European Neuropsychopharmacology (v.16, #3)

The relevance of neurosteroids to clinical psychiatry: From the laboratory to the bedside by Rael D. Strous; Rachel Maayan; Abraham Weizman (155-169).
Neurosteroids are important neuroactive molecules with suggested central involvement in several neurophysiological and psychiatric disease processes. The discovery of neurosteroids followed the revelation that the brain exhibited the capacity to synthesize its own steroids in situ and thus be a potential site of steroidogenesis. In contrast to some steroids that exhibit traditional genomic steroid actions, most neurosteroids appear to regulate neuronal function by means of “non-genomic” mechanisms influencing neuronal excitability. Neurosteroids are synthesized either from CNS cholesterol or from peripheral steroid precursors and exhibit a wide range of modulatory effects on neurotransmitter receptor activity, most notably at the gamma-aminobutyric acid A (GABAA) receptor. Neurosteroids play an important role in neurodevelopment and neuroprotective effects, many aspects of which may have particular applicability to psychiatric disorders including various gender differences. Neurosteroids appear to be relevant to the pathophysiology and pharmacological treatment of many psychiatric disorders including the most notable mood and anxiety disorders, but also psychotic, childhood, eating, dementia, stress and postpartum disorders. It has been suggested that neurosteroids may become potential targets for pharmacological intervention in the future with further neurosteroid investigation contributing to a more comprehensive understanding of human behavior and psychopathology.
Keywords: Neurosteroid; Neuroactive steroid; GABA receptor;

The present study was conducted to investigate a possible protection of ferulic acid against excitotoxic effects of maternal intragastric (ig) administration of monosodium glutamate (MSG) at a late stage of pregnancy on developing mouse fetal brain. [3H]-labeled glutamate was used as radiotracer to study the effect of ferulic acid on distribution of MSG in mouse fetal brain. MSG dissolved in distilled water (2.0 g/kg body weight, 640 kBq of [3H]glutamate/mouse, ig) or/and sodium ferulate (SF) (20, 40, 80 mg/kg body weight, ip), was given to pregnant mice at 17–19 days; the distribution of [3H] glutamate in the mouse fetal brains was measured at 30, 60, 90, 120 min after administration of MSG or/and SF. Maternal mice were given MSG (1.0, 2.0, 4.0 g/kg body weight, ig) or/and SF (20, 40, 80 mg/kg body weight, ip) simultaneously at 17–19 days of pregnancy, and then behavioral tests and histopathological observations were used to analyze glutamate-induced functional and morphological changes of the brains of their offspring, and Western blot analysis was performed for examining expressions of bcl-2 and caspase-3. The results showed that SF obviously inhibited the uptake of labeled glutamate in fetal brain. In addition, SF countered the effects of MSG on behavior, histopathology, genetic toxicity, and expression of apoptosis-related gene. The results suggest that ferulic acid is a novel competitive N-methyl-d-aspartate (NMDA) receptor antagonist and neuroprotector. In conclusion, maternal administration of ferulic acid has potent protective effects against glutamate-induced neurotoxicity in their filial mice.
Keywords: Kunming mouse; Excitotoxicity; Behavioral disturbance; Histopathological lesion; Genetic toxicity; Apoptosis-related gene; Ferulic acid; NMDA receptor antagonist; Protective effects against neurotoxicity;

The aim of the present study was to investigate the influence of tricyclic antidepressants (TADs: imipramine, amitriptyline, clomipramine, and desipramine), selective serotonin reuptake inhibitors (SSRIs: fluoxetine and sertraline) and novel antidepressant drugs (mirtazapine and nefazodone) on the activity of CYP3A measured as a rate of testosterone 2β- and 6β-hydroxylation. The reaction was studied in control liver microsomes in the presence of the antidepressants, as well as in microsomes of rats treated intraperitoneally (i.p.) for 1 day or 2 weeks with pharmacological doses of the drugs (imipramine, amitriptyline, clomipramine, nefazodone 10 mg kg1 i.p.; desipramine, fluoxetine, sertraline 5 mg kg1 i.p.; mirtazapine 3 mg kg1 i.p.), in the absence of the antidepressants in vitro. The investigated antidepressants added to control liver microsomes produced some inhibitory effects on CYP3A activity, which were very weak (most of TADs, K i  = 145–212 μM), modest (clomipramine and sertraline, K i  = 67.5 and 62 μM, respectively) or moderate (nefazodone and fluoxetine, K i  = 42 and 43 μM, respectively). Mirtazapine did not display this kind of properties. One-day exposure of rats to TADs substantially decreased the activity of CYP3A in liver microsomes, which was maintained during chronic treatment. The observed decreases in the enzyme activity were in contrast to the increased CYP3A protein level found after chronic treatment with TADs. On the other hand, sertraline increased the activity of the enzyme after its prolonged administration and its effect correlated positively with the observed elevation in CYP3A protein level. Fluoxetine, mirtazapine and nefazodone did not change the activity of CYP3A in liver microsomes after their administration to rats. Three different mechanisms of the antidepressants–CYP3A interaction are postulated: 1) a direct inhibition of CYP3A by nefazodone, SSRIs and clomipramine, shown in vitro, with the inhibitory effect of nefazodone being the strongest, but weaker than the effects of this drug on human CYP3A4; 2) in vivo inhibition of CYP3A produced by 1 day and maintained during chronic treatment with TADs, which suggests inactivation of the enzyme by reactive metabolites; 3) in vivo induction by sertraline of CYP3A produced only by chronic treatment with the antidepressant, which suggests its influence on the enzyme regulation.
Keywords: Antidepressants; Rat; CYP3A; Direct effect; One-day treatment; Chronic treatment;

Many reports indicate that the incidence and prevalence of diabetes mellitus is increased in schizophrenic patients and related to antipsychotic treatment. In an exploratory cross-sectional study we assessed the prevalence of type 2 diabetes mellitus in 266 chronic schizophrenic and schizoaffective inpatients and investigated whether the duration of antipsychotic treatment was related to the development of diabetes mellitus.We measured the non-fasting plasma glucose level in 266 inpatients with DSM IV diagnosis of schizophrenia or schizoaffective disorder in 5 different long-stay wards in the Netherlands. Measured variables were: age, sex, ethnicity, BMI, current antipsychotic treatment, duration of illness and duration of antipsychotic treatment.The overall prevalence of type 2 diabetes mellitus was 9%, which is significantly higher than the prevalence of 4.9% in the general population (OR 1.89, CI 1.14–3.13; p  < 0.014). The prevalence was increased in two age cohorts: 30–39 years (3.8% vs. 0.3%, OR = 13.29, CI = 2.17–81.36, p  = < 0.005) and 40–49 years (9.3% vs. 1.5%, OR = 6.74, CI = 2.77–16.38, p  = 0.000). No new cases of diabetes mellitus were detected during the course of the study. The increased prevalence was found to be related to overweight and obesity. The time of exposure to antipsychotic treatment was not significantly correlated with the prevalence of diabetes mellitus when adjusted for age (F  = 0.804, df  = 1, p  = 0.371, respectively, F  = 0.194, df  = 1, p  = 0.660). Both typical and atypical antipsychotics contributed equally to the prevalence of diabetes mellitus.No significant relation between long-term antipsychotic treatment and prevalence of diabetes mellitus was found. The high prevalence of diabetes mellitus in schizophrenic patients warrants screening of these patients already at young age for glucose disturbance.
Keywords: Schizophrenia; Diabetes mellitus type 2; Neuroleptics; Long-term treatment;

Dopaminergic drugs may counteract behavioral and biochemical changes induced by models of brain injury by V. Micale; T. Incognito; A. Ignoto; L. Rampello; M. Spartà; F. Drago (195-203).
The dopaminergic drugs, bromocriptine, cabergoline, dihydroergocryptine, pergolide and ropinirole were injected subcutaneously (s.c.) at the dose of 0.1, 0.5 and 1 mg/kg/day for 7 days into male rats of the Sprague–Dawley strain. The drug pre-treatment reverted amnesia induced in rats by hypobaric hypopxia and tested in active and passive avoidance tasks. A restoration of memory retention, as assessed in a step-through passive avoidance task, was found in animals with a 2-month brain occlusive ischemia and exposed to dopaminergic drugs for 7 days. For behavioral effects in both active and passive avoidance tests in both experimental models, the rank of relative potency was ropirinole > bromocriptine = cabergoline > pergolide > dihydroergocryptine. Spontaneous ambulation of animals with brain occlusive ischemia was increased by the higher doses of drugs. All dopaminergic drugs reduced kainate mortality rate. The rank of relative potency for this effect was ropirinole = bromocriptine = cabergoline > pergolide = dihydroergocryptine. However, no change was found in other seizure parameters (latency to first convulsion and total number of convulsions) after drug treatment. A biochemical analysis of glutathione redox index (glutathione reduced/glutathione oxidized ratio) in discrete brain areas revealed that exposure to dopaminergic drugs increased this parameter in frontal cortex, striatum and hippocampus of animals subject to hypobaric hypoxia and brain occlusive ischemia. For this effect, the relative potency rank was ropirinole > bromocriptine = cabergoline >> pergolide = dihydroergocryptine. These behavioral and biochemical findings suggest that dopaminergic drugs may counteract either behavioral or biochemical changes induced by experimental models of brain injury. This activity was found after protective activity (as found in animals pre-treated with these drugs and exposed to hypobaric hypoxia) or reversal of brain injury (as found in animals treated after 2-month occlusive brain ischemia). Their neuroprotective activity probably involves the reduction/oxidation balance of the glutathione system in the brain.
Keywords: Bromocriptine; Cabergoline; Dihydroergocryptine; Pergolide; Ropirinole; Active and passive avoidance; Hypobaric hypoxia; Brain occlusive ischemia; Kainate-induced convulsions; Glutathione redox index;

Caffeine modulates P50 auditory sensory gating in healthy subjects by Eduardo S. Ghisolfi; Alice Schuch; Ivo M. Strimitzer; Gustavo Luersen; Fabíola F. Martins; Fernanda L.P. Ramos; Jefferson Becker; Diogo R. Lara (204-210).
The P50 suppression paradigm is an index of sensory gating assumed to reflect an inhibitory process. Adenosine is a neuromodulator with mostly inhibitory activity that is released by physiological stimuli and can be blocked by non-selective adenosine receptor antagonists such as theophylline and caffeine. A previous study showed that a single dose of theophylline decreased P50 suppression in healthy volunteers. Here we investigated the effect of caffeine (0, 100, 200 and 400 mg p.o.) on P50 sensory gating in 24 healthy volunteers (15 habitual caffeine high-users and 9 low-users). The 200 and 400 mg doses reduced P50 gating, whereas 100 mg produced a non-significant effect. The effect of caffeine was independent of gender and habitual caffeine intake. High caffeine users also showed baseline differences, with lower S2 amplitudes compared to low-users. These results reinforce the participation of adenosine in the modulation of P50 sensory gating and suggest that caffeine ingestion should be controlled for in the P50 sensory gating paradigm.
Keywords: Sensory; Gating; Evoked potentials; Caffeine; Adenosine; Auditory; Schizophrenia;

Distinct gene expression profiles in adult rat brains after acute MK-801 and cocaine treatments by Markus Storvik; Pekka Tiikkainen; Martijn van Iersel; Garry Wong (211-219).
Uncompetitive N-methyl-d-aspartate (NMDA) receptor antagonists have been suggested to attenuate the self-administration and rewarding effects of psychostimulants. Microarrays containing 14,500 rat cDNAs were hybridized to identify alterations in gene expression levels in rat brain regions elicited by the uncompetitive NMDA receptor antagonist MK-801 (dizocilpine, 1 mg/kg), the dopamine agonist cocaine (20 mg/kg), or combined treatment (MK-801 15 min prior to cocaine) 4 h after injections. Total genes up regulated (Z-ratio > 2) in parietal cortex and nucleus accumbens were 111 and 158, respectively. Total genes down regulated (Z-ratio < 2) in the same tissues were 360 and 166, respectively. These genes fell into multiple molecular function gene ontology (GO) categories, but were highly represented in catalytic activities (44% of all genes), signal transduction (14%), protein (20%), nucleotide (18%), and nucleic acid (15%) binding. In nucleus accumbens, genes up regulated by MK-801 (87 genes) did not overlap those up regulated by cocaine (46 genes). Genes down regulated by MK-801 (33 genes) consisted of 2 overlapping genes with those down regulated by cocaine (89 genes). In parietal cortex, low numbers of overlapping regulated genes were also observed. Combined treatments also indicated low numbers (0–10) of genes commonly regulated when compared with single treatments alone. In situ hybridisation studies indicated significant increases in b-ZIP transcription factors (CREM, ICER, CBP, and c-fos) elicited by MK-801 and decreases in c-fos elicited by cocaine. The results indicate independent gene expression signatures following acute MK-801 and cocaine administration that appears to be largely non-overlapping and context dependent.
Keywords: MK-801; Cocaine; Gene expression; Microarray; Glutamate; Dopamine; Addiction;

α-[11C]Methyl-l-tryptophan trapping in the orbital and ventral medial prefrontal cortex of suicide attempters by Marco Leyton; Vincent Paquette; Paul Gravel; Pedro Rosa-Neto; Francine Weston; Mirko Diksic; Chawki Benkelfat (220-223).
Low serotonin neurotransmission is thought to increase vulnerability to suicidal behavior. To test this hypothesis, we measured brain regional serotonin synthesis, as indexed by PET and α-[11C]methyl-l-tryptophan trapping, in 10 patients who had made a high-lethality suicide attempt and 16 healthy controls. Compared to healthy controls, suicide attempters had reduced normalized α-[11C]methyl-l-tryptophan trapping in orbital and ventromedial prefrontal cortex. α-[11C]Methyl-l-tryptophan trapping in these regions correlated negatively with suicide intent. Low serotonin synthesis in the prefrontal cortex might lower the threshold for suicidal behavior.
Keywords: Suicide; Vulnerability; Serotonin; Impulsivity; Depression;

ECNP consensus meeting March 2003 guidelines for the investigation of efficacy in substance use disorders by W. Van den Brink; S.A. Montgomery; J.M. Van Ree; B.J. van Zwieten-Boot (224-230).