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/metabolismoRESUMEN
RATIONALE: Orexin knockout (KO) mice exhibit a phenotype that is similar to human narcolepsy, and monoamine-related compounds, such as psychostimulants and 5-HT uptake inhibitors, have been used for the treatment of narcoleptic disorders. However, little information is available regarding the pathophysiological features of orexin KO mice, particularly with respect to their narcoleptic-like disorder and how it is affected by monoamine-related compounds. OBJECTIVES: The present study was designed to investigate both the nature of the neuronal changes in orexin KO mice and the therapeutic effects of monoamine-related compounds on the sleep disorder in orexin KO mice. RESULTS: A decrease in locomotor activity in the dark phase was observed in orexin KO mice, and psychostimulants and 5-HT-related compounds, such as 8-OH-DPAT (5-HT1A receptor agonist) and DOI (5-HT2 receptor agonist), inhibited this hypolocomotion. We also found that 5-HT1A receptor mRNA levels, but not those for 5-HT2 or dopamine receptors, were significantly decreased in the prefrontal cortex of orexin KO mice in the dark period and were accompanied by compromising the increase in 5-HT metabolite levels. In addition, the sleep disorder in orexin KO mice, as analyzed by a polysomnography during the dark period, was completely normalized by 8-OH-DPAT. CONCLUSION: These results suggest that a dysfunction of 5-HT1A receptors is involved in the narcoleptic-like sleep dysfunction in orexin KO mice, and such dysfunction may participate in orexin deficiency-induced sleep disorders. Further, the use of 5-HT1A receptor agonist could be useful for treating the sleep disorder under a deficiency of orexin.
Asunto(s)
8-Hidroxi-2-(di-n-propilamino)tetralin/uso terapéutico , Narcolepsia/tratamiento farmacológico , Narcolepsia/metabolismo , Orexinas/deficiencia , Receptor de Serotonina 5-HT1A/metabolismo , Agonistas del Receptor de Serotonina 5-HT1/uso terapéutico , 8-Hidroxi-2-(di-n-propilamino)tetralin/farmacología , Animales , Relación Dosis-Respuesta a Droga , Masculino , Ratones , Ratones de la Cepa 129 , Ratones Endogámicos C57BL , Ratones Noqueados , Microdiálisis/métodos , Polisomnografía/métodos , Agonistas del Receptor de Serotonina 5-HT1/farmacología , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéuticoRESUMEN
Psychostimulant abuse has been a serious social problem worldwide for a long time. Bupropion, which is used as an antidepressant and to aid smoking cessation in the US, is considered to have psychostimulant-like activity. Although activation of the dopaminergic system induces several behavioral effects and bupropion can activate the dopaminergic system, the abuse potential and other behavioral effects of bupropion have not been fully investigated. Therefore, in this study we compared the behavioral effects of bupropion to those of psychostimulants in mice. Both methamphetamine and bupropion induced sensitization to locomotor activity, and cross-sensitized each other. Methamphetamine and bupropion also induced robust rewarding effects as measured by the conditioned place preference paradigm, although the conditioned reward with bupropion extinguished faster than that with methamphetamine. Furthermore, unlike psychostimulants, bupropion did not disrupt prepulse inhibition, even in bupropion-sensitized mice. These findings constitute evidence that bupropion and methamphetamine have similar pharmacological profiles, particularly with regard to dopamine-related behaviors. However, bupropion has lower abuse potential and side effects than methamphetamine.