European Neuropsychopharmacology (v.18, #12)

Contents (OBC).

Facilitation of contextual fear memory extinction and anti-anxiogenic effects of AM404 and cannabidiol in conditioned rats by Rafael M. Bitencourt; Fabrício A. Pamplona; Reinaldo N. Takahashi (849-859).
The present study investigated the central effects of the eCB uptake/metabolism inhibitor AM404 and the phytocannabinoid cannabidiol (CBD) on the extinction of contextual fear memories in rats. Rats were conditioned and 24 h later subjected to three consecutive 9-min non-reinforced exposures to the conditioning context (extinction sessions, 24 h intervals). AM404 or CBD was injected i.c.v. 5 min before each extinction session and a 3-min drug-free test of contextual memory was performed 24 h after the last extinction session. AM404 (1.0 µg/µl, i.c.v.) and CBD (2.0 µg/µl, i.c.v.) facilitated extinction of contextual fear memory, with persistent effects. These responses were antagonized by the CB1-selective antagonist SR141716A (0.2 mg/kg, i.p.), but not by the TRPV1-selective antagonist capsazepine (5.0 µg/µl, i.c.v.). The effect of the anxiolytic drug Diazepam (DZP) on the extinction of contextual fear memory was also investigated. In contrast with the CBD and AM404 results, DZP induced a general reduction in the expression of conditioned freezing. Both AM404 and CBD induced anti-anxiogenic effect in the fear-potentiated plus-maze test, whereas DZP was anxiolytic in conditioned and unconditioned rats. In conclusion, CBD, a non-psychoactive phytocannabinoid could be an interesting pharmacological approach to reduce the anxiogenic effects of stress and promote the extinction of fear memories.
Keywords: Cannabinoid; Fear conditioning; Extinction; AM404; Cannabidiol; Anxiety;

In major depressive disorder (MDD), there is increasing evidence of a relationship between neuroendocrine and immunological alterations. Therefore, we investigated the influence of cortisol and dexamethasone on the in vitro production of TNF-α and IL-6 in blood cells of depressed inpatients at admission, in the course of MDD and in healthy controls. Patients were psychopathologically classified as responders and non-responders after a 6-week antidepressant treatment. At admission in the responder subgroup, incubation with both steroids under basal conditions resulted in an increase of TNF-α levels, which decreased after treatment. After stimulation with phytohemagglutinin, an enhancement of TNF-α suppression by steroids was detectable after successful antidepressive treatment. A significant relationship was seen between the cortisol-induced modulation of TNF-α levels and the psychopathology in this subgroup. Under basal conditions, IL-6 levels were increased after treatment with both steroids. The data suggest a normalization of the altered effects of glucocorticoids on TNF-α production in the responder subgroup only.
Keywords: Cortisol; Dexamethasone; Tumor-necrosis factor-α; Interleukin-6; Immune response; Major depressive disorder;

Attenuation of methamphetamine-induced effects through the antagonism of sigma (σ) receptors: Evidence from in vivo and in vitro studies by Rae R. Matsumoto; Jamaluddin Shaikh; Lisa L. Wilson; Shreedeepalakshmi Vedam; Andrew Coop (871-881).
Methamphetamine (METH) and many other abused substances interact with σ receptors. σ receptors are found on dopaminergic neurons and can modulate dopaminergic neurotransmission. Antisense knock down of σ receptors also mitigates METH-induced stimulant effects, suggesting that these proteins are viable medication development targets for treating psychostimulant abuse. In the present study, AC927, a σ receptor antagonist, was evaluated for its ability to attenuate METH-induced effects in vivo and in vitro. Radioligand binding studies showed that AC927 had preferential affinity for σ receptors compared to 29 other receptors, transporters and ion channels. Pretreatment of male, Swiss Webster mice with AC927 significantly attenuated METH-induced locomotor stimulation, striatal dopamine depletions, striatal dopamine transporter reductions, and hyperthermia. When the neurotoxicity of METH was further examined in vitro under temperature-controlled conditions, co-incubation with AC927 mitigated METH-induced cytotoxicity. Together, the results demonstrate that AC927 protects against METH-induced effects, and suggests a new strategy for treating psychostimulant abuse.
Keywords: Dopamine; Dopamine transporter; Hyperthermia; Locomotor activity; Methamphetamine; NG108-15 cells; Sigma receptors; Striatum;

Reduced serum concentrations of nerve growth factor, but not brain-derived neurotrophic factor, in chronic cannabis abusers by Francesco Angelucci; Valerio Ricci; Gianfranco Spalletta; Massimiliano Pomponi; Federico Tonioni; Carlo Caltagirone; Pietro Bria (882-887).
Chronic cannabis use produces effects within the central nervous system (CNS) which include deficits in learning and attention tasks and decreased brain volume. Neurotrophins, in particular nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), are proteins that serve as survival factors for CNS neurons. Deficits in the production and utilization of these proteins can lead to CNS dysfunctions including those associated with cannabis abuse.In this study we measured by enzyme-linked immunosorbent assay (ELISA) the NGF and BDNF serum levels in two groups of subjects: cannabis-dependent patients and healthy subjects. We found that NGF serum levels were significantly reduced in cannabis abusers as compared to healthy subjects.These findings indicate that NGF may have a role in the central action of cannabis and potentially in the neurotoxicity induced by this drug. These data also suggest that chronic cannabis consumption may be a risk factor for developing psychosis among drug users.
Keywords: Cannabis; NGF; BDNF; Serum levels; Abusers;

Nucleus accumbens dopamine is implicated in the primary and conditioned reinforcing properties of abused drugs. In the present study, specific impairments in responding for intravenous cocaine (0.3 mg/inf/0.1 ml/5 s) under a fixed-ratio 1 (FR-1) or second-order schedule (FI 15 min (FR10:S)) were investigated following infusion of the dopamine antagonist, α-flupenthixol, into either the nucleus accumbens core or shell. Infusion of α-flupenthixol into the core decreased cocaine intake under the FR-1 and second-order schedules. By comparison, blockade of nucleus accumbens shell dopamine receptors increased cocaine intake under the FR-1 schedule. Under the second-order schedule, cocaine intake and the number of responses was decreased. Effects on responding were more apparent after self-administered cocaine, when impairments in the latency to receive cocaine infusions were no longer evident. These results are discussed with reference to a role for nucleus accumbens shell dopamine in instrumental responding, and a role of nucleus accumbens core dopamine in incentive motivation, perhaps under the control of contextual stimuli.
Keywords: Addiction; Conditioning; Self-administration; Lever press; Rat;

Taq1A polymorphism in the dopamine D2 receptor gene as a predictor of clinical response to aripiprazole by Jun Soo Kwon; Euitae Kim; Do-Hyung Kang; Jung Seok Choi; Kyung-Sang Yu; In-Jin Jang; Sang-Goo Shin; APLUS study group (897-907).
We investigated whether the clinical response to aripiprazole differed according to the Taq1A polymorphism in the dopamine D2 receptor (DRD2) gene.In this 26-week, prospective, open-label, double-blind, parallel-group study, 90 patients with schizophrenia, schizoaffective disorder, or schizophreniform disorder were recruited and divided into two groups according to their DRD2 genotype (A1A1, n  = 14; A1A2+A2A2, n  = 76). The efficacy assessment included Positive and Negative Syndrome Scale (PANSS) scores and Clinical Global Impression (CGI) scores. Extrapyramidal symptoms were assessed using the Simpson–Angus Scale (SAS), Abnormal Involuntary Movement Scale (AIMS), and Barnes Akathisia Rating Scale (BAS). Plasma prolactin levels were also measured.Patients with the A1A1 genotype showed a more favorable therapeutic response to aripiprazole when assessed using the PANSS ratio. The changes in the SAS score from baseline to week 4 also differed according to the genotype group. There were no significant differences in the changes in the CGI, AIMS, and BAS scores or plasma prolactin level between the two genotype groups.The results suggest an association between the DRD2 Taq1A polymorphism status and the variation in the clinical response to aripiprazole.
Keywords: Antipsychotics; Pharmacogenetics; ANKK1; C957T; Schizophrenia;

The triple monoaminergic reuptake inhibitor DOV 216,303 has antidepressant effects in the rat olfactory bulbectomy model and lacks sexual side effects by M.E. Breuer; J.S.W. Chan; R.S. Oosting; L. Groenink; S.M. Korte; U. Campbell; R. Schreiber; T. Hanania; E.M.S. Snoeren; M. Waldinger; B. Olivier (908-916).
Current antidepressants have a delayed onset of action and disturbing side effects, including inhibition of sexual behavior. It is hypothesized that novel drugs, hitting multiple disease-relevant targets, may yield a new generation of superior antidepressants. One such approach is simultaneous inhibition of serotonin, norepinephrine and dopamine transporters. We tested the triple uptake inhibitor (TUI), DOV 216,303 (5, 10 and 20 mg/kg) after 1, 7 and 14 days administration in the olfactory bulbectomized (OBX) rat depression model, and in a model of rat sexual behavior to detect putative sexual side effects. Chronic, but not acute treatment of DOV 216,303 (20 mg/kg) normalized OBX-induced hyperactivity in the open field, similar to the effect of imipramine (20 mg/kg). None of the doses of DOV 216,303 had any effect on sexual behavior at any time point. The results indicate that DOV 216,303 displays antidepressant efficacy and is devoid of sexual side effects.
Keywords: Depression; TUI; Sexual behavior; Olfactory bulbectomy; Antidepressant; Rats;

Variations in circulating cytokine levels during 52 week course of treatment with SSRI for major depressive disorder by María Eugenia Hernández; Danelia Mendieta; Daniel Martínez-Fong; Frida Loría; Julia Moreno; Iris Estrada; Rafael Bojalil; Lenin Pavón (917-924).
Major depressive disorder (MDD) is a psychiatric condition characterized by hypercortisolism and variations in circulatory cytokines. Previously it has been reported that administration of selective serotonin reuptake inhibitors (SSRI) in MDD patients modify cortisol and cytokine levels but these studies only evaluated changes over a short time period. This work reports the long-term effects of administration of SSRI on the cortisol levels and pro-/anti-inflammatory cytokine profile in a group of MDD patients treated for 52 weeks. A total of 31 patients diagnosed with MDD received anti depressant treatment with SSRI. HDRS and BDI were administered over a year, and levels of interleukin IL-1β, IL-10, IL-2, IFN-γ, IL-4, IL-13, and 24-h urine cortisol were determined at weeks (W) 0, 5, 20, 36 and 52 of treatment. Before treatment we found high levels of cortisol, IL-4, IL-13 (Th2) and IL-10 in MDD patients when compared with healthy volunteers. At W20 psychiatric scales indicated a remission of the depressive episode concomitantly with increments in IL-2 and IL-1β but without changes in cortisol. Towards the end of the treatment (W52) we observed a significant reduction (p  < 0.01) in cortisol levels, with an increment in IL-1β and IFN-γ and a decrease in Th2 cytokines. Our results suggest that depressed patients only reach a partial reestablishment of HPA axis function after the long-term administration of SSRI.
Keywords: MDD; SSRI; Cytokines; Cortisol; HPA axis; HDRS;