Mechanisms of amitriptyline induced hypothermia in the rat

Effects of amitriptyline on rectal temperature of male rats were studied at the ambient temperature of 25 degrees C. Drugs were administered intraperitoneally. Amitryptyline elicited a dose related hypothermia. The hypothermia was attenuated by phenoxybenzamine 10 mg/kg, haloperidol 2 mg/kg, diphenhydramine 5 mg/kg, atropine 20 mg/kg, and cyproheptadine 5 mg/kg. Propranolol, at a dose of 5 mg/kg, had no effect on the hypothermia. Theophylline 50 mg/kg and dibutyryl cyclic AMP 20 mg/kg inhibited the hypothermia produced by anitriptyline. Pretreatment with parachloroamphetamine (PCA), 2 or 5 mg/kg daily for 3 days, strongly antagonized the hypothermia. In addition, pretreatment with parachlorophenylalanine (PCPA), 100 mg/kg daily for three days, reduced the brain 5-hydroxytryptamine (5-HT) concentration to 20% of the control level and completely blocked the hypothermia response. When brain 5-HT concentration recovered to 50% of the control level in PCPA treated rats following the administration of 10 mg/kg 5-hydroxytryptophan (5-HTP) the hypothermia induced by amitriptyline was restored. However, the administration of 5-HT, 5 mg/kg, to PCPA treated rats did not increase brain 5-HT concentration or restore the amitriptyline induced hypothermia (AIH). Results suggest that amitriptyline interacts with several transmitter substances to produce hypothermia. Since the ability of amitriptyline to produce hypothermia was correlated with brain 5-HT content, 5-HT might play an important role in the mediation of AIH.