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Open Access Dissertation

Date of Award


Degree Type


Degree Name




First Advisor

George S. Borszcz


Activation of the dopaminergic mesolimbic reward circuitry that originates in the ventral tegmental area (VTA) is postulated to preferentially suppress affective reactions to noxious stimuli (affective analgesia, AA). VTA dopamine neurons are activated via cholinergic inputs, and we have observed that microinjections of the acetylcholine agonist carbachol suppressed vocalizations of rats that occur following administration of brief (1 sec) tail-shocks (vocalization afterdischarges = VAD). VADs are a validated rodent model of pain affect. In addition, the capacity of carbachol to support reinforcement appears to be regionally dependent within VTA. Ikemoto and Wise (2002) reported that carbachol was self-administered in the posterior VTA (pVTA), but not the anterior VTA (aVTA). We have previously reported that carbachol preferentially increased the threshold current intensity for eliciting VADs in aVTA and pVTA, but not midVTA. This carbachol-induced AA is mediated by muscarinic receptors within the pVTA and by both muscarinic and nicotinic receptors within the aVTA. Using the conditioned place preference paradigm (CPP), the present study evaluated the muscarinic versus nicotinic involvement in intra-VTA carbachol-induced CPP learning by administering atropine (muscarinic antagonist) and mecamylamine (nicotinic antagonist) into the VTA prior to carbachol treatment. The present study indicates that unilateral carbachol (4 µg/0.25 µl) supports the CPP learning in aVTA and pVTA, but not midVTA. Additionally, both atropine (60 µg/0.25 µl) and mecamylamine (45 µg/0.25 µl) reliably prevented the development of carbachol-induced CPP in the aVTA and pVTA. Thus, this study is the first to directly compare the extent of overlap between cholinergically mediated reward and affective analgesia within different VTA regions. The results are discussed in terms of anatomical and physiological properties of the VTA, with emphasis of cholinergically activated mesolimbic and mesocortical systems. Finally, based on two of the most prominent hypotheses regarding the role of DA in general, a framework is provided for understanding the role of DA in pain, analgesia, and reward in the context of DA function.

Grant R01 NS045720 from the National Institute of Neurological Disorders and Stroke supported this research.