Midbrain dopamine (DA) neurons project from the ventral tegmental area (VTA) to the prefrontal cortex (PFC) and ventral striatum (NAc and OT) forming a key part of the well-defined mesocorticolimbic system, as well as the hippocampal-VTA loop. The mesocorticolimbic system, at least partly, mediates the rewarding effects of drugs of abuse, such as nicotine. The VTA receives cholinergic projections from the pedunculopontine tegmental and laterodorsal tegmental nuclei (PPTg, LDTg). Previous studies have shown that selective bilateral cholinergic lesions of the posterior PPTg or LDTg can be achieved by directly infusing diphtheria-urotensin II toxin (Dtx-UII) into either region. This thesis aimed to selectively destroy the cholinergic input from both mesopontine nuclei to the posterior VTA (pVTA) by injection of Dtx-UII here. Unilateral or bilateral infusion of Dtx-UII into the pVTA did not destroy cholinergic terminals at any of the time points analysed. There was no evidence of neurodegeneration (as measured by Fluoro-jade C) present in the pVTA, PPTg or LDTg. A non-lesion approach was also adopted to better understand the actions of cholinergics in the pVTA. The effects of nicotine self-administered into the VTA or (as a point of contrast in the circuitry of the VTA) the dorsal hippocampus (dHPC) were assessed by measuring lever pressing and quantifying the expression of immediate early gene (IEG) c-fos as a marker of neural activation. Fos expression was quantified in the VTA and in structures on which VTA activity has effect - the shell and core of the NAc, the dorsal striatum and the dHPC. Fos was measured under two conditions: at the end of the very first exposure to nicotine and (in other groups) after repeated exposure. These results demonstrated that rats will lever press to directly administer nicotine into the VTA or dHPC, but that nicotine-induced Fos expression is not correlated with lever pressing. In addition, intra-VTA, but not intra-dHPC nicotine, activated all regions of interest. This demonstrates that intra-VTA nicotine mediates its effects through regions of the mesocorticolimbic system, but that intra-dHPC nicotine must mediate its effects through other brain regions and systems. These results raise questions about the nature of reward processing in the brain.
|Date of Award||31 Mar 2017|
- University Of Strathclyde
|Sponsors||BBSRC (Biotech & Biological Sciences Research Council) & University of Strathclyde|
|Supervisor||Philip Winn (Supervisor) & Ben Pickard (Supervisor)|