Serotonergic functions in arousal and motor activity.

Changes in motor activity have long been used to characterize the effects of serotonergic manipulations. The prevailing view has been that serotonin typically inhibits motor output, often in reciprocity with catecholaminergic systems. Recent findings, however, indicate that the release of presynaptic serotonin by indirect agonists leads to a profound locomotor activation. Studies were performed in a behavioral pattern monitor (BPM). The BPM is an automated holeboard/activity apparatus measuring 30.5 x 61 cm, that allows detailed sequential analyses of both locomotor and investigatory behaviors. When tested under comparable conditions, direct agonists at both 5-HT1 and 5-HT2 receptors decrease locomotor activity in rats. With hallucinogenic 5-HT2 agonists, this effect is dependent upon the novelty of the test environment, indicating that these compounds increase the responsiveness of the animal to the threatening aspects of the novel environment. Indirect serotonin agonists, however, increase locomotor activity and decrease investigation of discrete stimuli in the environment. The activating effects of indirect agonists such as 3,4-methylenedioxy-methamphetamine (MDMA), para-chloroamphetamine (PCA), or alpha-ethyltryptamine are dependent upon the release of serotonin from presynaptic terminals and are mimicked by direct agonists at 5-HT1B receptors. Both behavioral analyses and studies with synthesis inhibitors and receptor antagonists clearly distinguish the MDMA-induced hyperactivity from that induced by amphetamine-like releasers of dopamine. Further supporting the relevance of 5-HT1B receptors to the activating effects of serotonin-releasing agents, MDMA exhibits reciprocal cross-tolerance with the 5-HT1B agonist RU 24969, but not with either 5-HT1A or 5-HT2 agonists or amphetamine. Thus, studies of locomotor and investigatory responses can be used to demonstrate and differentiate the effects of direct agonists at 5-HT1A, 5-HT1B, and 5-HT2 receptors as well as indirect serotonin agonists. The fact that the predominant effect of serotonin releasers is locomotor activation, apparently mediated via post-synaptic 5-HT1B receptors, suggests that some endogenous serotonergic systems may normally activate rather than suppress motor output.