European Neuropsychopharmacology (v.10, #5)

Objective: To compare the emergent sexual effects of moclobemide and selective serotonin reuptake inhibitors (SSRIs) during acute and maintenance therapy in routine practice. Method: 268 patients were evaluated for sexual function at baseline, 6 weeks, 3 and 6 months of treatment using physician ratings and self-rating questionnaires. Patients received moclobemide, an reversible monoamine oxidase A inhibitor (RIMA), or a SSRI (fluoxetine, fluvoxamine, paroxetine, sertraline). Results: Baseline values were similar in all groups. Incidences of impairments of sexual functioning with treatment, whether clinically relevant or not, were 24.3% with moclobemide and 61.5% with SSRIs (physician ratings), with no significant tolerance to these effects. There was a suggestion of differences between the SSRIs in their specific dysfunctions they cause. SSRIs (21.6% of patients) had about ten times the moclobemide rate (1.9%) of sexual dysfunction reported as adverse events. Antidepressant efficacy was comparable between treatments. Conclusion: In patients for whom sexual function is important or sexual dysfunction is present, moclobemide should be considered a first line antidepressant.
Keywords: Depression; Sexual dysfunction; Tolerability; Efficacy; Moclobemide; Fluoxetine; Fluvoxamine; Paroxetine; Sertraline; Rating scales;

The effects of antipsychotic drugs on serotonergic activity in the rat hippocampus by Katerina Antoniou; Stathis Bekris; Melania Saranti; Pantelis Stathis; Michael Rimikis; Zetta Papadopoulou-Daifoti (315-324).
The serotonergic activity in hippocampus was investigated following acute and chronic treatment with the antipsychotic drugs haloperidol and risperidone. Acute administration of risperidone, the serotonin2 (5-HT2) receptor antagonist ketanserin, and the dopamine (DA)-D2 receptor antagonist raclopride increased the 5-hydroxyindoleacetic acid/serotonin (5-HIAA/5-HT) ratio. In contrast, acute administration of haloperidol did not affect this ratio. Chronic administration of risperidone maintained the increased 5-HIAA/5-HT ratio; a challenge dose of risperidone after the chronic treatment and the subsequent washout period also maintained the increased ratio. Chronic administration of haloperidol as well as a challenge dose of haloperidol following chronic treatment did not affect the serotonergic activity in hippocampus. Administration of ketanserin or raclopride after chronic treatment and the washout period induced an additional increase in the 5-HIAA/5-HT ratio in risperidone-treated rats. Moreover, a challenge dose of ketanserin, but not raclopride, increased the 5-HIAA/5-HT ratio in haloperidol-treated rats. The present results indicate that acute and chronic treatment of haloperidol or risperidone modified serotonergic activity in the hippocampus in a different way. Moreover, the augmentation of serotonergic activity induced by risperidone did not seem to be solely related to dopaminergic or serotonergic properties and may be of particular relevance for the amelioration of schizophrenia symptoms.
Keywords: Hippocampus; Risperidone; Haloperidol; Raclopride; Ketanserin; Serotonin;

Preclinical and clinical studies suggest that the mesolimbic dopamine system plays a major role in mediating the reinforcing effects of drugs of abuse, including alcohol and psychostimulants, and that pharmacological blockade of dopamine D1 and/or D2 receptors may reduce intake of these drugs, as well as relapse rates. The neuroleptic flupenthixol, which has dopamine D1 and D2 receptor antagonist properties and which may be given intramuscularly in order to improve compliance, has been studied as a possible anti-craving drug in substance abuse disorders. Flupenthixol has been shown to attenuate the discriminative stimulus effects of psychostimulants, as well as their intake in animal models of drug abuse. In addition, the compound was found to reduce alcohol intake in a rat model of alcoholism, but the ‘anti-alcohol’ effect appeared to be only weakly selective and nonspecific. Clinically, the drug has been studied in alcoholics, cocaine addicts and in patients with comorbid psychiatric disorders. Although the data base is still limited and a number of recent trials have not been completely analyzed, these studies suggest that flupenthixol may be useful in decreasing cocaine consumption. Recent studies in alcoholism, however, have shown disappointing results. A number of pilot studies suggest that probably the most promising area may be the treatment of substance abuse/dependence in patients with comorbid psychiatric disorders. Future studies should focus on dosing issues, the differentiation between short- and long-term effects and the identification of subgroups of patients with particular psychopathology.
Keywords: Alcoholism; Anti-craving drug; cAA rat model of alcoholism; Psychostimulants;

Prevalence and characteristics of patients with pseudoakathisia by B.J. Havaki-Kontaxaki; V.P. Kontaxakis; G.N. Christodoulou (333-336).
Pseudoakathisia (PsA) is characterised by the typical motor features of akathisia but there is a lack of subjective awareness. A total of 153 in-patients on neuroleptic medication hospitalized in two representative wards of the Psychiatric Hospital of Attica in Athens were rated on the census date using the Rating Scale for Drug-Induced Akathisia [Barnes, Br. J. Psychiatry, 154 (1989) 672–676], the Rating Scale for Extrapyramidal Side-Effects [Simpson and Angus, Acta Psychiatr. Scand. 212 (Suppl.) (1970) 11–19] and the Abnormal Involuntary Movements Scale [US Department of Health, Education and Welfare, ECDEU Assessment Manual (1976) pp. 534–537]. Eight subjects of the total in-patient population were found to have PsA of chronic type (point prevalence 5.23%). The point-prevalence of PsA among schizophrenic patients was 4.76%. In addition to the diagnosis of chronic pseudoakathisia, five patients (62.5%) had a concurrent diagnosis of chronic parkinsonism. Among patients with PsA, significant correlations were found between parkinsonism score and current daily dose of neuroleptics or high potency neuroleptics. There is evidence of a relationship between chronic pseudoakathisia, chronic parkinsonism and daily dose of neuroleptic.
Keywords: Pseudoakathisia; Prevalence; Parkinsonism; Tardive dyskinesia;

Lymphocyte peripheral benzodiazepine receptor mRNA decreases in obsessive-compulsive disorder by Paola Rocca; Anna Maria Beoni; Carola Eva; Patrizia Ferrero; Giuseppe Maina; Filippo Bogetto; Luigi Ravizza (337-340).
The relative content of peripheral benzodiazepine receptor (pBR) mRNA was examined by reverse transcriptase-polymerase chain reaction in lymphocytes of obsessive-compulsive disorder (OCD) patients, according to their clinical course of illness. pBR mRNA significantly decreased only in chronic OCD patients (n=8) as compared to controls (n=10), whereas no significant changes were observed in episodic OCD patients (n=7). We suggest that modulation of pBR gene expression might delineate a clinical heterogeneity in OCD.
Keywords: Peripheral benzodiazepine receptor mRNA; Obsessive-compulsive disorder; Anxiety disorders; Clinical subtypes;

Changes of cerebrospinal fluid monoamine metabolites during long-term antidepressant treatment by Jakob Bäckman; Christer Alling; Margot Alsén; Göran Regnéll; Lil Träskman-Bendz (341-349).
This study describes the changes in cerebrospinal fluid (CSF) monoamine metabolites during antidepressant treatment for more than 6 months. Eight patients, who received antidepressant treatment after attempted suicide and then underwent lumbar punctures every 3 or 4 months, were included. Plasma drug concentrations and the clinical outcome were also measured. Consistent with previous reports about antidepressant treatment for between 3 and 6 weeks, both 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) and 5-hydroxyindoleacetic acid (5-HIAA) were significantly decreased after treatment for a mean of 15 weeks compared to pretreatment. However, after continued treatment for a mean of 30 weeks the MHPG concentration remained significantly lower than at pretreatment while 5-HIAA had returned to the pretreatment level. The clinical outcome was significantly correlated to the pretreatment 5-HIAA/MHPG ratio. These results suggest that the frequently reported reduction in CSF 5-HIAA after antidepressant treatment does not remain during long-term treatment.
Keywords: Antidepressants; Cerebrospinal fluid; 5-HIAA; MHPG;

1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane (DOI) decreases alcohol intake by alcohol-preferring cAA rats more selectively than fluoxetine in a two-bottle alcohol vs. water paradigm. We report now that availability of sucrose or saccharin in a 3rd bottle does not affect (1) alcohol intake, supporting further the validity of this model of alcoholism, nor (2) the selectivity profile of the alcohol intake-reducing effects of these compounds. It is hypothesized that reduction of alcohol intake by DOI is not simply due to decreased intake of palatable fluids.
Keywords: Alcoholism; Animal model; 1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane (DOI); Fluoxetine; Palatability;

Effects of antipsychotic drugs on cholecystokinin and preprotachykinin (substance P) mRNA expression in the rat hippocampal formation by Olof Zachrisson; George G. Nomikos; Monica M. Marcus; Torgny H. Svensson; Nils Lindefors (355-363).
To assess the involvement of substance P (SP) and cholecystokinin (CCK) in the effects of antipsychotic drugs, preprotachykinin-A (PPT-A) and CCK mRNA expression was studied in the hippocampal formation using in situ hybridisation following 21 daily i.p. injections with the typical antipsychotic drug haloperidol (1 mg/kg) and the atypical drug clozapine (15 mg/kg). PPT-A mRNA levels were increased in the hippocampal CA3 subregion and in the entorhinal cortex after haloperidol, whereas a decrease was observed in the CA1 after clozapine. CCK mRNA levels increased in the CA1, the entorhinal cortex and in hilus, following both haloperidol and clozapine. It is suggested that earlier findings of increased SP levels in the hippocampal formation of schizophrenics may be a consequence of haloperidol treatment and that reduced hippocampal CCK and CCK mRNA levels found earlier in schizophrenics do not result from antipsychotic drug treatment. These results are consonant to the hypothesis that increased cortical CCK transmission may be beneficial in the treatment of psychosis.
Keywords: Antipsychotic; Tachykinin; Cholecystokinin; Hippocampus; Entorhinal cortex; Rat;

Temporal changes of dopaminergic and glutamatergic receptors in 6-hydroxydopamine-treated rat brain by Tsutomu Araki; Hiroaki Tanji; Hiroyuki Kato; Yutaka Imai; Michinao Mizugaki; Yasuto Itoyama (365-375).
Quantitative receptor autoradiography was used to examine the sequential patterns of changes in dopaminergic and glutamatergic receptors in the brain of rats lesioned with 6-hydroxydopamine. The animals were unilaterally lesioned in the medial forebrain bundle and the brains were analyzed at 1, 2, 4 and 8 weeks of postlesion. Degeneration of the nigrostriatal pathway caused a significant increase in dopamine D2 receptors in the ipsilateral striatum from 1 to 8 weeks of postlesion. In the ipsilateral substantia nigra (SN), a significant decrease in dopamine D2 receptors was also observed from 1 to 8 weeks of postlesion. On the other hand, dopamine D1 receptors were increased in the ipsilateral ventromedial striatum from 2 to 4 weeks of postlesion. In the ipsilateral SN, a transient increase in dopamine D1 receptors was observed only 1 week after lesioning. However, other regions in both ipsilateral and contralateral sides showed no significant change in dopamine D1 and D2 receptors during postlesion except for a transient change in a few regions. N-Methyl-d-aspartate (NMDA) receptors showed no significant changes in all brain regions studied during the postlesion. In contrast, a transient increase in excitatory amino acid transport sites was observed only in the frontal cortex and ventromedial striatum of the ipsilateral side at 2 weeks of postlesion. However, glycine receptors showed a significant change in any brain areas of both ipsilateral and contralateral sides after lesioning. The change in the brain areas of contralateral side was more pronounced than that of ipsilateral side for glycine receptors. In addition, dopamine uptake sites showed a severe damage in the ipsilateral striatum from 1 to 8 weeks after lesioning. In the contralateral side, in contrast, no significant change in dopamine uptake sites was found in the striatum during the postlesion. These results indicate that unilateral injection of 6-hydroxydopamine in the medial forebrain bundle can cause a significant increase in dopamine D1 and D2 receptors in the striatum. The increase in dopamine D2 receptors was more pronounced than that in dopamine D1 receptors in the striatum after 6-hydroxydopamine treatment. In contrast, dopamine uptake sites showed a severe damage in the striatum during the postlesion. Furthermore, our results support the existence of dopamine D2 receptors on the neurons of SN, but not dopamine D1 receptors. For glutamatergic receptor system, the present study suggests that the changes in glycine receptors may be more susceptible to degeneration of nigrostriatal pathway than NMDA receptors and excitatory amino acid transport sites. Thus, our findings are of interest in relation of degeneration of the nigrostriatal pathway that occurs in Parkinson’s disease
Keywords: Dopamine receptors; Dopamine uptake sites; NMDA receptors; Excitatory amino acid transport sites; Glycine binding sites; Receptor autoradiography; 6-Hydroxydopamine; Nigrostriatal pathway; Rats;

Taurine and ethanol preference: a microdialysis study using Sardinian alcohol-preferring and non-preferring rats by Etienne Quertemont; Frédéric Lallemand; Giancarlo Colombo; Philippe De Witte (377-383).
Recent intracerebral microdialysis studies of different rat brain regions have shown that an acute ethanol injection induced a rapid dose-dependent increase in taurine microdialysate content during the first 60-min period. In taurine-supplemented rats, a reduced aversion for high ethanol doses was observed in a place conditioning paradigm, suggesting that taurine may be implicated in the regulation of some adverse effects of ethanol. The present study compares the effects of acute ethanol injections (1.0 and 2.0 g/kg, i.p.) on taurine nucleus accumbens microdialysate content in Sardinian ethanol-preferring (sP) and Sardinian ethanol-non-preferring (sNP) rats. While neither saline nor 1.0 g/kg ethanol injections had significant effect on taurine microdialysate concentration, 2.0 g/kg ethanol administration induced a rapid and significant increase in taurine microdialysate content in both sP and sNP rats. However, this ethanol-induced taurine release was significantly reduced in sP rats by comparison to sNP rats. As taurine is suggested to be released by brain cells to modulate different ethanol adverse effects, this lower taurine responsiveness to ethanol in sP rats by comparison to both sNP and Wistar rats may be a relevant indicator of reduced ethanol aversive effects in such animals and therefore be related to their higher alcohol consumption.
Keywords: Ethanol; Taurine; Microdialysis; Amino acids; Alcohol-preferring rats; Alcohol-non-preferring rats;

Olanzapine and obsessive–compulsive symptoms by Lefteris Lykouras; Ioannis M. Zervas; Rossetos Gournellis; Meni Malliori; Andreas Rabavilas (385-387).
Clozapine and risperidone have been implicated in the development of obsessive–compulsive symptoms. We present three cases in which olanzapine caused a significant exacerbation of obsessive–compulsive symptoms in schizophrenia (two cases) and obsessive–compulsive disorder (one case).
Keywords: Olanzapine; Obsessive–compulsive symptoms; Schizophrenia; Obsessive–compulsive disorder;

Evidence for the involvement of the hippocampus in the pathophysiology of schizophrenia by Doron Gothelf; Noam Soreni; Ricardo P. Nachman; Sam Tyano; Yehuda Hiss; Orly Reiner; Abraham Weizman (389-395).
The hippocampus, a medial temporal lobe structure, is often considered to play an important role in the pathophysiology of schizophrenia. Recent developments of neuroimaging and molecular postmortem techniques have significantly increased our ability to study the role of discrete brain regions in the pathophysiology of schizophrenia. This article describes animal models, structural, histological, molecular biology, and neuropsychological evidence for the involvement of the hippocampus in the pathophysiology of schizophrenia. The major findings in schizophrenic patients are decreased volumes, hypometabolism, and cytoarchitectural abnormalities which are more robust on the left hippocampus, as well as verbal memory impairment. It is yet to be determined whether these changes are neurodevelopmental or neurodegenerative in nature. Overall, these findings indicate that there are subtle changes in the hippocampus of schizophrenic patients. More comprehensive and focused hippocampal research in schizophrenia is required to elucidate the contribution of this intriguing brain structure to the pathophysiology of schizophrenia.
Keywords: Schizophrenia; Pathophysiology; Hippocampus; Neuroanatomy; Gene expression;

Effect of nicotine on sniffing induced by dopaminergic receptor stimulation by Mohammad-Reza Zarrindast; Gisou Mohaddess; Mozafar Rezvani-Pour (397-400).
Effects of nicotine on sniffing induced by amphetamine and apomorphine have been tested in rats. Intraperitoneal (i.p.) administration of nicotine (0.5 and 1 mg/kg), amphetamine (1–6 mg/kg) or apomorphine (0.1–1 mg/kg) induced sniffing. Nicotine (0.25–1 mg/kg) potentiates sniffing induced by amphetamine (1 mg/kg). Nicotine (1 mg/kg) also potentiates the response induced by different doses (0.1–1 mg/kg) of apomorphine. Atropine induced sniffing and increased the response of both amphetamine and nicotine. Higher doses of hexamethonium decreased the sniffing response induced by amphetamine and the response induced by combination of amphetamine and nicotine. Sulpiride reduced the response induced by nicotine or amphetamine plus nicotine, while SCH23390 reduced normal sniffing behaviour of the animals and sniffing induced by either amphetamine or amphetamine plus nicotine. The data may indicate that nicotinic receptor mechanism(s) may be involved in the sniffing induced by dopaminergic receptor stimulation.
Keywords: Amphetamine; Apomorphine; Nicotine; Sniffing; Rats;

Twenty male Sprague–Dawley rats received five oral doses of clomipramine 20 mg/kg at 4-h intervals. The animals were decapitated 1, 2, 3, 5 and 12 h after the last dose for determination of clomipramine and desmethylclomipramine in serum and frontal cerebral cortex. Time dependent concentrations of clomipramine and desmethylclomipramine paralleled in serum and brain. Half-lives were similar in serum and brain with 7.8 versus 6.2 h and 5.5 versus 5.0 h for clomipramine and desmethylclomipramine, respectively. Absolute concentrations, however, were markedly higher in brain than in serum — 12.5 fold for clomipramine and 7.4 fold for desmethylclomipramine. The data indicate that serum and brain concentrations of clomipramine and its demethylated metabolite are rapidly exchanged between blood and brain. Assuming that blood and brain kinetics in man and rat are comparable, it is concluded that monitoring blood concentrations of clomipramine and desmethylclomipramine is a useful way to evaluate brain concentrations.
Keywords: Clomipramine; Desmethylclomipramine; Steady state; Serum concentration; Brain concentration;

Involvement of dynorphin in immobilization stress-induced antinociception in the mouse by Hong W Suh; Dong K Song; Sung O Huh; Yung H Kim (407-413).
The effect of antiserum against [Met5]-enkephalin, [Leu5]-enkephalin, β-endorphin, or dynorphin A-(1-13) administered intracerebroventricularly (i.c.v.) or intrathecally (i.t.) on immobilization-induced antinociception was studied in ICR mice. Antinociception was assessed by the tail-flick assay. Immobilization of the mouse increased inhibition of the tail-flick response at least 1 h. The i.c.v. or i.t. injection with antiserum against dynorphin A-(1-13) at the dose of 200 μg significantly attenuated immobilization-induced inhibition of the tail-flick response. However, antiserum against [Met5]-enkephalin, [Leu5]-enkephalin, or β-endorphin did not affect the immobilization stress-induced antinociception. Furthermore, i.c.v. or i.t. injection with nor-binaltorphimine (Nor-BNI; from 1 to 20 μg) effectively inhibited immobilization stress-induced inhibition of the tail-flick response in a dose-dependent manner. However, β-FNA (from 0.5 to 2 μg) or naltrindole (from 1 to 20 μg) administered i.c.v. or i.t. did not affect immobilization stress-induced antinociception. Our results suggest that supraspinally and spinally located dynorphin appears to be involved in the production of immobilization stress-induced antinociception via stimulating κ-opioid receptors.
Keywords: Immobilization; Antinociception; Spinal and supraspinal dynorphin; κ-Opioid receptors.;

The effects of single dose of methamphetamine on lipid peroxidation levels in the rat striatum and prefrontal cortex by Osman Açikgöz; Sevil Gönenç; Berkant Muammer Kayatekin; Çetin Pekçetin; Nazan Uysal; Ayfer Dayi; İlgi Şemin; Ataman Güre (415-418).
The administration of methamphetamine to experimental animals results in damage to dopaminergic neurons. In the present study, we demonstrated that a single dose (15 mg/kg) of methamphetamine results in production of oxidative stress as demonstrated by increased thiobarbituric acid reactive substances levels in the rat striatum and prefrontal cortex. In conclusion, the results of present study provide further evidence in support of the notion that oxidative stress may play an important role in the methamphetamine-induced neurotoxicity.
Keywords: Dopamine; Methamphetamine; Oxidative stress; Lipid peroxidation; Striatum; Prefrontal cortex;

Effects of low-dose cholecystokinin on respiratory function in healthy volunteers by K Schruers; N Caycedo; T Overbeek; H Büchold; M Bourin; E Griez (419-421).
Injection of high doses of cholecystokinin tetrapeptide (CCK-4), a recent experimental model for panic, causes panic attacks and respiratory stimulation, a key feature of panic, in healthy volunteers. However, it has not yet been established whether respiratory stimulation is specifically linked to panic or merely an effect of arousal in general. Results of the present study show that respiratory stimulation is not merely linked to higher arousal and suggest a link between CCK-provoked panic and respiratory stimulation.
Keywords: Panic; Cholecystokinin; Respiration;