European Neuropsychopharmacology (v.13, #3)

Effect of controlled-release melatonin on sleep quality, mood, and quality of life in subjects with seasonal or weather-associated changes in mood and behaviour by Sami Leppämäki; Timo Partonen; Olli Vakkuri; Jouko Lönnqvist; Markku Partinen; Moshe Laudon (137-145).
This study aimed to explore the effects of melatonin on sleep, waking up and well being in subjects with varying degrees of seasonal or weather-associated changes in mood and behaviour. Fifty-eight healthy adults exhibiting subsyndromal seasonal affective disorder (s-SAD) and/or the negative or positive type of weather-associated syndrome (WAS) were randomised to either 2 mg of sustained-release melatonin or placebo tablets 1–2 h before a desired bedtime for 3 weeks. Outcome measures were changes from baseline in sleep quality, sleepiness after waking, atypical depressive symptoms and health-related quality of life by week three. Early morning salivary melatonin concentrations were measured at baseline and treatment cessation in all subjects. Melatonin administration significantly improved the quality of sleep (P=0.03) and vitality (P=0.02) in the subjects with s-SAD, but attenuated the improvement of atypical symptoms and physical parameters of quality of life compared to placebo in the subjects with WAS, positive type.
Keywords: Circadian; Melatonin; Mood; Quality of life; Sleep;

Interaction between angiotensin-converting enzyme and catechol-O-methyltransferase genotypes in schizophrenics with poor response to conventional neuroleptics by Ari Illi; Olli Kampman; Sami Anttila; Markus Roivas; Kari M. Mattila; Terho Lehtimäki; Esa Leinonen (147-151).
Angiotensin-converting enzyme (ACE) modulates dopamine turnover in the brain and catechol-O-methyltransferase (COMT) enzyme is an important agent in the metabolic inactivation of dopamine and norepinephrine. Functional polymorphism in the COMT and ACE genes causes variation in enzyme activities. We investigated the relationship of COMT and ACE gene polymorphism with response to conventional neuroleptic treatment in schizophrenia. In this study population we had earlier detected that COMT genotype is associated with unsatisfactory drug response. A total of 94 schizophrenic patients were evaluated either as responders (n=43) or non-responders (n=51). The responders had experienced a fair and steady response to conventional neuroleptics. The non-responders had failed to achieve an acceptable response to conventional neuroleptics. We also used a control population of 94 age- and gender-matched blood donors. Genotyping of the COMT and ACE genes was performed by polymerase chain reaction. The risk of having both low activity COMT and high activity ACE genotypes was over 10 times higher (odds ratio=10.89, 95%CI 1.14–103.98, P=0.04) in the non-responders compared to responders. ACE genotype alone did not differ between any groups. This finding may suggest a possible interaction with low activity COMT and high activity ACE genotype in association with poor response to conventional neuroleptics.
Keywords: Schizophrenia; COMT; ACE; Drug response; Polymorphism; Genotype;

5-HT1A responsivity in patients with panic disorder before and after treatment with aerobic exercise, clomipramine or placebo by Andreas Broocks; T. Meyer; M. Opitz; U. Bartmann; U. Hillmer-Vogel; A. George; G. Pekrun; D. Wedekind; E. Rüther; B. Bandelow (153-164).
Blunted neuroendocrine and physiological responses to the selective 5-HT1A receptor agonist, ipsapirone, have been observed in patients with panic disorder and/or agoraphobia (PDA). In order to examine whether this hyporesponsiveness to ipsapirone is modified by pharmacological or non-pharmacological therapeutic interventions, challenges with an oral dose of ipsapirone (0.3 mg/kg) and placebo were performed in patients with PDA before and after 10 weeks of treatment with clomipramine, aerobic exercise and placebo. Before treatment, administration of ipsapirone was followed by significant increases of cortisol, anxiety and other psychopathological symptoms in comparison to the placebo challenge. In addition, a significant decrease of body temperature was observed. After the 10-week treatment period, the psychological responses to ipsapirone were significantly reduced in the clomipramine and the exercise group. In contrast, there was a non-significant trend towards higher cortisol responses after clomipramine and exercise treatment. The hypothermic response to ipsapirone was significantly reduced by clomipramine treatment. In conclusion, our results demonstrate that effective treatment of panic disorder has divergent effects on the psychological, neuroendocrine and temperature responses to ipsapirone.
Keywords: Panic disorder; 5-HT1A receptors; Ipsapirone; Aerobic exercise; Clomipramine;

In this study, the antinociceptive effect of imipramine and adenosine agents, and interactions between imipramine with adenosine drugs in mice in the formalin test, have been investigated. Intraperitoneal administration of different doses of imipramine (10, 20, 30 and 40 mg/kg) induced a dose dependent antinociception in mice, in both the first and second phases of the formalin test. The adenosine A1 receptor agonists, R-(N 6-phenylisopropyl)-adenosine (0.015, 0.03 and 0.1 mg/kg) and 5′-N-ethylcarboxamide adenosine (0.001, 0.005, 0.01 mg/kg), but not 2-chloroadenosine (0.1 and 0.5 mg/kg), and the adenosine receptor antagonist, 8-phenyltheophylline (0.1, 0.5 and 1 mg/kg), but not 1,3-dipropyl-7-methyl-xanthine (0.5 and 5 mg/kg), also produced an antinociceptive response. Lower dose of the adenosine receptor antagonist theophylline induced antinociception, while a higher dose of the drug caused hyperalgesia. Theophylline reduced the response induced by imipramine. It is concluded that adenosine systems are not involved in imipramine responses in the formalin test.
Keywords: Imipramine; Adenosine drugs; Formalin test; Mouse;

We used unbiased stereological principles to determine whether long-term administration of lithium at human therapeutic levels, with or without haloperidol, affects the number or sizes of cerebellar Purkinje cells or the volume of histological layers in the rat cerebellum. Twenty-eight rats were randomly divided into three groups, receiving either no treatment, lithium, or lithium combined with haloperidol. The serum lithium levels ranged from 0.50 to 0.77 mmol/l. Haloperidol was given at a daily dose of 1 mg/kg. After 30 weeks of treatment, the animals were killed and the cerebelli were histologically prepared. No statistically significant differences were observed between the groups with respect to the cerebellar measures.
Keywords: Lithium; Haloperidol; Rats; Neurotoxicity; Cerebellum; Stereology;

The present study investigated potential anti-cataleptic properties of the prototype atypical antipsychotic clozapine and two newly developed atypical antipsychotics, olanzapine and quetiapine, which are structurally related and display similar pharmacological profiles to clozapine. Clozapine (2.5 mg kg−1, s.c.), but not olanzapine (2.0 mg kg−1, s.c.) and quetiapine (20.0 mg kg−1, s.c.), blocked catalepsy induced either by the dopamine D1/5 receptor antagonist SCH 23390 (50.0 μg kg−1, s.c) or the selective dopamine D2/3 receptor antagonist raclopride (4.0 mg kg−1, s.c.). Such findings are consistent with the beneficial effects of clozapine in the management of drug-induced psychosis in parkinsonian patients, and suggest that neither olanzapine nor quetiapine may be a safe alternative to clozapine in this field. Furthermore, the results indicate that clozapine has a unique pharmacological profile that distinguishes it from olanzapine and quetiapine. The mechanisms underlying anti-cataleptic or anti-parkinsonian properties of clozapine are unclear but may be related to dopamine D1 receptor agonism of clozapine.
Keywords: Atypical antipsychotics; Clozapine; Olanzapine; Quetiapine; Catalepsy; Parkinson’s disease;

DRD4 exon III polymorphism and response to risperidone in Israeli adolescents with schizophrenia: a pilot pharmacogenetic study by Gil Zalsman; Amos Frisch; Shaul Lev-Ran; Andrés Martin; Elena Michaelovsky; Daniela Bensason; Doron Gothelf; Eitan Nahshoni; Samuel Tyano; Abraham Weizman (183-185).
This study examined the possible association between the polymorphism in the dopamine receptor DRD4 gene and response to risperidone among 24 Israeli Jewish adolescent inpatients with first-episode schizophrenia. Response was categorically determined by a change of >40% on the Brief Psychiatric Rating Scale (BPRS). No significant association was found between the DRD4 genotype and clinical response, although carriers of <7 repeat alleles demonstrated higher response rate (10/20 vs. 0/4, P=0.11). Studies in larger groups of adolescent schizophrenia patients are warranted to clarify the possible association between DRD4 exon III repeat alleles and the response to risperidone.
Keywords: Pharmacogenetics; Risperidone; Polymorphism; Dopamine; Adolescence;

Prepulse inhibition of the acoustic startle response is a behavioural tool applied to assess sensorimotor gating processes in humans and rats. Schizophrenic patients show deficits in prepulse inhibition of the acoustic startle response. The animal model of neurodevelopmental disorders such as schizophrenia, as purported in earlier reports and the present study, is based on the assumption that damage to brain structures early in life (on day 7) disrupts brain maturation of structures connected to the damaged areas, measurable by behavioural changes, whereas similar damage later in life (on day 21) does not result in these behavioural changes. Locomotor activity, the acoustic startle response and its prepulse inhibition were investigated in adult rats lesioned in the amygdala or ventral hippocampus on day 7 or 21 of life. The acoustic startle response was increased in animals lesioned in the amygdala on day 7 or 21 of life, but not in animals lesioned in the ventral hippocampus. Prepulse inhibition was impaired and locomotor activity enhanced in animals lesioned in the amygdala or ventral hippocampus on day 7, but not in animals lesioned in these structures on day 21 of life. The results on the acoustic startle response are suggestive of amygdaloid influences on modulation of the acoustic startle response. The effects of early postnatal lesions on prepulse inhibition and locomotor activity are in support of the animal model of neurodevelopmental disorders like schizophrenia.
Keywords: Amygdala; Hippocampus; Prepulse inhibition; Startle; Animal model; Schizophrenia;

This article has been retracted at the request of the editor.Reason: This article has been retracted at the request of the editor owing to erroneous duplicate publication of the article: Chronic lithium and sodium valproate both decrease the concentration of myoinositol and increase the concentration of inositol monophosphates in rat brain. O'Donnell T, Rotzinger S, Nakashima TT, Hanstock CC, Ulrich M, Silverstone PH. Brain Research 2000; 880(1–2): 84–91.

Effects of 8-OH-DPAT on open field performance of young and aged rats prenatally exposed to diazepam: a tool to reveal 5-HT1A receptor function by C Cannizzaro; M Martire; E Cannizzaro; R Monastero; M Gagliano; A Mineo; G Provenzano (209-217).
Central GABAergic and serotoninergic systems interact with one another and are implicated in controlling different behaviours. A gentle early long-lasting handling can prevent the deficits in locomotion and exploration in open field (O.F.) in 3-month-old male rats prenatally exposed to diazepam (DZ). Purpose of this study was to extend the research to older handled rats prenatally exposed to DZ and to assess the activity of 5-HT1A receptors (Rs), evaluating the performance in O.F. at 3 and 18 months of age following 8-OH-DPAT administration. A single daily s.c. injection of DZ (1.5 mg/kg) from gestation day 14 to gestation day 20 induced in aged, but not in young rats, a decrease in total distance travelled (TDT) and in rearing frequency (RF) and an increase of transitions from the periphery to the centre of the arena (CNT) and in the time spent in the centre of the arena (CAT), compared to controls. 8-OH-DPAT (0.150 mg/kg s.c.), given 1 h before testing, increased TDT and decreased RF, CNT and CAT in both vehicle- and DZ-exposed young rats. In aged rats prenatally exposed to DZ, 8-OH-DPAT induced an increase in TDT and a slight decrease in RF, CNT and CAT. These findings indicate that the effects of handling and of 8-OH-DPAT in prenatally DZ-exposed rats are age-dependent and suggest that O.F. test can represent a valid tool to identify the changes in 5-HT1A Rs activity following drug treatment.
Keywords: Rats; Prenatal diazepam; Long-lasting handling; Aging; 8-OH-DPAT; Open field test;