Christina J. Perry

Role of cues and contexts on drug-seeking behaviour

Environmental stimuli are powerful mediators of craving and relapse in substance‐abuse disorders. This review examined how animal models have been used to investigate the cognitive mechanisms through which cues are able to affect drug‐seeking behaviour. We address how animal models can describe the way drug‐associated cues come to facilitate the development and persistence of drug taking, as well as how these cues are critical to the tendency to relapse that characterizes substance‐abuse disorders. Drug‐associated cues acquire properties of conditioned reinforcement, incentive motivation and discriminative control, which allow them to influence drug‐seeking behaviour. Using these models, researchers have been able to investigate the pharmacology subserving the behavioural impact of environmental stimuli, some of which we highlight. Subsequently, we examine whether the impact of drug‐associated stimuli can be attenuated via a process of extinction, and how this question is addressed in the laboratory. We discuss how preclinical research has been translated into behavioural therapies targeting substance abuse, as well as highlight potential developments to therapies that might produce more enduring changes in behaviour.

A role for the ventral pallidum in context-induced and primed reinstatement of alcohol seeking.

The ventral pallidum (VP) is a major target of projections from the nucleus accumbens, and has been implicated in the reinstatement of psychostimulant seeking as part of a cortical–striatal–pallidal ‘final common pathway’ for relapse. Here, we studied the role of the VP in context‐induced and primed reinstatement of alcoholic beer seeking, using a combination of microinjections and tract tracing studies. In experiment 1, rats were trained to respond to alcoholic beer in one context (A), and then extinguished in a second context (B), prior to testing for reinstatement (ABA renewal) and extinction (ABB). VP microinjection of the μ‐opioid receptor (MOR) antagonist CTAP prevented reinstatement. In experiment 2, VP microinjection of CTAP also prevented the primed reinstatement of alcoholic beer seeking after rats were trained, extinguished, and tested in the same context. In experiment 3, we employed retrograde neural tract tracing together with c‐Fos immunohistochemistry to identify the VP afferents recruited during context‐induced reinstatement of alcoholic beer seeking. There was evidence for the recruitment of accumbens core→VP, basolateral amygdala→VP and paraventricular thalamus→VP pathways during context‐induced reinstatement. These results indicate that the VP MORs are critical for context‐induced reinstatement, and that the VP receives inputs from a number of regions known to be important in reinstatement of drug seeking.

μ-Opioid receptors in the nucleus accumbens shell mediate context-induced reinstatement (renewal) but not primed reinstatement of extinguished alcohol seeking.

Opioid antagonists reduce the rate of relapse to drinking in clinical trials and reduce reinstatement in animal models of drug seeking. However, the neuroanatomical locus for this effect remains poorly understood. We examined the role of nucleus accumbens shell (AcbSh) μ-opioid receptors in two different forms of recovery of alcoholic beer seeking. Rats were trained to nosepoke for alcoholic beer in a distinctive context and this response was then extinguished. Response recovery was produced via renewal (context-induced reinstatement) (Experiment 1) or primed reinstatement (Experiment 2). Rats received microinjections of the μ-opioid receptor antagonist CTAP before these tests. AcbSh microinfusion of 2.5 μg CTAP attenuated the ABA renewal of alcoholic beer seeking in a neuroanatomically specific manner. In contrast, AcbSh microinfusion of 2.5 μg or 5 μg CTAP had no effect on the primed reinstatement of alcoholic beer seeking. These findings indicate a role for AcbSh μ-opioid receptors in renewal of alcoholic beer seeking and suggest that there are dissociable ventral striatal substrates for different forms of recovery of extinguished alcoholic beer seeking.

Extinction of a cocaine-taking context that protects against drug-primed reinstatement is dependent on the metabotropic glutamate 5 receptor.

We investigated the effects of extinguishing action‐reward versus context‐reward associations on drug‐primed reinstatement, and the potential role of the metabotropic glutamate 5 receptor (mGlu5) in these different types of extinction in rats that self‐administer cocaine. We observed that daily context extinction (non‐reinforced exposures to the cocaine‐taking context with retracted levers) was just as effective as daily lever extinction in reducing cocaine‐primed reinstatement compared with passive abstinence. Additionally, systemic injections of the mGlu5 negative allosteric modulator MTEP (3‐[(2‐methyl‐1,3‐thiazol‐4‐yl)ethynyl]‐pyridine) following each extinction session significantly impaired the ability of context extinction to reduce cocaine‐primed reinstatement, without affecting reinstatement after lever extinction or passive abstinence.

Role of Dopamine 2 Receptor in Impaired Drug-Cue Extinction in Adolescent Rats

Adolescent drug users display resistance to treatment such as cue exposure therapy (CET), as well as increased liability to relapse. The basis of CET is extinction learning, which involves dopamine signaling in the medial prefrontal cortex (mPFC). This system undergoes dramatic alterations during adolescence. Therefore, we investigated extinction of a cocaine-associated cue in adolescent and adult rats. While cocaine self-administration and lever-alone extinction were not different between the two ages, we observed that cue extinction reduced cue-induced reinstatement in adult but not adolescent rats. Infusion of the selective dopamine 2 receptor (D2R)-like agonist quinpirole into the infralimbic cortex (IL) of the mPFC prior to cue extinction significantly reduced cue-induced reinstatement in adolescents. This effect was replicated by acute systemic treatment with the atypical antipsychotic aripiprazole (Abilify), a partial D2R-like agonist. These data suggest that adolescents may be more susceptible to relapse due to a deficit in cue extinction learning, and highlight the significance of D2R signaling in the IL for cue extinction during adolescence. These findings inspire new tactics for improving adolescent CET, with aripiprazole representing an exciting potential pharmacological adjunct for behavioral therapy.

Nucleus incertus corticotrophin-releasing factor 1 receptor signalling regulates alcohol seeking in rats.

Alcoholism is a chronic relapsing disorder, and stress is a key precipitant of relapse. The nucleus incertus (NI) is highly responsive to corticotrophin‐releasing factor (CRF) and psychological stressors, receives a CRF innervation and expresses CRF1 and CRF2 receptor mRNA. Furthermore, the ascending NI relaxin‐3 system is implicated in alcohol seeking in rats. Therefore, in alcohol‐preferring rats, we examined the effect of bilateral injections into the NI of the CRF1 receptor antagonist, CP376395 or the CRF2 receptor antagonist, astressin‐2B on yohimbine‐induced reinstatement of alcohol seeking. Using quantitative PCR analysis of NI micropunches, we assessed the effects of chronic alcohol consumption on gene expression profiles for components of the relaxin‐3 and CRF systems. Bilateral intra‐NI injections of CP376395 (500 ng/0.25 µl) attenuated yohimbine‐induced reinstatement of alcohol seeking. In contrast, intra‐NI injections of astressin‐2B (200 ng/0.25 µl) had no significant effect. In line with these data, CRF1, but not CRF2, receptor mRNA was upregulated in the NI following chronic ethanol intake. Relaxin family peptide 3 receptor mRNA was also increased in the NI following chronic ethanol. Our quantitative PCR analysis also identified CRF mRNA within the rat NI, and the existence of a newly identified population of CRF‐containing neurons was subsequently confirmed by detection of CRF immunoreactivity in rat and mouse NI. These data suggest that NI neurons contribute to reinstatement of alcohol seeking, via an involvement of CRF1 signalling. Furthermore, chronic ethanol intake leads to neuroadaptive changes in CRF and relaxin‐3 systems within rat NI.

Postnatal development of neurotransmitter systems and their relevance to extinction of conditioned fear

HighlightsRelapse‐resistant extinction in juvenile rodents may be due to high NMDA‐NR2B, mGlu5, and/or nicotinic receptor signaling in the amygdala.Extinction deficit in adolescence may be due to low NMDA‐NR2B, and/or low D2R relative to D1R signaling in the PFC.High corticotropin releasing factor, and/or reduced cannabinoid signaling in the amygdala may be related to impaired extinction in adolescence.Changes in the localization of oxytocin receptors in the amygdala may explain transition from effective to ineffective extinction across development. Abstract Remembering and forgetting are fundamental features of an organism. Extinction is a type of forgetting where there is a decrease in the significance and/or the meaning of an associative memory when elements of that memory no longer predict one another. The neural mechanisms underlying extinction of fear memories have been extensively studied in the laboratory because extinction processes are clinically relevant to exposure therapies that treat anxiety disorders. However, only in the last decade have we begun to unveil the similarities and differences in plasticity underlying extinction across development. So far it is clear that extinction is a developmentally dissociated process in behavior and in pharmacology, however there are many large gaps in the literature in understanding how the developmental trajectory of different neurotransmitters contribute to changes in the nature of extinction across development. We attempt to address these gaps in the present review. Major neurotransmitter systems including the glutamatergic and GABAergic systems, the monoamines, the endogenous opioid and cannabinoid systems, acetylcholines, and neuropeptides such as oxytocin have all been identified to play some role in extinction of fear memories and have been covered in this review. We hope to facilitate more research into mechanisms of extinction at different stages of life, especially noting that mental disorders are increasingly classified as neurodevelopmental disorders.

The metabotropic glutamate 5 receptor is necessary for extinction of cocaine-associated cues.

There is currently no medication approved specifically to treat cocaine addiction. Behavioural interventions such as cue exposure therapy (CET) rely heavily on new learning. Antagonism of the metabotropic glutamate 5 (mGlu5) receptor has emerged as a potential treatment, by reducing the reinforcing properties of cocaine. However, mGlu5 receptor activity is necessary for learning; therefore, such agents could interfere with behavioural treatments. We used a novel rodent model of CET to test the effects of mGlu5 negative and positive allosteric modulators (NAM and PAM) on behavioural therapy.

Cognitive Decline and Recovery in Alcohol Abuse

Alcohol consumption triggers a neuroinflammatory response which, if prolonged, can lead to substantial volume loss in both gray and white matter. This brain injury is associated with characteristic cognitive deficits, and, in extreme cases, with dementia. Even mild cognitive impairment creates a significant hurdle for alcohol rehabilitation, because the domains that are affected tend to be those important for sustaining abstinence. Thus, cognitive decline induced by alcohol contributes to the persistence of alcoholism. Here, I present converging data from animal and clinical studies that show how alcohol affects the brain and behavior. Although there is currently no targeted treatment for overcoming alcohol-induced cognitive decline, emerging evidence suggests that physical activity is both protective and restorative. This is a potential avenue for future programs targeted at treating alcohol abuse.

Naloxone prevents the rapid reacquisition but not acquisition of alcohol seeking.

Opioid receptors are involved in reinstatement of alcohol seeking, yet there are no reports of their role in reacquisition of an extinguished alcohol seeking response. Here we investigated the effects of the opioid antagonist naloxone on reacquisition and compared these effects with those on acquisition. Rats were trained, extinguished, then retrained to respond for alcoholic beer. Upon retraining, a second group of rats with no prior experience with the contingency between response and reinforcer was trained under the same conditions. Reacquisition was faster than acquisition. Systemic injection of naloxone (1.25 or 5 mg/kg) reduced reacquisition but had no effect on acquisition. These results suggest that reacquisition and acquisition of alcohol seeking have dissociable neurochemical substrates.