Date

June 2012

Document Type

Dissertation

Degree Name

Ph.D.

Department

Dept. of Behavioral Neuroscience

Institution

Oregon Health & Science University

Abstract

Methamphetamine (METH) reward is, in part, mediated by the ability of METH to release dopamine (DA) within the nucleus accumbens (NAc). The DA cell bodies located in the ventral tegmental area (VTA) receive acetylcholine (ACh) projections from the laterodorsal (LDT) and pedunculopontine tegmental nuclei (PPT). These ACh projections mediate DA cell firing, DA release, reward and psychostimulant locomotor activity and stereotypy. However, it is unknown if METH acts through the LDT or PPT to induce neurochemical changes or reward. Therefore, experiments sought to characterize the role of the LDT and PPT in METH-induced levels of ACh and DA within the mesolimbic pathway and determine if mesopontine ACh projections are important for METH reward. Chapter 2. In these experiments, in vivo microdialysis in the mouse was used to test METH’s effects on ACh and somatodendritic DA levels within the VTA. Following a systemic METH injection, or an intra-VTA perfusion of METH, DA levels were significantly increased in the VTA. Systemic METH injection induced a significant increase in ACh which persisted for 2 to 3 h post injection. However, intra-VTA METH perfusion did not affect VTA ACh levels. These experiments suggest that METH is acting outside of the VTA to induce increases in extracellular ACh levels within the VTA. Chapter 3. The aim of these experiments was to characterize the role of PPT- and LDT-derived ACh in METH-induced (1) ACh levels within the VTA, (2) DA levels within the NAc, and (3) locomotor activity. Reversible inhibition of the LDT ACh neurons via microinjection of the M2-type preferring receptor agonist oxotremorine sesquifumarate (OXO) significantly inhibited locomotor activity following an intraperitoneal (IP) injection of METH or saline. Intra-LDT OXO microinjections dose-dependently attenuated METH-induced increases in ACh within the VTA, but had no effect on DA levels within the NAc. Conversely, intra-PPT OXO microinjections had no effect on METH-induced ACh levels in the VTA or DA levels in the NAc. Chapter 4. These experiments examined the contribution of the LDT cholinergic neurons in METH reward, as measured by conditioned place preference (CPP). Bilateral electrolytic lesions of the LDT significantly decreased the number of LDT ACh neurons compared to sham operated controls. LDT lesion was negatively correlated with locomotor activity, but had no effect on the expression or acquisition of METH preference. In addition, there was no effect of LDT lesion on the extinction or reconditioning of METH CPP. These experiments showed that METH indirectly activates the LDT, but not the PPT, to stimulate increases in ACh levels within the VTA; however, this effect is independent of METH-induced DA levels in the NAc and METH reward. Although it is well known that ACh can alter DA release and stimulate reward, METH can induce DA release independently of neuronal stimulation. This likely masks any DA-potentiating effects of LDT ACh on METH-induced DA levels and reward.

Identifier

doi:10.6083/M45X26ZG

School

School of Medicine

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