Differential role of mineralocorticoid and glucocorticoid receptors in the genesis of dexamphetamine-induced sensitization of mesolimbic, alpha 1 adrenergic receptors in the ventral striatum.

The present study was carried out to investigate the role of corticosteroids in the dexamphetamine-induced sensitization of the mesolimbic, noradrenergic system. The experimental design of adrenalectomy and hormone replacement was chosen for exploration of this question. The dexamphetamine-induced sensitization of mesolimbic, alpha 1 adrenergic receptors in the ventral striatum was studied by administering intra-accumbens injections of the alpha 1 agonist, phenylephrine (10 micrograms), given 24 h after a priming injection of intra-accumbens administered dexamphetamine (10 micrograms), which itself elicits an increase in locomotor activity. In this paradigm phenylephrine produces an increase in locomotor activity, an effect which does not occur in rats which are not sensitized by dexamphetamine. Adrenalectomy produced a slight, but significant, attenuation of the response to the priming injections of dexamphetamine. Replacement treatments (500 micrograms/kg per drug) with corticosterone or deoxycorticosterone, agents which preferentially bind with mineralocorticoid receptors, did not affect the dexamphetamine response, whereas replacement treatment with dexamethasone, which preferentially binds with glucocorticoid receptors, strongly potentiated this response. In view of the fact that the adrenalectomy-induced fall in corticosteroids can produce an up-regulation of glucocorticoid receptors, but not mineralocorticoid receptors, these data led to the conclusion that glucocorticoid receptors which are present in the cell bodies of noradrenergic, serotonergic and dopaminergic neurons are critical for the dexamphetamine response in drug-naive rats. The phenylephrine response was also strongly enhanced in adrenalectomized rats treated with dexamethasone. Since the magnitude of the dexamphetamine response is known to determine the magnitude of the phenylephrine response, the role of glucocorticoid receptors in the dexamphetamine-induced sensitization of the phenylephrine response remains to be established. Conversely, adrenalectomy nearly completely abolished the dexamphetamine-induced sensitization of the phenylephrine response. The latter response was reinstated by replacement treatment with corticosterone or deoxycorticosterone. These data show that mineralocorticoid receptors, which are present among others in the ventral striatum, are critical for the dexamphetamine-induced sensitization of mesolimbic, alpha 1 adrenergic receptors in the ventral striatum. The present study opens the perspective that secretion of corticosteroids in response to stressful stimuli--be it pharmacological or environmental--is the key to the question of why dexamphetamine and environmental challenges are interchangeable in the development of sensitization of mesolimbic, alpha 1 adrenergic receptors.