Ontogeny of neurokinin-1 receptor mediation of methamphetamine neurotoxicity in the striatum of the mouse brain

Abstract

We studied the role of the peptide substance P, signaling through the neurokinin-1 (NK-1) receptor, on methamphetamine-induced loss of dopamine transporter sites, a well-documented marker of toxicity in the striatum of the mouse brain, because this peptide is under dynamic regulation by the neurotransmitter dopamine. Methamphetamine is a psychostimulant that induces dopamine overflow from dopamine terminals of the striatum. Mice were given four injections of methamphetamine (7.5 mg/kg of body weight) at two-hour intervals and were sacrificed three days after the treatment. Dopamine transporter levels in the striatum were assessed by receptor autoradiography with [(125)I]RTI-121. Exposure to methamphetamine resulted in significant loss of dopamine transporters in the caudate-putamen. This loss was prevented by preexposure (30 min before the first injection of methamphetamine) of the neurokinin-1 receptor antagonist L-733,060. The inactive enantiomer of L-733,060 (L-733,061) failed to protect dopamine transporter sites from methamphetamine, suggesting specificity for the neurokinin-1 receptor. Moreover, the protective effect of L-733,060 was observed in mice that were 10 weeks of age or older (dopamine transporter sites in mice six and eight weeks old were not protected from methamphetamine by the neurokinin-1 receptor antagonist). The results demonstrate that the deleterious effect of methamphetamine on dopamine transporter sites of the striatum is mediated via the neurokinin-1 receptor. The involvement of the NK-1 receptor appears after the eighth week of postnatal life, suggesting that the link between dopamine transporters and the neurokinin-1 receptor becomes functional at approximately the time when the mouse reaches reproductive age.