An investigation of the role of 5-hydroxytryptamine in the attenuation of presynaptic alpha 2-adrenoceptor-mediated responses by antidepressant treatments.
Changes in the function of presynaptic alpha 2-adrenoceptors in the brain were assessed by rating the hypoactivity (sedation) response of mice to clonidine (0.1 mg/kg). A single injection of 5,7-dihydroxytryptamine (5,7-DHT, 75 micrograms ICV) or administration of p-chlorophenylalanine (PCPA; 200 mg/kg) daily for 11-15 days produced 62-77% reductions in brain 5-HT concentrations and marked supersensitivity of 5-HT2 receptor function, as indicated by the enhancement of the head-twitch response to 5-methoxy-N,N-dimethyltryptamine (2 mg/kg). Clonidine-induced hypoactivity was moderately enhanced after 5,7-DHT lesioning, but not after repeated PCPA injection. In addition, 5,7-DHT lesioning prevented the adaptive attenuation of this alpha 2-adrenoceptor-mediated response produced by daily injection of desipramine (10 mg/kg) for 14 days, but had no effect on the reduction caused by five electroconvulsive shocks (ECS, 200 V, 2 s) spread over 10 days. In contrast, repeated PCPA treatment did not prevent the reduction of clonidine-induced hypoactivity produced by repeated desipramine or ECS administration. Together, these results indicate that 5-HT (or possibly a cotransmitter contained within 5-hydroxytryptamine neurones) influences presynaptic alpha 2-adrenoceptor function. Furthermore, an intact 5-HT neuronal input is a prerequisite for the attenuation of clonidine-induced hypoactivity by desipramine, but not ECS. The probable explanation for a contrasting requirement for a functional 5-HT input is that desipramine and ECS induce this common adaptive response by different pharmacological mechanisms.
Heal
D J
DJ
Research Department, Boots Company PLC, Nottingham, UK.
Hurst
E M
EM
Prow
M R
MR
Buckett
W R
WR
D015116:5,7-Dihydroxytryptamine / Q000494:pharmacology; D006916:5-Hydroxytryptophan / Q000494:pharmacology*; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D015306:Biogenic Monoamines / Q000378:metabolism; D001923:Brain Chemistry / Q000187:drug effects; D003000:Clonidine / Q000494:pharmacology; D003891:Desipramine / Q000494:pharmacology; D004597:Electroshock; D010134:Fenclonine / Q000494:pharmacology; D008297:Male; D008732:Methoxydimethyltryptamines / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects*
D000928:Antidepressive Agents; D015306:Biogenic Monoamines; D008732:Methoxydimethyltryptamines; D011942:Receptors, Adrenergic, alpha; D015116:5,7-Dihydroxytryptamine; D006916:5-Hydroxytryptophan; D003000:Clonidine; D010134:Fenclonine; D003891:Desipramine