European Neuropsychopharmacology (v.14, #5)

Dr. Paul Janssen (1926–2003) by P.J. Lewi (353).

Time-dependent changes in alcohol-seeking behaviour during abstinence by Przemyslaw Bienkowski; Artur Rogowski; Agnieszka Korkosz; Pawel Mierzejewski; Katarzyna Radwanska; Leszek Kaczmarek; Anna Bogucka-Bonikowska; Wojciech Kostowski (355-360).
Exposure of alcohol addicts to alcohol-related environmental cues may elicit alcohol-seeking behaviour even after protracted abstinence. The purpose of the present study was to assess time-dependent changes in alcohol-seeking behaviour in rats trained to respond for alcohol. The rats were re-exposed to alcohol-associated stimuli after 1, 28 or 56 days of withdrawal. During the re-exposure session, the rats were first allowed to respond in extinction. Then, reinstatement of alcohol-seeking behaviour was evoked by a complex of discrete alcohol-associated cues (auditory and light cues combined with taste and smell of alcohol). Extinction behaviour depended on abstinence duration with maximal responding after 28-day abstinence. Reinstatement of alcohol-seeking behaviour evoked by the discrete cues was highest after 56-day abstinence. No correlations were found between individual alcohol intakes, extinction behaviour and cue-induced reinstatement. These results suggest that: (i) alcohol-seeking behaviour may become more intense after long-term imposed abstinence; (ii) alcohol self-administration, extinction behaviour, and reinstatement of alcohol-seeking behaviour may be regulated by separate neural mechanisms.
Keywords: Operant alcohol self-administration; Extinction; Cue-induced reinstatement; Abstinence; Rat;

Norharman and alcohol-dependency in male Wistar rats by Durk Fekkes; Bert F. Bernard; Susanne L.T. Cappendijk (361-366).
We examined the effects of ethanol ingestion to rats on levels of the β-carboline norharman in plasma, brain and liver at the end of ethanol ingestion and 10 h after withdrawal. We also investigated the effect of exogenously administered norharman on the behavioural signs of alcohol withdrawal. Ethanol was given by a liquid diet for 21 days. Norharman plasma levels in alcohol fed rats were significantly elevated compared to both control rats and to rats 10 h after withdrawal. Norharman levels in brains and livers showed a similar pattern. The capacity of the livers of both alcohol-dependent and withdrawal rats to catabolise norharman was significantly reduced compared to control rats. Norharman injected intraperitoneally (6.3 mg/kg) attenuated the behavioural signs of alcohol withdrawal significantly. The mechanism behind the increased norharman levels in alcohol-dependent rats may be inhibition of the synthesis and/or activity of liver enzyme(s) responsible for the breakdown of norharman.
Keywords: Alcohol; Rats; Norharman; Withdrawal;

Using sleep to evaluate comparative serotonergic effects of paroxetine and citalopram by S.J. Wilson; J.E. Bailey; A.S. Rich; M. Adrover; J. Potokar; D.J. Nutt (367-372).
Background: SSRIs suppress rapid eye movement (REM) sleep, probably by increasing serotonin in the brainstem, and also increase sleep fragmentation. Although in the UK, paroxetine (PAR) and citalopram (CIT) have recommended doses of 20 mg/day for the treatment of depression, the recommended dose of CIT in USA is higher (40 mg). If similar doses of PAR and CIT have similar effects on central serotonin then they should have similar effects on sleep measures in volunteers. Method: This was a randomised, double blind placebo controlled crossover study in 12 healthy volunteers. Subjects took PAR 20 mg mane, CIT 20 mg mane or placebo mane for 3 days and sleep was recorded overnight at home on the third night. Standard measures of sleep were derived. Results: REM sleep was significantly suppressed and sleep fragmentation increased by both drugs. Measures of REM sleep and sleep continuity previously found to be altered by SSRIs were considered together and compared with placebo as a ‘serotonin response’; this was significantly greater in the PAR group. Conclusions: Sleep effects typical of SSRIs were greater with PAR 20 mg/day than CIT 20 mg/day, suggesting greater effects on 5HT uptake blockade.
Keywords: SSRI; Paroxetine; Citalopram; REM sleep;

Prepulse inhibition in fawn-hooded rats: increased sensitivity to 5-HT1A receptor stimulation by Sally Martin; Andrew J. Lawrence; Maarten van den Buuse (373-379).
Prepulse inhibition of startle is a model of sensorimotor gating, which is disrupted in alcoholism, as well as mental illnesses such as schizophrenia. The fawn-hooded (FH) rat strain has been used as an animal model of alcoholism. FH rats showed significantly lower startle amplitude than Wistar–Kyoto (WKY) rats and Sprague–Dawley (SD) rats. Increasing doses of the 5-HT1A receptor agonist 8-OH-DPAT caused disruption of PPI, with the effect being significantly greater in FH rats compared to WKY rats. In all strains, treatment with 0.5 mg/kg of 8-OH-DPAT significantly reduced PPI. In contrast, 0.1 mg/kg of 8-OH-DPAT caused disruption only in the FH strain. Treatment with amphetamine, apomorphine and MK-801 also significantly reduced PPI, however, there was no difference between the strains. This study shows increased sensitivity of FH rats to the disruption of PPI caused by 5-HT1A receptor stimulation, suggesting a link between 5-HT1A receptors, sensorimotor gating and aspects of the FH rat phenotype.
Keywords: Alcoholism; Prepulse inhibition; Serotonin; Fawn-hooded rat; Startle;

Dieting and weight loss do not affect on the platelet serotonin 5-HT2A receptor by Ingegerd Rahm; Olav Spigset; Tom Mjörndal (381-383).
Alterations related to the serotonin 5-HT2A receptor have been reported in various psychiatric disorders, and the 5-HT2A receptor is also one of the receptors mediating the effects of serotonin on feeding and satiety. The present study was carried out in order to investigate the association between the serotonin 5-HT2A receptor and weight loss during dieting in overweight subjects. In nine women studied before, during and after a 6-month period of dieting, body weight loss was not found to affect the platelet 5-HT2A receptor status. This finding implies that although body weight decrease is a common feature in many psychiatric disorders, the reported alterations in serotonin 5-HT2A receptor status in these disorders do not seem to be caused by the weight loss per se.
Keywords: Dieting; Obesity; Platelets; Serotonin; Serotonin receptors; Weight loss;

Antipsychotic drug-induced side effects of weight gain and sexual dysfunction have clinical significance adversely affecting both compliance and morbidity. This study evaluated the effects of haloperidol and the atypical antipsychotic risperidone (0.1–1.0 mg/kg) on weight gain, food and water intake, the oestrous cycle and uterine weight in female hooded Lister rats. Haloperidol and risperidone treated rats displayed marked weight gain, although only risperidone induced significant increases in food consumption over the 21-day period. Neither haloperidol nor risperidone influenced water consumption. Marked disruption of the oestrous cycle was observed in risperidone- and haloperidol-treated animals (0.5 and 1.0 mg/kg), which was supported by significantly reduced uterine weights. The findings presented here suggest that the weight gain and sexual dysfunction induced by antipsychotics may be modelled in rodents. This model may offer insight into the mechanisms involved in mediation of such side effects.
Keywords: Antipsychotics; Haloperidol; Risperidone; Weight gain; Sexual dysfunction; Side effects;

Stress and hippocampal abnormalities in psychiatric disorders by M. Sala; J. Perez; P. Soloff; S. Ucelli di Nemi; E. Caverzasi; J.C. Soares; P. Brambilla (393-405).
The hippocampus plays a main role in regulating stress response in humans, but is itself highly sensitive to neurotoxic effects of repeated stressful episodes. Hippocampal atrophy related to experimental stress has been reported in laboratory studies in animals. Several controlled brain imaging studies have also shown hippocampal abnormalities in psychiatric disorders, including posttraumatic stress disorder (PTSD), major depressive disorder (MDD), and borderline personality disorder (BPD). This paper reviews the physiological role of the hippocampus in stress circuitry and the effects of stress on cognitive functions mediated by the hippocampus. We also review brain imaging studies investigating hippocampus in PTSD, MDD, and BPD. This literature suggests that individuals with PTSD, MDD, and BPD may suffer hippocampal atrophy as a result of stressors associated with these disorders. Prospective, longitudinal studies will be needed in high-risk offspring and first-episode subjects to explore the relationship between stress and hippocampal atrophy in these neuropsychiatric illnesses.
Keywords: Posttraumatic stress disorder; Borderline personality disorder; Depression; MRI; MRS; PET;

7-Acetyl-5-(4-aminophenyl)-8,9-dihydro-8-methyl-7H-1,3-dioxolo-4,5H-2,3-benzodiazepine hydrochloride (LY 300164; a selective noncompetitive AMPA/kainate antagonist; 2 mg/kg) and N 6-2-(4-aminophenyl)ethyl-adenosine (APNEA; a nonselective adenosine A1/A3 receptor agonist; 2 and 3 mg/kg) significantly raised the threshold for electroconvulsions in mice. In contrast, 5′-N-ethylcarboxamidoadenosine (NECA; a nonselective adenosine A1/A2 receptor agonist; up to 1 mg/kg) did not affect the electroconvulsive threshold. The combined treatment of LY 300164 with NECA or APNEA was superior to single-drug medication as regards their protective action in this seizure model. Moreover, the combinations of LY 300164 with either NECA or APNEA were devoid of motor impairment, although they produced a significant long-term memory deficit. Measurement of the plasma levels of LY 300164 alone and in combination with APNEA or NECA did not suggest pharmacokinetic phenomena as an explanation for the interaction between these drugs. APNEA did not influence the plasma concentration of LY 300164. Moreover, NECA even significantly decreased the plasma levels of the AMPA/kainate antagonist.The present study clearly indicates a strong positive interaction in terms of anticonvulsant activity between LY 300164 and the drugs acting via adenosine receptors.
Keywords: LY 300164; NECA; APNEA; Electroconvulsive threshold; Seizures;

Behavioural effects of rapid intravenous administration of meta-chlorophenylpiperazine in patients with panic disorder and controls by Nic J.A. van der Wee; Jasha Fiselier; Harold J.G.M. van Megen; Herman G.M. Westenberg (413-417).
Oral and intravenous challenge paradigms with the direct 5-HT agonist meta-chlorophenylpiperazine (m-CPP) in panic disorder (PD) have shown only moderate sensitivity or selectivity of the panicogenic effects in PD. However, the results of a study examining the effects of rapid intravenous administration of 0.1 mg/kg of m-CPP in healthy volunteers suggested that this approach may be a more selective and sensitive panicogenic paradigm in PD. We therefore compared the behavioural, neuroendocrine and physiological effects of rapid intravenous administration of 0.1 mg/kg of m-CPP in 10 patients with PD and 10 healthy controls. Panic attacks were significantly more provoked in patients with PD (90%) compared to healthy controls (0%). Effects on the behavioural, but not on the neuroendocrine and physiological parameters, were significantly greater in patients. Our data suggests that the behavioural effects of rapid intravenous administration of 0.1 mg/kg of m-CPP in patients with PD indeed show a unique combination of high sensitivity and selectivity.
Keywords: Panic disorder; 5-HT receptor agonists; 5-HT; Panic attacks; m-CPP;

Intracerebroventricular injection of trazodone produces 5-HT receptor subtype mediated anti-nociception at the supraspinal and spinal levels by Rihui Zhang; Tomonari Nagata; Takayuki Hayashi; Mariko Miyata; Yoriko Kawakami (419-424).
Serotonin (5-HT) mediated anti-nociceptive effects induced by an anti-depressant, trazodone, are related to 5-HT1A receptor activities at the supraspinal level. 5-HT3 receptor activation via the descending anti-nociceptive pathways may contribute to the trazodone mediated anti-nociception at the spinal level. Intracerebroventricular (i.c.v.) injection of trazodone dose-dependently impaired nociceptive responses in the formalin test in mice. Six and 15 μg of trazodone inhibited the early (P<0.05 or 0.01) and the late phases of the formalin test (P<0.05 or 0.01), while 3 μg had no effect. We examined the effects of a selective 5-HT1A receptor antagonist, WAY-100635, a single injection of which induced hyperalgesia (P<0.05), and blocked the anti-nociceptive effects of trazodone (P<0.01) when the two were simultaneously injected i.c.v. Intrathecal (i.t.) injection of a selective 5-HT3 receptor antagonist, 3-tropanylindole-3-carboxylate hydrochloride, blocked the anti-nociceptive effects of i.c.v. trazodone (P<0.01), while WAY-100635 (i.t.) did not impair trazodone mediated anti-nociception. Trazodone mediated anti-nocicepton is related to serotonergic activity at both the supraspinal and the spinal level.
Keywords: Pain; WAY-100635; Trazodone; Formalin test; 5-HT1A receptor; 5-HT3 receptor;

ECNP Consensus Meeting, March 2003. Guidelines for the investigation of efficacy in social anxiety disorder by S.A. Montgomery; Y. Lecrubier; D.S. Baldwin; S. Kasper; M. Lader; R. Nil; D. Stein; J.M. van Ree (425-433).
Keywords: ECNP consensus; Meeting; Social anxiety disorder;

Corrigendum to “Gender in obsessive-compulsive disorder: clinical and genetic findings” [Eur. Neuropsychopharmacol. 14 (2) (2004) 105–113] by Christine Lochner; Sian M.J. Hemmings; Craig J. Kinnear; Johanna C. Moolman-Smook; Valerie A. Corfield; James A. Knowles; Dana J.H. Niehaus; Dan J. Stein (435).

Corrigendum to “Gender in obsessive–compulsive disorder: clinical and genetic findings” [Eur. Neuropsychopharmacol. 14/2 (2004) 105–113] by Christine Lochner; Sian M.J. Hemmings; Craig J. Kinnear; Johanna C. Moolman-Smook; Valerie A. Corfield; James A. Knowles; Dana J.H. Niehaus; Dan J. Stein (437-445).
Background: There is increasing recognition that obsessive–compulsive disorder (OCD) is not a homogeneous entity. It has been suggested that gender may contribute to the clinical and biological heterogeneity of OCD. Methods: Two hundred and twenty patients (n=220; 107 male, 113 female) with DSM-IV OCD (age: 36.40±13.46) underwent structured interviews. A subset of Caucasian subjects (n=178), including subjects from the genetically homogeneous Afrikaner population (n=81), and of matched control subjects (n=161), was genotyped for polymorphisms in genes involved in monoamine function. Clinical and genetic data were statistically analyzed across gender. Results: Compared with females, males with OCD (1) had an earlier age of onset, and a trend toward having more tics and worse outcome, (2) had somewhat differing patterns of OCD symptomatology and axis I comorbidity, and (3) in the Caucasian group, were more likely to have the high activity T allele of the EcoRV variant of the monoamine oxidase A (MAO-A) gene compared to controls, and (4) in the Afrikaner subgroup, were more frequently homozygous for the G allele at the G861C variant of the 5HT 1Dβ gene than controls. Females with OCD (1) reported more sexual abuse during childhood than males, (2) often noted changes in obsessive–compulsive symptoms in the premenstrual/menstrual period as well as during/shortly after pregnancy, and with menopause, and (3) in the Caucasian subgroup, were more frequently homozygous for the low activity C allele of the EcoRV variant of the MAO-A gene compared to controls, with this allele also more frequent in female patients than controls. Conclusion: This study supports the hypothesis that gender contributes to the clinical and biological heterogeneity of OCD. A sexually dimorphic pattern of genetic susceptibility to OCD may be present. Further work is, however, needed to delineate the mechanisms that are responsible for mediating the effects of gender.
Keywords: Obsessive–compulsive disorder; Gender; Phenomenology; Genetics;