Browsing by Subject "Cholinergic mechanisms"
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Item Cholinergic interneurons and synaptic reorganization within the nucleus accumbens shell and core: potential neural substrates underlying drug addiction(2006) Berlanga, Monica Lisa; Alcantara, Adriana A.Drug abuse and dependence are among the most challenging public health issues facing America today. The acute treatment of drugs of abuse such as psychostimulants (Trantham-Davidson and Lavin, 2004) and opiates (Harris and Williams, 1991) produce transient changes in cellular activity and synaptic signaling. Repeated drug treatment, however, results in persistent cellular and behavioral changes, such as altered dendritic morphology and behavioral sensitization (Robinson and Kolb, 1999b). Synaptic changes in the brain are posited to underlie a repertoire of drug-induced persistent behaviors, including sensitization, psychosis and relapse. Direct evidence of drug-induced synaptic plasticity, however, has not been demonstrated. The present studies were designed to examine cholinergic neurons and synaptic rewiring as potential neural substrates involved in acute and chronic drug exposure. The proposed studies tested the hypotheses that 1) cholinergic interneurons within the nucleus accumbens (NAcc) are activated by the acute self-administration of cocaine, 2) dopamine (DA) D5 and D2 receptors localized on cholinergic interneurons potentially undergo cocaine-induced neuroadaptation, and 3) repeated administration of cocaine leads to an increase, while repeated administration of morphine leads to a decrease, in the number of synapses within the NAcc, whereas an increase in the number of synapses occurs in the NAcc core of animals exhibiting behavioral sensitization. These studies revealed that accumbal cholinergic interneurons are activated by acute cocaine self-administration and elucidate the specific localization of DA receptor subtypes, D5 and D2, on these cells, suggesting their potential role in mediating druginduced DA changes within the NAcc. The final study provided the first ultrastructural evidence that an increase in the number of excitatory synapses in the NAcc shell occurs following 4-weeks of cocaine and morphine treatment followed by 3 weeks abstinence and that cocaine sensitization is associated with an increase in the number of excitatory synapses in the NAcc core. These findings provide the groundwork for future studies examining the precise cellular and synaptic substrates underlying a repertoire of druginduced behaviors that contribute to the persistence of addiction. Improved pharmacotherapeutic and behavioral treatments can then target the specific cellular and synaptic microcircuitry critically involved in the different stages of drug abuse and dependence.Item Involvement and neuroplasticity of cholinergic interneurons of the nucleus accumbens in initiation and excessive alcohol drinking(2007-12) Camp, Marguerite Charlotte, 1980-; Alcantara, Adriana A.; Jones, Theresa A.Alcoholism is a complex disease that exists as a specific set of behaviors, such as the preoccupation with obtaining alcohol and compulsive alcohol drinking. Currently, more than 18 million adults in the United States suffer from alcohol abuse or alcoholism. This disease poses serious medical and economic consequences for society. Identifying the neurobiological mechanisms that underlie alcohol drinking, specifically the transition from initiation to binge drinking is critical for improved treatments for alcoholics and the vulnerability for relapse in those recovering. Many studies have identified brain regions and molecular mechanisms that underlie various stages of alcohol abuse; however few have investigated the role of specific cell types within these areas. The overarching hypothesis of the studies in this dissertation is that cholinergic interneurons of the nucleus accumbens (NAc) are key neural substrates that underlie alcohol drinking, and as drinking continues; neuroadaptations within these cells then facilitate such behaviors as compulsive alcohol drinking. More specifically, these studies tested whether 1) cholinergic cell ablation in the NAc causes a decrease in alcohol drinking in C57BL/6J mice, 2) neuroadaptive changes in dopamine (DA) D2 receptor and cyclin dependent kinase 5 (Cdk5) occur within these cells following initiation alcohol drinking, and to a greater extent following binge alcohol drinking in C57BL/6J mice, and 3) neuroadaptive changes in DA D2 receptor and Cdk5 also occur in brain regions that have been implicated in the rewarding and reinforcing effects of alcohol in inbred alcohol-preferring (iP) rats. The present findings report a causal role for accumbal cholinergic neurons in binge alcohol drinking and identify DA D2 receptor and Cdk5 neuroadaptations following initiation and binge alcohol drinking. These studies identify the involvement of cholinergic interneurons in binge drinking and reveal alcohol-induced region- and cell-specific receptor and molecular changes that occur with continued drinking. These findings contribute to the understanding of the neurobiological mechanisms that underlie alcohol drinking, and provide the basis for cholinergic targeted treatments designed to attenuate binge drinking. These data also provide the groundwork for future studies aimed to examine receptor and intracellular molecular changes that occur with compulsive alcohol drinking, craving, and relapse.