1 We examined the involvement of the frontal cortex in the 5-HT 1A receptor-induced inhibition of 5-HT neurones in the dorsal raphe nucleus (DRN) of the anaesthetized rat using single-unit recordings complemented by Fos-immunocytochemistry. 2 Both transection of the frontal cortex as well as ablation of the medial region of the prefrontal cortex (mPFC) signi®cantly attenuated the inhibition of 5-HT neurones induced by systemic administration of the 5-HT 1A receptor agonist, 8-OH-DPAT (0.5 ± 16 mg kg 71 , i.v.). In comparison, the response to 8-OH-DPAT was not altered by ablation of the parietal cortex. The inhibitory e ect of 8-OH-DPAT was reversed by the 5-HT 1A receptor antagonist, WAY 100635 (0.1 mg kg 71 , i.v.) in all neurones tested. 3 In contrast, cortical transection did not alter the sensitivity of 5-HT neurones to iontophoretic application of 8-OH-DPAT into the DRN. Similarly, cortical transection did not alter the sensitivity of 5-HT neurones to systemic administration of the selective 5-HT reuptake inhibitor, paroxetine (0.1 ± 0.8 mg kg 71 , i.v.). 4 8-OH-DPAT evoked excitation of mPFC neurones at doses (0.5 ± 32 mg kg 71 , i.v.) in the range of those which inhibited 5-HT cell ®ring. At higher doses (32 ± 512 mg kg 71 , i.v.) 8-OH-DPAT inhibited mPFC neurones. 8-OH-DPAT (0.1 mg kg 71 , s.c.) also induced Fos expression in the mPFC. The neuronal excitation and inhibition, as well as the Fos expression, were antagonized by WAY 100635. 5 These data add further support to the view that the inhibitory e ect of 5-HT 1A receptor agonists on the ®ring activity of DRN 5-HT neurones involves, in part, activation of a 5-HT 1A receptormediated postsynaptic feedback loop centred on the mPFC.

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Current neurobiological concepts attribute a central role of the hippocampal formation in cognitive and affective processes. Recent studies indicate that the hippocampus is affected in human depression, and antidepressant drugs induce hippocampal adaptive changes that are thought to be associated with their therapeutic action. In the present study, we investigated the action of various antidepressant drugs on the activity of the septo-hippocampal system, its oscillatory activity in particular. The acute effects of the norepinephrine (NE) reuptake inhibitors reboxetine and desipramine, and the selective serotonin reuptake inhibitor fluvoxamine were evaluated. Extracellular single-unit recordings were performed from the medial septum/diagonal band of Broca (MS/DBv), with simultaneous hippocampal EEG recordings of anesthetized rats. Systemic administration of reboxetine synchronized hippocampal EEG, resulting in a significant increase in power at theta frequency, and an increase in frequency and power of gamma-wave activity. Parallel to EEG synchrony, reboxetine induced or enhanced theta oscillation of MS/DBv neurons. Oscillatory frequencies of MS/DBv neurons were identical, and phase locked to the corresponding hippocamapal theta frequencies. Under the same experimental conditions, reboxetine induced a two-fold increase in extracellular NE (but not serotonin) levels in the hippocampus as revealed by microdialysis. Desipramine, but not the serotonin reuptake inhibitor fluvoxamine, evoked responses similar to those of reboxetine regarding septo-hippocampal theta activity. The present findings indicate that even though both NE and serotonin reuptake inhibitors are clinically effective antidepressant drugs, their action on the septo-hippocampal oscillatory behavior is different. It is presumed that selective NE reuptake inhibitors could modulate various cognitive processes associated with hippocampal oscillatory activity.

Atypical antipsychotic treatment has been associated with serious metabolic adverse events, such as glucose dysregulation and development of type 2 diabetes. As part of our studies on possible underlying mechanisms, we investigated the acute effects of various typical and atypical antipsychotics on plasma glucose and insulin in FVB/N mice, a strain that showed a more pronounced hyperglycemic response to clozapine than C57BL/6 and CD-1 mice. Acute administration of high doses of clozapine, olanzapine, quetiapine, perphenazine, or chlorpromazine significantly increased plasma glucose by 100%-140% above basal levels without significant effects on insulin levels. In contrast, risperidone reduced plasma glucose (-30%) and markedly enhanced plasma insulin levels. Doses of ziprasidone that gave 50-fold higher free plasma concentrations than therapeutic plasma levels, as well as high doses of aripiprazole and haloperidol, did not significantly alter either glucose or insulin levels. Clozapine- and olanzapine-induced hyperglycemia occurred at free plasma concentrations that were within, or one order of magnitude above, the range of therapeutic plasma levels. Pretreatment with either the ganglionic blocker hexamethonium, or the alpha(2) adrenergic receptor antagonist yohimbine, blocked the clozapine- and chlorpromazine-induced increase in glucose levels. Taken together, these results suggest that typical and atypical antipsychotics with known metabolic liability produce acute hyperglycemia in mice and that this effect is likely driven by activation of the sympathetic autonomic nervous system via a central mechanism.