Although alcohol (EtOH) is one of the oldest known drugs of abuse, the neuroliogical mechanisms underlying EtOH's actions are not fully known and as such, it remains difficult to understand how one may lose control of normal EtOH drinking resulting in alcoholism. Alcoholism is often found to be comorbid with anxiety and stress disorders, and while the eitology of this comorbidity is not fully known it has been proposed that since EtOH has long been known as an anxiolytic agent, some may imbibe as a way to selfmedicate their anxious or stressed states. Withdrawal from high EtOH levels has also been shown to result in an enhancement of anxious/stressed states, which may result in continued EtOH use and abuse. Therefore, it is hypothesized that EtOH may predominantly effect areas of the central nervous system (CMS) which mediate stress responses and anxiety, such as the basolateral amygdala (BLA). GABAergic synapses in the BLA have been shown to play a major role in emotional responses such as anxiety. Extensive research has shown that at least part of EtOH's effects in the CMS are due to an increase in GABAergic neurotransmission in numerous brain regions through both pre- and post-synaptic sites. Norepinephrine (NE), which is intimately linked to stress and anxiety disorders, has been shown increase GABA release in the BLA. Our preliminary data shows that NE receptor antagonists can block the potentiating effect of EtOH at a subset of GABAergic interneurons. Therefore it is hypothesized that EtOH enhances GABAergic transmission in the BLA in part via NE-receptor activity. The first specific aim is to determine the mechanisms by which acute EtOH enhances GABAergic neurotransmission at two subset of interneurons in the BLA.
This aim will rely on whole-cell patch clamp electrophysiological methods to determine if the effects of bath application of EtOH on slices of BLA tissue are pre- and/or post-synaptic utilizing a combination of protocols focusing mainly on evoked inhibitory postsynaptic currents (IPSCs) spontaneous and miniature IPSCs and paired-pulses facilitation studies to isolate pre- and post-synaptic components of the EtOH enhancement of GABAergic neurotransmission. The second specific aim will determine the mechanism by which NE interacts with EtOH at BLA GABAergic synapse and which NE-receptor subtype mediates this effect. We will be using similar methods as described above as well as combinations of NE receptor agonists and antagonists to isolate the mechanism of the proposed NE-EtOH interaction in this brain region. The third specific aim will focus on the effects of chonic intermittent EtOH exposure via inhalation chamber exposure on subsequent acute EtOH exposure and the NE-EtOH interaction studied aims 1 and 2. ? ? ?
| Silberman, Yuval; Ariwodola, Olusegun J; Weiner, Jeff L (2012) ?1-adrenoceptor activation is required for ethanol enhancement of lateral paracapsular GABAergic synapses in the rat basolateral amygdala. J Pharmacol Exp Ther 343:451-9 |
| Silberman, Yuval; Ariwodola, Olusegun J; Chappell, Ann M et al. (2010) Lateral paracapsular GABAergic synapses in the basolateral amygdala contribute to the anxiolytic effects of beta 3 adrenoceptor activation. Neuropsychopharmacology 35:1886-96 |
| Silberman, Yuval; Ariwodola, Olusegun J; Weiner, Jeff L (2009) Differential effects of GABAB autoreceptor activation on ethanol potentiation of local and lateral paracapsular GABAergic synapses in the rat basolateral amygdala. Neuropharmacology 56:886-95 |
| Silberman, Yuval; Bajo, Michal; Chappell, Ann M et al. (2009) Neurobiological mechanisms contributing to alcohol-stress-anxiety interactions. Alcohol 43:509-19 |
