Role of prefrontal dopaminergic neurotransmission in glucocorticoid receptor-mediated modulation of methamphetamine-induced hyperactivity.

Glucocorticoids are involved in psychostimulant-induced hyperactivity, but the exact mechanism is not known. This study used the selective glucocorticoid receptor antagonist, RU-43044, to determine whether prefrontal neurotransmission is involved in glucocorticoid-mediated modulation of methamphetamine (METH)-induced hyperactivity in mice. Pretreatment with RU-43044 (10-30 mg/kg) attenuated the increased spontaneous locomotor activity induced by METH (1-2 mg/kg). The psychostimulant effect of METH was also attenuated by adrenalectomy. RU-43044 inhibited METH-induced increases in extracellular dopamine (DA), but not serotonin (5-HT), levels in the prefrontal cortex, but did not affect METH-induced increases in extracellular DA levels in the nucleus accumbens shell, although it inhibited increases in extracellular 5-HT levels. Adrenalectomy also attenuated the METH-induced increases in extracellular DA levels in the prefrontal cortex. RU-43044 did not affect METH-induced increases in plasma corticosterone levels. These findings suggest that glucocorticoid receptors are involved in METH-induced hyperactivity, and that prefrontal dopaminergic neurotransmission plays a role in glucocorticoid-mediated modulation of METH-induced behavioral changes.

Antidepressant-like effects of the glucocorticoid receptor antagonist RU-43044 are associated with changes in prefrontal dopamine in mouse models of depression.

Chronic corticosterone and isolation rearing paradigms may provide reliable mouse models of depression. Using these models, the present study examined if the specific glucocorticoid receptor antagonist, RU-43044, has an antidepressant-like effect, and studied the possible role of prefrontal neurotransmission on the behavioral effects. Chronic administration of corticosterone and isolation rearing increased the immobility time in the forced swim and tail suspension tests. Subchronic treatment with RU-43044 decreased the immobility time in the forced swim test in chronic corticosterone-treated and isolation-reared mice, but not the control mice. Chronic corticosterone decreased the levels of cortical glucocorticoid receptors and stress-induced increases in plasma corticosterone levels, and blocked the response of plasma corticosterone to dexamethasone, while isolation rearing did not cause any changes in the glucocorticoid receptor system. Both chronic corticosterone and isolation rearing markedly increased high K+ -induced dopamine release, but not serotonin release, in the prefrontal cortex. Subchronic RU-43044 reversed the enhanced release of dopamine in the prefrontal cortex of chronic corticosterone-treated and isolation-reared mice. These results suggest that chronic corticosterone and isolation rearing increase the depressive-like behavior in glucocorticoid receptor-dependent and independent manners, respectively, and that RU-43044 shows an antidepressant-like effect, probably via an inhibition of enhanced prefrontal dopaminergic neurotransmission in these mouse models.

[Involvement of prefrontal serotonergic neurons in methamphetamine-induced behavioral sensitization].

Repeated administration of psychostimulants in rodents can enhance the stimulating effect on locomotor activity, a phenomenon called behavioral sensitization. This has been widely used as animal models for schizophrenia as well as addiction and psychosis, because of the similarity to its process in acquisition and progression. However, there are no studies demonstrating whether the drugs improve the psychostimulant-induced behavioral sensitization when administered after establishment of the sensitization, while previous studies have mainly focused on the analyses of the development (induction) phase of the sensitization. We demonstrated that the activation of serotonin (5-HT) receptors or blockade of 5-HT2 receptors, given after establishment of the sensitization, attenuates the expression of methamphetamine-induced behavioral sensitization in mice. In addition, we also showed that repeated administration of methamphetamine induces the increased reactivity of prefrontal serotonergic neurons specifically. These observations suggest that the 5-HT system is a neurochemical basis for the behavioral sensitization, and imply that 5-HT1A and 5-HT2 receptors may have potential therapeutic values in the remission of methamphetamine abuse or psychosis. Here, we provide an overview of the roles of serotonergic neurons in the psychostimulant-induced behavioral sensitization.