate the conditioning of contexts vs cues (Itzhak et al. 2010). Parallel place conditioning studies in laboratory animals and humans, including brain imaging studies in humans, will provide insight into the neural circuitry (Siddiqi et al. 2022). Interestingly, VR procedures used in both laboratory animals (Krishnan et al. 2022; Williams et al. 2019) and humans (Shipman et al 2006) offer an excellent opportunity to study the mechanisms involved in the acquisition and retrieval of conditioned place preferences and aversions.

Conclusion

In summary, we compared human with nonhuman animal research using the place conditioning model to study the conditioned rewarding or aversive effects of a drug. In doing so, we identified translational opportunities and challenges that arise. We highlighted that through assessments of subjective states or ratings obtained by self-reports, human studies can provide a unique form of validation for the assumptions of reward or aversion made in the place conditioning procedure in non-verbal animals. We concluded that the measure of time spent in the conditioned chambers is an important objective dependent variable that enables cross-species comparisons. We elaborated on the information gained, the caveats and questions raised from human studies on place conditioning and proposed future directions to bridge the translational gap. Our view is that concordance between animal and human studies is a necessary step to support generalizations that are made in animal models when studying a human problem like addiction. This in turn enables tangible links to be made between the two models when understanding the neural circuitry and identifying pharmacotherapies.