RESUMEN
Orexinergic neurons, which are closely associated with narcolepsy, regulate arousal and reward circuits through the activation of monoaminergic neurons. Psychostimulants as well as 5-HT-related compounds have potential in the treatment of human narcolepsy. Previous studies have demonstrated that orexin receptor antagonists as well as orexin deficiencies affect the pharmacological effects of psychostimulants. However, little information is available on the consequences of psychostimulant use under orexin deficiency. Therefore, the present study was designed to investigate the abuse liability of psychostimulants in orexin knockout (KO) mice. In the present study, conditioned place preferences induced by methamphetamine and methylphenidate were not altered in orexin KO mice. Interestingly, we found that MDMA induced a conditioned place preference in orexin KO mice, but not in wild type (WT) mice. In addition, MDMA produced methylphenidate/methamphetamine-like discriminative stimulus effects in orexin KO mice, but not WT mice. Increases in 5-HT and dopamine release in the nucleus accumbens induced by MDMA were not altered by knockout of orexin; the steady-state level of G protein activation was higher in the limbic forebrain of orexin KO mice. In substitution tests using a drug discrimination procedure, substitution of 5-HT1A receptor agonist for the discriminative stimulus effects of methylphenidate was enhanced in orexin KO mice. These findings indicate that the orexinergic system is involved the rewarding effects of psychostimulants. However, there is a risk of establishing rewarding effects of psychostimulants even under orexin deficiency. On the other hand, deficiencies in orexin may enhance the abuse liability of MDMA by changing a postsynaptic signal transduction accompanied by changes in discriminative stimulus effects themselves.
Asunto(s)
Estimulantes del Sistema Nervioso Central/farmacología , Condicionamiento Clásico/efectos de los fármacos , Metanfetamina/farmacología , Metilfenidato/farmacología , N-Metil-3,4-metilenodioxianfetamina/farmacología , Orexinas/deficiencia , Recompensa , Agonistas del Receptor de Serotonina 5-HT1/farmacología , Aprendizaje Espacial/efectos de los fármacos , Animales , Conducta Animal/efectos de los fármacos , Giro del Cíngulo/efectos de los fármacos , Giro del Cíngulo/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/metabolismoAsunto(s)
Sensibilización del Sistema Nervioso Central , Etanol/farmacología , Mesencéfalo/metabolismo , Morfina/farmacología , Núcleo Accumbens/metabolismo , Simportadores/metabolismo , Consumo de Bebidas Alcohólicas , Animales , Locomoción , Mesencéfalo/efectos de los fármacos , Mesencéfalo/fisiología , Ratones , Ratones Endogámicos ICR , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/fisiología , Simportadores/genética , Cotransportadores de K ClRESUMEN
The present study examined the effects of dronabinol, a United States FDA-approved synthetic cannabinoid receptor agonist, on morphine (a prototypic µ-opioid receptor agonist)-induced dopamine-related behaviors in animals. Dronabinol suppressed the rewarding effects of morphine in rats and its emetic effects in ferrets. Furthermore, the morphine-induced increase in dopamine release from the nucleus accumbens was significantly attenuated by dronabinol, which indicated that the suppressive effects of dronabinol on morphine-induced behaviors are at least in part mediated by regulation of the dopaminergic system. Since cannabinoid receptor agonists have been shown to enhance the antinociceptive effects of morphine, the use of dronabinol as an adjuvant could be useful for preventing the adverse effects of µ-opioid receptor agonists when used to control pain.
