Investigating the function of cholinergic innervation to the ventral tegmental area in morphine-mediated reward
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The Ventral Tegmental Area (VTA) is central to the brain's mesolimbic reward circuitry. Rewarding stimuli cause a switch in VTA dopaminergic firing patterns from tonic to phasic, leading to increased dopamine release. This switch to phasic firing is believed to be critical in the formation of reward behaviors and is known to coincide with increased acetylcholine (ACh) in the VTA. The only source of cholinergic input to the VTA is believed to come from the Pedunculopontine and Laterodorsal tegmental nuclei (PPTg/LDTg). In this experiment we investigated the role of VTA cholinergic innervation in the formation of reward behaviors. Ibotenic acid lesions of the PPTg, which are non-selective for neuronal type, block the acquisition of morphine conditioned place preference (CPP) but not cocaine CPP. However, it is not known which PPTg neuron subtypes are responsible for this deficit. Using an Urotensin II/Diphtheria fusion toxin (Dtx-UII), we are able to selectively lesion cholinergic neurons of the PPTg/LDTg which express the Urotensin II receptor (UII-R). We also use Dtx-UII to target presynaptic UII-R of the PPTg and LDTg in the VTA causing a selective retrograde lesion of VTA-projecting cholinergic neurons. In this experiment, Dtx-UII was infused bilaterally into the VTA, PPTg, or LDTg of rats. Upon lesion formation, animals underwent CPP with either morphine (5mg/kg) or cocaine (10mg/kg) to test their ability to form reward behaviors. Results show that rats with lesions of cholinergic PPTg or LDTg neurons do not form morphine CPP. Those with selective lesions of VTA projecting cholinergic neurons do. All groups formed cocaine CPP. Comparing these results with those reported in earlier excitotoxic lesion studies suggests that VTA projecting cholinergic neurons may not be necessary for the formation of morphine-mediated reward behaviors and may implicate instead cholinergic projections to other structures.