European Neuropsychopharmacology (v.19, #3)

Contents (OBC).

Dopamine antagonism inhibits anorectic behavior in an animal model for anorexia nervosa by Linda A.W. Verhagen; Mieneke C.M. Luijendijk; Jacquelien J.G. Hillebrand; Roger A.H. Adan (153-160).
Excessive physical activity is commonly described as symptom of Anorexia Nervosa (AN). Activity-based anorexia (ABA) is considered an animal model for AN. The ABA model mimics severe body weight loss and increased physical activity. Suppression of hyperactivity by olanzapine in anorectic patients as well as in ABA rats suggested a role of dopamine and/or serotonin in this trait. Here, we investigated the effect of a non-selective dopamine antagonist in the ABA model. A dose–response curve of chronic treatment with the non-selective dopaminergic antagonist cis-flupenthixol was determined in the ABA model. Treatment reduced activity levels in both ad libitum fed and food-restricted rats. Treated ABA rats reduced body weight loss and increased food intake. These data support a role for dopamine in anorexia associated hyperactivity. Interestingly, in contrast to leptin treatment, food-anticipatory activity still persists in treated ABA rats.
Keywords: Anorexia; Dopamine antagonism; Food restriction; Hyperactivity; Food-anticipatory activity; Leptin;

Cerebrolysin lowers kynurenic acid formation — An in vitro study by Halina Baran; Berthold Kepplinger (161-168).
The therapeutic effect of Cerebrolysin in the treatment of dementia and brain injury has been proposed because of neurotrophic properties of this compound. Since an increased kynurenine metabolism has been documented in several brain pathologies including dementia the aim of the present study was to investigate the biochemical properties of Cerebrolysin with respect to kynurenic acid (KYNA) formation in an in vitro study. KYNA is an endogenous metabolite of the kynurenine pathway of tryptophan degradation and is an antagonist of the glutamate ionotropic excitatory amino acid and of the nicotine cholinergic receptors. The activities of the KYNA synthesizing enzymes kynurenine aminotransferases I, II and III (KAT I, KAT II and KAT III) in rat liver, and rat and human brain homogenates were analysed in the presence of Cerebrolysin. KAT I, II and III activities were measured using a radio-enzymatic method in the presence of 1 mM pyruvate and 100 µM [H3]l-kynurenine. Cerebrolysin, dose-dependently and significantly reduced KAT I, KAT II and KAT III activities of rat liver homogenate. Furthermore, Cerebrolysin exerted a dose-dependent inhibition of rat and human brain KAT I, KAT II and KAT III activities, too. The inhibitory effect of Cerebrolysin was more pronounced for KAT I than for KAT II and KAT III. The present study for the first time demonstrates the ability of Cerebrolysin to lower KYNA formation in rat liver as well as in rat and human brain homogenates. We propose Cerebrolysin as a compound susceptible of therapeutic exploitation in some disorders associated with elevated KYNA metabolism in the brain and/or other tissues. We suggest that the anti-dementia effect of Cerebrolysin observed in Alzheimer patients could be in part due to Cerebrolysin induced reduction of KYNA levels, thus modulating the cholinergic and glutamatergic neurotransmissions.
Keywords: Kynurenic acid; Kynurenine aminotransferases; NMDA receptor; Cholinergic receptor; Dementia; Cerebrolysin;

Objective: remission of depression in primary care by Marc Ansseau; Koen Demyttenaere; Jan Heyrman; André Migeotte; Sophie Leyman; Annick Mignon (169-176).
Treatment of depression should result in the absence of symptoms, i.e. remission, in order to restore the functional status of the patient and reduce the risk for relapse. The study assessed the current remission rates in primary care and determined the influencing factors.10 consecutive depressive patients treated by antidepressants for at least 3 months and not more than 12 months were screened by each investigator. Remission rates were defined using the Hamilton-Depression scale 7 items (score of 3 or less) as well as the Carroll self rating scale (score of 7 or less). In addition, patients completed the Sheehan Disability Scale (SDS). Initial severity of depression, type of treatment and socio-economic factors were collected.292 general practitioners screened a total of 2630 patients. Results indicated low remission rates: 28.3% according to the clinician and 17.1% according to the patient. Absence of remission was associated with higher impairment in work, social and family life. The most frequently reported residual symptoms in nonremitters were general somatic symptoms (92%), depressed mood (92%), psychic anxiety (91%) and impaired work and activities (89%). No differences were observed in remission rates between men and women. Remission rates were significantly lower in patients living alone as compared to those living in couple or family (25.1% vs 30.2%, p  = 0.03), in patients with lower education (21.3% vs 32.3%, p<  0.001), in patients speaking French as compared to Dutch (24.0% vs 34.0% p<  0.001), and unemployed patients compared to patients having an occupation (17.1% vs 39.0%, p<  0.001). Higher initial severity and number of previous episodes decreased remission rates (p<  0.001).This study shows low remission rates in depressed patients treated in general practice. The absence of remission is associated with impairment in work, social and family life. Special attention should be given to identify patients who do not reach remission.
Keywords: Major depression; Remission; General practice;

Asenapine is a psychopharmacologic agent being developed for schizophrenia and bipolar disorder. This study electrophysiologically characterized the in vivo effects of asenapine at dorsal raphe nucleus (DRN) and hippocampus serotonin-1A (5-HT1A), ventral tegmental area D2, locus coeruleus 5-HT2A, and α2-adrenergic receptors in anesthetized rats. Asenapine displayed potent antagonistic activity at α2-adrenoceptors (ED50, 85 ± 2 µg/kg), 5-HT2A (ED50, 75 ± 2 µg/kg) and D2 receptors (ED50, 40 ± 2 µg/kg) as evidenced by its reversal of clonidine-, DOI-, and apomorphine-induced inhibition of norepinephrine and dopamine neurons. In contrast, asenapine acted as a partial agonist at 5-HT1A receptors in DRN and hippocampus, as indicated by blockade of its inhibitory effect on neuronal firing by the 5-HT1A antagonist WAY 100635 and the partial inhibition of the suppressant action of 5-HT when co-applied by microiontophoresis. These results confirm that asenapine displays potent antagonistic activity at 5-HT2A, D2, α2-adrenergic receptors and provide evidence to support its 5-HT1A partial agonistic activity.
Keywords: Asenapine; Schizophrenia; Dopamine; Norepinephrine; Serotonin; Electrophysiology;

Modulation of anxiety-like behaviour by Transient Receptor Potential Vanilloid Type 1 (TRPV1) channels located in the dorsolateral periaqueductal gray by Ana Luisa B. Terzian; Daniele C. Aguiar; Francisco S. Guimarães; Fabrício A. Moreira (188-195).
The endocannabinoid anandamide is a possible agonist at the Transient Receptor Potential Vanilloid Type 1 (TRPV1) channel, in addition to its agonist activity at cannabinoid type 1 (CB1) receptor. In the midbrain dorsolateral periaqueductal gray (dlPAG) our previous data showed that CB1 activation induces anxiolytic-like effects. However, the role of TRPV1 has remained unclear. Thus, in the present study we tested the hypothesis that this channel would contribute to the modulation of anxiety-like behaviour in the dlPAG. Male Wistar rats received local injections of the TRPV1 antagonist capsazepine (10–60 nmol) and were submitted to the elevated plus-maze (EPM) and to the Vogel test. In addition, animals received local injections of capsaicin (0.01–1 nmol), a TRPV1 agonist, and were tested in the same models. In accordance with our hypothesis, capsazepine produced anxiolytic-like effects both in the EPM and in the Vogel test. Capsaicin mimicked these results, which might be attributed to its ability to quickly desensitize the channel. Altogether, our data suggest that, while CB1 receptors seem to inhibit aversive responses in the dlPAG, TRPV1 could facilitate them. Thus, CB1 and TRPV1 may have opposite functions in modulating anxiety-like behaviour in this region.
Keywords: Anandamide; Endocannabinoids; Endovanilloids; Anxiety; Elevated plus-maze; Vogel test;

CB1 receptor knockout mice are hyporesponsive to the behavior-stimulating actions of d-amphetamine: Role of mGlu5 receptors by Eleni T. Tzavara; Aldemar Degroot; Mark R. Wade; Richard J. Davis; George G. Nomikos (196-204).
Blockade of the cannabinoid CB1 receptors (CB1R) has been shown to reduce psychostimulant-induced hyperactivity, an effect that we sought to further characterize here. The CB1R antagonist SR141716A dose-dependently decreased d-amphetamine-induced hyperactivity. Also, d-amphetamine-induced hyperlocomotion was reduced in CB1R knockout (KO) mice. However, CB1R KO and wild-type mice showed a similar d-amphetamine-induced increase in nucleus accumbens DA release. Hence, we investigated whether CB1R antagonism/invalidation reduces d-amphetamine-induced hyperlocomotion through a mechanism involving changes in glutamatergic neurotransmission. Blockade of metabotropic-glutamate-receptors-5 (mGluR5) with MPEP, but not blockade of N-methyl-d-aspartate-receptors (NMDA) with MK-801, restored to a great extent the blunted d-amphetamine-induced hyperlocomotion seen after CB1R antagonism/invalidation. Thus, hyporesponsiveness to the psychostimulant effects of d-amphetamine as a result of CB1R antagonism/invalidation is not due to an ensuing decrease in d-amphetamine-induced DA release in the nucleus accumbens, but rather due to a hyperglutamatergic state and facilitation of glutamatergic neurotransmission at the mGlu5, but not NMDA, receptors.
Keywords: CB1 receptor; mGluR5; d-amphetamine; MK-801; Locomotor activity; Dopamine; Microdialysis;

Bipolar disorder is characterized by dysregulated motivation and increased hedonistic drive. d-Amphetamine induces manic symptoms in humans and exacerbates mania in bipolar disorder patients, effects that are counteracted by mood stabilizers. We utilized intracranial self-stimulation (ICSS) to examine how lithium (LiCl), valproate (VPA) or their combination that is commonly used in the clinic affect brain reward function in rats, and how these drugs affect d-amphetamine's reward-facilitating effects. Acute intraperitoneal (i.p.) administration of LiCl (100, 200 mg/kg), VPA (400 mg/kg) or combined administration of subthreshold doses of LiCl (50 mg/kg) and VPA (200 mg/kg) increased ICSS thresholds. LiCl (100 mg/kg) and combined administration of LiCl and VPA (50 and 200 mg/kg), but not VPA alone (200, 400 mg/kg), attenuated d-amphetamine's reward-facilitating effects. These results suggest that ICSS combined with d-amphetamine constitutes a useful model to explore the elation and increased hedonistic drive observed in bipolar patients and ultimately help to identify novel pharmacotherapies for bipolar disorder.
Keywords: Brain stimulation reward;; Mood stabilizers;; d-Amphetamine;; Reinforcement;; Animal model;

Chronic stressful life events are risk factors for contracting depression, the pathophysiology of which is strongly associated with impairments in serotonergic (5-HT) neurotransmission. Indeed, in rodents, exposure to chronic unpredictable stress (CUS) produces depressive-like behaviours such as behavioural despair and anhedonia. To date, there have not been many studies that especially explore in vivo changes in 5-HT neurotransmission associated with CUS in the rat. Therefore, using in vivo electrophysiology, we evaluated whether CUS that induces anhedonia-like behaviours concurrently impairs midbrain raphe 5-HT neuronal activity. Unlike unstressed and acutely stressed rats, CUS produced progressive reductions in sucrose intake and preference (anhedonia-like). These were associated with a decrease in the spontaneous firing activity (35.4%) as well as in the number of spontaneously active 5-HT neurons, and a desensitization of somatodendritic 5-HT1A autoreceptors in the dorsal raphe. These results suggest that CUS dramatically decreases 5-HT neural activity and 5-HT1A autoreceptor sensitivity, and may represent endophenotypic features of depressive-like states.
Keywords: Chronic unpredictable stress; Serotonin; 5-HT1A; Depression; Dorsal raphe nucleus; Anhedonia;