Another proposal we tested was whether inactivation of ACh would reduce the behavioral reinforcing effect of cocaine (as measured by decreased cocaine self-administration). Specific pharmacological agents that block or enhance muscarinic receptors in the LDTg change ACh levels in the VTA. We determined that ACh output in the VTA was attenuated by direct, bilateral microinjection of the selective muscarinic type-2 (M2) autoreceptor agonist oxotremorine·sesquifumarate (OxoSQ; Fig. 6). Due to its ability to reduce an excitatory (cholinergic) input onto DA neurons, we hypothesized that OxoSQ would reduce the motivation of rats to self-administer both natural and drug rewards. Animals were therefore tested on progressive ratio (PR) schedules of reinforcement for food pellets and cocaine. We found that OxoSQ microinjection in the LDTg, compared to aCSF, significantly reduced both the number of self-administered pellets and cocaine infusions during the initial half of the session and this reduction was dose-dependent [63]. These data suggest that Inactivation of ACh input to the VTA results in lower motivation for both food and cocaine self-administration.
