Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2017 Jun 15.
Published in final edited form as: Brain Res. 2016 Jan 7;1641(Pt B):207–216. doi: 10.1016/j.brainres.2016.01.002

Norepinephrine at the Nexus of Arousal, Motivation and Relapse

Rodrigo A España 1,✉, Brooke E Schmeichel 2, Craig W Berridge 3
PMCID: PMC4879075  NIHMSID: NIHMS755526  PMID: 26773688

Abstract

Arousal plays a critical role in cognitive, affective and motivational processes. Consistent with this, the dysregulation of arousal-related neural systems is implicated in a variety of psychiatric disorders, including addiction. Noradrenergic systems exert potent arousal-enhancing actions that involve signaling at α1- and β-noradrenergic receptors within a distributed network of subcortical regions. The majority of research into noradrenergic modulation of arousal has focused on the nucleus locus coeruleus. Nevertheless, anatomical studies demonstrate that multiple noradrenergic nuclei innervate subcortical arousal-related regions, providing a substrate for differential regulation of arousal across these distinct noradrenergic nuclei. The arousal-promoting actions of psychostimulants and other drugs of abuse contribute to their widespread abuse. Moreover, relapse can be triggered by a variety of arousal-promoting events, including stress and re-exposure to drugs of abuse. Evidence has long-indicated that norepinephrine plays an important role in relapse. Recent observations suggest that noradrenergic signaling elicits affectively-neutral arousal that is sufficient to reinstate drug seeking. Collectively, these observations indicate that norepinephrine plays a key role in the interaction between arousal, motivation, and relapse.

Keywords: stimulants, addiction, amphetamine, catecholamines, noradrenergic, locus coeruleus

Introduction

Our ability to interact with the environment and, ultimately, to survive is highly dependent on the appropriate regulation of arousal. Noradrenergic systems are important modulators of arousal (Berridge et al., 2012). Cognitive and motivational processes display a pronounced dependency on arousal (Yerkes and Dodson, 1908). Clinically, dysregulated arousal and motivation are key features of a variety of behavioral disorders, including drug abuse disorders. Historically, dopamine has been the focus of research into the neurotransmitter regulation of motivation and drug taking. However, amassing evidence indicates a critical role for noradrenergic signaling in motivation, particularly in an arousal-sensitive context. In the following sections we briefly review evidence demonstrating an important influence of noradrenergic signaling in the modulation of arousal and motivated behavior that involves a network of noradrenergic nuclei and subcortical terminal fields. These observations suggest a likely prominent role of NE neurotransmission in disorders associated with dysregulated motivation, including addiction.

1. Noradrenergic Regulation of Arousal

1.1 Locus coeruleus-noradrenergic modulation of arousal

Evidence has long-implicated the noradrenergic nucleus, locus coeruleus (LC), in the regulation of arousal (for review, Berridge and Waterhouse, 2003). The LC is a small cluster of NE-synthesizing neurons located in the pontine brainstem adjacent to the fourth ventricle. Despite a restricted size, LC neurons extend immensely ramified axons that project widely throughout the neuraxis (Swanson and Hartman, 1975; Foote et al., 1983; Berridge and Waterhouse, 2003). Early observations suggested this nucleus was the sole source of the noradrenergic innervation of the hippocampus and neocortex (Foote et al., 1983; Robertson et al., 2013). However, recent studies indicate other noradrenergic nuclei provide a significant contribution to the noradrenergic innervation of select subfields of the prefrontal cortex and other neocortical sites (Robertson et al., 2013).

Seminal electrophysiological experiments first observed that LC neurons display state-dependent firing with higher discharge rates during waking than during sleep (Hobson et al., 1975). Importantly, changes in LC neuron discharge preceded transitions from sleep to waking and from waking to sleep (Hobson et al., 1975; Foote et al., 1980). Further evidence of state dependency in LC unit activity was also observed within waking, with increases in discharge rates observed during periods of elevated arousal, including those associated with reward or stress (Foote et al., 1980; Aston-Jones and Bloom, 1981; Abercrombie and Jacobs, 1987; Dunn, 1988). These observations gave rise to the hypothesis that NE exerts arousal-promoting actions.

1.2 Selective activation and suppression of LC alters EEG/behavioral state

Pharmacological studies provide strong evidence that the LC-NE system regulates sleep/wake processes. NE binds to three major receptor families, α1, α2, and β, each comprised of multiple subtypes, as well as the dopamine D4 receptor (Newman-Tancredi et al., 1997; Cummings et al., 2010). α1- and β receptors are thought to exist primarily postsynaptically whereas, α2-receptors are present both pre- and postsynaptically (see Berridge and Waterhouse, 2003). It has long been known that systemic or central treatment with α2 agonists, which suppress NE release by activating presynaptic autoreceptors (Laverty and Taylor, 1969; Kleinlogel et al., 1975; Pastel and Fernstrom, 1984), or combined α1- and β-antagonists (Berridge and España, 2000) elicits profound sedation. However, these approaches lack the anatomical resolution to determine unambiguously the site of action involved in the sedative actions of these noradrenergic drug manipulations. Subsequent research used electrophysiological recordings to guide small infusions (35–150 nl) of drugs immediately adjacent to the LC, to selectively examine the effects of LC activation and suppression on electroencephalographic (EEG) indices of arousal in anesthetized rats (Berridge and Foote, 1991; Berridge et al., 1993). It was observed that LC activation driven by peri-LC infusions of a cholinergic agonist elicited robust and bilateral activation of forebrain EEG that closely tracked the time-course of LC activation (Berridge and Foote, 1991). Conversely, pharmacological suppression of LC activity bilaterally elicited a robust increase in EEG indices of sedation (e.g. increased slow-wave activity) in lightly anesthetized rats that also tracked closely the time course of drug-induced suppression of LC discharge activity (Berridge et al., 1993). Importantly, less than 10% of LC neuronal activity in one hemisphere was sufficient to maintain EEG indices of arousal under these conditions.

More recent optogenetic activation and suppression of LC has yielded similar effects in unanesthetized animals (Carter et al., 2010). Brief optogenetic stimulation of the LC (1–10 seconds) elicited rapid transitions from sleep to waking and, within waking, prolonged time spent awake and increased behavioral activity. Conversely, 1 hour optogenetic inhibition of LC decreased time spent awake.

Collectively, these and other observations demonstrate that LC activity is both sufficient and necessary for the promotion and maintenance of alert waking.

1.3 Site of action: Noradrenergic α1- and β-receptors promote arousal in a network of subcortical regions

Subcortically, the general regions of the medial septal area (MSA), the substantia innominata (SI), the medial preoptic area (MPOA), and the lateral hypothalamus (LH; including LH proper, the dorsomedial hypothalamus, and the perifornical area) participate in the regulation of arousal (Buzsaki et al., 1983; Kumar et al., 1986; Buzsaki et al., 1988; Metherate et al., 1992). Each of these regions also receive LC-noradrenergic input (Swanson and Hartman, 1975; Zaborszky, 1989; Cullinan and Zaborszky, 1991; Zaborszky et al., 1991; Zaborszky and Cullinan, 1996; España and Berridge, 2006). To determine whether NE action in these regions modulates sleep-wake state, small volumes (150–250 nl) of NE, an α1-agonist, or a β-agonist were made in sleeping animals using remote controlled infusions designed to avoid waking/disturbing the animal (see Berridge and Foote, 1996). It was observed that α1- and β receptor activation in the MSA, the MPOA, or the LH produce robust and additive increases in EEG and behavioral indices of waking (Kumar et al., 1984; Berridge et al., 1996; Berridge and Foote, 1996; Sood et al., 1997; Berridge and O’Neill, 2001; Berridge et al., 2003; Schmeichel and Berridge, 2013). Infusions immediately outside these regions were devoid of wake-promoting actions (Berridge et al., 1996; Berridge and Foote, 1996; Berridge and O’Neill, 2001; Berridge et al., 2003; Schmeichel and Berridge, 2013). Within all regions the wake-promoting actions of α1- and β-receptor stimulation are additive (Berridge et al., 2003; Schmeichel and Berridge, 2013). Interestingly, the wake-promoting actions of NE within the LH are not associated with an activation of arousal-related hypocretin/orexin neurons (Schmeichel and Berridge, 2013).

The SI, situated immediately lateral to both the MSA and MPOA, provides a potent activating influence on EEG, in part through the actions of cholinergic projections to the neocortex (Buzsaki and Gage, 1989; Metherate et al., 1992). Therefore, it is somewhat surprising that the SI is not a site of action for the arousal-promoting effects of NE, α1- or β-agonists, or the indirect NE agonist, amphetamine (Berridge et al., 1996; Berridge and Foote, 1996; Berridge et al., 1999; Berridge and O’Neill, 2001). The only exception to this was observed with a high concentration of NE that produced a moderate wake-promoting effect (Cape and Jones, 1998; Berridge and O’Neill, 2001). In this case, the latency to waking was substantially longer and the time spent awake substantially reduced, relative to infusion into the MPOA (Berridge and O’Neill, 2001). This pattern of results suggests that at high concentrations NE diffuses from the SI to the MPOA where it acts to increase waking.

1.4 Differential noradrenergic input across arousal promoting regions

The above-described observations provide clear evidence that LC neurons exert a robust excitatory influence on forebrain activity state that involves the additive actions of α1- and β-receptors located across a network of subcortical sites. However, anatomical tracing studies demonstrate that the LC is not the only source of noradrenergic innervation to these regions. Moreover, the proportion of NE innervation arising from the LC vs. other noradrenergic nuclei is not uniform across these arousal-related regions. For example, although the LC provides the majority (~50%) of noradrenergic input to the MSA and MPOA, significant noradrenergic innervation to these areas arises from the A1 and A2 noradrenergic nuclei (~25% each; España and Berridge, 2006). In the case of the LH, the LC provides a remarkably small proportion of innervation (~10%), with significantly larger contributions from A1 (~50%), and A2 (~22%; España et al., 2005; Yoshida et al., 2006). Thus, while it is clear that the LC exerts strong arousal modulatory actions, NE-dependent regulation of arousal and arousal-dependent processes likely involves multiple noradrenergic nuclei. It is important to note that the LC appears unique among noradrenergic nuclei in receiving prominent input from forebrain regions associated with higher cognitive and affective function (e.g., prefrontal cortex, amygdala; Arnsten and Goldman-Rakic, 1984; Berridge and Waterhouse, 2003). Together, these observations suggest that noradrenergic regulation of arousal and arousal-dependent processes involves a complex network of noradrenergic nuclei, receptors, and terminal fields that may be differentially recruited under varying conditions. The extent to which the LC, A1 and A2 are differentially activated across varying conditions is an important question for future studies.

1.5 Summary

Noradrenergic systems exert potent arousal promoting actions that involve α1 and β-receptors in a network of subcortical regions. Although activation of either α1 or β-receptors in any single region is sufficient to elevate behavioral and EEG/EMG indices under low-arousal conditions, blockade of both receptors globally in the brain is required to observe maximal sedation under conditions associated with higher arousal levels required for alert waking. The source of the noradrenergic innervation to subcortical NE-arousal regions varies across regions, with both the MSA and MPOA receiving the majority of input from the LC while the LHA receives a significantly smaller LC innervation.

2. Arousal-Related NE Contributions to Motivated Behavior

Drug addiction represents a significant public health problem, with considerable personal and economic costs. For many drugs, particularly psychostimulants and nicotine, the reinforcing1 actions are superimposed on drug-induced elevations in arousal. Moreover, the arousal-promoting effects of these drugs contributes to their widespread use and abuse. As such, the ability of certain drugs of abuse to elevate arousal independent of their rewarding effects may represent a significant contributing factor in the development of addiction/abuse. Relapse represents one of the most significant impediments to the successful treatment of addiction. It is estimated that 40%–60% of abstinent drug addicts will relapse (McLellan et al., 2000). Further, it is well documented that relapse is highly sensitive to arousing, stressful conditions (e.g. Kosten et al., 1986; Koob, 1999; Kalivas and McFarland, 2003; Mantsch et al., 2015). Combined with the above-reviewed information, these observations suggest the hypothesis that through the modulation of arousal state, NE could participate in multiple aspects of addiction. Evidence related to this hypothesis is reviewed below.

2.1 NE contribution to psychostimulant-induced arousal

Psychostimulants are a widely abused class of drugs, originally defined by their potent arousal-enhancing, motor activating, and reinforcing actions. These drugs have long been used (both prescribed and illicitly) to sustain arousal beyond typical circadian rhythm, representing a potential ‘gateway’ for the development of abuse/addiction. Neurochemically, psychostimulants disrupt dopamine, NE, and serotonin transporters, thereby elevating extracellular levels of these transmitters (Florin et al., 1994; Florin et al., 1995). Given the strong arousal-promoting actions of NE combined with the NE-elevating actions of psychostimulants, it is not surprising that amphetamine-induced arousal involves drug action in all identified noradrenergic arousal-related terminal fields: MSA, MPOA and LH (Berridge et al., 1999; Schmeichel and Berridge, 2014). Consistent with this, the arousal-promoting effects of psychostimulants are closely aligned with elevations in extracellular NE levels (Berridge and Stalnaker, 2002) and, at least in anesthetized animals, can be blocked by pretreatment with α1- or β-receptor antagonists (Berridge and Morris, 2000). Together these observations, demonstrate that the arousal-promoting actions of psychostimulants involve, in part, elevated NE signaling in subcortical arousal-related regions. Interestingly, when infused directly into the MSA, MPOA and the LH, amphetamine lacks locomotor activating effects (Berridge et al., 1999; Schmeichel and Berridge, 2014), indicating the arousal-promoting and locomotor-activating actions of psychostimulants are dependent on distinct anatomical circuitry.

2.2 NE and the reinstatement of drug seeking: Potential role of arousal

Stress is a well-documented trigger for relapse (e.g. Kosten et al., 1986; Koob, 1999; Kalivas and McFarland, 2003). In animals, a variety of stressors have been documented to reinstate previously extinguished drug seeking behavior, as measured in both conditioned place preference (CPP) and self-administration paradigms (for review, Koob, 1999; Shaham et al., 2000a; Kalivas and McFarland, 2003; Mantsch et al., 2014; Mantsch et al., 2015). Elevated arousal represents a critical aspect of stress. As reviewed above, NE systems are activated in stress and exert robust arousal-promoting actions (Berridge and Waterhouse, 2003). Consistent with these observations, substantial evidence indicates a prominent role of NE in stress-related reinstatement of drug seeking that is independent of stressor and whether drug seeking involves instrumental or classical conditioning (for review, Weinshenker and Schroeder, 2007; Mantsch et al., 2014). Given this has been reviewed extensively elsewhere, we only briefly review stress-related reinstatement herein.

Evidence for a noradrenergic contribution to stress-related reinstatement includes the ability of pharmacological suppression of NE release (α2-agonists), α1- or β-receptor blockade, or inhibition of NE synthesis to attenuate stressor-induced reinstatement of psychostimulant- (Erb et al., 2000; Schroeder et al., 2013), alcohol- (Lê et al., 2005; Lê et al., 2011) and opiate-seeking in rats (Shaham et al., 2000b; Leri et al., 2002; Ventura et al., 2005) in both CPP and self-administration paradigms. Similar observations have been made in human psychostimulant and opioid addicts (Sinha et al., 2007; Jobes et al., 2011). Together, these observations indicate that NE signaling is necessary for the ability of stress to reinstate previously extinguished drug seeking. Consistent with this, evidence demonstrates that increases in NE signaling are sufficient to reinstate psychostimulant- (Lee et al., 2004; Brown et al., 2009; Mantsch et al., 2010; Brown et al., 2011; Schroeder et al., 2013), and alcohol-seeking (Lê et al., 2005). Collectively, these observations indicate a significant role for NE in stress-related relapse of drug seeking.

CPP and self-administration involve at least partially distinct circuitry, as do the reinforcing effects of different drug classes (e.g. opiates vs. psychostimulants). The above-reviewed observations indicate that the ability of stress and NE to reinstate drug seeking is largely independent of reinforcement type or drug class. Therefore, NE modulation of arousal may represent a common mechanism by which noradrenergic signaling influences drug-related behavior, independent of drug type and associational process.

Re-exposure to drugs or drug-associated cues also reinstate drug seeking. Arguably, these relapse triggers are also of an arousing nature. Limited data support a role of NE in reinstatement elicited by drug-associated cues for psychostimulants (e.g. cocaine; Platt et al., 2007). The degree to which NE participates in drug-induced reinstatement is less clear, a topic that has been most commonly examined in the context of psychostimulants. In rodents and monkeys, α1-antagonists or α2-agonists, prevented the ability of noncontingent psychostimulant administration to reinstate cocaine self-administration (Zhang and Kosten, 2005; Platt et al., 2007). However, in other studies, neither α1-antagonists, β-antagonists, α2 agonists (to suppress NE release) or NE synthesis inhibitors affected cocaine-induced reinstatement (Shaham et al., 2000a; Mantsch et al., 2010; Cooper et al., 2014). While the discrepant nature of the literature might indicate that NE does not play a prominent role in psychostimulant-induced reinstatement, there are a couple of important issues that need to be considered prior to drawing strong conclusions. First, the arousal-promoting actions of NE involve both α1and β-receptor signaling and blocking only one receptor can lack significant impacts on behavioral and EEG/EMG measures of arousal (see above; Berridge and España, 2000). Thus negative effects of a single receptor-selective antagonist need to be interpreted cautiously. While α2 agonists should suppress NE signaling at α1 and β receptors, the degree to which this occurs in an unanesthetized animal treated under all relevant experimental conditions is unclear. Moreover, these drugs display a complex pharmacology (acting at post-synaptic and non-noradrenergic imidazoline receptors), which can cloud interpretation of experimental results obtained with their use (Arnsten et al., 1996). Second, the dose and frequency of psychostimulant used in a given study may be an important variable in the degree to which NE modulates drug-induced reinstatement. For example, the most robust suppression of cocaine-induced reinstatement of cocaine self-administration by an α1 antagonist was observed at the lowest doses of cocaine (5 mg/kg vs. 20 mg/kg; Zhang and Kosten, 2005). As dose of psychostimulant increases, the concentration of NE increases (Kuczenski and Segal, 1992; Florin et al., 1994). Thus, at high doses, it may be difficult to fully block NE receptor signaling.

Finally, it is important to segregate the topics of sufficiency vs. necessity when discussing the involvement of NE in reinstatement/relapse. Multiple arousal-related systems are implicated in reinstatement/relapse, including CRF, dopamine and serotonin (for review, Lê et al., 2000; Shaham et al., 2000a; Self, 2004; Lê et al., 2006; Lê et al., 2009). Thus, blocking one transmitter alone may be insufficient to prevent drug-induced reinstatement, particularly at high doses of psychostimulants that are activating multiple reinstatement-related transmitter systems. The inability of a drug that interferes with NE neurotransmission to block drug-induced reinstatement demonstrates that target of that drug is not necessary for this form of reinstatement. However, given NE receptor activation is sufficient to induce reinstatement and at least some drugs of abuse increase NE signaling, one can reasonably conclude that NE likely contributes to some aspects of drug-induced reinstatement.

2.3 Arousal-related neurocircuitry involved in NE-related reinstatement

Consistent with the prominent role of NE in stress and arousal, evidence indicates that stress-related reinstatement of drug seeking involves subcortical arousal-related systems (e.g. MSA, bed nucleus of the stria terminalis, central nucleus of the amygdala, LHA; Highfield et al., 2000; Leri et al., 2002) for review, Stewart, 2000; Weinshenker and Schroeder, 2007). This suggests the hypothesis that stress-related reinstatement of drug seeking may involve arousal-related activation of motivational systems. However, given that negative affect is a known contributing factor in relapse (Baker et al., 2004; George and Koob, 2010), stress-related reinstatement of drug seeking could reflect the induction of a negative affective state independent of fluctuations in arousal.

Related to this issue, we recently observed that amphetamine acts within the LH to promote affectively-neutral arousal (Schmeichel and Berridge, 2013; Schmeichel and Berridge, 2014). Specifically, intra-LH amphetamine infusions elicited a robust increase in time spent awake (Figure 1), while lacking reinforcing or aversive actions as measured in CPP (Figure 2). Nonetheless, intra-LH amphetamine infusion produced a robust reinstatement of a previously extinguished CPP produced with systemic amphetamine treatment (Schmeichel and Berridge, 2014).

Figure 1. The lateral hypothalamus (LH) is a site involved in the arousal promoting actions of norepinephrine (NE) and amphetamine (AMPH).

Figure 1

Open in a new tab

A: Dashed lines indicate a region within general LH area (LHA) in which infusions of NE, α1-agonist and β-agonist infusion elicits an increase in waking. This region encompasses LH proper as well as the dorsomedial hypothalamus (DMH). For this schematic, circles indicate location of amphetamine infusions that elicited waking depicted in Panel C. Numbers are proportional to time awake. Numbers >2 indicate time spent awake following the infusion that exceed that seen in baseline conditions and following vehicle infusions. α1- and β-receptors within this region exert additive wake-promoting effects. Similar wake-promoting effects of NE manipulations are observed with infusions into the medial septal area and the medial preoptic area. 3V, third ventricle; fx, fornix; VMH, ventromedial hypothalamus. B: Symbols indicate time (seconds) spent awake in 30-minute epochs before (PRE) and following (POST) remote-controlled infusions of vehicle (VEH) or varying concentrations of the NE α1-agonist, phenylephrine (PHEN). All infusions were unilateral within the LHA except for a group receiving 20 nmol PHEN bilaterally. PHEN produced a dose-dependent increase in time spent awake. Bilateral infusions elicited a larger increase in waking than unilateral infusions. C: Intra-LH AMPH infusions elicited a dose-dependent increase in waking identical to that seen with NE receptor activation. AMPH induced waking occurred in the absence of a pronounced locomotor activation. See B for description of axis labels. *P<0.05; **P<0.01, relative to PRE1. Figures modified from (Schmeichel and Berridge, 2013; Schmeichel and Berridge, 2014).

Figure 2. Arousal promoting intra-lateral hypothalamus (LH) infusions of amphetamine (AMPH) are affectively neutral while reinstating AMPH seeking.

Figure 2

Open in a new tab

A: Left panel demonstrates that systemic treatment with 0.25 mg/kg subcutaneous AMPH elicited a significant conditioned place preference (CPP) as measured by a significant increase in time spent in the drug-paired chamber in a post-conditioning test (POST COND) relative to a pre-conditioning test (PRE COND). In contrast, intra-LH infusion of an arousal promoting concentration of AMPH (25 nmol, bilaterally) failed to produce either a CPP or conditioned place aversion. These observations indicate that AMPH acts in the LH to elicit affectively neutral arousal. B: Intra-LH AMPH infusion reinstates (AMPH REINST) an extinguished CPP (EXTINCTION) elicited by systemic treatment with AMPH (0.25 mg/kg; PRE COND vs. POST COND). **P<0.01 vs. PRE COND; ##P <0.01 vs. POST COND; %P <0.05 vs. EXTINCTION. Data from (Schmeichel and Berridge, 2014).

Collectively, these observations indicate that affectively-neutral arousal is sufficient to reinstate psychostimulant seeking. As reviewed above, NE acts at α1 and β receptors in the LH to similarly promote arousal. Given amphetamine infusions into the LH elevate extracellular NE levels, it is posited that NE plays a significant role in the arousal-related reinstating effects of intra-LH amphetamine infusions. These observations raise important questions for future studies. These include whether the arousal-promoting actions of NE signaling in the LH or other subcortical regions associated with NE-driven arousal (e.g. MSA, MPOA) are: 1) affectively neutral; 2) sufficient to trigger reinstatement, and 3) necessary for the reinstating effects of either local or systemic psychostimulant treatment. It is important to note that the posited role of NE-dependent arousal in the reinstatement of drug seeking does not argue against a role of either negative affect or other neurotransmitter (e.g. dopamine) signaling in drug/psychostimulant relapse. Indeed, evidence strongly indicates an involvement of these other processes in drug addiction. However, the evidence reviewed above additionally suggests a potentially important role of the (affectively-neutral) arousal-promoting actions of NE in the reinstatement of drug seeking.

2.4 NE involvement in the reinforcing actions of drugs of abuse

The above-described observations indicate that NE-dependent elevation in arousal likely contributes to stress-related and potentially other forms of reinstatement. A separate question is whether NE contributes to the reinforcing actions of drugs of abuse. This is a topic that has not received extensive exploration in part given limited and mixed results of early studies (see Weinshenker and Schroeder, 2007). It is important to note, as reviewed above, the arousal-promoting actions of NE involve multiple receptor subtypes acting in multiple brain regions. Thus, negative observations with methods that only partially impair NE signaling need to be interpreted cautiously.

Nonetheless, several observations indicate that disruption of NE signaling reduces drug taking and seeking, in both self-administration and CPP paradigms. In terms of self-administration, disruption to NE neurotransmission has been shown to reduce intake of a variety of drugs of abuse. Specifically, inhibition of NE synthesis has been observed to reduce morphine (Brown et al., 1978) and ethanol administration (Amit et al., 1977; Brown et al., 1977; Weinshenker et al., 2000), while reduced NE transmission via activation of α2 autoreceptors attenuated alcohol intake (Lê et al., 2005). Likewise, blockade of either α1 or β receptors reduced intake of cocaine and ethanol (Goldberg and Gonzalez, 1976; Harris et al., 1996; Gilpin and Koob, 2010; Skelly and Weiner, 2014). Additionally, mice engineered to lack α1 receptors display reduced oral cocaine and morphine preference relative to their wild-type counterparts (Drouin et al., 2002). Of course, the knockout approach is subject to long-term compensatory responses that may modify normal physiology, complicating interpretation of results obtained with this approach. Finally, increasing NE activity via NE transporter (NET) knockouts or α2-receptor antagonists has been observed to increase cocaine and alcohol intake, respectively (Rocha, 2003; Lê et al., 2005).

Similar effects of NE disruption are observed when the rewarding actions of drugs of abuse are measured using CPP. For instance, depletion of NE, suppression of NE release, or blockade of α1- or β-receptors blocks CPP for psychostimulants and opiates (Hand et al., 1989; Zarrindast et al., 2002; Ventura et al., 2003; Sahraei et al., 2004; Ventura et al., 2005; Fitzgerald et al., 2016). Consistent with this, DBH or α1-receptors knockout mice display reduced CPP for morphine (Drouin et al., 2002; Olson et al., 2006). Importantly, the attenuation of CPP elicited by the disruption of NE signaling does not appear to be related to generalized failures in learning given DBH knockout mice are capable of expressing CPP for food and conditioned taste aversion to lithium chloride (Weinshenker et al., 2000; Olson et al., 2006; Schank et al., 2006). In contrast to the effects of NE disruption, enhanced NE signaling in NET knockouts or via α2-antagonist treatment increases CPP for psychostimulants and opiates (Xu et al., 2000; Zarrindast et al., 2002; Sahraei et al., 2004).

Despite this evidence, several other studies indicate that disruptions to NE signaling fail to alter cocaine or ethanol self-administration (Roberts et al., 1977; Richardson and Novakovski, 1978; Wee et al., 2006). Moreover, inhibition of NE signaling has also been noted to decrease food intake, an observation that has been interpreted to argue against a role of NE, specifically in the reinforcing actions of drugs of abuse (Weinshenker and Schroeder, 2007). However, if a minimal arousal level is required for motivated behavior, NE contributions to motivation may not be selective to drug-related motivation.

While the available evidence argues for a role of NE signaling in the reinforcing actions of drugs of abuse, the nature of this involvement, including the extent to which this reflects NE-modulation of arousal, is unclear and represents an important area for future study.

3. Conclusions

In conclusion, arousal is known to impact motivated behavior and a large body of evidence demonstrates a critical role of central noradrenergic systems in the regulation of arousal. NE-dependent modulation of arousal involves multiple noradrenergic nuclei that display differential innervation patterns across arousal related regions. Intriguingly, limited data suggest the hypotheses that affectively-neutral arousal contributes to relapse and that NE α1- and β-receptors located in subcortical arousal-related regions play an important role in this process. The degree to which NE-signaling in arousal-related regions contributes to drug reinforcement and the reinstatement of drug seeking for varying classes of drugs and differing forms of reinforcement is an important topic for future research.

Highlights.

  • Arousal is a critical component of motivational processes

  • Norepinephrine (NE) promotes arousal via action in a network of subcortical regions

  • Relapse likely involves NE-dependent increases in affectively-neutral arousal

Acknowledgments

This work was supported by PHS grants DA10681, DA00389, MH081843, DA031900, the University of Wisconsin Graduate School, and the National Institute on Drug Abuse, Intramural Research Program.

Footnotes

1

We deliberately use the term ‘reinforcement’ over ‘reward’ as it can be challenging to measure the subjective experience typically denoted by the term ‘reward’, particularly in animals. In contrast, the reinforcing actions of drugs can be readily measured in both humans and animals, and can be either positive or negative. However, given multiple cognitive, affective and motivational processes participate in the reinforcing actions of drugs (see Berridge and Robinson, 2003; Salamone and Correa, 2012; Salamone et al., 2012; Schultz, 2015), it can be difficult to identify the underlying behavioral processes associated with alterations in drug seeking as measured in reinforcement paradigms.

The authors declare no conflict of interest.

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

References

  1. Abercrombie ED, Jacobs BL. Single-unit response of noradrenergic neurons in the locus coeruleus of freely moving cats. II. Adaptation to chronically presented stressful stimuli. J Neurosci. 1987;7:2844–2848. doi: 10.1523/JNEUROSCI.07-09-02844.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Amit Z, Brown ZW, Levitan DE, Ogren SO. Noradrenergic mediation of the positive reinforcing properties of ethanol: I. Suppression of ethanol consumption in laboratory rats following dopamine-beta-hydroxylase inhibition. Arch Int Pharmacodyn Ther. 1977;230:65–75. [PubMed] [Google Scholar]
  3. Arnsten AF, Goldman-Rakic PS. Selective prefrontal cortical projections to the region of the locus coeruleus and raphe nuclei in the rhesus monkey. Brain Res. 1984;306:9–18. doi: 10.1016/0006-8993(84)90351-2. [DOI] [PubMed] [Google Scholar]
  4. Arnsten AF, Steere JC, Hunt RD. The contribution of alpha 2-noradrenergic mechanisms of prefrontal cortical cognitive function. Potential significance for attention-deficit hyperactivity disorder. Arch Gen Psychiatry. 1996;53:448–55. doi: 10.1001/archpsyc.1996.01830050084013. [DOI] [PubMed] [Google Scholar]
  5. Aston-Jones G, Bloom FE. Activity of norepinephrine-containing locus coeruleus neurons in behaving rats anticipates fluctuations in the sleep-waking cycle. J Neurosci. 1981;1:876–886. doi: 10.1523/JNEUROSCI.01-08-00876.1981. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Baker TB, Piper ME, McCarthy DE, Majeskie MR, Fiore MC. Addiction motivation reformulated: an affective processing model of negative reinforcement. Psychol Rev. 2004;111:33–51. doi: 10.1037/0033-295X.111.1.33. [DOI] [PubMed] [Google Scholar]
  7. Berridge CW, Foote SL. Effects of locus coeruleus activation on electroencephalographic activity in neocortex and hippocampus. J Neurosci. 1991;11:3135–3145. doi: 10.1523/JNEUROSCI.11-10-03135.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Berridge CW, Page ME, Valentino RJ, Foote SL. Effects of locus coeruleus inactivation on electroencephalographic activity in neocortex and hippocampus. Neuroscience. 1993;55:381–393. doi: 10.1016/0306-4522(93)90507-c. [DOI] [PubMed] [Google Scholar]
  9. Berridge CW, Bolen SJ, Manley MS, Foote SL. Modulation of forebrain electroencephalographic activity in halothane-anesthetized rat via actions of noradrenergic beta-receptors within the medial septal region. J Neurosci. 1996;16:7010–7020. doi: 10.1523/JNEUROSCI.16-21-07010.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Berridge CW, Foote SL. Enhancement of behavioral and electroencephalographic indices of waking following stimulation of noradrenergic beta-receptors within the medial septal region of the basal forebrain. J Neurosci. 1996;16:6999–7009. doi: 10.1523/JNEUROSCI.16-21-06999.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Berridge CW, O’Neil J, Wifler K. Amphetamine acts within the medial basal forebrain to initiate and maintain alert waking. Neuroscience. 1999;93:885–896. doi: 10.1016/s0306-4522(99)00271-7. [DOI] [PubMed] [Google Scholar]
  12. Berridge CW, España RA. Synergistic sedative effects of noradrenergic alpha(1)- and beta- receptor blockade on forebrain electroencephalographic and behavioral indices. Neuroscience. 2000;99:495–505. doi: 10.1016/s0306-4522(00)00215-3. [DOI] [PubMed] [Google Scholar]
  13. Berridge CW, Morris MF. Amphetamine-induced activation of forebrain EEG is prevented by noradrenergic beta-receptor blockade in the halothane-anesthetized rat. Psychopharmacology (Berl) 2000;148:307–313. doi: 10.1007/s002130050055. [DOI] [PubMed] [Google Scholar]
  14. Berridge CW, O’Neill J. Differential sensitivity to the wake-promoting actions of norepinephrine within the medial preoptic area and the substantia innominata. Behav Neurosci. 2001;115:165–174. doi: 10.1037/0735-7044.115.1.165. [DOI] [PubMed] [Google Scholar]
  15. Berridge CW, Stalnaker TA. Relationship between low-dose amphetamine-induced arousal and extracellular norepinephrine and dopamine levels within prefrontal cortex. Synapse. 2002;46:140–149. doi: 10.1002/syn.10131. [DOI] [PubMed] [Google Scholar]
  16. Berridge CW, Isaac SO, España RA. Additive wake-promoting actions of medial basal forebrain noradrenergic alpha1- and beta-receptor stimulation. Behav Neurosci. 2003;117:350–359. doi: 10.1037/0735-7044.117.2.350. [DOI] [PubMed] [Google Scholar]
  17. Berridge CW, Waterhouse BD. The locus coeruleus-noradrenergic system: modulation of behavioral state and state-dependent cognitive processes. Brain Res Brain Res Rev. 2003;42:33–84. doi: 10.1016/s0165-0173(03)00143-7. [DOI] [PubMed] [Google Scholar]
  18. Berridge CW, Schmeichel BE, Espana RA. Noradrenergic modulation of wakefulness/arousal. Sleep Med Rev. 2012;16:187–97. doi: 10.1016/j.smrv.2011.12.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Berridge KC, Robinson TE. Parsing reward. Trends Neurosci. 2003;26:507–13. doi: 10.1016/S0166-2236(03)00233-9. [DOI] [PubMed] [Google Scholar]
  20. Brown ZJ, Tribe E, D’Souza NA, Erb S. Interaction between noradrenaline and corticotrophin-releasing factor in the reinstatement of cocaine seeking in the rat. Psychopharmacology (Berl) 2009;203:121–30. doi: 10.1007/s00213-008-1376-4. [DOI] [PubMed] [Google Scholar]
  21. Brown ZJ, Nobrega JN, Erb S. Central injections of noradrenaline induce reinstatement of cocaine seeking and increase c-fos mRNA expression in the extended amygdala. Behav Brain Res. 2011;217:472–6. doi: 10.1016/j.bbr.2010.09.025. [DOI] [PubMed] [Google Scholar]
  22. Brown ZW, Amit Z, Levitan DE, Ogren SO, Sutherland EA. Noradrenergic mediation of the positive reinforcing properties of ethanol: II. Extinction of ethanol-drinking behavior in laboratory rats by inhibition of dopamine-beta-hydroxylase. Implications for treatment procedures in human alcoholics. Arch Int Pharmacodyn Ther. 1977;230:76–82. [PubMed] [Google Scholar]
  23. Brown ZW, Amit Z, Sinyor D, Rockman GE, Ogren SO. Suppression of voluntary ingestion of morphine by inhibition of dopamine-beta-hydroxylase. Arch Int Pharmacodyn Ther. 1978;232:102–10. [PubMed] [Google Scholar]
  24. Buzsaki G, Leung LW, Vanderwolf CH. Cellular bases of hippocampal EEG in the behaving rat. Brain Res. 1983;287:139–171. doi: 10.1016/0165-0173(83)90037-1. [DOI] [PubMed] [Google Scholar]
  25. Buzsaki G, Bickford RG, Ponomareff G, Thal LJ, Mandel R, Gage FH. Nucleus basalis and thalamic control of neocortical activity in the freely moving rat. J Neurosci. 1988;8:4007–4026. doi: 10.1523/JNEUROSCI.08-11-04007.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Buzsaki G, Gage FH. The cholinergic nucleus basalis: a key structure in neocortical arousal. EXS. 1989;57:159–171. doi: 10.1007/978-3-0348-9138-7_16. [DOI] [PubMed] [Google Scholar]
  27. Cape EG, Jones BE. Differential modulation of high-frequency gamma-electroencephalogram activity and sleep-wake state by noradrenaline and serotonin microinjections into the region of cholinergic basalis neurons. J Neurosci. 1998;18:2653–66. doi: 10.1523/JNEUROSCI.18-07-02653.1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Carter ME, Yizhar O, Chikahisa S, Nguyen H, Adamantidis A, Nishino S, Deisseroth K, de Lecea L. Tuning arousal with optogenetic modulation of locus coeruleus neurons. Nat Neurosci. 2010;13:1526–33. doi: 10.1038/nn.2682. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Cooper DA, Kimmel HL, Manvich DF, Schmidt KT, Weinshenker D, Howell LL. Effects of pharmacologic dopamine beta-hydroxylase inhibition on cocaine-induced reinstatement and dopamine neurochemistry in squirrel monkeys. J Pharmacol Exp Ther. 2014;350:144–52. doi: 10.1124/jpet.113.212357. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Cullinan WE, Zaborszky L. Organization of ascending hypothalamic projections to the rostral forebrain with special reference to the innervation of cholinergic projection neurons. J Comp Neurol. 1991;306:631–667. doi: 10.1002/cne.903060408. [DOI] [PubMed] [Google Scholar]
  31. Cummings DF, Ericksen SS, Goetz A, Schetz JA. Transmembrane Segment Five Serines of the D4 Dopamine Receptor Uniquely Influence the Interactions of Dopamine, Norepinephrine, and Ro10-4548. The Journal of Pharmacology and Experimental Therapeutics. 2010;333:682–695. doi: 10.1124/jpet.109.164962. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Drouin C, Darracq L, Trovero F, Blanc G, Glowinski J, Cotecchia S, Tassin JP. Alpha1b-adrenergic receptors control locomotor and rewarding effects of psychostimulants and opiates. J Neurosci. 2002;22:2873–84. doi: 10.1523/JNEUROSCI.22-07-02873.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Dunn AJ. Stress-related changes in cerebral catecholamine and indoleamine metabolism: lack of effect of adrenalectomy and corticosterone. J Neurochem. 1988;51:406–412. doi: 10.1111/j.1471-4159.1988.tb01053.x. [DOI] [PubMed] [Google Scholar]
  34. Erb S, Hitchcott PK, Rajabi H, Mueller D, Shaham Y, Stewart J. Alpha-2 adrenergic receptor agonists block stress-induced reinstatement of cocaine seeking. Neuropsychopharmacology. 2000;23:138–50. doi: 10.1016/S0893-133X(99)00158-X. [DOI] [PubMed] [Google Scholar]
  35. España RA, Vlasaty J, McCormack SL, Llewellyn-Smith IJ, Scammell TE. Aminergic inputs to the hypocretin/orexin neurons. Society for Neuroscience Meeting 2005 [Google Scholar]
  36. España RA, Berridge CW. Organization of noradrenergic efferents to arousal-related basal forebrain structures. J Comp Neurol. 2006;496:668–683. doi: 10.1002/cne.20946. [DOI] [PubMed] [Google Scholar]
  37. Fitzgerald MK, Otis JM, Mueller D. Dissociation of beta1- and beta2-adrenergic receptor subtypes in the retrieval of cocaine-associated memory. Behav Brain Res. 2016;296:94–9. doi: 10.1016/j.bbr.2015.08.030. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Florin SM, Kuczenski R, Segal DS. Regional extracellular norepinephrine responses to amphetamine and cocaine and effects of clonidine pretreatment. Brain Res. 1994;654:53–62. doi: 10.1016/0006-8993(94)91570-9. [DOI] [PubMed] [Google Scholar]
  39. Florin SM, Kuczenski R, Segal DS. Effects of reserpine on extracellular caudate dopamine and hippocampus norepinephrine responses to amphetamine and cocaine: mechanistic and behavioral considerations. J Pharmacol Exp Ther. 1995;274:231–41. [PubMed] [Google Scholar]
  40. Foote SL, Aston-Jones G, Bloom FE. Impulse activity of locus coeruleus neurons in awake rats and monkeys is a function of sensory stimulation and arousal. Proc Natl Acad Sci U S A. 1980;77:3033–3037. doi: 10.1073/pnas.77.5.3033. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Foote SL, Bloom FE, Aston-Jones G. Nucleus locus ceruleus: new evidence of anatomical and physiological specificity. Physiol Rev. 1983;63:844–914. doi: 10.1152/physrev.1983.63.3.844. [DOI] [PubMed] [Google Scholar]
  42. George O, Koob GF. Individual differences in prefrontal cortex function and the transition from drug use to drug dependence. Neurosci Biobehav Rev. 2010;35:232–47. doi: 10.1016/j.neubiorev.2010.05.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Gilpin NW, Koob GF. Effects of beta-adrenoceptor antagonists on alcohol drinking by alcohol-dependent rats. Psychopharmacology (Berl) 2010;212:431–9. doi: 10.1007/s00213-010-1967-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Goldberg SR, Gonzalez FA. Effects of propranolol on behavior maintained under fixed-ratio schedules of cocaine injection or food presentation in squirrel monkeys. J Pharmacol Exp Ther. 1976;198:626–34. [PubMed] [Google Scholar]
  45. Hand TH, Stinus L, Le Moal M. Differential mechanisms in the acquisition and expression of heroin-induced place preference. Psychopharmacology (Berl) 1989;98:61–7. doi: 10.1007/BF00442007. [DOI] [PubMed] [Google Scholar]
  46. Harris GC, Hedaya MA, Pan WJ, Kalivas P. beta-adrenergic antagonism alters the behavioral and neurochemical responses to cocaine. Neuropsychopharmacology. 1996;14:195–204. doi: 10.1016/0893-133X(95)00089-V. [DOI] [PubMed] [Google Scholar]
  47. Highfield D, Clements A, Shalev U, McDonald R, Featherstone R, Stewart J, Shaham Y. Involvement of the medial septum in stress-induced relapse to heroin seeking in rats. Eur J Neurosci. 2000;12:1705–13. doi: 10.1046/j.1460-9568.2000.00037.x. [DOI] [PubMed] [Google Scholar]
  48. Hobson JA, McCarley RW, Wyzinski PW. Sleep cycle oscillation: reciprocal discharge by two brainstem neuronal groups. Science. 1975;189:55–58. doi: 10.1126/science.1094539. [DOI] [PubMed] [Google Scholar]
  49. Jobes ML, Ghitza UE, Epstein DH, Phillips KA, Heishman SJ, Preston KL. Clonidine blocks stress-induced craving in cocaine users. Psychopharmacology. 2011;218:83–88. doi: 10.1007/s00213-011-2230-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Kalivas PW, McFarland K. Brain circuitry and the reinstatement of cocaine-seeking behavior. Psychopharmacology (Berl) 2003;168:44–56. doi: 10.1007/s00213-003-1393-2. [DOI] [PubMed] [Google Scholar]
  51. Kleinlogel H, Scholtysik G, Sayers AC. Effects of clonidine and BS 100–141 on the EEG sleep pattern in rats. Eur J Pharmacol. 1975;33:159–63. doi: 10.1016/0014-2999(75)90151-x. [DOI] [PubMed] [Google Scholar]
  52. Koob GF. Stress, corticotropin-releasing factor, and drug addiction. Ann N Y Acad Sci. 1999;897:27–45. doi: 10.1111/j.1749-6632.1999.tb07876.x. [DOI] [PubMed] [Google Scholar]
  53. Kosten TR, Rounsaville BJ, Kleber HD. A 2.5-year follow-up of depression, life crises, and treatment effects on abstinence among opioid addicts. Arch Gen Psychiatry. 1986;43:733–8. doi: 10.1001/archpsyc.1986.01800080019003. [DOI] [PubMed] [Google Scholar]
  54. Kuczenski R, Segal DS. Regional norepinephrine response to amphetamine using dialysis: comparison with caudate dopamine. Synapse. 1992;11:164–9. doi: 10.1002/syn.890110210. [DOI] [PubMed] [Google Scholar]
  55. Kumar V, Datta S, Chhina GS, Gandhi N, Singh B. Sleep-awake responses elicited from medial preoptic area on application of norepinephrine and phenoxybenzamine in free moving rats. Brain Res. 1984;322:322–5. doi: 10.1016/0006-8993(84)90125-2. [DOI] [PubMed] [Google Scholar]
  56. Kumar VM, Datta S, Chhina GS, Singh B. Alpha adrenergic system in medial preoptic area involved in sleep-wakefulness in rats. Brain Res Bull. 1986;16:463–468. doi: 10.1016/0361-9230(86)90174-7. [DOI] [PubMed] [Google Scholar]
  57. Laverty R, Taylor KM. Behavioural and biochemical effects of 2-(2,6-dichlorophenylamino)-2-imidazoline hydrochloride (St 155) on the central nervous system. Br J Pharmacol. 1969;35:253–64. doi: 10.1111/j.1476-5381.1969.tb07984.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Lê AD, Harding S, Juzytsch W, Watchus J, Shalev U, Shaham Y. The role of corticotrophin-releasing factor in stress-induced relapse to alcohol-seeking behavior in rats. Psychopharmacology (Berl) 2000;150:317–24. doi: 10.1007/s002130000411. [DOI] [PubMed] [Google Scholar]
  59. Lê AD, Harding S, Juzytsch W, Funk D, Shaham Y. Role of alpha-2 adrenoceptors in stress-induced reinstatement of alcohol seeking and alcohol self-administration in rats. Psychopharmacology. 2005;179:366–373. doi: 10.1007/s00213-004-2036-y. [DOI] [PubMed] [Google Scholar]
  60. Lê AD, Funk D, Harding S, Juzytsch W, Fletcher PJ, Shaham Y. Effects of dexfenfluramine and 5-HT3 receptor antagonists on stress-induced reinstatement of alcohol seeking in rats. Psychopharmacology (Berl) 2006;186:82–92. doi: 10.1007/s00213-006-0346-y. [DOI] [PubMed] [Google Scholar]
  61. Lê AD, Funk D, Harding S, Juzytsch W, Fletcher PJ. The role of noradrenaline and 5-hydroxytryptamine in yohimbine-induced increases in alcohol-seeking in rats. Psychopharmacology (Berl) 2009;204:477–88. doi: 10.1007/s00213-009-1481-z. [DOI] [PMC free article] [PubMed] [Google Scholar]
  62. Lê AD, Funk D, Juzytsch W, Coen K, Navarre BM, Cifani C, Shaham Y. Effect of prazosin and guanfacine on stress-induced reinstatement of alcohol and food seeking in rats. Psychopharmacology. 2011;218:89–99. doi: 10.1007/s00213-011-2178-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  63. Lee MG, Manns ID, Alonso A, Jones BE. Sleep-wake related discharge properties of basal forebrain neurons recorded with micropipettes in head-fixed rats. J Neurophysiol. 2004;92:1182–1198. doi: 10.1152/jn.01003.2003. [DOI] [PubMed] [Google Scholar]
  64. Leri F, Flores J, Rodaros D, Stewart J. Blockade of stress-induced but not cocaine-induced reinstatement by infusion of noradrenergic antagonists into the bed nucleus of the stria terminalis or the central nucleus of the amygdala. J Neurosci. 2002;22:5713–8. doi: 10.1523/JNEUROSCI.22-13-05713.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  65. Mantsch JR, Weyer A, Vranjkovic O, Beyer CE, Baker DA, Caretta H. Involvement of noradrenergic neurotransmission in the stress- but not cocaine-induced reinstatement of extinguished cocaine-induced conditioned place preference in mice: role for beta-2 adrenergic receptors. Neuropsychopharmacology. 2010;35:2165–78. doi: 10.1038/npp.2010.86. [DOI] [PMC free article] [PubMed] [Google Scholar]
  66. Mantsch JR, Vranjkovic O, Twining RC, Gasser PJ, McReynolds JR, Blacktop JM. Neurobiological mechanisms that contribute to stress-related cocaine use. Neuropharmacology. 2014;76:383–394. doi: 10.1016/j.neuropharm.2013.07.021. [DOI] [PMC free article] [PubMed] [Google Scholar]
  67. Mantsch JR, Baker DA, Funk D, Le AD, Shaham Y. Stress-Induced Reinstatement of Drug Seeking: 20 Years of Progress. Neuropsychopharmacology. 2015 doi: 10.1038/npp.2015.142. [DOI] [PMC free article] [PubMed] [Google Scholar]
  68. McLellan AT, Lewis DC, O’Brien CP, Kleber HD. Drug dependence, a chronic medical illness: implications for treatment, insurance, and outcomes evaluation. Jama. 2000;284:1689–95. doi: 10.1001/jama.284.13.1689. [DOI] [PubMed] [Google Scholar]
  69. Metherate R, Cox CL, Ashe JH. Cellular bases of neocortical activation: modulation of neural oscillations by the nucleus basalis and endogenous acetylcholine. J Neurosci. 1992;12:4701–4711. doi: 10.1523/JNEUROSCI.12-12-04701.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  70. Newman-Tancredi A, Audinot-Bouchez V, Gobert A, Millan MJ. Noradrenaline and adrenaline are high affinity agonists at dopamine D4 receptors. Eur J Pharmacol. 1997;319:379–83. doi: 10.1016/s0014-2999(96)00985-5. [DOI] [PubMed] [Google Scholar]
  71. Olson VG, Heusner CL, Bland RJ, During MJ, Weinshenker D, Palmiter RD. Role of Noradrenergic Signaling by the Nucleus Tractus Solitarius in Mediating Opiate Reward. Science. 2006;311:1017–1020. doi: 10.1126/science.1119311. [DOI] [PubMed] [Google Scholar]
  72. Pastel RH, Fernstrom JD. The effects of clonidine on EEG wavebands associated with sleep in the rat. Brain Res. 1984;300:243–55. doi: 10.1016/0006-8993(84)90835-7. [DOI] [PubMed] [Google Scholar]
  73. Platt DM, Rowlett JK, Spealman RD. Noradrenergic mechanisms in cocaine-induced reinstatement of drug seeking in squirrel monkeys. J Pharmacol Exp Ther. 2007;322:894–902. doi: 10.1124/jpet.107.121806. [DOI] [PubMed] [Google Scholar]
  74. Richardson JS, Novakovski DM. Brain monoamines and free choice ethanol consumption in rats. Drug Alcohol Depend. 1978;3:253–64. doi: 10.1016/0376-8716(78)90079-0. [DOI] [PubMed] [Google Scholar]
  75. Roberts DCS, Corcoran ME, Fibiger HC. On the role of ascending catecholaminergic systems in intravenous self-administration of cocaine. Pharmacol Biochem Behav. 1977;6:615–620. doi: 10.1016/0091-3057(77)90084-3. [DOI] [PubMed] [Google Scholar]
  76. Robertson SD, Plummer NW, de Marchena J, Jensen P. Developmental origins of central norepinephrine neuron diversity. Nat Neurosci. 2013;16:1016–23. doi: 10.1038/nn.3458. [DOI] [PMC free article] [PubMed] [Google Scholar]
  77. Rocha BA. Stimulant and reinforcing effects of cocaine in monoamine transporter knockout mice. Eur J Pharmacol. 2003;479:107–15. doi: 10.1016/j.ejphar.2003.08.061. [DOI] [PubMed] [Google Scholar]
  78. Sahraei H, Ghazzaghi H, Zarrindast MR, Ghoshooni H, Sepehri H, Haeri-Rohan A. The role of alpha-adrenoceptor mechanism(s) in morphine-induced conditioned place preference in female mice. Pharmacol Biochem Behav. 2004;78:135–41. doi: 10.1016/j.pbb.2004.03.004. [DOI] [PubMed] [Google Scholar]
  79. Salamone JD, Correa M. The mysterious motivational functions of mesolimbic dopamine. Neuron. 2012;76:470–85. doi: 10.1016/j.neuron.2012.10.021. [DOI] [PMC free article] [PubMed] [Google Scholar]
  80. Salamone JD, Correa M, Nunes EJ, Randall PA, Pardo M. The behavioral pharmacology of effort-related choice behavior: dopamine, adenosine and beyond. J Exp Anal Behav. 2012;97:125–46. doi: 10.1901/jeab.2012.97-125. [DOI] [PMC free article] [PubMed] [Google Scholar]
  81. Schank JR, Ventura R, Puglisi-Allegra S, Alcaro A, Cole CD, Liles LC, Seeman P, Weinshenker D. Dopamine beta-hydroxylase knockout mice have alterations in dopamine signaling and are hypersensitive to cocaine. Neuropsychopharmacology. 2006;31:2221–30. doi: 10.1038/sj.npp.1301000. [DOI] [PubMed] [Google Scholar]
  82. Schmeichel BE, Berridge CW. Wake-promoting actions of noradrenergic alpha1 - and beta-receptors within the lateral hypothalamic area. Eur J Neurosci. 2013;37:891–900. doi: 10.1111/ejn.12084. [DOI] [PMC free article] [PubMed] [Google Scholar]
  83. Schmeichel BE, Berridge CW. Amphetamine acts within the lateral hypothalamic area to elicit affectively neutral arousal and reinstate drug-seeking. Int J Neuropsychopharmacol. 2014;17:63–75. doi: 10.1017/S1461145713000734. [DOI] [PMC free article] [PubMed] [Google Scholar]
  84. Schroeder JP, Epps SA, Grice TW, Weinshenker D. The selective dopamine beta-hydroxylase inhibitor nepicastat attenuates multiple aspects of cocaine-seeking behavior. Neuropsychopharmacology. 2013;38:1032–8. doi: 10.1038/npp.2012.267. [DOI] [PMC free article] [PubMed] [Google Scholar]
  85. Schultz W. Neuronal Reward and Decision Signals: From Theories to Data. Physiol Rev. 2015;95:853–951. doi: 10.1152/physrev.00023.2014. [DOI] [PMC free article] [PubMed] [Google Scholar]
  86. Self DW. Regulation of drug-taking and -seeking behaviors by neuroadaptations in the mesolimbic dopamine system. Neuropharmacology. 2004;47(Suppl 1):242–55. doi: 10.1016/j.neuropharm.2004.07.005. [DOI] [PubMed] [Google Scholar]
  87. Shaham Y, Erb S, Stewart J. Stress-induced relapse to heroin and cocaine seeking in rats: a review. Brain Res Brain Res Rev. 2000a;33:13–33. doi: 10.1016/s0165-0173(00)00024-2. [DOI] [PubMed] [Google Scholar]
  88. Shaham Y, Highfield D, Delfs J, Leung S, Stewart J. Clonidine blocks stress-induced reinstatement of heroin seeking in rats: an effect independent of locus coeruleus noradrenergic neurons. European Journal of Neuroscience. 2000b;12:292–302. doi: 10.1046/j.1460-9568.2000.00899.x. [DOI] [PubMed] [Google Scholar]
  89. Sinha R, Kimmerling A, Doebrick C, Kosten TR. Effects of lofexidine on stress-induced and cue-induced opioid craving and opioid abstinence rates: preliminary findings. Psychopharmacology (Berl) 2007;190:569–74. doi: 10.1007/s00213-006-0640-8. [DOI] [PubMed] [Google Scholar]
  90. Skelly MJ, Weiner JL. Chronic treatment with prazosin or duloxetine lessens concurrent anxiety-like behavior and alcohol intake: evidence of disrupted noradrenergic signaling in anxiety-related alcohol use. Brain Behav. 2014;4:468–83. doi: 10.1002/brb3.230. [DOI] [PMC free article] [PubMed] [Google Scholar]
  91. Sood S, Dhawan JK, Ramesh V, John J, Gopinath G, Kumar VM. Role of medial preoptic area beta adrenoceptors in the regulation of sleep-wakefulness. Pharmacol Biochem Behav. 1997;57:1–5. doi: 10.1016/s0091-3057(96)00384-x. [DOI] [PubMed] [Google Scholar]
  92. Stewart J. Pathways to relapse: the neurobiology of drug- and stress-induced relapse to drug-taking. J Psychiatry Neurosci. 2000;25:125–36. [PMC free article] [PubMed] [Google Scholar]
  93. Swanson LW, Hartman BK. The central adrenergic system. An immunofluorescence study of the location of cell bodies and their efferent connections in the rat utilizing dopamine-beta-hydroxylase as a marker. J Comp Neurol. 1975;163:467–505. doi: 10.1002/cne.901630406. [DOI] [PubMed] [Google Scholar]
  94. Ventura R, Cabib S, Alcaro A, Orsini C, Puglisi-Allegra S. Norepinephrine in the prefrontal cortex is critical for amphetamine-induced reward and mesoaccumbens dopamine release. J Neurosci. 2003;23:1879–85. doi: 10.1523/JNEUROSCI.23-05-01879.2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  95. Ventura R, Alcaro A, Puglisi-Allegra S. Prefrontal cortical norepinephrine release is critical for morphine-induced reward, reinstatement and dopamine release in the nucleus accumbens. Cereb Cortex. 2005;15:1877–86. doi: 10.1093/cercor/bhi066. [DOI] [PubMed] [Google Scholar]
  96. Wee S, Wang Z, He R, Zhou J, Kozikowski AP, Woolverton WL. Role of the increased noradrenergic neurotransmission in drug self-administration. Drug Alcohol Depend. 2006;82:151–7. doi: 10.1016/j.drugalcdep.2005.09.002. [DOI] [PubMed] [Google Scholar]
  97. Weinshenker D, Rust NC, Miller NS, Palmiter RD. Ethanol-associated behaviors of mice lacking norepinephrine. J Neurosci. 2000;20:3157–64. doi: 10.1523/JNEUROSCI.20-09-03157.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  98. Weinshenker D, Schroeder JP. There and back again: a tale of norepinephrine and drug addiction. Neuropsychopharmacology. 2007;32:1433–1451. doi: 10.1038/sj.npp.1301263. [DOI] [PubMed] [Google Scholar]
  99. Xu F, Gainetdinov RR, Wetsel WC, Jones SR, Bohn LM, Miller GW, Wang YM, Caron MG. Mice lacking the norepinephrine transporter are supersensitive to psychostimulants. Nat Neurosci. 2000;3:465–71. doi: 10.1038/74839. [DOI] [PubMed] [Google Scholar]
  100. Yerkes RM, Dodson JD. The relation of strength of stimulus to rapidity of habit-formation. Journal of Comparative Neurology and Psychology. 1908;18:459–482. [Google Scholar]
  101. Yoshida K, McCormack S, España RA, Crocker A, Scammell TE. Afferents to the orexin neurons of the rat brain. J Comp Neurol. 2006;494:845–861. doi: 10.1002/cne.20859. [DOI] [PMC free article] [PubMed] [Google Scholar]
  102. Zaborszky L. Afferent connections of the forebrain cholinergic projection neurons, with special reference to monoaminergic and peptidergic fibers. Exs. 1989;57:12–32. doi: 10.1007/978-3-0348-9138-7_2. [DOI] [PubMed] [Google Scholar]
  103. Zaborszky L, Cullinan WE, Braun A. Afferents to basal forebrain cholinergic projection neurons: an update. Adv Exp Med Biol. 1991;295:43–100. doi: 10.1007/978-1-4757-0145-6_2. [DOI] [PubMed] [Google Scholar]
  104. Zaborszky L, Cullinan WE. Direct catecholaminergic-cholinergic interactions in the basal forebrain. I. Dopamine-beta-hydroxylase- and tyrosine hydroxylase input to cholinergic neurons. J Comp Neurol. 1996;374:535–54. doi: 10.1002/(SICI)1096-9861(19961028)374:4<535::AID-CNE5>3.0.CO;2-2. [DOI] [PubMed] [Google Scholar]
  105. Zarrindast MR, Bahreini T, Adl M. Effect of imipramine on the expression and acquisition of morphine-induced conditioned place preference in mice. Pharmacol Biochem Behav. 2002;73:941–9. doi: 10.1016/s0091-3057(02)00951-6. [DOI] [PubMed] [Google Scholar]
  106. Zhang XY, Kosten TA. Prazosin, an alpha-1 adrenergic antagonist, reduces cocaine-induced reinstatement of drug-seeking. Biol Psychiatry. 2005;57:1202–4. doi: 10.1016/j.biopsych.2005.02.003. [DOI] [PubMed] [Google Scholar]

RESOURCES