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 phenom ena can be observed, so that its behavioural effects are enhanced. Since th is phenomenon is long-lasting, it was of interest to study which persistent alterations in the activity of dopaminergic neurones or of endogenous opio id systems downstream of dopaminergic synapses in the basal ganglia are inv olved 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 d ays 1-6 and cocaine on day 7 ("acute cocaine"), or saline was injected on d ays 1-7 ("saline group"). The "repeated cocaine" schedule led to a signific ant sensitization to the locomotor activation produced by cocaine on day 7 or on day 17, 10 days after the end of sensitization protocol. Microdialysi s in the nucleus accumbens which was performed after administration of coca ine (10 mg/kg i.p.) on day 7, or after an administration of the same dose 1 0 days after the last administration of cocaine, respectively, revealed sig nificant acute increases of extracellular dopamine to about 200% of basal v alues. These increases were similar in "acute cocaine" and in "repeated coc aine" animals both after 7 days and after 17 days. For in situ hybridizatio n studies, rats were sacrificed on day 7, 4.5 h after the last cocaine or s aline 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" grou p as compared with the "saline group". In contrast, there were no differenc es between the three groups in the mRNAs of preprodynorphin or preproenkeph alin levels measured in the nucleus accumbens (core and shell). These results suggest that sensitization phenomena to cocaine are not neces sarily connected with alterations in the dopaminergic activity in the mesol imbic system or in the transcription of precursors of endogenous opioid pep tides which are located downstream of the dopaminergic synapses.