Gustavo González-Cuevas

The pharmacology of the endocannabinoid system: functional and structural interactions with other neurotransmitter systems and their repercussions in behavioral addiction

Addiction is a chronic, recurring and complex disorder. It is characterized by anomalous behaviors that are linked to permanent or long‐lasting neurobiological alterations. Furthermore, the endocannabinoid system has a crucial role in mediating neurotransmitter release as one of the main neuromodulators of the mammalian central nervous system. The purpose of the present review is to instruct readers about the functional and structural interactions between the endocannabinoid system and the main neurotransmitter systems of the central nervous system in the context of drug addiction. With this aim, we have systematically reviewed the main findings of most of the existing literature that explores cross‐talk in the five brain areas that are most traditionally implicated in addiction: amygdala, prefrontal cortex, nucleus accumbens, hippocampus and ventral tegmental area (VTA). The neurotransmission systems influenced by the pharmacology of the endocannabinoid system in these brain areas, which are reviewed here, are gamma‐aminobutyric acid (GABA), glutamate, the main biogenic amines (dopamine, noradrenaline and serotonin), acetylcholine and opioids. We show that all of these neurotransmitter systems can be modulated differentially in each brain area by the activation or deactivation of cannabinoid CB1 brain receptors. Specifically, most of the studies relate to the hippocampus and nucleus accumbens. Moreover, the neurotransmitter with the fewest number of related studies is acetylcholine (excepting in the hippocampus), whereas there is a large number that evaluates GABA, glutamate and dopamine. Finally, we propose a possible interpretation of the role of the endocannabinoid system in the phenomenon of addiction.

Effects of the cannabinoid CB1 receptor antagonist rimonabant on distinct measures of impulsive behavior in rats

RationalePathological impulsivity is a prominent feature in several psychiatric disorders, but detailed understanding of the specific neuronal processes underlying impulsive behavior is as yet lacking.ObjectivesAs recent findings have suggested involvement of the brain cannabinoid system in impulsivity, the present study aimed at further elucidating the role of cannabinoid CB1 receptor activation in distinct measures of impulsive behavior.Materials and methodsThe effects of the selective cannabinoid CB1 receptor antagonist, rimonabant (SR141716A) and agonist WIN55,212-2 were tested in various measures of impulsive behavior, namely, inhibitory control in a five-choice serial reaction time task (5-CSRTT), impulsive choice in a delayed reward paradigm, and response inhibition in a stop-signal paradigm.ResultsIn the 5-CSRTT, SR141716A dose-dependently improved inhibitory control by decreasing the number of premature responses. Furthermore, SR141716A slightly improved attentional function, increased correct response latency, but did not affect other parameters. The CB1 receptor agonist WIN55,212-2 did not change inhibitory control in the 5-CSRTT and only increased response latencies and errors of omissions. Coadministration of WIN55,212-2 prevented the effects of SR141716A on inhibitory control in the 5-CSRTT. Impulsive choice and response inhibition were not affected by SR141716A at any dose, whereas WIN55,212-2 slightly impaired response inhibition but did not change impulsive choice.ConclusionsThe present data suggest that particularly the endocannabinoid system seems involved in some measures of impulsivity and provides further evidence for the existence of distinct forms of impulsivity that can be pharmacologically dissociated.

Long-Lasting Increase of Alcohol Relapse by the Cannabinoid Receptor Agonist WIN 55,212-2 during Alcohol Deprivation

Alcoholism is characterized by successive relapses. Recent data have shown a cross-talk between the cannabinoid system and ethanol. In this study, male Wistar rats with a limited (30 min sessions), intermittent, and extended background of alcohol operant self-administration were used. The relapse to alcohol after 1 week of alcohol deprivation was evaluated. Two weeks later, the animals were treated with the cannabinoid agonist WIN 55,212-2 (R-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate) (0, 0.4, 2.0, and 10.0 mg/kg, s.c.) during a similar alcohol deprivation period, and alcohol relapse during 2 weeks was assessed. A conditioned place preference (CPP) paradigm was used to study the rewarding properties of the cannabinoid agonist. Locomotor activity was also recorded. All doses of WIN 55,212-2 produced aversion in the CPP paradigm. The doses of 2.0 and 10.0 mg/kg resulted in an important suppression of spontaneous locomotor activity and a progressive weight loss during the next 2 weeks. The single alcohol deprivation was followed by a transient increase in their responding for alcohol from a range of 20-24 lever presses at baseline to a range of 38-48 responses in the first and second days (alcohol deprivation effect). However, the administration of WIN 55,212-2 during ethanol deprivation produced similar increased responses for alcohol but in a long-term way (at least over 2 weeks). These findings suggest that noncontingent chronic exposure to cannabinoids during alcohol deprivation can potentiate the relapse into alcohol use, indicating that functional changes in the cannabinoid brain receptor may play a key role in ethanol relapse.

Cannabinoid-induced increase in relapse-like drinking is prevented by the blockade of the glycine-binding site of N-methyl-D-aspartate receptors.

The endocannabinoid system is a neuromodulatory system which controls the release of multiple neurotransmitters, including glutamate and both, the endocannabinoid and glutamatergic systems, have been implicated in alcohol relapse. Cannabinoid agonists induce an increase in relapse-like drinking whereas glutamate receptor antagonists could prevent it. Here we hypothesize that cannabinoid-induced increases in relapse-like alcohol drinking could be mediated by glutamatergic N-methyl-d-aspartate (NMDA) receptors. To test this hypothesis, Wistar rats with a background of alcohol operant self-administration were treated with the cannabinoid receptor agonist (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl), pyrrolo [1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate (WIN 55.212-2, WIN) (2.0 mg/kg) during periods of alcohol deprivation. For five consecutive days, 30 min before the reintroduction of alcohol, rats were injected with the NMDA/glycine receptor antagonist 7-chloro-4-hydroxy-3-(3-phenoxy)phenylquinolin-2-[1H]-one (L-701) (1.25-5.0 mg/kg) and alcohol reinforcement was evaluated. Our results clearly show that L-701 prevented the cannabinoid-induced increase in relapse-like drinking in a dose-dependent manner, whereas L-701 alone, in the absence of WIN treatment, did not significantly alter alcohol intake. The potentiation of relapse-like drinking induced by WIN is not caused by nonspecific anxiogenic effects, since no effect was observed in the elevated-plus maze test. These alcohol-related behaviors are linked to differential changes in CNR1 and NR1 subunit mRNA transcripts. In WIN-treated rats, an increase in CNR1 transcript levels was observed in the hypothalamus and striatum, whereas in the amygdala and anterior cingulate cortex, brain regions involved in emotional processing, a decrease was observed. Interestingly, such changes were blocked after L-701 treatment. Finally, WIN treatment also caused a reduction in NR1 mRNA levels in the amygdala. In conclusion, pharmacological inactivation of the glycine-binding site of NMDA receptors may control cannabinoid-induced relapse-like drinking, which is associated with altered expression of CNR1 and NR1 gene expression as observed after WIN treatment.

Changed accumbal responsiveness to alcohol in rats pre-treated with nicotine or the cannabinoid receptor agonist WIN 55,212-2

Alcohol, nicotine, and cannabinoid acutely increase the activity of the mesolimbic dopamine (DA) pathway. Although polysubstance consumption is a common pattern of abuse in humans, little is known about dopamine release following pre-exposure to these drugs. The purpose of this study was to test whether alcohol-induced dopamine release into the nucleus accumbens (NAc) shell is modified by different pre-treatments: water (i.g.), alcohol (1 g/kg, i.g.), nicotine (0.4 mg/kg, s.c.), and WIN 55,212-2 (1 mg/kg, s.c.). Male Wistar rats were treated (i.g.) for 14 days with either water or alcohol. In the following 5 days rats were injected (s.c.) with vehicle, nicotine, or WIN 55,212-2. Finally, a cannula was surgically implanted into the NAc shell and alcohol-induced extracellular dopamine release was monitored in freely moving rats. Alcohol (1 g/kg; i.g.) only increased the release of dopamine when animals were previously treated with water. This DA increase was markedly inhibited by (subchronic) treatment (5 days) with nicotine or WIN 55-212-2 as well as by previous (chronic) exposure to alcohol (14 days). These data demonstrate that pre-treatment with nicotine and the cannabinoid agonist WIN 55,212-2 is able to change the sensitivity of the NAc shell in response to a moderate dose of alcohol. Therefore, cannabinoid and nicotine exposure may have important implications on the rewarding effects of alcohol, because these drugs lead to long-lasting changes in accumbal dopamine transmission.

Subchronic cannabinoid agonist (WIN 55,212-2) treatment during cocaine abstinence alters subsequent cocaine seeking behavior.

The co-abuse of marijuana with cocaine is widespread, but it has not been until recently that the relationship between the behavioral effects of cannabinoids and cocaine has begun to be unveiled in animal models. Male Wistar rats were trained to intravenously self-administer cocaine until a stable baseline was reached. Rats then were subjected to a 5-day cocaine deprivation period during which they were treated daily with the cannabinoid receptor agonist WIN 55,212-2 (R-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate) (0, 0.3, 1, and 3 mg/kg; i.p.). Following this subchronic treatment, rats were tested, in counterbalanced order, in a test of anxiety (elevated plus-maze), as well as extinction and cue-induced reinstatement tests, the latter conducted according to a between-within procedure. Subchronic administration of WIN 55,212-2 was found to produce dose-dependent alterations of performance in the extinction, reinstatement, and anxiety tests with the lowest dose of WIN 55,212-2 producing the highest resistance to extinction and reinstatement, and the highest dose of WIN 55,212-2 producing the highest anxiolytic activity. Subchronic treatment with WIN 55,212-2 in rats without a history of cocaine self-administration did not affect anxiety levels. The results suggest an important role of the cannabinoid system in neuronal processes underlying cocaine seeking behavior. However, further studies will be necessary to understand possible implications of these findings for a role of the cannabinoid system as a treatment target for human cocaine abuse.

The CB1 cannabinoid receptor antagonist rimonabant chronically prevents the nicotine-induced relapse to alcohol

Preclinical and clinical research shows that the cannabinoid brain receptor type 1 (CB(1)) modulates alcohol- and nicotine-related behaviors. Throughout the nicotine-induced relapse to alcohol, the rats were pre-treated for 10 days with the CB(1) cannabinoid receptor antagonist rimonabant (0, 0.03, 0.3 and 3.0 mg/kg i.p.). In this condition, a long-lasting nicotine-induced relapse to alcohol was observed, and this effect was reversed in a dose-dependent manner with rimonabant. Surprisingly, rats that were not exposed to nicotine developed tolerance to the effects of rimonabant from the sixth day. Also, 3.0 mg/kg of rimonabant reduced the responses for sucrose. Evaluation in the Elevated Plus-Maze after nicotine treatment did not reveal anxiogenic effects. Finally, at the conclusion of rimonabant treatment, a rapid reinstatement of alcohol consumption was detected. These results suggest that rimonabant can prevent the relapse to alcohol, even when an interaction with nicotine exists-the most frequent situation in human alcohol abuse.

Administration of MDMA to ethanol-deprived rats increases ethanol operant self-administration and dopamine release during reinstatement

Recreational use of (±)-3,4-methylenedioxymethamphetamine (MDMA, ecstasy) is often associated with other drugs, among which ethanol (EtOH) is one of the most common. However, little is known about how neurochemical sensitization produced by MDMA can modulate EtOH abuse. In this study we used EtOH operant self-administration tasks to investigate the effect of several low doses (0.33, 1.0 and 3.0 mg/kg) of MDMA in Dark Agouti rats. Motor activity was recorded after each MDMA administration. Changes in extracellular dopamine in the nucleus accumbens following a single EtOH injection (1.5 g/kg i.p.) were measured using intracerebral microdialysis in vivo after 1 wk of abstinence from EtOH, in order to mimic the dopaminergic response associated with reinstatement into EtOH consumption. Animals exposed to higher doses of MDMA (1.0 and 3.0 mg/kg) showed significantly enhanced EtOH self-administration during reinstatement and an increased EtOH-induced dopamine efflux. MDMA treatment acutely elevated motor activity after each administration in a dose-dependent manner. These findings suggest that repeated administration of MDMA, a relatively common drug of abuse, even at low doses, can alter subsequent vulnerability to EtOH consumption.

Unique treatment potential of cannabidiol for the prevention of relapse to drug use: preclinical proof of principle

Cannabidiol (CBD), the major non-psychoactive constituent of Cannabis sativa, has received attention for therapeutic potential in treating neurologic and psychiatric disorders. Recently, CBD has also been explored for potential in treating drug addiction. Substance use disorders are chronically relapsing conditions and relapse risk persists for multiple reasons including craving induced by drug contexts, susceptibility to stress, elevated anxiety, and impaired impulse control. Here, we evaluated the “anti-relapse” potential of a transdermal CBD preparation in animal models of drug seeking, anxiety and impulsivity. Rats with alcohol or cocaine self-administration histories received transdermal CBD at 24 h intervals for 7 days and were tested for context and stress-induced reinstatement, as well as experimental anxiety on the elevated plus maze. Effects on impulsive behavior were established using a delay-discounting task following recovery from a 7-day dependence-inducing alcohol intoxication regimen. CBD attenuated context-induced and stress-induced drug seeking without tolerance, sedative effects, or interference with normal motivated behavior. Following treatment termination, reinstatement remained attenuated up to ≈5 months although plasma and brain CBD levels remained detectable only for 3 days. CBD also reduced experimental anxiety and prevented the development of high impulsivity in rats with an alcohol dependence history. The results provide proof of principle supporting potential of CBD in relapse prevention along two dimensions: beneficial actions across several vulnerability states and long-lasting effects with only brief treatment. The findings also inform the ongoing medical marijuana debate concerning medical benefits of non-psychoactive cannabinoids and their promise for development and use as therapeutics.

Unique treatment potential of cannabidiol for the prevention of relapse to drug use

Cannabidiol (CBD), the main non-psychoactive and non-addictive constituent of Cannabis sativa, has long received interest as a therapeutic for numerous psychiatric and neurologic disorders (e.g., ref. [1]). Recently, investigations on the scope of CBD’s medical benefits have encompassed its potential to treat substance use disorders. Both clinical and preclinical data are overall promising in this regard. However, presently available data are scattered across several classes of abused drugs (i.e., tetrahydrocannabinol, nicotine, opiates, alcohol) and several stages of the addiction cycle (i.e., self-administration, withdrawal, drug seeking, abstinence). Moreover, both positive and negative findings have been obtained such that scope and nature of CBD’s effects on addictive behavior remained to be more clearly established [2]. Among the studies of CBD’s “anti-addiction” potential, a major positive finding reported by Hurd and colleagues [3] was that CBD attenuates cue-induced heroin reinstatement with effects that outlasted treatment by two weeks. Intrigued by these findings, we focused our efforts specifically on the anti-relapse potential of CBD and identified distinct leads in the literature suggestive of potential for several indications critical for relapse prevention. Many general behavioral effects of CBD, including anxiolytic, antistress, anti-depressant, and anti-compulsive actions (e.g., ref. [1]), are predictive of therapeutic benefit also for drug seeking and relapse. Moreover, CBD interacts with signaling mechanisms within the brain circuitry that regulates anxiety, drug desire associated with drug-related cues/contexts, and effects of stress on drug seeking. Lastly, CBD has both neuroprotective and proneurogenic actions [4]. The former includes attenuation of ethanol-induced neurodegeneration, an intoxication-induced deficit contributing to impaired impulse control in alcoholics. The proneurogenic effects of CBD have been implicated in the drug’s anti-anxiety actions, and are predictive of anti-craving effects given emerging evidence implicating neurogenesis as an important factor in inhibiting drug seeking. We therefore predicted that CBD may be suitable for targeting several relapse-promoting factors: craving associated with drug cue exposure, susceptibility to stress, heightened anxiety, and impaired impulse control. Testing this prediction in animal models of drug seeking (reinstatement), anxiety (elevated plus maze), and impulsivity (delay discounting), using rats with alcohol or cocaine self-administration histories, we found that CBD attenuated context-induced and stress-induced reinstatement of drug seeking without producing tolerance, sedative effects, or interfering with normal motivation. Following treatment termination, the attenuation of both context and stress-induced reinstatement remained unabated for the duration of the experiments (up to ≈5 months). CBD also reduced experimental anxiety in rats with alcohol and cocaine histories, and prevented the development of high impulsivity in rats with a dependence-inducing alcohol intoxication history [5]. These findings reveal a profile of potential benefits of CBD in relapse prevention that is unique in several respects: (1) Effects relevant for multiple vulnerability states that are often experienced concurrently by drug addicts and likely interact to exacerbate relapse risk. Therefore, the concurrent amelioration of these states by CBD is likely to be more effective in preventing relapse than treatment drug effects that target only a single state. (2) Long-lasting protective effects that far outlast treatment. Identification of mechanisms underlying these effects may lead improved understanding of neuroplasticity responsible for chronic susceptibility to relapse, as well as the development of more effective “anti-relapse” medications. (3) Efficacy across multiple drugs of abuse, that include not only cocaine and alcohol [5] but also opiates [3], including tentative anti-craving effects in early phase clinical trials [6]. Since co-abuse of opiates and cocaine with alcohol is common, the reported anti-reinstatement actions of CBD across three major classes of abused drugs further add to the putative treatment drug promise of this phytocannabinoid.