Trulson NE, Jacobs BL.
“Behavioral Evidence for Denervation Supersensitivity After Destruction of Serotoninergic Nerve Terminals”.
Behavioral evidence for denervation supersensitivity after destruction of central serotonergic nerve terminals is reported. A complex behavioral syndrome in the rat, which consists of tremor, rigidity, reciprocal forepaw treading, Straub tail, hindlimb abduction, and lateral head weaving, is a reflection of enhanced activity in central 5HT-mediated synapses and thus provides a potentially useful tool for assessing supersensitivity in the serotonergic system. Male Sprague-Dawley (250-300 g) rats had 25 mg/kg i.p. desmethylimipramine HCI, 1 hr prior to surgery, were anesthetized with 40 mg/kg i.p. sodium pentobarbital, and injected with 5,7-dibydroxytryptamine (5,7-DHT) 50 mcg into the lateral ventricle. Control rats were treated with vehicle only. Behavioral observations were made on animals, and the effect of 5,7-DHT treatment on the efficacy of various agents in inducing the syndrome determined. Effects on brain and spinal-cord noradrenaline, dopamine on 5-HT levels were measured. Of the compounds tested, L-5-hydroxytryptophan (L-5-HTP) produced the greatest degree of supersensitivity in 5,7-DHT-treated rats, with the ED50 decreasing to about 200f that observered in controls. A lesser degree of supersensitivity was observed in response to L-tryptophan (after pargyline pretreatment), 5-methoxy-N,N-dimethyltryptamine (5-MDMT) or LSD, with the ED50 in each case approximately half of the value noted in controls. In contrast to the supersensitivity to the above agents, a marked subsensitivity to fenfluramine was observed after destruction of serotonergic nerve terminals with 5,7-DHT. The ED50 value for 5,7-DHT-treated rats was approximately 2500f the ED50 value in controls. The effects of fenfluramine in 5,7-DHT-injected rats were potentiated by pretreatment with pargyline but still did not produce a supersensitive syndrome. In order to determine whether supersensitivity occurs when 5-HT is depleted without nerve terminal destruction, L-5-HTP, 5-MDMT and LSD were administered to rats that had received chronic p-chlorophenylalanine (p-CPA) methyl ester HCl (400 mg/kg i.p. every 3 days for 24 days) or vehicle. Chronic p-CPA did not induce supersensitivity to L-5-HTP, 5-MDMT or LSD given 1 day after the final p-CPA injection. Chronic 1 or 10 mg/ kg/day methysergide for 14 consecutive days, also produced no evidence for supersensitivity to L-5-HTP. The behavioral response was potentiated by 10 mg/kg i.p. Lilly-110140.