Cocaine sensitization does not alter SP effects on locomotion or excitatory synaptic transmission in the NAc of rats

Substance P (SP) and cocaine employ similar mechanisms to modify excitatory synaptic transmission in the nucleus accumbens (NAc), a region implicated in substance abuse. Here we explored, using NAc slices, whether SP effects on these synaptic responses were altered in rats that have been sensitized to cocaine and whether SP could mimic cocaine in triggering increased locomotion in sensitized rats. Intraperitoneal (IP) injection of na\uefve rats with cocaine (15 mg/kg) caused increased locomotion by 408.5 \ub1 85.9% (n = 5) which further increased by 733.1 \ub1 157.8% (n = 5) following a week of cocaine sensitization. A similar challenge with 10 mg/kg of SP after cocaine sensitization did not produce significant changes in locomotion (170.6 \ub1 61.0%; n = 4). In contrast to cocaine, IP injection of rats with SP or SP5\u201311 (10\u2013100 mg/kg) with or without phosphoramidon did not elicit changes in locomotion. In electrophysiological studies, both cocaine and SP depressed evoked NMDA and non-NMDA receptor-mediated excitatory synaptic currents (EPSCs) in slices obtained from na\uefve rats. In slices derived from cocaine-sensitized rats, cocaine but not SP produced a more profound decrease in non-NMDA compared to NMDA responses. Similar to that in na\uefve rats, cocaine\u2019s effect on the EPSCs in these sensitized rats occluded those of SP. Thus, although SP and cocaine may employ similar mechanisms to depress EPSCs in the NAc, IP injection of SP does not mimic cocaine-induced hyperlocomotion indicating that not all of cocaine\u2019s effects are mimicked by SP.Peer reviewed: YesNRC publication: Ye