GABA mechanisms in the pedunculopontine tegmental nucleus influence particular aspects of nicotine self-administration selectively in the rat

Abstract.

Rationale: The pedunculopontine tegmental nucleus (PPTg) is part of the neuronal circuit activated by self-administered nicotine. The cholinergic neurons of the PPTg comprise a prominent projection to midbrain dopamine neurons. However, anatomical studies of Fos expression suggest that nicotine targets primarily non-cholinergic neurons in the PPTg, especially GABAergic and glutamatergic neurons. Objective: The objective of these experiments was to examine the role of GABA manipulations in the PPTg on nicotine self-administration. Methods and results: Rats trained to self-administer nicotine or cocaine intravenously were prepared with brain microcannulae directed to the PPTg. Intra-PPTg microinfusions of the GABA agonists muscimol (10–50 ng) and baclofen (30–60 ng) reduced nicotine self-administration maintained on a fixed-ratio schedule of reinforcement (30 µg/kg per infusion); self-administration of cocaine (0.3 mg/kg per infusion) under an identical schedule was not affected. Muscimol and baclofen were also examined after intra-PPTg microinfusion in animals trained to self-administer nicotine on a progressive-ratio schedule (10 and 30 µg/kg per infusion). Progressive-ratio responding was sensitive to pharmacological manipulations such as a change in the nicotine dose available for self-administration, or intra-PPTg microinfusion of the nicotinic antagonist dihydro-β-erythroidine (30 µg). However, nicotine self-administration on a progressive-ratio schedule was not altered by intra-PPTg microinfusions of GABA agonists. Conclusions: These data confirm that the PPTg is involved in nicotine self-administration, a conclusion that is independent of the schedule of reinforcement that is used. GABAergic mechanisms in the PPTg play a selective role in nicotine reinforcement compared to cocaine, and that role is restricted to the characteristics of reinforcement measured by fixed-ratio responding.