clozapine and 6-chloro-2-(1-piperazinyl)pyrazine

Dorsal root-evoked stimulation of sensory afferents in the hemisected in vitro rat spinal cord produces reflex output, recorded on the ventral roots. Transient spinal 5-HT(2C) receptor activation induces a long-lasting facilitation of these reflexes (LLFR) by largely unknown mechanisms. Two Sprague-Dawley substrains were used to characterize network properties involved in this serotonin (5-HT) receptor-mediated reflex plasticity. Serotonin more easily produced LLFR in one substrain and a long-lasting depression of reflexes (LLDR) in the other. Interestingly, LLFR and LLDR were bidirectionally interconvertible using 5-HT(2A/2C) and 5-HT(1A) receptor agonists, respectively, regardless of substrain. LLFR was predominantly Abeta afferent fiber mediated, consistent with prominent 5-HT(2C) receptor expression in the Abeta fiber projection territories (deeper spinal laminae). Reflex facilitation involved an unmasking of polysynaptic pathways and an increased receptive field size. LLFR emerged even when reflexes were evoked three to five times/h, indicating an activity independent induction. Both the NMDA and AMPA/kainate receptor-mediated components of the reflex could be facilitated, and facilitation was dependent on 5-HT receptor activation alone, not on coincident reflex activation in the presence of 5-HT. Selective blockade of GABA(A) and/or glycine receptors also did not prevent reflex amplification and so are not required for LLFR. Indeed, a more robust response was seen after blockade of spinal inhibition, indicating that inhibitory processes serve to limit reflex amplification. Overall we demonstrate that the serotonergic system has the capacity to induce long-lasting bidirectional changes in reflex strength in a manner that is nonassociative and independent of evoked activity or activation of ionotropic excitatory and inhibitory receptors.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Amphetamines; Analysis of Variance; Animals; Animals, Newborn; Clozapine; Dose-Response Relationship, Radiation; Drug Interactions; Electric Stimulation; Female; Ganglia, Spinal; Immunohistochemistry; In Vitro Techniques; Male; Pyrazines; Rats; Rats, Sprague-Dawley; Reaction Time; Receptor, Serotonin, 5-HT2C; Receptors, Serotonin, 5-HT2; Reflex; Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Spinal Cord; Time Factors

The ability of atypical and typical antipsychotics to antagonize serotonin (5-HT) receptor-mediated temperature and neuroendocrine responses was tested in rats. Clozapine, melperone and setoperone, three atypical neuroleptics, blocked in a dose-dependent manner, the hyperthermic response to the 5-HT agonist, MK-212, whereas chlorpromazine and haloperidol were ineffective. The hypothermic response to the 5-HT1A agonist, 8-OH-DPAT, was unaltered by any of the atypical neuroleptics tested. Similarly, MK-212-induced corticosterone secretion was blocked in a dose-related manner by clozapine, melperone and setoperone but was relatively unaffected by either haloperidol or chlorpromazine. The increase in corticosterone secretion observed following 8-OH-DPAT administration was not attenuated by pretreatment with the atypical or typical antipsychotics tested. These data indicate that atypical neuroleptics are effective 5-HT2 but not 5-HT1A antagonists in vivo. Conversely, the typical neuroleptics, haloperidol and chlorpromazine do not block the 5-HT receptors involved in activation of the hypothalamic-pituitary-adrenal axis or thermoregulation.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Animals; Antipsychotic Agents; Body Temperature; Butyrophenones; Chlorpromazine; Clozapine; Corticosterone; Haloperidol; Male; Neurosecretory Systems; Pyrazines; Pyrimidinones; Rats; Rats, Inbred Strains; Receptors, Serotonin; Serotonin Antagonists; Tetrahydronaphthalenes