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Rationale Long-term cannabis and cocaine use has been associated with impairments in reversal learning. However, how acute cannabis and cocaine administration affect reversal learning in humans is not known. Objective In this study, we aimed to establish the acute effects of administration of cannabis and cocaine on valence-dependent reversal learning as a function of DRD2 Taq1A (rs1800497) and COMT Val108/158Met (rs4680) genotype. Methods A double-blind placebo-controlled randomized 3-way crossover design was used. Sixty-one regular poly-drug users completed a deterministic reversal learning task under the influence of cocaine, cannabis, and placebo that enabled assessment of both reward- and punishment-based reversal learning. Results Proportion correct on the reversal learning task was increased by cocaine, but decreased by cannabis. Effects of cocaine depended on the DRD2 genotype, as increases in proportion correct were seen only in the A1 carriers, and not in the A2/A2 homozygotes. COMT genotype did not modulate drug-induced effects on reversal learning. Conclusions These data indicate that acute administration of cannabis and cocaine has opposite effects on reversal learning. The effects of cocaine, but not cannabis, depend on interindividual genetic differences in the dopamine D2 receptor gene. Electronic supplementary material The online version of this article (doi:10.1007/s00213-015-4141-5) contains supplementary material, which is available to authorized users.

Rationale Accumulating evidence indicates that the cognitive effects of dopamine depend on the subtype of dopamine receptor that is activated. In particular, recent work with animals as well as current theorizing has suggested that cognitive flexibility depends on dopamine D2 receptor signaling. However, there is no evidence for similar mechanisms in humans. Objectives We aim to demonstrate that optimal dopamine D2 receptor signaling is critical for human cognitive flexibility. Methods To this end, a pharmacological pretreatment design was employed. This enabled us to investigate whether effects of the dopamine receptor agonist bromocriptine on task-set switching were abolished by pretreatment with the D2 receptor antagonist sulpiride. To account for individual (genetic) differences in baseline levels of dopamine, we made use of a common variable number of tandem repeat (VNTR) polymorphism in the 3′-untranslated region of the dopamine transporter gene, DAT1. Results Bromocriptine improved cognitive flexibility relative to placebo, but only in subjects with genetically determined low levels of dopamine (n = 27). This beneficial effect of bromocriptine on cognitive flexibility was blocked by pretreatment with the selective dopamine D2 receptor antagonist sulpiride (n = 14). Conclusions These results provide strong evidence in favor of the hypothesis that human cognitive flexibility implicates dopamine D2 receptor signaling. Electronic supplementary material The online version of this article (doi:10.1007/s00213-011-2340-2) contains supplementary material, which is available to authorized users.

Item does not contain fulltext RATIONALE: A deregulation in concentrations of the neurosteroids (allo)pregnanolone and 3alpha,5alpha-tetrahydrodeoxycorticosterone (3alpha,5alpha-TH DOC) has been found in depressed patients. These levels normalize following treatment with selective serotonin reuptake inhibitors (SSRIs). Furthermore, administration of the neurosteroid dehydroepiandrosterone (DHEA) to depressed patients is associated with an improvement in the symptoms of depression. OBJECTIVE: The aim of the present review is to clarify the mechanisms whereby neurosteroids, particularly allopregnanolone and DHEA, are involved in depression and to discuss the effect of SSRIs on allopregnanolone concentration. METHODS: Literature on preclinical and clinical research has been analyzed in relation to the pathophysiology of depression. RESULTS: Decreased plasma and cerebrospinal fluid concentrations of allopregnanolone in depressed patients increase to normal levels following effective psychopharmacological treatment. This might either be a physiological aspect of improvement in the symptoms of depression or a pharmacologically induced alteration. Several findings support the hypothesis of an antidepressant effect of allopregnanolone. These include an antidepressant effect demonstrated in an animal model of depression and a suppressing effect on corticotropin-releasing hormone (CRH) and arginine-vasopressin (AVP) gene expression. SSRIs increase levels of allopregnanolone, but this effect is not confined to this class of drugs alone. The beneficial effect of DHEA administration in depressed patients might result from its sigma 1 receptor-mediated enhancement of noradrenaline and serotonin neurotransmission, antiglucocorticoid effects, and cognition enhancing effects. CONCLUSIONS: Indirect genomic (allopregnanolone) and non-genomic (allopregnanolone and DHEA) mechanisms are involved in the neurosteroidogenic pathophysiology of depression. Clinical studies in homogeneous groups of non-pharmacologically treated depressed patients are required to elucidate this relationship further.