Evidence for alterations in alpha2-adrenergic receptor sensitivity in rats exposed to repeated cocaine administration.
It is well established that cocaine stimulates monoamine transmission by blocking reuptake of norepinephrine (NE), dopamine and serotonin into nerve cells, yet few investigations have addressed the effects of chronic cocaine on NE function. In the present study, we examined the effects of repeated cocaine injections on neuroendocrine responses evoked by the alpha2-adrenergic receptor agonist, clonidine. Previous findings show that clonidine increases pituitary growth hormone (GH) secretion by a central mechanism involving postsynaptic alpha2-adrenergic receptors. Male rats previously fitted with indwelling jugular catheters received two daily injections of cocaine (15 mg/kg, i.p.) or saline for 7 days. At 42 h and 8 days after treatment, rats were challenged with clonidine (25 microg/kg, i.v.) or saline, and serial blood samples were withdrawn. Plasma GH and corticosterone levels were measured by radioimmunoassay. Prior cocaine exposure did not affect basal levels of either hormone. However, cocaine-pretreated rats displayed a significant reduction in clonidine-evoked GH secretion at 42 h, and this blunted response was still apparent 8 days later. Corticosterone responses produced by clonidine were similar regardless of pretreatment. The present data suggest that withdrawal from repeated cocaine injections may be accompanied by desensitization of postsynaptic alpha2-adrenoreceptors coupled to GH secretion. Since human patients with depression often exhibit blunted GH responses to clonidine, our findings provide evidence that cocaine withdrawal might produce depressive-like symptoms via dysregulation of NE mechanisms.
Baumann
M H
MH
Clinical Psychopharmacology Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, PO Box 5180, 5500 Nathan Shock Drive, Baltimore, MD 21224, USA. mbaumann@irp.nida.nih.gov
Milchanowski
A B
AB
Rothman
R B
RB
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D003000:Clonidine / Q000276:immunology / Q000494:pharmacology; D003042:Cocaine / Q000494:pharmacology*; D019970:Cocaine-Related Disorders / Q000378:metabolism* / Q000503:physiopathology; D003345:Corticosterone / Q000097:blood / Q000378:metabolism; D003866:Depressive Disorder / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D004334:Drug Administration Schedule; D013006:Growth Hormone / Q000097:blood / Q000378:metabolism; D008297:Male; D009638:Norepinephrine / Q000378:metabolism*; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects* / Q000378:metabolism; D013375:Substance Withdrawal Syndrome / Q000378:metabolism / Q000503:physiopathology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology
D000316:Adrenergic alpha-Agonists; D018341:Receptors, Adrenergic, alpha-2; D013006:Growth Hormone; D003042:Cocaine; D003000:Clonidine; D003345:Corticosterone; D009638:Norepinephrine