Intra-median raphe infusions of muscimol and the substance P analogue DiMe-C7 produce hyperactivity: role of serotonin neurons

Injections into the midbrain median raphe nucleus (MR) of the metabolically stable substance P analogue, DiMe-C7, produce dose-dependent increases in locomotor activity (LMA). Ibotenic acid (8.0 micrograms in 2.0 microliter vehicle) lesions of the MR block the hyperkinetic effects of optimal doses of both DiMe-C7 (1.0 microgram in 0.5 microliter vehicle) and the GABAA agonist, muscimol (100 ng in 0.5 microliter vehicle). This observation indicates that the increases in LMA produced by intra-MR DiMe-C7 and muscimol infusion are not due to diffusion to sites outside the MR. Intra-MR administration of the selective serotonin (5-HT) neurotoxin, 5,7-dihydroxytryptamine (6.0 micrograms in 1.5 microliter vehicle), following pretreatment with the norepinephrine and dopamine reuptake inhibitor, nomifensine maleate (15 mg/kg, i.p.), blocked the hyperactivity induced by intra-MR infusions of DiMe-C7 (1.0 microgram) but not that of muscimol (100 ng). These observations suggest that the LMA effects of intra-MR DiMe-C7 and muscimol administration are mediated by different neural mechanisms. The LMA effects of DiMe-C7 depend on intact 5-HT neurons in the MR, whereas the effects of muscimol depend on intact non-5-HT MR cells.