Behavioral and neurochemical studies of opioid effects in the pedunculopontine nucleus and mediodorsal thalamus.

The brain circuitry mediating spontaneous and psychostimulant-induced locomotion comprises, in part, connections between the ventral tegmental area, nucleus accumbens and ventral pallidum. Two primary efferent projections from the ventral pallidum are to the mediodorsal thalamic nucleus (MD) and the pedunculopontine nucleus (PPN), including the mesencephalic motor area. To assess the functional role of the PPN and MD in this motor circuit, the behavioral and neurochemical effects of intra-PPN and intra-MD administration of the mu opioid receptor agonist Tyr-D-Ala-Gly-MePhe-Gly(ol) (DAMGO) were examined. Bilateral microinjections of DAMGO into either the PPN or MD elicited a dose-dependent increase in motor activity which was blocked by pretreatment with naloxone (2.0 mg/kg i.p.). Three studies were conducted to evaluate a role for mesoaccumbens dopamine transmission in DAMGO-induced motor activity. Systemic administration of the dopamine antagonist, heloperidol (0.1 mg/kg i.p.) produced a partial antagonism of the motor effect elicited by DAMGO in the MD, but abolished the response to DAMGO in the PPN. Inhibition of dopamine neurons by microinjecting the gamma-aminobutyric acidB agonist, baclofen (0.15 nmol/side), into the ventral tegmental area attenuated the motor activity elicited by DAMGO in the PPN but was without effect on DAMGO in the MD. Finally, microdialysis revealed that DAMGO microinjection into either the PPN or MD elicited a dose-related increase in extracellular dopamine content in the nucleus accumbens. However, only after DAMGO in the PPN were extracellular levels of dopamine metabolites increased. These results demonstrate that the motor stimulant response to DAMGO in the PPN is dopamine dependent and involves stimulation of mesoaccumbens dopamine neurons. In contrast, the motor response by DAMGO in the MD only partly involves dopaminergic mechanisms, perhaps via a presynaptic action because the effect was not altered by inhibiting impulse flow in mesoaccumbens dopamine neurons with baclofen.