Cerebral metabolic effects of serotonin drugs and neurotoxins.

The functional effects of serotonin (5-HT) drugs and toxins on regional cerebral metabolic rates for glucose (rCMRglc) have been determined in rats with the in vivo, quantitative, autoradiographic [14C]2-deoxyglucose technique. Serotonin agents produced rCMRglc patterns different and more specific that one would predict from binding studies. At low doses 5-HT1 agonists reduced rCMRglc in limbic areas and at high doses increased rCMRglc in brain motor regions. The 5-HT2 agonists dose-dependently decreased rCMRglc in proencephalic areas and increased it in thalamic nuclei. 5-HT3 receptor antagonism resulted in rCMRglc decreases in limbic, auditory and visual areas and agents with 5-HT3 receptor activity increased rCMRglc in brain regions with high 5-HT3 receptor densities. Serotonin anxiolytics (e.g. azapirones) and antidepressants (e.g. tryciclic and non-tryciclic 5-HT reuptake inhibitors) reduced rCMRglc selectively in limbic areas and in brainstem monoaminergic nuclei. Dose, time from administration, receptor affinity, behavioral and neurochemical correlates, 5-HT system lesion and circulating glucocorticoid were all relevant factors in determining the rCMRglc effects of 5-HT drugs. Acutely neurotoxic amphetamines markedly increased rCMRglc in brain regions such as the nucleus accumbens that are thought to mediate amphetamine reinforcing properties; on the long term, toxic or electrolytic lesions or chronic treatment with 5-HT agonists produced minimal rCMRglc alterations in spite of marked and persistent changes in 5-HT function. In lesioned or chronically treated rats, acute challanges with 5-HT and non 5-HT agonists demonstrated specific deficits that were not detected in a resting state. Serotonin neuromodulation has been studied in humans by using positron emission tomography with 15O-water. Sequential measurements of regional cerebral blood flow (rCBF) were obtained during combined pharmacological challange with the 5-HT1A agonist buspirone and cognitive activation. Buspirone increased a memory related rCBF activation in task specific regions. This technique can provide a strong theoretical basis for the understanding of 5-HT drug mode of action in normal human brain and in neuropsychiatric diseases. Brain metabolism studies in animals will still be needed to elucidate the factors (e.g. pharmacokinetic and pharmacodynamic) relevant to the cerebral response to 5-HT drugs in humans.