Effect of cocaine on responsiveness of alpha(1)-adrenergic receptors in rat cerebral cortex: modulation by GABA-mimetic drugs.

We investigated the effects of single doses of cocaine (10 mg/kg, ip) and the gamma-aminobutyric acid (GABA)-mimetics tiagabine (10 mg/kg, ip) and vigabatrin (150 mg/kg, ip) injected separately or concomitantly with cocaine, on the responsiveness of cerebral cortical alpha(1)-adrenergic receptors. The accumulation of noradrenaline-stimulated inositol phosphates was estimated in vitro at 2 and 24 h after the drug injection. Cocaine significantly enhanced alpha(1)-adrenergic receptor responsiveness to noradrenaline. Neither tiagabine nor vigabatrin influenced the accumulation of inositol phosphates. Finally, the cocaine-evoked augmentation of alpha(1)-adrenoceptor responsiveness was counteracted by tiagabine but not by vigabatrin. This effect may represent a characteristic feature of tiagabine, not necessarily shared by other GABA-mimetic drugs.

Effect of cocaine sensitization on alpha1-adrenoceptors in brain regions of the rat: an autoradiographic analysis.

We investigated the effects of repeated intermittent cocaine treatment, resulting in behavioral sensitization, on the density of alpha(1)-adrenoceptors in the rat brain measured by quantitative in vitro autoradiography of [(3)H]prazosin. Animals were decapitated following a short (2 h) and long (48 h) withdrawal period after an injection of cocaine (10 mg/kg) on day 10 given to either cocaine-naive (saline daily, days 1-5) or cocaine-sensitized (cocaine 10 mg/kg daily, days 1-5) rats. In cocaine-naive rats, significant decreases in alpha(1)-adrenoceptors 2 h after a single dose of cocaine were observed in the amygdaloid nuclei and hippocampus; the decreases in the centromedial nucleus of the amygdala persisted until 48th hour of withdrawal. On the contrary, increases in alpha(1)-adrenoceptors after 2-h withdrawal were seen in the nucleus accumbens core and retrosplenial cortex. In cocaine-sensitized rats, the density of alpha(1)-adrenoceptors 2 h after the challenge with cocaine increased in the centrolateral amygdala, while in the granular retrosplenial cortex and in the most of thalamic nuclei, the densities of alpha(1)-adrenoceptors decreased. After 48-h withdrawal, the density of alpha(1)-adrenoceptors increased in the nucleus accumbens core and shell (by 21% and 58%, respectively), and in the amygdaloid centromedial and basolateral nuclei (by ca. 24%), while the decline was still observed in some thalamic nuclei. Our study shows for the first time that cocaine sensitization produces significant (dependent on the withdrawal time) alterations in the alpha(1)-adrenoceptor density, and the changes in some parts of the thalamus seem to be related to processes of cocaine relapses.

Nicotine produces antidepressant-like actions: Behavioral and neurochemical evidence.

Converging lines of evidence indicate the involvement of nicotinic acetylcholine receptors in depressive illness and antidepressant drug action. We investigated the effects of sub-chronic and chronic treatment with imipramine, nicotine and their combination on: (a) the ability of a dopamine-mimetic challenge to produce locomotor stimulation and (b) cortical density of beta-adrenoceptors. One week of treatment with imipramine (10 mg/kg, twice daily) did not result in an altered response to the apomorphine (0.15 mg/kg) challenge, but after 2 weeks, the imipramine-treated rats demonstrated hyperactivity. Conversely, such increased locomotor response was observed in rats treated with nicotine (0.4 mg/kg, twice daily) for 1 but not for 2 weeks. Groups treated with nicotine+imipramine for 1 and 2 weeks demonstrated equally high hyperactivity in response to the apomorphine challenge. This effect was not different from the effects of 1-week treatment with nicotine or 2-week treatment with imipramine. The density of beta-adrenoceptors was equally decreased by 2 (but not 1) weeks of the treatment with imipramine, nicotine and their combination. The present behavioral and neurochemical data suggest the antidepressant-like effect of the chronic treatment with nicotine. It appears that the potentiation of the dopamine-mimetic-induced hyperactivity cannot be explained by beta-adrenoceptor down-regulation.