Cannabidiol regulation of emotion and emotional memory processing: relevance for treating anxiety-related and substance abuse disorders

Learning to associate cues or contexts with potential threats or rewards is adaptive and enhances survival. Both aversive and appetitive memories are therefore powerful drivers of behaviour, but the inappropriate expression of conditioned responding to fear- and drug-related stimuli can develop into anxiety-related and substance abuse disorders respectively. These disorders are associated with abnormally persistent emotional memories and inadequate treatment, often leading to symptom relapse. Studies show that cannabidiol, the main non-psychotomimetic phytocannabinoid found in Cannabis sativa, reduces anxiety via 5-HT1A and (indirect) cannabinoid receptor activation in paradigms assessing innate responses to threat. There is also accumulating evidence from animal studies investigating the effects of cannabidiol on fear memory processing indicating that it reduces learned fear in paradigms that are translationally relevant to phobias and post-traumatic stress disorder. Cannabidiol does so by reducing fear expression acutely and by disrupting fear memory reconsolidation and enhancing fear extinction, both of which can result in a lasting reduction of learned fear. Recent studies have also begun to elucidate the effects of cannabidiol on drug memory expression using paradigms with translational relevance to addiction. The findings suggest that cannabidiol reduces the expression of drug memories acutely and by disrupting their reconsolidation. Here, we review the literature demonstrating the anxiolytic effects of cannabidiol before focusing on studies investigating its effects on various fear and drug memory processes. Understanding how cannabidiol regulates emotion and emotional memory processing may eventually lead to its use as a treatment for anxiety-related and substance abuse disorders

Pharmacol Rev

A widely held dogma in the preclinical addiction field is that females are more vulnerable than males to drug craving and relapse. Here, we first review clinical studies on sex differences in psychostimulant and opioid craving and relapse. Next, we review pre-clinical studies on sex differences in psychostimulant and opioid reinstatement of drug seeking after extinc-tion of drug self-administration, and incubation of drug craving (time-dependent increase in drug seeking during abstinence). We also discuss ovarian hormones’ role in relapse and craving in humans and animal models and speculate on brain mechanisms underlying their role in cocaine craving and relapse in rodent models. Finally, we discuss imaging studies on brain responses to cocaine cues and stress in men and women. The results of the clinical studies reviewed do not appear to support the notion that women are more vulnerable to psychostimulant and opioid craving and relapse. However, this conclusion is tentative because most of the studies reviewed were correlational, not suffi-ciently powered, and not a priori designed to detect sex differences. Additionally, imaging studies suggest sex differences in brain responses to cocaine cues and stress. The results of the preclinical studies reviewed pro-vide evidence for sex differences in stress-induced reinstatement and incubation of cocaine craving but not cue-or cocaine-induced reinstatement of cocaine seeking. These sex differences are modulated in part by ovarian hormones. In contrast, the available data do not support the notion of sex differences in craving and relapse/reinstatement for methamphetamine or opioids in rodent models. Significance Statement——This systematic review summarizes clinical and preclinical studies on sex differences in psychostimulant and opioid craving and relapse. Results of the clinical studies reviewed do not appear to support the notion that women are more vulnerable to psychostimulant and opioid craving and relapse. Results of preclinical studies reviewed pro-vide evidence for sex differences in reinstatement and incubation of cocaine seeking but not for reinstatement or incubation of methamphetamine or opioid seeking. © 2022, American Society for Pharmacology and Experimental Therapy. All rights reserved

Aberrant Brain Neuroplasticity and Function in Drug Addiction: A Focus on Learning-Related Brain Regions

This chapter will review the altered brain structure and function associated to drug addiction, with a focus on brain regions involved in learning and motivated behavior. As evidenced by both clinical and preclinical studies, repeated drug exposure affects whole brain neuroplasticity including the mesolimbic system which is a main locus for reward, an action-control center such as the dorsal striatum, and limbic brain regions such as the prefrontal cortex, the hippocampus, and the amygdala that are involved in behavioral control, memory, and mood. In this way, the drug-seeking actions that were initially intentional responses become involuntary habits governed by the dorsal striatum. Drug addiction may also curse with a reduced ability to experience rewards that are unrelated to drugs and emotional dysregulation, while the impairment on limbic regions contributes to generate cognitive symptoms. These entail persistent memories for previous experiences with the drug contrasting with a global cognitive decline that may hamper the acquisition of new, adaptive learnings. Overall, these features promote a desire for the drug, leading to relapse in drug use. Further drug exposure, in turn, aggravates its consequences on the brain and behavior, creating the harmful “addiction cycle.

A Polypharmacological Approach to Relapse Prevention in an Animal Model of Heroin Addiction

Chemical compounds that target dopamine (DA) D1 or D3 receptors have shown promise as potential interventions in animal models of cue-induced relapse. However, undesirable side effects or pharmacodynamic profiles have limited the advancement of new compounds in preclinical studies when administered as independent treatments. In this series of experiments, we explored the effects of co-administration of a D1-recepter partial agonist (SKF 77434) and a D3-receptor antagonist (NGB 2904) in heroin-seeking rats within a ‘conflict’ model of abstinence and cue-induced relapse. Rats were first trained to press a lever to self-administer heroin and drug delivery was paired contingently with cues (e.g., light, pump noise). Self-initiated abstinence was facilitated by applying electrical current to the flooring in front of the levers. Lastly, a relapse response was provoked by noncontingent presentation of conditioned cues. Prior to provocation, rats received a systemic injection of SKF 77434, NGB 2904, or a combination of both compounds to assess treatment effects on lever pressing. Results indicated that the co-administration of low (i.e., independently ineffective) doses of both compounds was more effective in reducing cue-induced relapse to heroin seeking than either compound alone, with some evidence of drug synergism. Follow-up studies indicated that this reduction was not due to motoric impairment nor enhanced sensitivity to the electrified flooring and that this treatment did not significantly affect motivation for food. Implications for the treatment of opiate use disorder and recommendations for further research are discussed

Addictions

Addiction, increasingly perceived as a heterogeneous brain disorder, is one of the most peculiar psychiatric pathologies in that its management involves various, often non-overlapping, resources from the biological, psychological, medical, economical, social, and legal realms. Despite extensive efforts from the players of these various fields, to date there are no reliably effective treatments of addiction. This may stem from a lack of understanding of the etiology and pathophysiology of this disorder as well as from the lack of interest into the potential differences among patients in the way they interact compulsively with their drug. This book offers an overview of the psychobiology of addiction and its current management strategies from pharmacological, social, behavioural, and psychiatric points of view

Role of Prefrontal Cortex Dopamine and Noradrenaline Circuitry in Addiction

Understanding the mechanisms of drug dependence has been the goal of a large number of neuroscientists, pharmacologists and clinicians who carried out research with the hope of individuating and proposing an efficacious therapy for this disorder (Sofuoglu, 2010; Kalivas and Volkow, 2011). Unfortunately, although huge efforts, drug dependence is still a relevant health, social and economical problem (Popova et al., 2012; Hiscock et al., 2011; Shorter and Kosten, 2011). Treatments for drug abuse are for the most part ineffective because the molecular and cellular mechanisms through which drugs of abuse alter neuronal circuitry are still unexplained and above all, because drugs of abuse determine a global alteration of cerebral functions that govern behaviour through decision formation, making therefore unfocused the identification of a pharmacological target (Volkow et al., 2011; Schultz 2011). One of the first strategies pursued in drug dependence therapy was directed to removal of pleasure associated with drug taking, but the compliance with the treatment has been always limited, although it could improve when it was supported by psychology based motivational therapy as in alcohol dependence (Krampe and Ehrenreich, 2010; Simkin and Grenoble, 2010). On the other hand it is not infrequent that heavy smokers or heavy drinkers stop suddenly dependence just because their will overcome year-long habits. Decision making is a process based on the interaction between prefrontal cortex (PFC) and subcortical regions involved in reward and motivation, therefore it is likely that failure in self-regulatory behavior, that is common in addicted subjects, could be dependent upon the alteration of interactions between the prefrontal cortex and subcortical regions (Heatherton and Wagner, 2011). In this chapter we will review the role of PFC in addiction with particular attention to dopamine and norepinephrine transmission

Non-pharmacological factors that determine drug use and addiction

Based on their pharmacological properties, psychoactive drugs are supposed to take control of the natural reward system to finally drive compulsory drug seeking and consumption. However, psychoactive drugs are not used in an arbitrary way as pure pharmacological reinforcement would suggest, but rather in a highly specific manner depending on non-pharmacological factors. While pharmacological effects of psychoactive drugs are well studied, neurobiological mechanisms of non-pharmacological factors are less well understood. Here we review the emerging neurobiological mechanisms beyond pharmacological reinforcement which determine drug effects and use frequency. Important progress was made on the understanding of how the character of an environment and social stress determine drug self-administration. This is expanded by new evidence on how behavioral alternatives and opportunities for drug instrumentalization generate different patterns of drug choice. Emerging evidence suggests that the neurobiology of non-pharmacological factors strongly determines pharmacological and behavioral drug action and may, thus, give rise for an expanded system’s approach of psychoactive drug use and addiction

Augmentation of Extracellular Glutamate in the Ventromedial Prefrontal Cortex and its Role During the Incubation of Cocaine Craving in Rats

Incubation of craving is the phenomenon in which craving intensifies over the course of abstinence. Although understanding craving may be key in understanding why relapse occurs, not much is known about craving, especially the underlying mechanisms that occur in the brain. Clinical and preclinical models have recently implicated the ventromedial prefrontal cortex as one of the key regions in this phenomenon. In order to further characterize this region’s role in incubation, a variety of behavioral, pharmacological, and molecular techniques are used to examine how withdrawal from long access cocaine self-administration directly affects the glutamatergic system. The series of experiments detailed in this dissertation aim to: (1) characterize extracellular glutamate fluctuations in the vmPFC during the incubation of cocaine-seeking, (2) characterize metabotropic glutamate receptor (mGlu) 2/3 changes during both short term and long term withdrawal, and (3) to determine the functional relevance of endogenous glutamate in the two subregions of the vmPFC. Taken together, these experiments suggest that although there seem to be no changes in mGlu2/3 at either point of withdrawal, glutamate in the prelimbic cortex of the vmPFC is functionally relevant in the incubation of cocaine seeking. Together, these results suggest pharmacotherapeutic strategies geared toward damping excitatory glutamate drive within corticofugal projections from the prelimbic cortex may be effective to prevent incubated cue-induced craving during protracted abstinence

Dopamine Modulation of Emotional Learning in the Medial Prefrontal Cortex

Dopamine (DA) transmission plays a critical role in the processing of emotionally salient information and in associative learning and memory processes. Within the mammalian brain, neurons within the medial prefrontal cortex (mPFC) are involved critically in the encoding, expression, and extinction of emotionally salient learned information. Within the mPFC, DAergic transmission is involved importantly in controlling attention related and motivational processes, particularly within the context of emotionally salient sensory information. Considerable evidence suggests differential roles for DA D1-like versus D2-like receptors, including the D4-receptor subtype, in the regulation of neuronal activity and emotional processing within the mPFC. Using behavioural models of emotional learning and memory in rats, including olfactory fear-conditioning and conditioned place preference assays, we compared the roles of DA D1-receptor versus D4-receptor activation during the encoding and recall phases of emotional learning and memory. We report that specific activation of DA D4-receptors within the mPFC strongly potentiates the salience of normally nonsalient emotional associative fear memories and blocks the encoding of suprathreshold conditioned fear associations and has no effect on memory recall. In addition, the bidirectional effect demonstrated by D4-receptor activation in the mPFC depends upon downstream signaling via CaMKII, cyclic-AMP/PKA, and PP1 substrates In contrast, intra-mPFC D1-receptor activation failed to increase the emotional salience of subthreshold fear stimuli but completely blocked the expression of previously learned aversive and rewarding memories. Interestingly, both intra-PLC D1-receptor mediated block of either fear-related or reward-related associative memories were dependent upon downstream cAMP signaling as both effects were rescued by co-administration of a cAMP inhibitor. Taken together these results demonstrate that DA D4 versus D1 subtype receptor transmission within the mPFC plays distinct functional roles in the processing of emotionally salient versus nonsalient associative information and differentially modulates the encoding versus recall phases of emotional memory within the mPFC through distinct molecular signaling pathways. A clearer understanding of the specific roles of DA D1 and D4 receptor transmission during emotional learning and memory may help elucidate how abnormalities in the mPFC neural circuitry may lead to aberrant associative learning and memory processes in disorders such as schizophrenia, drug addiction, PTSD and ADHD

Addictive behaviour in experimental animals: prospects for translation.

Since the introduction of intravenous drug self-administration methodology over 50 years ago, experimental investigation of addictive behaviour has delivered an enormous body of data on the neural, psychological and molecular mechanisms of drug reward and reinforcement and the neuroadaptations to chronic use. Whether or not these behavioural and molecular studies are viewed as modelling the underpinnings of addiction in humans, the discussion presented here highlights two areas-the impact of drug-associated conditioned stimuli-or drug cues-on drug seeking and relapse, and compulsive cocaine seeking. The degree to which these findings translate to the clinical state of addiction is considered in terms of the underlying neural circuitry and also the ways in which this understanding has helped develop new treatments for addiction. The psychological and neural mechanisms underlying drug memory reconsolidation and extinction established in animal experiments show particular promise in delivering new treatments for relapse prevention to the clinic.This article is part of a discussion meeting issue 'Of mice and mental health: facilitating dialogue between basic and clinical neuroscientists'