Effects of repeated cocaine administration on the thyrotropin-releasing hormone level and receptors in the rat brain.

The effects of single and repeated administration of cocaine on the thyrotropin-releasing hormone (TRH) level and receptors in discrete rat brain structures were evaluated. Male Wistar rats received saline or cocaine (15 mg/kg i.p., once an hour within 3 h, for 8 days). The animals were killed by decapitation at 45 min and 72 h (chronic group only) after the last injection. A radioimmunoassay (RIA) study showed that a single dose of cocaine increased the TRH level in the striatum by 68%, but had no significant effect on the peptide content in the nucleus accumbens, hippocampus, amygdala, septum, hypothalamus, frontal and prefrontal cortex at 45 min after the drug injection. Repeated administration of cocaine increased the TRH level in the striatum by 89% at 45 min, and in the hippocampus by 26% at 72 h after the last dose. No changes in the TRH level were found in other brain structures. In vitro cocaine (10(-6)-10(-4) M) inhibited the K(+)-stimulated release in a concentration-dependent manner, but had no effect on the basal release of TRH from the striatum and nucleus accumbens of naive rats. Acute cocaine decreased the Bmax of TRH receptors in the striatum, but had no effect on the density and affinity of TRH receptors in other brain regions. Repeated administration of cocaine evoked a long-lasting decrease in the Bmax of TRH receptors in the striatum (by c. 30%), whereas an increase in that parameter was observed in the frontal cortex. The Bmax and affinity of TRH receptors following repeated cocaine remained unchanged in the nucleus accumbens. The results obtained indicate that cocaine affects the TRH system mainly in the striatum, and to a lesser extent in the nucleus accumbens, cortex and hippocampus. Furthermore, the above changes do not resemble those induced by amphetamine, which points to certain differences in adaptation of the TRH neuronal system to these psychostimulants. On the other hand, the increase in the hippocampal TRH level during both chronic cocaine and morphine withdrawal is a common feature of the mechanism of dependence on these drugs.