Cannabinoid Neurotransmission Research Articles

First-in-human in vivo imaging and quantification of monoacylglycerol lipase in the brain: a PET study with 18F-T-401.

Monoacylglycerol lipase (MAGL) regulates cannabinoid neurotransmission and the pro-inflammatory arachidonic acid pathway by degrading endocannabinoids. MAGL inhibitors may accordingly act as cannabinoid-potentiating and anti-inflammatory agents. Although MAGL dysfunction has been implicated in neuropsychiatric disorders, it has never been visualized in vivo in human brain. The primary objective of the current study was to visualize MAGL in the human brain using the novel PET ligand 18F-T-401. Seven healthy males underwent 120-min dynamic 18F-T-401-PET scans with arterial blood sampling. Six subjects also underwent a second PET scan with 18F-T-401 within 2weeks of the first scan. For quantification of MAGL in the human brain, kinetic analyses using one- and two-tissue compartment models (1TCM and 2TCM, respectively), along with multilinear analysis (MA1) and Logan graphical analysis, were performed. Time-stability and test-retest reproducibility of 18F-T-401-PET were also evaluated. 18F-T-401 showed rapid uptake and gradual washout from the brain. Logan graphical analysis showed linearity in all subjects, indicating reversible radioligand kinetics. Using a metabolite-corrected arterial input function, MA1 estimated regional total distribution volume (VT) values by best identifiability. VT values were highest in the cerebral cortex, moderate in the thalamus and putamen, and lowest in white matter and the brainstem, which was in agreement with regional MAGL expression in the human brain. Time-stability analysis showed that MA1 estimated VT values with a minimal bias even using truncated 60-min scan data. Test-retest reliability was also excellent with the use of MA1. Here, we provide the first demonstration of in vivo visualization of MAGL in the human brain. 18F-T-401 showed excellent test-retest reliability, reversible kinetics, and stable estimation of VT values consistent with known regional MAGL expressions. PET with 18F-T-401-PET is promising tool for measurement of central MAGL.

Chronic high-fat diet affects food-motivated behavior and hedonic systems in the nucleus accumbens of male rats

Environmental variations can influence eating and motivated behaviors, as well as the brain's feeding circuits to predisposing overweight and obesity. The identification of mechanisms through which a long-term consumption of caloric-dense palatable foods and its association with early life stress can cause neuroadaptations and possible modify motivational behaviors are relevant to elucidate the mechanisms associated with obesity. Here, we investigated the long-term effects of a chronic high-fat diet (HFD), and its interaction with early social isolation on hedonic feeding responses in adult rats. Rats were subjected, or not, to social isolation between postnatal days 21–28 and were fed a control diet or HFD, for 10 weeks post weaning. Hedonic feeding behavior was evaluated during adulthood and parameters related to the dopaminergic, cannabinoid, and opioid systems were measured in the nucleus accumbens. Animals with chronic HFD intake were less motivated to obtain sweet palatable foods. This reduced motivation did not appear to be associated with less pleasure upon tasting sweet food, as no alteration in reactivity to sweet taste was observed. Interestingly, the animals receiving HFD presented decreased immunocontents of the D1 and CB1 receptors, while the stressed group displayed a reduction in dopamine turnover. In summary, chronic HFD causes a significant motivational impairment for sweet palatable foods; these changes may be associated with a decreased dopaminergic and cannabinoid neurotransmission in the nucleus accumbens. In contrast, a brief social isolation during the prepubertal period was unable to alter the behavioral parameters studied but caused a decreased dopaminergic turnover in the nucleus accumbens of adult rats. These findings highlight the importance of long-term HFD exposure on the modulation of hedonic feeding behavior and related neurochemical systems.

The Acute and Chronic Cognitive and Cerebral Blood-Flow Effects of Nepalese Pepper (Zanthoxylum armatum DC.) Extract-A Randomized, Double-Blind, Placebo-Controlled Study in Healthy Humans.

Background: Zanthoxylum armatum DC. (ZA) is a traditional Asian culinary spice and medicinal compound, which is rich in monoterpenes and hydroxy α-sanshool. Mechanistic interactions with the monoamine, cholinergic and cannabinoid neurotransmission systems, as well as transient receptor potential (TRP) and potassium ion channels, may predispose ZA to modulate human brain function. Objectives: To investigate the effects of a single dose and 56-days supplementation with a lipid extract of ZA on cognitive function, mood and cerebral blood-flow (CBF) parameters in the pre-frontal cortex during cognitive task performance. Design: Double-blind, randomized, parallel groups study with N = 82 healthy males and females between the ages of 30 and 55 years. Assessments were undertaken pre-dose and at 1, 3 and 5 h post-dose on the first (Day 1) and last (Day 56) days of supplementation. Results: A single dose of ZA (Day 1) resulted in acute improvements on a ‘Speed of Attention’ factor and the Rapid Visual Information Processing (RVIP) task, in comparison to placebo. However, following ZA participants were less accurate on the name-to-face recall task. After 56 days of ZA consumption (Day 56), speed was enhanced on a global ‘Speed of Performance’ measure, comprising data from all of the timed tasks in the computerized battery. Participants also completed more correct Serial 3s Subtractions at the 3 h assessment and were less mentally fatigued throughout the day than participants consuming placebo. These effects were complemented on both Day 1 and Day 56 by modulation of CBF parameters, as assessed by Near Infrared Spectroscopy (NIRS). The primary finding here was a reduced hemodynamic response during the RVIP task. Conclusion: ZA improves aspects of cognitive performance, in particular the speed of performing tasks, in healthy humans and results in concomitant reductions in hemodynamic responses in the frontal cortex during task performance. The findings suggest an increase in neural efficiency following ZA.

Cannabinoid Modulation of the Stressed Hippocampus

Exposure to stressful situations is one of the risk factors for the precipitation of several psychiatric disorders, including Major Depressive Disorder, Posttraumatic Stress Disorder and Schizophrenia. The hippocampal formation is a forebrain structure highly associated with emotional, learning and memory processes; being particularly vulnerable to stress. Exposure to stressful stimuli leads to neuroplastic changes and imbalance between inhibitory/excitatory networks. These changes have been associated with an impaired hippocampal function. Endocannabinoids (eCB) are one of the main systems controlling both excitatory and inhibitory neurotransmission, as well as neuroplasticity within the hippocampus. Cannabinoids receptors are highly expressed in the hippocampus, and several lines of evidence suggest that facilitation of cannabinoid signaling within this brain region prevents stress-induced behavioral changes. Also, chronic stress modulates hippocampal CB1 receptors expression and endocannabinoid levels. Moreover, cannabinoids participate in mechanisms related to synaptic plasticity and adult neurogenesis. Here, we discussed the main findings supporting the involvement of hippocampal cannabinoid neurotransmission in stress-induced behavioral and neuroplastic changes.

Enhanced endocannabinoid signaling boosts signal propagation through the hippocampal trisynaptic circuit and facilitates safety learning

Anxiety disorders like post-traumatic stress disorder or obsessive-compulsive disorder are frequently diagnosed and often occur in combination with other mental illnesses. Exposure-based therapies along with medication are widely used as treatment for most of these brain based diseases. The frequently used benzodiazepines are usually considered second-line due their impact on amnestic functions. In contrast, substances targeting the endocannabinoid system were found to be effective anxiolytics without disadvantages on memory function. However, the changes in millisecond-scale brain circuit dynamics that might underlie their therapeutic actions remain elusive. Here, enabled by a recently developed voltage-sensitive dye imaging assay in mouse brain slices, we compared the impact of diazepam and the cannabinoid neurotransmission enhancer AM404 on neuronal activity propagations through the entire trisynaptic circuitry of the hippocampus (“HTC”: perforant path dentate gyrus-area CA3-CA1 output subfield). Bath applied diazepam (1 µM) depressed activity propagations (“HTC-Waves”), which coincided with impaired safety learning. In contrast, bath applied AM404 (10 µM) boosted HTC-Waves in CA regions, and facilitated safety learning. These effects were absent in D1CB1-KO mice. Collectively, we demonstrate opposing effects of two anxiolytic drugs on the hippocampal network that might underlie their inverse impact on amnestic functions during exposition-based therapies.

Enhanced endocannabinoid signaling boosts signal propagation through the hippocampal trisynaptic circuit and facilitates safety learning

Anxiety disorders like post-traumatic stress disorder or obsessive-compulsive disorder are frequently diagnosed and often occur in combination with other mental illnesses. Exposure-based therapies along with medication are widely used as treatment for most of these brain based diseases. The frequently used benzodiazepines are usually considered second-line due their impact on amnestic functions. In contrast, substances targeting the endocannabinoid system were found to be effective anxiolytics without disadvantages on memory function. However, the changes in millisecond-scale brain circuit dynamics that might underlie their therapeutic actions remain elusive. Here, enabled by a recently developed voltage-sensitive dye imaging assay in mouse brain slices, we compared the impact of diazepam and the cannabinoid neurotransmission enhancer AM404 on neuronal activity propagations through the entire trisynaptic circuitry of the hippocampus (“HTC”: perforant path dentate gyrus-area CA3-CA1 output subfield). Bath applied diazepam (1 µM) depressed activity propagations (“HTC-Waves”), which coincided with impaired safety learning. In contrast, bath applied AM404 (10 µM) boosted HTC-Waves in CA regions, and facilitated safety learning. These effects were absent in D1CB1-KO mice. Collectively, we demonstrate opposing effects of two anxiolytic drugs on the hippocampal network that might underlie their inverse impact on amnestic functions during exposition-based therapies.

The cannabinoid receptor 2 agonist β-caryophyllene reduces voluntary alcohol intake and attenuated ethanol-induced place preference and sensitivity in mice

Introduction: Several recent studies have suggested that brain cannabinoid receptor 2 (CB2) plays a major role in alcohol reward. In fact, the implication of cannabinoid neurotransmission in the reinforcing effects of ethanol (EtOH) is becoming increasingly evident. Objectives: The CB2 receptor agonist β -caryophyllene (BCP) was used to investigate the role of the CB2 receptors in mediating alcohol intake and ethanol-induced conditioned place preference (EtOH-CPP) and sensitivity in mice. Material and methods: The effect of BCP on alcohol intake was evaluated using the standard two-bottle-choice drinking method. The mice were presented with increasing EtOH concentrations and its consumption was measured daily. Consumption of saccharin and quinine solutions were measured following the EtOH preference tests. Finally, the effect of BCP on alcohol reward and sensitivity was tested using an unbiased EtOH-CPP and loss of righting reflex (LORR) procedures, respectively. Results: BCP dose-dependently decreased alcohol consumption and preference. In addition, BCP-injected mice did not show any difference from vehicle mice in total fluid intake in a 24-hour paradigm or in their intake of graded concentrations of saccharin or quinine, suggesting that the CB2 receptor activation did not alter taste function. More importantly, BCP inhibited EtOH-CPP acquisition and exacerbated LORR duration. Interestingly, these effects were abrogated when mice were preinjected with a selective CB2 receptor antagonist, AM630. Conclusions: The CB2 receptor system appears to be involved in alcohol dependence and sensitivity and may represent a potential pharmacological target for the treatment of alcoholism. Acknowledgements: Dr Amine Bahi for supervising this project.

The cannabinoid receptor 2 agonist, β-caryophyllene, reduced voluntary alcohol intake and attenuated ethanol-induced place preference and sensitivity in mice

Several recent studies have suggested that brain CB2 cannabinoid receptors play a major role in alcohol reward. In fact, the implication of cannabinoid neurotransmission in the reinforcing effects of ethanol (EtOH) is becoming increasingly evident. The CB2 receptor agonist, β-caryophyllene (BCP) was used to investigate the role of the CB2 receptors in mediating alcohol intake and ethanol-induced conditioned place preference (EtOH-CPP) and sensitivity in mice. The effect of BCP on alcohol intake was evaluated using the standard two-bottle choice drinking method. The mice were presented with increasing EtOH concentrations and its consumption was measured daily. Consumption of saccharin and quinine solutions was measured following the EtOH preference tests. Finally, the effect of BCP on alcohol reward and sensitivity was tested using an unbiased EtOH-CPP and loss of righting-reflex (LORR) procedures, respectively. BCP dose-dependently decreased alcohol consumption and preference. Additionally, BCP-injected mice did not show any difference from vehicle mice in total fluid intake in a 24-hour paradigm nor in their intake of graded concentrations of saccharin or quinine, suggesting that the CB2 receptor activation did not alter taste function. More importantly, BCP inhibited EtOH-CPP acquisition and exacerbated LORR duration. Interestingly, these effects were abrogated when mice were pre-injected with a selective CB2 receptor antagonist, AM630. Overall, the CB2 receptor system appears to be involved in alcohol dependence and sensitivity and may represent a potential pharmacological target for the treatment of alcoholism.

Cannabinoid modulation of predator fear: involvement of the dorsolateral periaqueductal gray

The present study investigated the effects of systemic or intra-dorsolateral periaqueductal gray (dlPAG) administration of CB1 agonists on behavioural changes induced in rats by predator (a live cat) exposure, a model of panic responses. Since nitric oxide (NO) and cannabinoid neurotransmission are proposed to interact in the dlPAG to modulate defensive responses, we also investigated if NO is involved in the biphasic effects of anandamide (AEA) injected into the dlPAG. The results showed that systemic administration of WIN55,212-2 or intra-dlPAG AEA attenuated the defensive behaviours caused by cat exposure. Both compounds produced biphasic curves. The cannabinoid receptor type 1 (CB1) antagonist AM251 prevented the panicolytic effect of AEA whereas a neuronal NOS inhibitor turned the ineffective high dose of AEA into an effective one. These results suggest that modulation of the cannabinoid system could be a target in the treatment of panic disorders. However, the biphasic effects of these compounds could limit their therapeutic potential.

Modulation of the Endocannabinoids N-Arachidonoylethanolamine (AEA) and 2-Arachidonoylglycerol (2-AG) on Executive Functions in Humans

Animal studies point to an implication of the endocannabinoid system on executive functions. In humans, several studies have suggested an association between acute or chronic use of exogenous cannabinoids (Δ9-tetrahydrocannabinol) and executive impairments. However, to date, no published reports establish the relationship between endocannabinoids, as biomarkers of the cannabinoid neurotransmission system, and executive functioning in humans. The aim of the present study was to explore the association between circulating levels of plasma endocannabinoids N-arachidonoylethanolamine (AEA) and 2-Arachidonoylglycerol (2-AG) and executive functions (decision making, response inhibition and cognitive flexibility) in healthy subjects. One hundred and fifty seven subjects were included and assessed with the Wisconsin Card Sorting Test; Stroop Color and Word Test; and Iowa Gambling Task. All participants were female, aged between 18 and 60 years and spoke Spanish as their first language. Results showed a negative correlation between 2-AG and cognitive flexibility performance (r = −.37; p<.05). A positive correlation was found between AEA concentrations and both cognitive flexibility (r = .59; p<.05) and decision making performance (r = .23; P<.05). There was no significant correlation between either 2-AG (r = −.17) or AEA (r = −.08) concentrations and inhibition response. These results show, in humans, a relevant modulation of the endocannabinoid system on prefrontal-dependent cognitive functioning. The present study might have significant implications for the underlying executive alterations described in some psychiatric disorders currently associated with endocannabinoids deregulation (namely drug abuse/dependence, depression, obesity and eating disorders). Understanding the neurobiology of their dysexecutive profile might certainly contribute to the development of new treatments and pharmacological approaches.

Alterations to Melanocortinergic, GABAergic and Cannabinoid Neurotransmission Associated with Olanzapine-Induced Weight Gain

Background/AimSecond generation antipsychotics (SGAs) are used to treat schizophrenia but can cause serious metabolic side-effects, such as obesity and diabetes. This study examined the effects of low to high doses of olanzapine on appetite/metabolic regulatory signals in the hypothalamus and brainstem to elucidate the mechanisms underlying olanzapine-induced obesity.Methodology/ResultsLevels of pro-opiomelanocortin (POMC), neuropeptide Y (NPY) and glutamic acid decarboxylase (GAD65, enzyme for GABA synthesis) mRNA expression, and cannabinoid CB1 receptor (CB1R) binding density (using [3H]SR-141716A) were examined in the arcuate nucleus (Arc) and dorsal vagal complex (DVC) of female Sprague Dawley rats following 0.25, 0.5, 1.0 or 2.0 mg/kg olanzapine or vehicle (3×/day, 14-days). Consistent with its weight gain liability, olanzapine significantly decreased anorexigenic POMC and increased orexigenic NPY mRNA expression in a dose-sensitive manner in the Arc. GAD65 mRNA expression increased and CB1R binding density decreased in the Arc and DVC. Alterations to neurotransmission signals in the brain significantly correlated with body weight and adiposity. The minimum dosage threshold required to induce weight gain in the rat was 0.5 mg/kg olanzapine.ConclusionsOlanzapine-induced weight gain is associated with reduced appetite-inhibiting POMC and increased NPY. This study also supports a role for the CB1R and GABA in the mechanisms underlying weight gain side-effects, possibly by altering POMC transmission. Metabolic dysfunction can be modelled in the female rat using low, clinically-comparable olanzapine doses when administered in-line with the half-life of the drug.

The endocannabinoid system: a key modulator of emotions and cognition

The endocannabinoid system: a key modulator of emotions and cognition

Pharmacological manipulation of cannabinoid neurotransmission reduces neuroinflammation associated with normal aging

We have previously demonstrated that antagonism of glutamate NMDA receptors or activation of endocannabinoid receptors could reduce experimentally induced neuroinflammation within the hippocampus of young rats. In the current study, we investigated whether pharmacological manipulation of glutamate or endocannabinoid neurotransmission could reduce naturally-occurring neuroinflammation within the hippocampus of aged rats. We investigated whether UCM707, an inhibitor of endocannabinoid re-uptake, WIN- 55,212-2, an endocannabinoid receptor agonist, and URB597, an inhibitor of endocannabinoid catabolism, or memantine, a non-competitive, low-affinity, inhibitor of the open NMDA receptor channel, could reduce the number of MHC II-IR microglia within the hippocampus. All of the drugs, except URB597, reduced the number of reactive microglia, as compared to vehicle treated rats. The current results suggest potential pharmacological approaches that may mitigate the pathological consequences of chronic brain inflammation associated with numerous neurodegenerative diseases.

Cannabinoid CB1 and Dopamine D1 Receptors Partnership in the Modulation of Emotional Neural Processing

GENERAL COMMENTARY article Front. Behav. Neurosci., 13 October 2011Sec. Learning and Memory https://doi.org/10.3389/fnbeh.2011.00067

Interactions between the anxiogenic effects of CB1 gene disruption and 5-HT3 neurotransmission

Neuroanatomical findings revealed that CB1 cannabinoid and 5-HT3 receptors are coexpressed by a subtype of gamma-aminobutyric acid (GABA)ergic interneurons in the prefrontal cortex, hippocampus, and basolateral amygdala, three brain regions that are crucial for the control of anxiety. In these regions, serotonergic inputs increase GABA release through 5-HT3 receptors, the phenomenon being retrogradely controlled by cannabinoid neurotransmission. This suggests a functional interaction between 5-HT3 neurotransmission and CB1 signaling. In a first attempt to investigate the behavioral relevance of these interactions, we studied the effects of the selective 5-HT3 agonist 1-(m-chlorophenyl)-biguanide (mCPBG), on plus-maze behavior in NMRI, CD1 wild type, and CB1-KO mice. The genetic disruption of CB1 receptors consistently increased anxiety. This effect was significantly decreased by the 5-HT3 agonist, mCPBG. The dose-response curve was bell-shaped. Surprisingly, mCPBG did not affect the behavior of CD1 wild type and NMRI mice. We hypothesize that in the aforementioned regions, 5-HT3 activation decreases anxiety by promoting GABA release, but this effect is dampened by CB1 signaling. The disruption of CB1 receptors in CB1-KOs released GABA neurons from retrograde inhibition and made the effects of 5-HT3 stimulation conspicuous. Altogether, our findings reveal a functional interaction between 5-HT3 neurotransmission and CB1 signaling. Besides this interaction being an interesting aspect of anxiety control, it may also explain the notoriously inconsistent effects of 5-HT3 ligands on anxiety. If 5-HT3 neurotransmission and CB1 signaling interact, the anxiety-related effects of 5-HT3 ligands may depend on species, strain, and situation-related differences in both 5-HT3 and CB1 receptor expression and function.

Behavioral Pharmacology of Cannabinoids with a Focus on Preclinical Models for Studying Reinforcing and Dependence-Producing Properties

Cannabis preparations as recreational drugs are the most widely used illicit drugs in the world. Although cannabis derivatives produce clear subjective motivational responses in humans leading to drug-seeking behavior and in a specific proportion in repeated drug use, the reinforcing/rewarding attributes of these subjective effects are difficult to define in experimental animals. This led to the notion of cannabinoids being considered as "atypical" or "anomalous" drugs of abuse. To this end, our knowledge and understanding of the way cannabis and its main psychoactive constituent, Delta(9)-tetrahydrocannabinol (Delta(9)-THC), act in the central nervous system to exert their reinforcing/rewarding effects is far from complete. The aim of the present article is to review from a preclinical perspective the current status of what is known about the behavioral pharmacology of cannabinoids including the recently identified cannabinoid neurotransmission modifiers with a particular emphasis on their motivational/reinforcing and dependence-producing properties. We conclude that cannabinoids exhibit reinforcing/rewarding properties in experimental animals mostly under particular experimental conditions, which is not the case for other drugs of abuse, such as opiates, psychostimulants, alcohol and nicotine. The paper will discuss these findings critically and also point to open questions that should be addressed in the future in order to improve our understanding of these specific actions of cannabinoids that will also impact drug discovery and development efforts of related compounds as therapeutics in the clinic.

Mouse strain related effects of cannabinoid and serotonergic ligands on alcohol appetence

Because cannabinoid (CB) and serotonin (5-HT) systems have been proposed to play an important role in drug craving, we investigated whether CB1 and 5-HT1A receptor ligands could affect voluntary alcohol intake in two mouse strains, C57BL/6J and DBA/2J, with marked differences in native alcohol preference. When offered progressively (3% to 10% ethanol) in drinking water, in a free-choice procedure, alcohol intake was markedly lower (~70%) in DBA/2J than in C57BL/6J mice. In DBA/2J mice, chronic treatment with the CB receptor agonist WIN 55,212-2 increased alcohol intake. This effect was prevented by both chronic CB1 receptor blockade by rimonabant or chronic 5-HT1A receptor stimulation by 8-OH-DPAT, which, on their own, did not affect alcohol intake. In C57BL/6J mice, WIN 55,212-2 had no effect but CB1 receptor blockade or 5-HT1A receptor stimulation significantly decreased alcohol intake. Parallel autoradiographic investigations showed that chronic treatment with WIN55,212-2 significantly decreased 5-HT1A-mediated [35S]GTP-γ-S binding in the hippocampus of both mouse strains. Conversely, chronic rimonabant increased this binding in C57BL/6J mice.These results show that CB neurotransmission can exert a permissive control on alcohol intake, possibly through CB1-5-HT1A interactions. However, the differences between C57BL/6J and DBA/2J mice indicate that such modulations of alcohol intake are under genetic control.

Bidirectional cannabinoid modulation of social behavior in adolescent rats

Marijuana use in adolescents is a highly social activity, and interacting endocannabinoid and opioid systems may modulate social reward. However, cannabinoid exposure has been reported to reduce social behavior. The aim of this study was to elucidate the mechanisms underlying the paradoxical relationship between cannabinoid exposure and sociability. We investigated the effect of cannabinoid agonists with a different mechanism of action on social play behavior in adolescent rats. In addition, we examined whether endocannabinoid neurotransmission interacts with opioid and dopaminergic neurotransmission in the modulation of social play behavior. The direct CB1 cannabinoid receptor agonist WIN55,212-2 reduced social play. However, the indirect cannabinoid agonist URB597, which inhibits the hydrolysis of the endocannabinoid anandamide, enhanced social play. This effect of URB597 depended upon stimulation of opioid and dopamine receptors. The well-known stimulatory effect of morphine on social play was attenuated by the CB1 cannabinoid receptor antagonist SR141716A, but independent of dopamine receptor stimulation. Combined treatment with ineffective doses of URB597 and morphine increased social play. Cannabinoid neurotransmission can both enhance and inhibit social interaction in adolescent rats depending on how the endocannabinoid system is stimulated. Activation of cannabinoid receptors throughout the brain, which occurs during cannabis use, inhibits sociability. In contrast, on-demand release of endocannabinoids facilitates social interaction, which is magnified by indirect cannabinoid agonists through an interaction with opioid and dopaminergic neurotransmission. These results shed light on the paradoxical relationship between cannabis exposure and sociability and suggest that endocannabinoid degradation inhibitors hold promise for the treatment of social dysfunctions.

Cannabinoid–serotonin interactions in alcohol‐preferring vs. alcohol‐avoiding mice

Because cannabinoid and serotonin (5-HT) systems have been proposed to play an important role in drug craving, we investigated whether cannabinoid 1 (CB1) and 5-HT(1A) receptor ligands could affect voluntary alcohol intake in two mouse strains, C57BL/6 J and DBA/2 J, with marked differences in native alcohol preference. When offered progressively (3-10% ethanol) in drinking water, in a free-choice procedure, alcohol intake was markedly lower (approximately 70%) in DBA/2 J than in C57BL/6 J mice. In DBA/2 J mice, chronic treatment with the cannabinoid receptor agonist WIN 55,212-2 increased alcohol intake. WIN 55,212-2 effect was prevented by concomitant, chronic CB1 receptor blockade by rimonabant or chronic 5-HT(1A) receptor stimulation by 8-hydroxy-2-(di-n-propylamino)-tetralin, which, on their own, did not affect alcohol intake. In C57BL/6 J mice, chronic treatment with WIN 55,212-2 had no effect but chronic CB1 receptor blockade or chronic 5-HT(1A) receptor stimulation significantly decreased alcohol intake. Parallel autoradiographic investigations showed that chronic treatment with WIN 55,212-2 significantly decreased 5-HT(1A)-mediated [35S]guanosine triphosphate-gamma-S binding in the hippocampus of both mouse strains. Conversely, chronic rimonabant increased this binding in C57BL/6 J mice. These results show that cannabinoid neurotransmission can exert a permissive control on alcohol intake, possibly through CB1-5-HT(1A) interactions. However, the differences between C57BL/6 J and DBA/2 J mice indicate that such modulations of alcohol intake are under genetic control.

Depression in Parkinson's disease is related to a genetic polymorphism of the cannabinoid receptor gene (CNR1)

Depression is a common symptom in Parkinson's disease (PD) and it is present in up to 40% of the patients. The cause of depression in PD is thought to be related to disturbance of monoamine neurotransmission. The endogenous cannabinoid system mediates different brain processes that play a role in the control of behaviour and emotions. Cannabinoid function may be altered in neuropsychiatry diseases, directly or through interactions with monoamine, GABA and glutamate systems. For this reason, we have investigated whether there is a genetic risk factor for depression in PD linked to the polymorphisms of CB1 receptor gene. Depression was more frequent in patients with PD than in controls with osteoarthritis. The presence of depression did not correlate with the stage of the disease but it was more frequent in patients with pure akinetic syndrome than in those with tremoric or mixed type PD. The CB1 receptor gene polymorphism (AAT)n is considered to modify the transcription of the gene and, therefore, it may have functional relevance. We analysed the length of the polymorphic triplet (AAT)n of the gene that encodes CB1 (CNR1) receptor in 89 subjects (48 PD patients and 41 controls). In patients with PD, the presence of two long alleles, with more than 16 repeated AAT trinucleotides in the CNR1 gene, was associated with a reduced prevalence of depression (Fisher's exact test: P=0.003). This association did not reach significant differences in the control group, but the number of control individuals with depression was too small to allow for statistical analysis. Since the alleles with long expansions may have functional impact in cannabinoid neurotransmission, our data suggest that the pharmacological manipulation of cannabinoid neurotransmission could open a new therapeutic approach for the treatment of depression in PD and possibly in other conditions.