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Ethanol Enhancement of Two Distinct Inhibitory Pathways in the Rat Basolateral Amygdala: Implications for Anxiety and Alcoholism

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Ethanol Enhancement of Two Distinct Inhibitory Pathways in the Rat Basolateral Amygdala: Implications for Anxiety and Alcoholism
Silberman, Yuval
The basolateral amygdala (BLA) acts as a key interface between the interpretation of external stimuli and the production of emotional responses, such as fear and anxiety. As such, the BLA is activated in response to stressful stimuli, then integrates and projects this information to target brain regions, which in turn produce the appropriate behavioral response. Inappropriate BLA activation to non-threatening stimuli is thought to be an important component of the neurocircuitry underlying many types of anxiety disorders. Importantly, numerous studies have shown that decreased BLA activity typically leads to decreased anxiety-like behaviors. Therefore, GABAergic inhibition in the BLA is hypothesized to play an important role in the regulation of anxiety. Alcoholism is thought to be closely related to anxiety disorders. Acute EtOH intoxication is known to produce profound anxiolytic effects, while withdrawal from chronic EtOH exposure produces increased anxiety-like behaviors. This suggests that EtOH may interact with brain regions associated with the production of anxiety behaviors, such as the BLA. In addition, little tolerance develops to the acute anxiolytic properties of EtOH, which may lead to enhanced EtOH seeking during times of withdrawal to reduce negative affect states, thus leading to protracted bouts of EtOH binging and withdrawals. This has led to the hypothesis that the acute negatively reinforcing properties of EtOH intoxication are a key component in the development of alcoholism. EtOH is known to interact with GABAergic synaptic transmission in many brain regions. Since EtOH is known to be an anxiolytic drug and since increased GABAergic transmission in the BLA leads to decreased anxiety-like behaviors, it is hypothesized that one cellular mechanism by which EtOH produces its anxiolytic effects may occur via an enhancement of BLA GABAergic inhibition. To that end, the studies presented in this dissertation sought to determine the mechanism of EtOH action at GABAergic synapses in the BLA. Initial studies in Chapter II, utilizing immunohistochemical and electrophysiological techniques, showed that two distinct inhibitory pathways exist in the rat BLA: the local interneuron mediated pathway and the lateral paracapsular interneuron (lpcs) mediated pathway. EtOH enhanced both BLA inhibitory pathways, albeit via distinct mechanisms. EtOH enhancement of the local interneuron pathway appeared to involve a presynaptic facilitation of GABA release, which could be regulated by GABAB autoreceptors. In contrast, EtOH enhancement of the lpcs pathway did not appear to involve an increase in GABA release, but did require activation of adrenergic receptors (ARs). Chapter III further examined the disparate nature of EtOH enhancement of local and lpcs synapses and their contrasting regulation by GABAB autoreceptors. Synaptic pools of GABAB autoreceptors at lpcs interneurons appeared to be tonically active under control conditions, while synaptic pools of GABAB autoreceptors at local interneurons could be activated by paired-pulse protocols. Furthermore, while exogenous agonist activation of GABAB autoreceptors by baclofen could inhibit both local and lpcs synapses to a similar extent, baclofen pretreatment could only inhibit EtOH potentiation of local synapses. The effects of EtOH and GABAB modulators on spontaneous/miniature IPSCs mimicked that of local eIPSCs. These findings suggest that EtOH enhancement of local synapses is due to a presynaptic release of GABA under the regulation of GABAB receptors while further underscoring the differences between EtOH’s effects at local and lpcs synapses. Studies in Chapters IV and V further examined the requirement of AR activation in mediating the effects of EtOH at lpcs synapses. These studies determined that activation of β1-ARs at lpcs synapses are required, at least in part, for EtOH enhancement of lpcs synapses. In addition, β3-AR activation was also shown to selectively enhance lpcs inhibition and intra-BLA infusion of a β3-AR agonist decreased anxiety-like behaviors, providing initial evidence of a novel pathway that may play a role in anxiolysis and, potentially, in the treatment of alcoholism. Taken together, the studies in this dissertation are the first to show that EtOH enhances GABAergic synaptic transmission at two distinct BLA inhibitory pathways, consistent with the potent anxiolytic nature of this drug. Furthermore, these studies indicate two distinct mechanisms by which these BLA inhibitory pathways may be pharmacologically altered, thereby opening new avenues for the development of pharmacotherapies selectively targeting these two inhibitory pathways in the BLA for future treatments of both anxiety disorders and alcoholism.
Godwin, Dwayne (committee chair)
Jones, Sara (committee member)
McCool, Brian (committee member)
Martin, Jeff (committee member)
2009-10-21T19:30:38Z (accessioned)
2010-06-18T18:58:29Z (accessioned)
2009-10-21T19:30:38Z (available)
2010-06-18T18:58:29Z (available)
2009-10-21T19:30:38Z (issued)
Pharmacology (discipline)
http://hdl.handle.net/10339/14768 (uri)
en_US (iso)
Wake Forest University
Release the entire work for access only to the Wake Forest University system for one year from the date below. After one year, release the entire work for access worldwide. (accessRights)

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