Multiple High Doses of Methamphetamine Increase the Number of Preproneuropeptide Y mRNA-Expressing Neurons in the Striatum of Rat via a Dopamine D1 Receptor-Dependent Mechanism

Neuropeptide Y (NPY) is a neuropeptide that may be involved with emotional regulation and drug addiction and may act as a neuroprotective agent during toxic insults, such as is associated with multiple, high doses of methamphetamine (METH). The purpose of the present study was to elucidate the nature of METH-induced changes in the NPY system by examining the effect of multiple, high doses of METH on preproNPY (ppNPY) mRNA expression in the striatum and the role that dopamine (DA) D1 and D2 receptors might play in these changes. Rats were administered five injections of 10 mg/kg METH at 6-h intervals, along with the D1 receptor antagonist 7-chloro-8-hydoxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1 H -3-benazepine hydrochloride (SCH22390) or the D2 receptor antagonist eticlopride, and they were sacrificed 3 h after the last dose of METH. The number of neurons expressing ppNPY mRNA in striatum was examined using in situ hybridization histochemistry. An acute dose of METH as well as multiple, high doses of METH increased the number of neurons expressing ppNPY mRNA in all regions of striatum examined. There was no change in the number of prosomatostatin (pSOM) mRNA-containing neurons. The increase in the number of ppNPY mRNA-expressing neurons was abolished by pretreatment with SCH22390. Eticlopride alone increased the number of ppNPY mRNA-expressing neurons in striatum, and METH treatment did not further increase the number. These findings suggest that exposure to multiple, high doses of METH increases the number of neurons expressing detectable levels of ppNPY mRNA and that this phenomenon is dependent on DA D1-receptor activation.