Preliminary evaluation of oral anticonvulsant treatment in the quinpirole model of bipolar disorder.

A potential model for bipolar disorder, quinpirole-induced biphasic locomotion, was used for a preliminary evaluation of behavioral effects of oral anticonvulsant treatment. Quinpirole, a D2/D3 agonist, induces a biphasic locomotor response starting with inhibition and followed by excitation, resembling the oscillating nature of bipolar disorder. The present study developed a paradigm for oral administration of anticonvulsants that resulted in therapeutic blood levels and tested the effects of treatment on the quinpirole-induced response. Eleven days treatment with valproate (12 g/liter water), phenytoin (6 g/kg food), and carbamazepine (8 g/kg food) resulted in therapeutic blood levels and in a borderline significant reduction in quinpirole-induced hyperactivity without effects on the hypoactive phase. Valproate effects became more significant at the height of the hyperactivity response. Eleven days treatment with topiramate (30 mg/kg) resulted in a significant attenuation of quinpirole-induced hyperactivity, qualitatively similar to the effects of the other anticonvulsants. The results suggest that mood-stabilizing anticonvulsant drugs including topiramate may attenuate quinpirole-induced hyperactivity.

Abnormal protein phosphorylation in post-mortem brain tissue from bipolar patients.

Abnormal phosphorylation has been proposed to be involved in the pathogenesis of affective disorders. The present study investigated basal and cAMP-stimulated endogenous protein phosphorylation in human post-mortem brain tissue from bipolar and schizophrenic patients. Furthermore, basal kinase activity and stimulated protein kinase A activity were measured. The frontal and occipital cortex were analysed. Using [gamma-32P]ATP as phosphate donor, basal and cAMP-stimulated phosphorylation of endogenous proteins was measured in the absence or presence of 8-Br-cAMP, respectively. The proteins were separated on SDS-gels and the radioactivity in the individual bands was measured. We observed a significant reduction of 32P incorporation in three protein substrates (15, 16 and 21 kD) in frontal cortex of bipolar patients. However, there were no differences in the PKA activity between any of the groups. The present study demonstrates abnormal phosphorylation of specific proteins in brain tissue obtained from bipolar patients in comparison to schizophrenics and controls.

Inositol levels are decreased in postmortem brain of schizophrenic patients.

BACKGROUND: A previous study reported decreased levels of inositol in frontal cortex of postmortem brain from bipolar patients and suicide victims. The aim of the present study was to test the specificity of this finding. METHODS: Inositol and the enzyme that synthesizes it, inositol monophosphatase, were measured in postmortem brain tissue from frontal and occipital cortex and cerebellum from 10 schizophrenic patients and the previously reported controls. Inositol levels were assayed gas-chromatographically as trimethylsilyl derivatives with mannitol as an internal standard. Inositol monophosphatase activity in brain homogenates was measured as the difference between phosphate release from inositol-l-phosphate in the absence and in the presence of Li+. RESULTS: Inositol was significantly reduced in all three areas in the schizophrenic patient' brains: inositol monophosphatase was unchanged. Postmortem interval did not correlate with inositol levels and did not differ between control group and schizophrenic patients. CONCLUSIONS: These results suggest an abnormality of second messenger precursor availability in common with schizophrenia and affective psychopathology.

Reduced frontal cortex inositol levels in postmortem brain of suicide victims and patients with bipolar disorder.

OBJECTIVE: This study aimed to evaluate aspects of second messenger function in the brain of suicide victims and patients with bipolar disorder. METHOD: Inositol and its synthetic enzyme, inositol monophosphatase, were measured in postmortem brain samples of 10 suicide victims, eight patients with bipolar affective disorder, and 10 normal comparison subjects. RESULTS: The frontal cortex inositol levels of the suicide victims and the patients with bipolar disorder were significantly less than those of the normal comparison group. No differences in cerebellum or occipital cortex inositol levels were found among the three groups. The groups also showed no differences in inositol monophosphatase activity in any brain area. CONCLUSIONS: These results could suggest a deficiency of second messenger precursor in patients with bipolar disorder and suicide victims.

Guanine nucleotide-binding proteins in bipolar affective disorder. Effects of long-term lithium treatment.

BACKGROUND: This study examines recent suggestions from a number of investigators that signal-transducing guanine nucleotide-binding (G) proteins may be involved in the pathophysiology of bipolar affective disorder and may represent molecular targets for lithium's mood-stabilizing actions. METHODS: We used selective antibodies to quantitate the levels of the G protein alpha subunits that regulate adenylate cyclase activity (G alpha s and G alpha i2) and phosphoinositide turnover (G alpha q/11). We also quantitated levels of pertussis toxin-catalyzed phosphate 32-labeled adenosine diphosphate ([32P]ADP) ribosylation in platelet and leukocyte membranes from a group of 14 untreated (predominantly manic) patients with bipolar affective disorder, 20 lithium-treated euthymic patients with bipolar affective disorder, and 11 healthy controls. RESULTS: In both tissues, the immunolabeling of the 45-kd form of G alpha s was higher in the bipolar affective disorder group considered as a whole (treated or untreated) compared with controls, effects that reached statistical significance in the leukocyte membranes. There were no significant differences in the immunolabeling of G alpha i1/2, G alpha q/11, or pertussis toxin-catalyzed [32P]ADP ribosylation in either tissue in the untreated bipolar affective disorder group compared with controls. In both tissues, lithium-treated subjects demonstrated lower levels of G alpha q/11 and higher levels of pertussis toxin-catalyzed [32P]ADP-ribosylation, which reached significance in the platelet membranes. CONCLUSIONS: Our results are complementary to the previously reported findings of elevated G alpha s levels in postmortem brain tissue form patients with bipolar affective disorder and in mononuclear leukocytes obtained from depressed patients with bipolar (but not unipolar) affective disorder. The significantly higher levels of pertussis toxin-catalyzed [32P]ADP ribosylation in the subjects receiving long-term lithium-treatment replicates our findings in rat cortex and in healthy volunteers and adds to the growing body of evidence implicating G alpha i as a target of lithium's actions.

Platelet imipramine binding and serotonin uptake in obsessive-compulsive patients.

Platelet imipramine binding was measured in 16 drug-free nondepressed patients (aged 20-61 years, mean +/- SD 35 +/- 8) suffering from obsessive-compulsive disorder (OCD) and in 16 sex-, race- and age-matched healthy controls. Imipramine binding capacity and affinity were not different in the 2 groups. Platelet serotonin (5-HT) uptake capacity, Vmax, was also measured in 15 of these patients and their matched controls. Vmax was significantly higher in the patients (309 +/- 149 pmol/10(9) cells/min) than in the controls (181 +/- 110). An increase in platelet 5-HT uptake supports the involvement of 5-HT in OCD and may suggest that a hyperactive serotonergic system is present in this disorder.

Inhibition by antibiotic tetracyclines of rat cortical noradrenergic adenylate cyclase and amphetamine-induced hyperactivity.

Two antibiotic tetracyclines, demeclocycline (DMC) and minocycline, share several biochemical and behavioral properties with lithium (Li). DMC inhibited both noradrenaline- and chloradenosine-sensitive cyclic AMP accumulation in rat cerebral cortical slices both in vitro and ex vivo following two weeks of chronic dietary treatment. Minocycline, a lipophilic tetracycline, produced similar results in vitro. Both DMC and minocycline reduced open-field activity levels in rats following acute treatment, four hours prior to testing. Moreover, both drugs inhibited amphetamine-induced hyperactivity in the open field. Chronic treatment with 0.4% and 0.8% dietary DMC for two weeks attenuated amphetamine hyperactivity without affecting baseline activity levels in the open field. Neither DMC nor minocycline attenuated apomorphine-induced stereotypy at doses that attenuated amphetamine hyperactivity, a profile which is similar to that of lithium. Unlike lithium, however, DMC did not reverse reserpine-induced hypoactivity.