European Neuropsychopharmacology (v.20, #4)

Contents (OBC).

The effect of chronic antipsychotic drug administration on nitric oxide synthase activity and gene expression in rat penile tissues by Xiang Rong Zhang; Zhi Jun Zhang; Trisha A. Jenkins; Wei Rong Cheng; Gavin P. Reynolds (211-217).
Antipsychotic drug treatment may be associated with common and problematic sexual dysfunction, especially impotence, which can diminish quality of life and lead to treatment noncompliance. Nitric oxide synthase (NOS) is an important cellular modulator of erectile function. We have therefore investigated the effect of antipsychotic drug on activity and gene expression of NOS in rat penile tissues. The activity of constitutive NOS was significantly suppressed below control by a 21 days administration of 1 mg/kg haloperidol, which also significantly decreased expression of endothelial NOS (eNOS) and neural NOS mRNA. Risperidone at 0.5 mg/kg also reduced eNOS mRNA expression. Haloperidol or risperidone did not change gene expression and activity of inducible NOS (iNOS). Quetiapine significantly increased activity and mRNA expression of iNOS with 20 and 40 mg/kg doses. These preliminary results have important implications for enhancing our understanding of mechanisms by which antipsychotic drugs induce sexual dysfunction.
Keywords: Antipsychotic drug; Nitric oxide synthase; Penile tissues;

We have recently found that postsynaptic D3 dopamine (DA) receptors appear not to participate in the memory enhancing effects of the angiotensin AT4 receptor agonists angiotensin IV (Ang IV) and des-Phe6-Ang IV. In this study we evaluated role of the presynaptic DA D3 receptors in these effects. For that purpose effect of (+)-UH 232, a selective D3 DA receptors partial agonist preferring presynaptic sites, on the pro-cognitive action of intracerebroventricularly (icv) injected Ang IV and des-Phe6-Ang IV was examined. Male Wistar rats weighing 180–200 g were used. Both peptides given at the dose of 1 nmol facilitated recall of a passive avoidance (PA) behaviour, improved object recognition (OR), and increased apomorphine-induced stereotype behaviour. In the auxiliary tests performed to control for the unspecific influence of motor (open field, OF) and emotional (‘plus’ maze, PM) effects of our treatments on the results of the memory tests they had either no (OF) or negligible (PM) effects. Intraperitoneal pre-treatment of the animals with an ineffective on its own dose (1 mg/kg) of (+)-UH 232 abolished or markedly diminished effects of both peptides on PA and OR but did not influence enhancement of stereotypy caused by the peptides.
Keywords: Angiotensin IV; Des-Phe6-angiotensin IV; (+)-UH 232; Dopamine D3 receptor; Stereotype behaviour; Memory; Rat;

Animal literature suggests an important role for histamine in memory. In humans, this hypothesis has been scarcely tested and results from studies that have addressed this are conflicting. Second, impaired memory performance may be secondary to sedation. This study aimed to determine whether a centrally active antihistamine impairs memory performance and to dissociate such effects from sedation. Eighteen healthy volunteers received single oral doses of dexchlorpheniramine 4 mg, lorazepam 1 mg and placebo in a 3-way, double blind, crossover designed study. The active control lorazepam impaired episodic- and working memory performance and increased sedation, while dexchlorpheniramine only increased sedation.
Keywords: Antihistamines; Benzodiazepines; Cognition; Memory; Sedation; Event related potentials;

In previous studies, acutely administered oral methylphenidate (MPD, 3 mg/kg) prior to testing improved performance on the radial arm maze in juvenile rats. In order to examine the mechanisms producing this improvement we administered MPD once prior to each test of anxiety, locomotor activity and attention. On postnatal day (PND) 22 on an elevated plus maze, rats spent more time beyond the rails on the open arms and showed altered risk-assessment behaviors suggesting an anxiolytic-like effect of MPD. Grid crossings on the plus maze indicated that MPD increased locomotor activity, as did activity recording on PND 23. In another group of juveniles, MPD improved performance in a multi-trial attention task in an age-dependent fashion. These data suggest that oral MPD has multifaceted effects on juvenile rats that together improve performance on cognitive tests such as the radial arm maze. In addition, our data support human studies finding multifaceted effects of MPD.
Keywords: Attention; Elevated plus maze; Individual differences; Locomotor activity; Oral administration; Ritalin;

Endogenous cannabinoids in post-mortem brains of Cloninger type 1 and 2 alcoholics by Marko Lehtonen; Markus Storvik; Erkki Tupala; Petri Hyytiä; Jari Tiihonen; J.C. Callaway (245-252).
The endogenous cannabinoid (EC) system has been recently implicated in several neuropsychiatric disorders. This study analyzed post-mortem brain regions of Cloninger type 1 (n  = 9) and 2 (n  = 8) alcoholics and non-alcoholic controls (n  = 10) for ECs by quantitative liquid chromatography with triple quadrupole mass spectrometric detection. A significant difference was found in anandamide (AEA) levels in nucleus accumbens (NAcc) between the three groups (p  = 0.047). AEA levels were significantly lower when compared to controls in both perigenual anterior cingulate (p  = 0.017) and frontal cortices (p  = 0.018) of type 1 alcoholics. Similar trends were observed for dihomo-γ-linolenoyl ethanolamide and docosahexaenoyl ethanolamide, but not for 2-arachidonoylglycerol, palmitoyl ethanolamide, or oleoyl ethanolamide. Although preliminary, and from diagnostic groups with a relatively small number of subjects and substantially different mean ages for each group, these results suggest that the EC system may be hyperactive in type 2 alcoholics and hypoactive in type 1 alcoholics.
Keywords: Endocannabinoids; Anandamide; AEA; 2-Arachidonoylglycerol; 2-AG; Cloninger type 1 and 2; Alcoholism; Post-mortem brain;

Protein kinase M zeta (PKMζ), a constitutively active isoform of protein kinase C, has been implicated in protein synthesis-dependent maintenance of long-term potentiation and memory storage in the brain. Recent studies reported that local application of ZIP, a membrane-permeant PKMζ inhibitor, into the insular cortex (IC) of behaving rats abolished long-term memory of taste associations.This study assessed the long-term effects of local applications of ZIP microinjected immediately (1 h) or 10 days after predator scent stress exposure, in a controlled prospectively designed animal model for PTSD. Four brain structures known to be involved in memory processes and in anxiety were investigated: lateral ventricle (LV), dorsal hippocampus (DH), basolateral amygdala and IC. The outcome measures included behavior in an elevated plus maze and acoustic startle response 7 days after microinjection, and freezing behavior upon exposure to trauma-related cue 8 days after microinjection. Previously acquired/encoded memories associated with the IC were also assessed.Inactivation of PKMζ in the LV or DH within 1 h of exposure effectively reduced PTSD-like behavioral disruption and trauma cue response 8 days later. Inactivation of PKMζ 10 days after exposure had equivalent effects only when administered in the IC. The effect was demonstrated to be specific for trauma memories, whereas previously acquired data were unaffected by the procedure.Predator scent related memories are located in different brain areas at different times beginning with an initial hippocampus-dependent consolidation process, and are eventually stored in the IC. These bring the IC to the forefront as a potential region of significance in processes related to traumatic stress-induced disorders.
Keywords: Post-traumatic stress disorder; Animal model; Protein kinase M zeta; Memory consolidation; Extreme behavioral response; Minimal behavioral response;

The COMT val 158 variant has been associated with impaired cognitive function compared to the met 158 variant yet gene–gene interactions are not well described. In this study we demonstrate an interaction between this COMT polymorphism and a deletion variant of ADRA2B, the gene encoding the α2b-adrenergic receptor on episodic memory performance. Specifically, carriage of the ADRA2B deletion abolished the relative memory impairment in homozygous COMT val 158 carriers compared to met 158 carriers.
Keywords: Genetics; Emotional memory; Episodic memory; COMT; ADRA2B; Catecholamines; Noradrenaline;

How much more effective do depot antipsychotics have to be compared to oral antipsychotics before they are prescribed? by Johannes Hamann; Rosmarie Mendel; Stephan Heres; Stefan Leucht; Werner Kissling (276-279).
Antipsychotic depots are less frequently prescribed than oral compounds. In an experimental study involving N  = 106 psychiatrists we studied how much more effective with respect to relapse prevention depot antipsychotics have to be compared to oral antipsychotics before they are chosen for prescription.Most psychiatrists have to judge depot as clearly superior with respect to relapse prevention before they recommend it to patients. If psychiatrists judge depot as unpleasant for the patients and do not see much need for checking their patients' compliance they are less likely to prescribe depot. Other psychiatrist-related factors (e.g. age, gender, and work experience) did not influence attitudes toward depot.
Keywords: Schizophrenia; Antipsychotics; Depot; Effectiveness; Prescription rates;