Effects of brief pulse and ultrabrief pulse electroconvulsive stimulation on rodent brain and behaviour in the corticosterone model of depression.

Brief pulse electroconvulsive therapy (BP ECT; pulse width 0.5-1.5 ms) is the most effective treatment available for severe depression. However, its use is associated with side-effects. The stimulus in ultrabrief pulse ECT (UBP ECT; pulse width 0.25-0.3 ms) is more physiological and has been reported to be associated with less cognitive side-effects, but its antidepressant effectiveness is not yet well established. Using electroconvulsive stimulation (ECS), the animal model of ECT, we previously reported UBP ECS to be significantly less effective than well-established BP ECS in eliciting behavioural, molecular and cellular antidepressant-related effects in naïve rats. We have now compared the effects of BP and UBP ECS in an animal model of depression related to exogenous supplementation with the stress-induced glucocorticoid hormone, corticosterone. Corticosterone administration resulted in an increase in immobility time in the forced swim test (FST) (p < 0.01) and decreases in the expression of brain-derived neurotrophic factor (BDNF) (p < 0.05) and glial fibrillary acidic protein (GFAP) (p < 0.001) in the hippocampus and frontal cortex. There was no significant difference in the duration or type of seizure induced by BP (0.5 ms) or UBP (0.3 ms) ECS. UBP ECS proved to be as effective as BP ECS at inducing a behavioural antidepressant response in the FST with a significant decrease (p < 0.001) in immobility seen following administration of ECS. Both forms of ECS also induced significant increases in BDNF protein (p < 0.01) expression in the hippocampus. BP ECS (p < 0.05) but not UBP ECS induced a significant increase in GFAP levels in the hippocampus and frontal cortex. Overall, UBP ECS effectively induced antidepressant-related behavioural and molecular responses in the corticosterone supplementation model, providing the first preclinical data on the potential role of this form of ECS to treat a depression phenotype related to elevated corticosterone.

Dopamine D1 receptor-mediated intracellular responses in the hypothalamus after co-administration of caffeine with MDMA.

Markers of dopamine D(1) receptor activation were determined to elucidate intracellular mechanisms associated with the combined effects of caffeine and 3,4 methylenedioxymethamphetamine (MDMA), reported previously to produce increased toxicity, when compared with either drug alone. Caffeine (10 mg/kg) and MDMA (15 mg/kg) were administered to male Sprague Dawley rats alone and in combination. One hour after drug administration, core body temperature and phosphorylation of the dopamine D(1) -related intracellular markers, cAMP response element binding protein (CREB), the dopamine and c-AMP-regulated phosphoprotein of 32 kDa (DARPP-32) and expression of the immediate early gene and cellular activation marker c-fos were determined in the hypothalamus. Co-administration of caffeine with MDMA increased core body temperature when compared with MDMA or caffeine treatment alone. Pre-treatment with the dopamine D(1) receptor antagonist SCH 23390 (1 mg/kg, i.p.), 30 min. prior to caffeine and MDMA administration, produced a hypothermic response to MDMA that was unaffected by caffeine. Co-administration of caffeine with MDMA increased p-CREB, p-DARPP-32 and c-fos expression when compared with either treatment alone. Pre-treatment with SCH-23390 attenuated the changes in p-CREB, p-DARPP and c-fos. The results show an enhanced intracellular response when caffeine is combined with MDMA but not with either agent alone suggestive of synergistic intracellular actions convergent on a dopamine D(1) receptor signalling pathway. A dopamine-related synergy associated with the combined administration of caffeine and MDMA may have important use and safety implications for recreational drug users.

A role for adenosine A(1) receptor blockade in the ability of caffeine to promote MDMA "Ecstasy"-induced striatal dopamine release.

Co-administration of caffeine profoundly enhances the acute toxicity of 3,4 methylenedioxymethamphetamine (MDMA) in rats. The aim of this study was to determine the ability of caffeine to impact upon MDMA-induced dopamine release in superfused brain tissue slices as a contributing factor to this drug interaction. MDMA (100 and 300µM) induced a dose-dependent increase in dopamine release in striatal and hypothalamic tissue slices preloaded with [(3)H] dopamine (1µM). Caffeine (100µM) also induced dopamine release in the striatum and hypothalamus, albeit to a much lesser extent than MDMA. When striatal tissue slices were superfused with MDMA (30µM) in combination with caffeine (30µM), caffeine enhanced MDMA-induced dopamine release, provoking a greater response than that obtained following either caffeine or MDMA applications alone. The synergistic effects in the striatum were not observed in hypothalamic slices. As adenosine A(1) receptors are, one of the main pharmacological targets of caffeine, which are known to play an important role in the regulation of dopamine release, their role in the modulation of MDMA-induced dopamine release was investigated. 1µM 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), a specific A(1) antagonist, like caffeine, enhanced MDMA-induced dopamine release from striatal slices while 1µM 2,chloro-N(6)-cyclopentyladenosine (CCPA), a selective adenosine A(1) receptor agonist, attenuated this. Treatment with either SCH 58261, a selective A(2A) receptor antagonist, or rolipram, a selective PDE-4 inhibitor, failed to reproduce a caffeine-like effect on MDMA-induced dopamine release. These results suggest that caffeine regulates MDMA-induced dopamine release in striatal tissue slices, via inhibition of adenosine A(1) receptors.

A combined and comparative study of physiologic and behavioral parameters in a systemic toxicity test.

A knowledge of the acute systemic effects of materials that come into contact with body tissues and fluids is necessary to assess their clinical safety. Here we describe the use of bioradiotelemetry to record the heart rate, body temperature, and motor activity of freely behaving rats in conjunction with weight gain, food, and water consumption after administration of the bacterial endotoxin lipopolysaccharide and the heavy metal nickel chloride. The results of our study reveal that body temperature change was the more sensitive index of the two physiological parameters tested. Core body temperature can be monitored diurnally or nocturnally depending on whether a hyper- or hypothermic response, respectively, to the test solution is anticipated. Weight gain was the most sensitive index of all parameters monitored, but its use as an index requires that the test substance be administered nocturnally. Monitoring physiological parameters offers a complementary assessment of a systemic response, but these markers are not superior to conventional indices such as reduced weight gain. The use of two diverse toxic substances in the present study illustrates that test conditions are dictated by the nature of the systemic response induced by the substance tested.