Background: Longitudinal studies reporting the association between cannabis use and developing depression provide mixed results. The objective of this study was to establish the extent to which different patterns of use of cannabis are associated with the development of depression using meta-analysis of longitudinal studies.Method: Peer-reviewed publications reporting the risk of developing depression in cannabis users were located using searches of EMBASE, Medline, PsychINFO and ISI Web of Science. Only longitudinal studies that controlled for depression at baseline were included. Data on several study characteristics, including measures of cannabis use, measures of depression and control variables, were extracted. Odds ratios (ORs) were extracted by age and length of follow-up.Results: After screening for 4764 articles, 57 articles were selected for full-text review, of which 14 were included in the quantitative analysis (total number of subjects = 76058). The OR for cannabis users developing depression compared with controls was 1.17 [95% confidence interval (CI) 1.05–1.30]. The OR for heavy cannabis users developing depression was 1.62 (95% CI 1.21–2.16), compared with non-users or light users. Meta-regression revealed no significant differences in effect based on age of subjects and marginal difference in effect based on length of follow-up in the individual studies. There was large heterogeneity in the number and type of control variables in the different studies.Conclusions: Cannabis use, and particularly heavy cannabis use, may be associated with an increased risk for developing depressive disorders. There is need for further longitudinal exploration of the association between cannabis use and developing depression, particularly taking into account cumulative exposure to cannabis and potentially significant confounding factors.

The role of the D3 receptor has remained largely elusive before the development of selective research tools, such as selective radioligands, antibodies, various highly specific pharmacological agents and knock-out mice. The data collected so far with these tools have removed some of the uncertainties regarding the functions mediated by the D3 receptor. The D3 receptor is an autoreceptor that controls the phasic, but not tonic activity of dopamine neurons. The D3 receptor, via regulation of its expression by the brain-derived neurotrophic factor (BDNF), mediates sensitization to dopamine indirect agonists. This process seems responsible for side-effects of levodopa (dyskinesia) in the treatment of Parkinsons disease (PD), as well as for some aspects of conditioning to drugs of abuse. The D3 receptor mediates behavioral abnormalities elicited by glutamate/NMDA receptor blockade, which suggests D3 receptor-selective antagonists as novel antipsychotic drugs. These data allow us to propose novel treatment options in PD, schizophrenia and drug addiction, which are awaiting evaluation in clinical trials.

A polyclonal antibody was generated using synthetic peptides designed in a specific sequence of the rat D₃receptor (D₃R). Using transfected cells expressing recombinant D₃R, but not D₂receptor, this antibody labeled 45–80 kDa species in Western blot analysis, immunoprecipitated a soluble fraction of [¹²⁵I]iodosulpride binding, and generated immunofluorescence, mainly in the cytoplasmic perinuclear region of the cells. In rat brain, the distribution of immunoreactivity matched that of D₃R binding, revealed using [¹²⁵I]R(+)trans-7-hydroxy-2-[N-propyl-N-(3′-iodo-2′-propenyl)amino] tetralin ([¹²⁵I]7-trans-OH-PIPAT), with dense signals in the islands of Calleja and mammillary bodies, and moderate to low signals in the shell of nucleus accumbens (AccSh), frontoparietal cortex, substantia nigra (SN), ventral tegmental area (VTA) and lobules 9 and 10 of the cerebellum. Very low or no signals could be detected in other rat brain regions, including dorsal striatum, or in D₃R-deficient mouse brain. Labeling of perikarya of AccSh and SN/VTA appeared with a characteristic punctuate distribution, mostly at the plasma membrane where it was not associated with synaptic boutons, as revealed by synaptophysin immunoreactivity. In SN/VTA, D₃R immunoreactivity was found on afferent terminals, arising from AccSh, in which destruction of intrinsic neurons by kainate infusions produced a loss of D₃R binding in both AccSh and SN/VTA. D₃R-immunoreactivity was also found in all tyrosine hydroxylase (TH)-positive neurons observed in SN, VTA and A8 retrorubral fields, where it could represent D₃autoreceptors controlling dopamine neuron activities, in agreement with the elevated dopamine extracellular levels in projection areas of these neurons found in D₃R-deficient mice.

Drug dependence is a chronic, relapsing disorder in which compulsive drug-seeking and drug-taking behaviours persist despite serious negative consequences. Addictive substances, such as opioids, ethanol, psychostimulants and nicotine, induce pleasant states or relieve distress, effects that contribute to their recreational use. Dopamine is critically involved in drug addiction processes. However, the role of the various dopaminergic receptor subtypes has been difficult to delineate. Here, we will review the information collected implicating the receptors of the D1 family (DRD1 and DRD5) and of the D2 family (DRD2, DRD3 and DRD4) in drug addiction. We will summarize the distribution of these receptors in the brain, the preclinical experiments carried out with pharmacological and transgenic approaches and the genetic studies carried out linking genetic variants of these receptors to drug addiction phenotypes. A meta-analysis of the studies carried out evaluating DRD2 and alcohol dependence is also provided, which indicates a significant association. Overall, this review indicates that different aspects of the addiction phenotype are critically influenced by dopaminergic receptors and that variants of those genes seem to influence some addiction phenotypes in humans.

This review examines the development of cannabinoid CB₁ receptor antagonists as a new class of therapeutic agents for drug addiction. Abused drugs [alcohol, opiates, Δ⁹-tetrahydrocannabinol (Δ⁹-THC), and psychostimulants, including nicotine] elicit a variety of chronically relapsing disorders by interacting with endogenous neural pathways in the brain. In particular, they share the common property of activating mesolimbic dopamine brain reward systems, and virtually all abused drugs elevate dopamine levels in the nucleus accumbens. Cannabinoid CB₁ receptors are expressed in this brain reward circuit and modulate the dopamine-releasing effects of Δ⁹-THC and nicotine. Rimonabant (SR141716), a CB₁ receptor antagonist, blocks both the dopamine-releasing and discriminative and rewarding effects of Δ⁹-THC in animals. Blockade of CB₁ receptor activity by genetic invalidation also decreases rewarding effects of opiates and alcohol in animals. Although CB₁ receptor blockade is generally ineffective in reducing the self-administration of cocaine in rodents and primates, it reduces the reinstatement of extinguished cocaine-seeking behavior produced by cocaine-associated conditioned stimuli and cocaine-priming injections. Likewise, CB₁ receptor blockade is effective in reducing nicotine-seeking behavior induced by re-exposure to nicotine-associated stimuli. Some of these findings have been recently validated in humans. In clinical trials, Rimonabant blocks the subjective effects of Δ⁹-THC in humans and prevents relapse to smoking in exsmokers. Findings from both clinical and preclinical studies suggest that ligands blocking CB₁ receptors offer a novel approach for patients suffering from drug dependence that may be efficacious across different classes of abused drugs.