Biosynthesis of dopamine and serotonin in the rat brain after repeated cocaine injections: a microdissection mapping study.
The purpose of the present study was to examine the effects of chronic cocaine on dopamine (DA) and serotonin (5-HT) synthesis in several rat brain regions implicated in drug reinforcement. Male rats were treated twice daily with cocaine (15 mg/kg, ip) or saline for 1 week. After 42 hr of abstinence, rats were challenged with either cocaine (15 mg/kg, ip) or saline, followed by the aromatic L-amino acid decarboxylase inhibitor 3-hydroxybenzylhydrazine (NSD-1015; 100 mg/kg, ip). Animals were decapitated 30 min after NSD-1015 and discrete brain regions were microdisected from 300 microns frozen sections. Postmortem tissue levels of 3,4-dihydroxyphenylalanine (DOPA) and 5-hyroxytryptophan (5-HTP) were quantified by HPLC with electrochemical detection and used to estimate biosynthesis of DA and 5-HT, respectively. In chronic saline-treated rats, cocaine dramatically suppressed DA and 5-HT synthesis in all forebrain regions examined, including: medial prefrontal cortex, nucleus accumbens, caudate nucleus, olfactory tubercle, and basolateral amygdala. The degree of inhibition ranged from 35-65% and was more pronounced in 5-HT neurons compared to DA neurons in the same tissue sample. In general, chronic cocaine did not significantly alter basal levels of DOPA or 5-HTP; a notable exception was lateral hypothalamus, where chronic cocaine reduced basal DA synthesis to 75% of control. After repeated cocaine injections, the synthesis-inhibiting effect of a challenge injection of cocaine was attenuated in many brain areas. These data suggest that whereas acute cocaine decreases DA and 5-HT synthesis in forebrain, chronic cocaine is not neurotoxic to DA and 5-HT neurons. In addition, the mechanism(s) mediating cocaine-induced suppression of monoamine synthesis may become desensitized by chronic exposure to the drug.
Clinical Psychopharmacology Section, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland 21224.
M H
MH
Baumann
T J
TJ
Raley
J S
JS
Partilla
R B
RB
Rothman
D006916:5-Hydroxytryptophan / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D003042:Cocaine / Q000008:administration & dosage* / Q000494:pharmacology; D004295:Dihydroxyphenylalanine / Q000378:metabolism; D004210:Dissection; D004298:Dopamine / Q000096:biosynthesis*; D004563:Electrochemistry / Q000379:methods; D007267:Injections; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000096:biosynthesis*
D012701:Serotonin; D004295:Dihydroxyphenylalanine; D006916:5-Hydroxytryptophan; D003042:Cocaine; D004298:Dopamine