Inhibitory effects of osemozotan, a serotonin 1A-receptor agonist, on methamphetamine-induced c-Fos expression in prefrontal cortical neurons.

Psychostimulants induce hyperlocomotion in normal subjects, although, they are effective in producing a calming effect in hyperactive subjects. This paradoxical effect has been related to changes in serotonin (5-HT) neurotransmission in hyperactive dopamine transporter-knockout mice. In addition, we observed that hyperlocomotion in mice lacking pituitary adenylate cyclase-activating polypeptide was attenuated by amphetamine dependent on 5-HT(1A) receptor signaling and that amphetamine, when co-administered with a 5-HT(1A) agonist, produced a calming effect in wild-type mice. Here, in an attempt to address how 5-HT(1A) receptor signaling exerts the calming action of psychostimulants, we examined c-Fos expression in several brain regions after administration of methamphetamine and osemozotan, a selective 5-HT(1A) receptor agonist. The number of c-Fos-positive cells was increased in the medial prefrontal cortex, striatum and nucleus accumbens in methamphetamine (3 mg/kg body weight)-injected mice. Osemozotan (1 mg/kg) significantly reduced the methamphetamine-induced c-Fos expression in the medial prefrontal cortex and striatum, but not in the nucleus accumbens. This osemozotan action was completely blocked by the 5-HT(1A) receptor antagonist WAY-100635 (1 mg/kg). As the prefrontal cortex is considered to be involved in the beneficial actions of psychostimulant medications for attention-deficit/hyperactivity disorder, the present result showing 5-HT(1A)-mediated inhibition of corticostriatal activity may partly be related to this psychostimulant action.

An antihyperkinetic action by the serotonin 1A-receptor agonist osemozotan co-administered with psychostimulants or the non-stimulant atomoxetine in mice.

It has been demonstrated that treatment of hyperactive mice with psychostimulants produced a calming effect depending on serotonergic neurotransmission. Our previous study also showed that hyperactivity in mice lacking pituitary adenylate cyclase-activating polypeptide (PACAP) was ameliorated by amphetamine in a serotonin (5-HT)(1A)-dependent manner and that amphetamine calmed wild-type mice given the 5-HT(1A) agonist 8-OH-DPAT. Here, we examined if 5-HT(1A)-mediated pathways can be a determinant of the action of other psychostimulants as well as the non-stimulant atomoxetine by examining locomotor activity in mice co-administered with the 5-HT(1A) agonist osemozotan. Co-administration of osemozotan with either methamphetamine or amphetamine was not only antihyperkinetic, but also decreased locomotion to below basal levels. In contrast, osemozotan just nullified methylphenidate-induced hyperactivity. The non-stimulant atomoxetine did not induce hyperactivity, but co-administration of atomoxetine with osemozotan produced a calming effect. The adjunctive effect of osemozotan added to the psychostimulants was blocked by the 5-HT(1A) antagonist WAY-100635 at a low dose (0.1 mg/kg), suggesting the involvement of a presynaptic 5-HT(1A)-mediated mechanism. However, WAY-100635 (up to 1 mg/kg) did not block the effect of atomoxetine plus osemozotan. The present results may provide insights into the therapeutic mechanisms of the psychostimulants and atomoxetine for hyperkinetic disorders.

Lack of trimethyltin (TMT)-induced elevation of plasma corticosterone in PACAP-deficient mice.

Accumulating evidence implicates pituitary adenylate cyclase-activating polypeptide (PACAP) in a number of stress responses. By using PACAP-deficient mice, PACAP has been shown to have an in vivo role in the regulation of the sympathoadrenal axis, but a role in regulating the hypothalamo-pituitary-adrenal (HPA) axis has not been fully addressed. To elucidate the role of endogenous PACAP in HPA axis regulation during pathological conditions, mice lacking the Adcyap1 gene encoding the neuropeptide PACAP (Adcyap1-/-) were injected with trimethyltin (TMT), a neurotoxin known to induce neuronal damage and several systemic responses including elevated plasma corticosterone levels. In wild-type controls, TMT induced transient decreases in water and food intake, with a concomitant decrease in body weight; however, no significant changes were observed in Adcyap1-/- mice. Basal corticosterone levels were not significantly different between the mutant and wild-type mice. TMT induced a marked elevation of plasma corticosterone above basal levels in wild-type mice but no significant increase was seen in Adcyap1-/- mice. The present article suggests that PACAP is involved in the corticosterone release in some pathological conditions but not in the basal state.