A key issue in the alcohol field is identification of the neuronal circuits responsible for the loss of control over alcohol drinking in dependence. Loss of control has long been hypothesized to result from dysfunction of the frontal lobes and subsequent disinhibition (or activation) of subcortical systems that underlie stress, anxiety, reward, pain, and habits. Recent work has also causally implicated an ensemble in the central nucleus of the amygdala as required for excessive drinking and anxiety-like behavior during abstinence. The goal of the Neurocircuitry Component is to integrate these views by identifying the cortical pathways upstream (cortico- amygdalar) and downstream (amygdalo-cortical) of the CeA that contribute to the compulsivity of alcohol- drinking and negative emotional behavior. The first hypothesis in this proposal is that reduced infralimbic and greater anterior insula glutamatergic outflow to the amygdala promotes more compulsive drinking, with greater anxiety- and irritability-like behavior in abstinence. Reciprocally, the second hypothesis is that dysregulation of the prefrontal cortex partially results from activation of a neuronal ensemble in the CeA that promotes compulsive alcohol drinking and abstinence symptoms via recruitment of direct and indirect amygdalo-cortical projections to the infralimbic cortex and anterior insula. The third hypothesis is that dysregulated activation in cortico-amygdalo-cortical loops can be normalized by a selective glucocorticoid receptor antagonist or microtubule-associated protein-type 2 (MAP-2) ligand. This project may have a sustained and powerful impact on the field by (1) causally implicating specific cortico-amygdalo-cortico loops in the compulsivity of alcohol drinking and emergence of negative emotional states during abstinence and 2) identifying a circuit mechanism for the efficacy of glucocorticoid receptor antagonists and MAP-2 ligands to reduce drinking and negative emotional symptoms.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Comprehensive Center (P60)
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Special Emphasis Panel (ZAA1)
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Scripps Research Institute
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Mason, Barbara J; Quello, Susan; Shadan, Farhad (2018) Gabapentin for the treatment of alcohol use disorder. Expert Opin Investig Drugs 27:113-124
Varodayan, Florence P; Sidhu, Harpreet; Kreifeldt, Max et al. (2018) Morphological and functional evidence of increased excitatory signaling in the prelimbic cortex during ethanol withdrawal. Neuropharmacology 133:470-480
Matzeu, Alessandra; Martin-Fardon, Rémi (2018) Drug Seeking and Relapse: New Evidence of a Role for Orexin and Dynorphin Co-transmission in the Paraventricular Nucleus of the Thalamus. Front Neurol 9:720
Sidhu, Harpreet; Kreifeldt, Max; Contet, Candice (2018) Affective Disturbances During Withdrawal from Chronic Intermittent Ethanol Inhalation in C57BL/6J and DBA/2J Male Mice. Alcohol Clin Exp Res 42:1281-1290
Ehlers, Cindy L; Wills, Derek; Gilder, David A (2018) A history of binge drinking during adolescence is associated with poorer sleep quality in young adult Mexican Americans and American Indians. Psychopharmacology (Berl) 235:1775-1782
Pavon, Francisco J; Serrano, Antonia; Sidhpura, Nimish et al. (2018) Fatty acid amide hydrolase (FAAH) inactivation confers enhanced sensitivity to nicotine-induced dopamine release in the mouse nucleus accumbens. Addict Biol 23:723-734
Logrip, Marian L; Walker, John R; Ayanwuyi, Lydia O et al. (2018) Evaluation of Alcohol Preference and Drinking in msP Rats Bearing a Crhr1 Promoter Polymorphism. Front Psychiatry 9:28
Serrano, Antonia; Pavon, Francisco J; Buczynski, Matthew W et al. (2018) Deficient endocannabinoid signaling in the central amygdala contributes to alcohol dependence-related anxiety-like behavior and excessive alcohol intake. Neuropsychopharmacology 43:1840-1850
Spierling, Samantha R; Kreisler, Alison D; Williams, Casey A et al. (2018) Intermittent, extended access to preferred food leads to escalated food reinforcement and cyclic whole-body metabolism in rats: Sex differences and individual vulnerability. Physiol Behav 192:3-16
Blasio, Angelo; Wang, Jingyi; Wang, Dan et al. (2018) Novel Small-Molecule Inhibitors of Protein Kinase C Epsilon Reduce Ethanol Consumption in Mice. Biol Psychiatry 84:193-201

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