title: Chronic cocaine administration increases CNS tyrosine hydroxylase enzyme activity and mRNA levels and tryptophan hydroxylase enzyme activity levels.
abstract: Cocaine is an inhibitor of dopamine and serotonin reuptake by synaptic terminals and has potent reinforcing effects that lead to its abuse. Tyrosine hydroxylase (TH) and tryptophan hydroxylase (TPH) catalyze the rate-limiting steps in dopamine and serotonin biosynthesis, respectively, and are the subject of dynamic regulatory mechanisms that could be sensitive to the actions of cocaine. This study assessed the effects of chronic cocaine on brain TH and TPH activities. Cocaine was administered (0.33 mg/infusion, i.v.) to rats for 7 days every 8 min for 6 h per day. This administration schedule is similar to patterns of self-administration by rats when given ad libitum access to this dose. This chronic, response-independent administration increased TH enzyme activity in the substantia nigra (30%) and ventral tegmental area (43%). Moreover, TH mRNA levels were also increased (45 and 50%, respectively). In contrast to the enzymatic and molecular biological changes in the cell bodies, TH activity was unchanged in the terminal fields (corpus striatum and nucleus accumbens). Similarly, TPH activity was increased by 50% in the raphe nucleus (serotonergic cell bodies). In summary, the chronic response-independent administration of cocaine produces increases in the expression of TH mRNA and activity in both the cell bodies of motor (nigrostriatal) and reinforcement (mesolimbic) dopamine pathways. These increases are not manifested in the terminal fields of these pathways.
authors.affiliation: Department of Physiology and Pharmacology, Bowman Gray School of Medicine, Wake Forest University, Winston-Salem, North Carolina 27157-1083.
authors.forename: S L
authors.initials: SL
authors.lastname: Vrana
authors.forename: K E
authors.initials: KE
authors.lastname: Vrana
authors.forename: T R
authors.initials: TR
authors.lastname: Koves
authors.forename: J E
authors.initials: JE
authors.lastname: Smith
authors.forename: S I
authors.initials: SI
authors.lastname: Dworkin
mesh_terms: D000818:Animals; D015152:Blotting, Northern; D001921:Brain / Q000187:drug effects / Q000201:enzymology*; D003042:Cocaine / Q000008:administration & dosage / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects / Q000201:enzymology; D004298:Dopamine / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D016762:Genes, fos / Q000187:drug effects; D007262:Infusions, Intravenous; D008032:Limbic System / Q000187:drug effects / Q000201:enzymology; D012333:RNA, Messenger / Q000378:metabolism*; D011903:Raphe Nuclei / Q000201:enzymology; D051381:Rats; D011916:Rats, Inbred F344; D019966:Substance-Related Disorders / Q000201:enzymology; D013378:Substantia Nigra / Q000187:drug effects / Q000201:enzymology; D013997:Time Factors; D014158:Transcription, Genetic; D014365:Tryptophan Hydroxylase / Q000378:metabolism*; D014446:Tyrosine 3-Monooxygenase / Q000096:biosynthesis / Q000378:metabolism*
chemical_list: D012333:RNA, Messenger; D014446:Tyrosine 3-Monooxygenase; D014365:Tryptophan Hydroxylase; D003042:Cocaine; D004298:Dopamine