Withdrawal symptoms associated with the termination of long-term ethanol exposure are strong contributing factors for relapse in alcohol-dependent individuals. Rodent models permit detailed control and examination of these factors contributing to the development of alcohol dependence and withdrawal. One commonly used and validated method of inducing an ethanol dependence-like state in rodents is via vapor inhalation. Our laboratory observed that 10 days of chronic intermittent ethanol (CIE) exposure produces signs of ethanol dependence, (i.e., increased anxiety on the elevated plus maze [EPM], increased ethanol consumption) and neurophysiological changes in the basolateral amygdala (BLA)?a brain region strongly implicated in anxiety. The BLA receives sensory information from several upstream brain regions from projections via the external capsule and the stria terminalis. Furthermore, BLA neurons are differentially regulated after CIE exposure, depending on which pathway is stimulated. For instance, stimulation of the stria terminalis results in presynaptic ethanol adaptations that occur before postsynaptic ethanol changes at the external capsule in ethanol withdrawn animals compared to controls. Yet, little (if anything) is known about how the thalamic- and cortico-amygdala pathways contribute to anxiety?particularly anxiety produced by ethanol withdrawal. Preliminary data from our laboratory demonstrated that the posterior intralaminar thalamic (PIT) complex contributes to the behavioral and neurophysiological alterations that occur during ethanol withdrawal. Therefore, the current research project will test the novel hypothesis that presynaptic facilitation of PIT- BLA inputs early during a dependence-inducing exposure establishes both the behavioral and neurophysiological consequences of ethanol withdrawal. To test this hypothesis, an innovative series of experiments utilizing behavior, electrophysiology, and chemogenetic/optogenetic approaches will be used.
Aim 1 will demonstrate that the posterior intralaminar thalamic (PIT) complex mediates anxiety-like behavior following withdrawal from an ethanol dependence-like exposure.
Aim 2 will characterize the temporal relationship between pre- and postsynaptic glutamatergic adaptations at BLA principal neurons following CIE and withdrawal. Results from these experiments will yield valuable information on mechanisms involved in glutamatergic synaptic transmission in the BLA from upstream brain regions that are involved in the expression and maintenance of withdrawal-induced anxiety, which may ultimately lead to potential targets for therapeutics in the treatment of alcohol dependence.
Withdrawal from alcohol produces increases in anxiety, which may be associated with adaptations in glutamatergic synaptic transmission occurring in the basolateral amygdala (BLA). The purpose of the current research proposal is to determine how upstream brain regions interact within the BLA following a dependence- like state to regulate anxiety and neurophysiological changes that emerge during withdrawal. The present set of experiments will provide insight into the circuitry/mechanisms governing these behavioral and synaptic changes, and, therefore, opportunities for potential therapeutic targets.
|Morales, Melissa; McGinnis, Molly M; Robinson, Stacey L et al. (2018) Chronic Intermittent Ethanol Exposure Modulation of Glutamatergic Neurotransmission in Rat Lateral/Basolateral Amygdala is Duration-, Input-, and Sex-Dependent. Neuroscience 371:277-287|