Jordan T. Yorgason - US grants

DESCRIPTION (provided by applicant): Postweanling social isolation rearing produces long term changes in many behaviors, including increased locomotor novelty response, increased anxiety-like behavior, and increased ethanol consumption. In addition, isolates also show changes in dopaminergic activity, including increases in ventral tegmental dopamine neuron burst firing, increased accumbal dopamine, and increased dopamine turnover in the accumbens and amygdala. However, these previous studies are limited in that they do not reveal aspects of presynaptic terminal function. Fast scan cyclic voltammetry is a powerful tool for measuring presynaptic function due to its high temporal and spatial resolution. In the present study, we will investigate uptake rates and autoreceptor sensitivity as well as ethanol responsiveness in social isolation and group housing reared animals using voltammetry. We will be focusing on function within the nucleus accumbens and basolateral amygdala, as these areas believed to be important for ethanol's reinforcing properties. PUBLIC HEALTH RELEVANCE: The research proposed in this NRSA is significant as alcohol abuse is a major concern for public health and safety. Indeed, alcohol is reported as one of the most abused substances within the United States, representing ~40% of all admissions to drug abuse treatment facilities (SAMHSA, Treatment Episode Data Set, 2008). Because basic science research of alcohol abuse implements non-human animal models, it is important for translational purposes that these animal models somewhat reflect the disorder. For example, animal models of increased drinking may help elucidate the underlying neuronal substrates/mechanisms behind alcoholism. Rats raised in social isolation are a promising candidate for such a model. Similar to humans, socially isolated rats show increases in anxiety and impulsivity, that seemingly predict alcohol consumption levels. Dopamine's putative role in ethanol reinforcement, make it a prime candidate for studying the neural correlates of alcohol abuse. By studying the dopamine systems of these animals, we may gain important insight into underlying mechanisms that increase an animal's propensity to drink. This research is clinically relevant in that it may help direct the development of new drugs for treating alcoholism.

? DESCRIPTION (provided by applicant): Dopamine release in the nucleus accumbens is important for reinforcement learning of cues associated with natural and drug related rewards. Cocaine enhances dopamine signals in the accumbens through multiple mechanisms including reduced uptake which results in larger dopamine signals, as well as increases in frequency of spontaneous dopamine release events. Cocaine's mechanism of action for enhancing spontaneous release frequency is currently unknown. Recent studies have underscored the importance of cholinergic signaling onto dopamine terminals. Most notably, optogenetic stimulation of cholinergic interneurons is sufficient for driving dopamine release. Furthermore, cocaine enhances cholinergic firing, and inhibition of cholinergic activity during cocaine exposure reduces cocaine reward in condition place preference paradigms. Together, these observations indicate that the cholinergic neurons play a major role in modulating the release of dopamine within the accumbens during cocaine exposure. In preliminary experiments, spontaneous dopamine release was observed using voltammetry in brain slices containing the nucleus accumbens. These spontaneous dopamine events were infrequent, small and increased in the presence of cocaine. Furthermore, cocaine-enhanced spontaneous dopamine release was reduced by nicotinic acetylcholine receptor blockade. The overall goal of the current proposal is to investigate the origin of spontaneous dopamine signals. The hypothesis is that these spontaneous signals are driven by the activity of the cholinergic interneurons that result in the release of acetylcholine that act on nicotinic receptors on local terminals from dopamine neurons. This hypothesis will be tested using a combination of voltammetry and electrophysiology techniques in a paired recording configuration in coronal striatum mouse brain slices. Together, these results will reveal several important mechanisms underlying the local regulation of dopamine release in the nucleus accumbens and striatum. Furthermore, these studies will provide information on cocaine's effects on cholinergic activity important for drug reward/reinforcement.