Sensitization to the behavioural effects of cocaine: alterations in tyrosine hydroxylase or endogenous opioid mRNAs are not necessarily involved.
After repeated administration of cocaine at intervals, sensitization phenomena can be observed, so that its behavioural effects are enhanced. Since this phenomenon is long-lasting, it was of interest to study which persistent alterations in the activity of dopaminergic neurones or of endogenous opioid systems downstream of dopaminergic synapses in the basal ganglia are involved in the sensitization. Cocaine (10 mg/kg i.p.) was administered to rats on days 1, 3, 5 and 7 and saline on days 2, 4 and 6 ("repeated cocaine"), or saline was injected on days 1-6 and cocaine on day 7 ("acute cocaine"), or saline was injected on days 1-7 ("saline group"). The "repeated cocaine" schedule led to a significant sensitization to the locomotor activation produced by cocaine on day 7 or on day 17, 10 days after the end of sensitization protocol. Microdialysis in the nucleus accumbens which was performed after administration of cocaine (10 mg/kg i.p.) on day 7, or after an administration of the same dose 10 days after the last administration of cocaine, respectively, revealed significant acute increases of extracellular dopamine to about 200% of basal values. These increases were similar in "acute cocaine" and in "repeated cocaine" animals both after 7 days and after 17 days. For in situ hybridization studies, rats were sacrificed on day 7, 4.5 h after the last cocaine or saline administration. The mRNA for tyrosine hydroxylase (TH) in substantia nigra + ventral tegmental area was significantly elevated to about 140% of saline controls both in the "repeated cocaine" and the "acute cocaine" group as compared with the "saline group". In contrast, there were no differences between the three groups in the mRNAs of preprodynorphin or preproenkephalin levels measured in the nucleus accumbens (core and shell). These results suggest that sensitization phenomena to cocaine are not necessarily connected with alterations in the dopaminergic activity in the mesolimbic system or in the transcription of precursors of endogenous opioid peptides which are located downstream of the dopaminergic synapses.
Institute of Pharmacology and Toxicology, Faculty of Pharmacy, University of Marburg, Germany.
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D
Alvarez Fischer
M K
MK
Schäfer
B
B
Ferger
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S
Gross
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R
Westermann
E
E
Weihe
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K
Kuschinsky
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D003042:Cocaine / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism / Q000502:physiology; D004399:Dynorphins / Q000096:biosynthesis / Q000235:genetics*; D004745:Enkephalins / Q000096:biosynthesis / Q000235:genetics*; D017403:In Situ Hybridization; D008124:Locomotion / Q000187:drug effects; D008297:Male; D017551:Microdialysis; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D009714:Nucleus Accumbens / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D011498:Protein Precursors / Q000096:biosynthesis / Q000235:genetics*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D014444:Tyrosine Transaminase / Q000096:biosynthesis / Q000235:genetics*
D004745:Enkephalins; D011498:Protein Precursors; D012333:RNA, Messenger; C036448:pre-prodynorphin; D004399:Dynorphins; C033660:preproenkephalin; D014444:Tyrosine Transaminase; D003042:Cocaine; D004298:Dopamine