Evaluating the Effects of Cholinergic Depletion in the PPTg, LDTg, and VTA on Acoustic Startle Response and Morphine‐Related Reward
Authors: Gertz Steven , Santini Joseph , MacLaren Duncan , Clark Stewart 
Published: June 2021

Opiate abuse is a worldwide epidemic that costs nations billions of dollars to treat. Rewarding effects of opioids and other drugs of abuse are partially reliant on the activity of dopaminergic neurons located in reward centers of the brain such as the ventral tegmental area (VTA). The VTA receives cholinergic input from only two sources, the pedunculopontine tegmentum (PPTg) and the laterodorsal tegmentum (LDTg). Excitotoxic lesions to the PPTg in rats have previously been shown to reduce the rewarding effect of opiates (Bechara & van der Kooy, 1989; Olmstead & Franklin, 1997; Parker & van der Kooy, 1995). These studies were unable to identify the specific neuronal subtype responsible for the reduced rewarding effect, though they suggested the cholinergic neurons were responsible. By using a diphtheria‐UII fusion toxin to selectively ablate cholinergic neurons in the PPTg and LDTg we were able to test the role of cholinergic projections to the VTA. The toxin was injected bilaterally into the PPTg, LDTg, or VTA of male Sprague‐Dawley rats through stereotaxic surgery. Injection into the VTA creates a retrograde lesion that specifically ablates the cholinergic neurons of the PPTg and LDTg that innervate the VTA.

The animals were subjected to an acoustic startle reflex/pre‐pulse inhibition paradigm in weeks 4, 8, and 10 post‐surgery. Animals with cholinergic depletion in the PPTg were unable to startle to the point where pre‐pulse inhibition was unable to be measured. While not significant, there was a trend toward an increase in startle in animals that received a VTA retrograde lesion. These findings suggest that the cholinergic PPTg is necessary for integrating sensory processing and motor output. Cholinergic input to the VTA from both the PPTg and LDTg produced a novel effect. Ten weeks post‐surgery the rats were subjected to a morphine conditioned place preference paradigm (CPP), an extinction period, and then a cocaine CPP paradigm. Animals with lesions to the LDTg were able to form cocaine‐mediated CPP but not morphine‐mediated CPP. PPTg lesioned animals formed preference for both morphine and cocaine. Sham animals and the VTA retrograde animals also formed preference for both drugs. These findings suggest that cholinergic neurons in the LDTg that project to an area that is not the VTA likely play a role in morphine‐related reward, and that the cholinergic output from the PPTg is not required in the formation of morphine conditioned place preference. Taking the results of both experiments together, it can be inferred that the cholinergic LDTg plays a role in reward while the cholinergic PPTg plays a role in sensory processing. It is likely that these two areas work in concert to modulate a variety of behaviors. While these findings don't provide a treatment for opiate abuse, they help to further our understanding of the neuronal mechanisms that drive drug addiction.

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This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.