piperidines and xylamidine

Menopause-associated thermoregulatory dysfunction, including hot flushes and night sweats, is effectively treated by hormonal therapies that include estrogens. Evidence suggests that estrogen regulates serotonin 2A (5-HT(2A)) receptor expression and that 5-HT(2A) receptors are involved in thermoregulation. Therefore, the role of 5-HT(2A) receptors in thermoregulation was assessed in two rat models of ovariectomy-induced thermoregulatory dysfunction. The first model is based on measurement of the tail-skin temperature (TST) increase following naloxone-induced withdrawal in morphine-dependent ovariectomized (OVX) rats (MD model), while the second model relies on telemetric assessment of diurnal TST changes in ovariectomized rats (telemetry model). Treatment with a 5-HT(2A/2C) receptor agonist, (-)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI), prevented the naloxone-induced TST increase in the MD model and restored normal active-phase TST in the telemetry model. The selective 5-HT(2A) receptor antagonist, MDL-100907, had no effect on the naloxone-induced flush when administered alone in the MD model, but it decreased DOI's ability to abate the flush. In the telemetry model, MDL-100907 attenuated the DOI-induced decrease in active-phase TST. Interestingly, MDL-100907 increased TST in both models when given alone, with the TST increase occurring prior to the naloxone-induced flush in the MD model. To evaluate the role of central nervous system (CNS) 5-HT(2A) receptors in TST regulation, DOI was administered in combination with a known peripheral 5-HT(2A/2C) receptor antagonist, xylamidine, in the MD model. Xylamidine had no effect on DOI's ability to abate the naloxone-induced flush. These results indicate that activation of central 5-HT(2A) receptors restores temperature regulation in two rodent models of ovariectomy-induced thermoregulatory dysfunction.

Topics: Amidines; Amphetamines; Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Endocrine System Diseases; Estradiol; Estrogens; Female; Fluorobenzenes; Naloxone; Ovariectomy; Piperidines; Rats; Reaction Time; Receptor, Serotonin, 5-HT2A; Serotonin Antagonists; Serotonin Receptor Agonists; Skin Temperature; Substance Withdrawal Syndrome; Telemetry; Time Factors

d-Fenfluranine has previously been shown to reduce food-rewarded runway behaviour in the rat, an effect thought to be mediated through activation of central 5-HT pathways. We now examined in more detail the mechanism by which d-fenfluramine reduces runway performance and food intake in the 15-trial runway test. The non-selective 5-HT receptor antagonist, metergoline (1.0 mg/kg), significantly antagonised the effect of d-fenfluramine (2.5 mg/kg) in the runway test. In contrast, neither ritanserin, the potent 5-HT2 and 5-HT1C receptor antagonist (0.5 mg/kg), nor the peripheral 5-HT receptor antagonist, xylamidine (3.0 mg/kg), attenuated the effect of d-fenfluramine in this test situation. Metergoline, but not ritanserin or xylamidine significantly increased runway performance when administered alone. These data indicate that d-fenfluramine reduces runway performance and food intake through activation of 5-HT1 receptors. In addition, blockade of 5-HT1 receptors can attenuate the development of satiation normally observed under control conditions in the runway test.

Topics: Amidines; Animals; Feeding Behavior; Fenfluramine; Male; Metergoline; Piperidines; Rats; Receptors, Serotonin; Ritanserin; Satiation; Serotonin Antagonists

The effects of eight serotonin (5-HT) receptor antagonists on the anorectic effect of d-fenfluramine (3.0 mg/kg, IP) were examined in a test of sweet mash consumption, using non-deprived male rats. d-Fenfluramine's effect was attenuated by the mixed 5-HT1/5-HT2 receptor antagonists, methiothepin and metergoline; by the 5-HT2 receptor antagonist ritanserin; and by (+/-)cyanopindolol, a mixed 5-HT1A/5-HT1B receptor antagonist. In contrast, d-fenfluramine's effect was not antagonised by the 5-HT2 receptor antagonists ketanserin and ICI 169 369; the 5-HT3 receptor antagonist ICS 205 930; or by xylamidine, a peripheral 5-HT receptor antagonist. In this feeding model, none of the 5-HT antagonists, when tested alone, had any effect to increase palatable food consumption. The pattern of results obtained strongly suggest that central 5-HT1 receptors play an important role in the mediation of d-fenfluramine-induced anorexia.

Topics: Amidines; Animals; Appetite Depressants; Fenfluramine; Male; Metergoline; Pindolol; Piperidines; Rats; Receptors, Serotonin; Ritanserin; Serotonin Antagonists