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Selected Discoveries

Glutamatergic Mechanisms of Alcohol Self-Administration and Relapse

A main purpose of our research is to identify and validate novel mechanisms of the positive reinforcing effects of alcohol. Positive reinforcement is required for the etiology of addiction and may subserve initial adaptations that lead to escalated drug use. Our recent work has focused on glutamate receptor systems and downstream intracellular signaling pathways. We have moved the field forward in our understanding of metabotropic glutamate receptor regulation of alcohol self-administration, discrimination, and acute response and recently extended our efforts to include ionotropic AMPA-type glutamate receptors due to their prominent role in neuroplasticity and the lack of information in the field regarding AMPA regulation of alcohol self-administration. We have shown that glutamate signaling regulates self-administration and relapse via protein kinase signaling (ERK and CaMKII) in the amygdala and other limbic reward-associated brain regions. We are especially excited about our recent discoveries indicating that the AMPAR-CaMKII signaling pathway is both required for alcohol reinforcement and able to promote escalated self-administration. This bidirectional modulation is a strong indication of a mechanistic biological system that may underlie escalated alcohol intake that occurs during the initial stages of addiction when the positive reinforcing effects of alcohol predominate. This concept forms much of the basis for our continuing (proposed) work. Selected publications illustrating these discoveries:

  • Cannady R, Fisher KR, Durant B, Besheer J, Hodge CW. Enhanced AMPA receptor activity Increases operant alcohol self-administration and cue-Induced reinstatement. Addiction Biology 18(1):54-65; 2013
  • Agoglia AE, Holstein SE, Reid G, Hodge CW. CaMKIIα-GluA1 activity underlies vulnerability to adolescent binge alcohol drinking. Alcohol Clin Exp Res, 39(9):1680-90; 2015.
  • Faccidomo S, Reid GT, Agoglia AE, Ademola SA, Hodge CW. CaMKII inhibition in the prefrontal cortex specifically increases the positive reinforcing effects of alcohol in C57BL/6J mice. Behav Brain Res 298: 286–290; 2016.
  • Salling MC, Faccidomo SP, Li C, Psilos K, Galunas C, Spanos M, Agoglia AE, Kash TL, Hodge CW. Moderate alcohol drinking and the amygdala proteome: Identification and validation of CaMKII as a novel molecular mechanism of the positive reinforcing effects of alcohol. Biological Psychiatry 15;79(6):430-42; 2016.

 

Mesolimbic Dopamine Systems Regulate the Reinforcing Effects of Alcohol

Alcohol addiction is a complex degenerative condition that begins with repeated binge/intoxication episodes that are primarily controlled by the positive reinforcing effects of the drug. Dr. Hodge’s initial research in the alcohol field began as a postdoc at the University of Washington in Seattle with his mentor and friend, Dr. Hank Samson in 1991. Using Hank’s sucrose fading procedure combined with site-specific microinjection techniques in rats, our work addressed the seminal question of whether mesolimbic dopamine mechanistically regulates the positive reinforcing effects of alcohol. We showed that enhanced dopamine activity in the nucleus accumbens escalates operant alcohol self-administration. This was the first evidence that the brain’s reward pathway functionally escalates alcohol self-administration via dopamine. We also showed that dopamine and GABA receptor activity in the accumbens, VTA and PFC are required for the reinforcing effects of alcohol. We established critical analyses, including assessing the onset, maintenance, and termination of operant alcohol self-administration and published a total of 17 papers addressing mechanisms of alcohol reinforcement. Selected publications addressing dopamine:

  • Hodge CW, Samson HH, Chappelle AM. Alcohol self-administration: further examination of the role of dopamine receptors in the nucleus accumbens. Alcohol Clin Exp Res. 1997 Sep;21(6):1083-91. PubMed PMID: 9309321.
  • Hodge CW, Chappelle AM, Samson HH. Dopamine receptors in the medial prefrontal cortex influence ethanol and sucrose-reinforced responding. Alcohol Clin Exp Res. 1996 Dec;20(9):1631-8. PubMed PMID: 8986215.
  • Samson HH, Hodge CW, Tolliver GA, Haraguchi M. Effect of dopamine agonists and antagonists on ethanol-reinforced behavior: the involvement of the nucleus accumbens. Brain Res Bull. 1993;30(1-2):133-41. PubMed PMID: 8093596.
  • Hodge CW, Samson HH, Haraguchi M. Microinjections of dopamine agonists in the nucleus accumbens increase ethanol-reinforced responding. Pharmacol Biochem Behav. 1992 Sep;43(1):249-54. PubMed PMID: 1357676.

 

Neural Basis of the Interoceptive (Discriminative Stimulus) Effects of Alcohol

Dr. Hodge’s first R01 grant (awarded in 1994) sought to determine if the discriminative stimulus effects (subjective effects) of alcohol are regulated by GABAA and/or NMDA receptors in specific limbic brain regions. At the time, it was known that systemic GABAergics and NMDA antagonists would substitute for systemic alcohol in drug discrimination models. However, there was no information regarding brain regional regulation of this critical addiction-linked property of alcohol. We have shown that a microinjection of the GABAA agonist muscimol in the nucleus accumbens substitutes fully for a full systemic dose of alcohol (1 g/kg) and extended this work into several limbic brain regions. Overall, this work shows that the perception of alcohol (interoceptive stimulus) and self-administration are regulated by overlapping mechanisms and neural circuits, suggesting that the perception of alcohol regulates, or interacts with, self-administration. Accordingly, we developed a procedure to assess the discriminative stimulus effects of self-administered alcohol and found co-regulation of discrimination and self-administration by GABAA and NMDA receptors. This work underscores the critical importance of the subjective effects of alcohol.

  • Besheer J, Hodge CW. Pharmacological and anatomical evidence for an interaction between mGluR5- and GABA(A) alpha1-containing receptors in the discriminative stimulus effects of ethanol. Neuropsychopharmacology. 2005 Apr;30(4):747-57. PubMed PMID: 15549054; PubMed Central PMCID: PMC2892057.
  • Besheer J, Cox AA, Hodge CW. Coregulation of ethanol discrimination by the nucleus accumbens and amygdala. Alcohol Clin Exp Res. 2003 Mar;27(3):450-6. PubMed PMID: 12658110.
  • Hodge CW, Cox AA. The discriminative stimulus effects of ethanol are mediated by NMDA and GABA(A) receptors in specific limbic brain regions. Psychopharmacology (Berl). 1998 Sep;139(1-2):95-107. PubMed PMID: 9768547.
  • Hodge CW. Comparison of the discriminative stimulus function of ethanol following intracranial and systemic administration: evidence of a central mechanism. Pharmacol Biochem Behav. 1994 Mar;47(3):743-7. PubMed PMID: 8208795.

 

PKC-epsilon Regulates Alcohol Sensitivity, Interaction with GABA-A Receptors, and Self-Administration

In a variety of studies, our laboratory discovered that PKC-epsilon regulates alcohol and benzodiazepine sensitivity of GABAA receptors, which had major implications in alcohol self-administration and other responses. Accordingly, PKC-epsilon mice self-administer less alcohol, are more sensitive to the sedative and activating effects of alcohol, and show reduced withdrawal severity. Moreover, my laboratory discovered that PKC-epsilon mice show a dramatically blunted mesolimbic dopamine response to alcohol. Overall, these were the first studies to identify the behavioral and in vivo relevance of PKC-epsilon to the addictive properties of alcohol.

    • Olive MF, Mehmert KK, Messing RO, Hodge CW. Reduced operant ethanol self-administration and in vivo mesolimbic dopamine responses to ethanol in PKCepsilon-deficient mice. Eur J Neurosci. 2000 Nov;12(11):4131-40. PubMed PMID: 11069609.
    • Olive MF, Hodge CW. Co-localization of PKCepsilon with various GABA(A) receptor subunits in the mouse limbic system. Neuroreport. 2000 Mar 20;11(4):683-7. PubMed PMID: 10757500.
    • Hodge CW, Mehmert KK, Kelley SP, McMahon T, Haywood A, Olive MF, Wang D, Sanchez-Perez AM, Messing RO. Supersensitivity to allosteric GABA(A) receptor modulators and alcohol in mice lacking PKCepsilon. Nat Neurosci. 1999 Nov;2(11):997-1002. PubMed PMID: 10526339.

 

Novel Molecular Mechanisms of Anxiety and Depression

Based on our work with PKC-epsilon and GABAA receptors, we put forward the hypothesis that the kinase may influence anxiety-like behavior (via enhanced GABAA activity). As part of an ABMRF and State of California funded project, we showed that PKC-epsilon null mice exhibit an anxiolytic phenotype that is mediated by GABAA receptor activity. We also showed, in collaboration with the Baekkeskov lab, that GAD-65 null mice exhibit heightened anxiety-like behavior. We also showed that loss of the 5-HT3A molecular subunit produces an anxiolytic phenotype in mice. These studies were the first to identify these novel molecular mechanisms of anxiety and suggest new neural targets and treatment strategies for the medical management of anxiety.

    • Stevenson JR, Schroeder JP, Nixon K, Besheer J, Crews FT, Hodge CW. Abstinence following alcohol drinking produces depression-like behavior and reduced hippocampal neurogenesis in mice. Neuropsychopharmacology. 2009 Apr;34(5):1209-22. PubMed PMID: 18563059; PubMed Central PMCID: PMC2844649.
    • Kelley SP, Bratt AM, Hodge CW. Targeted gene deletion of the 5-HT3A receptor subunit produces an anxiolytic phenotype in mice. Eur J Pharmacol. 2003 Feb 7;461(1):19-25. PubMed PMID: 12568911.
    • Hodge CW, Raber J, McMahon T, Walter H, Sanchez-Perez AM, Olive MF, Mehmert K, Morrow AL, Messing RO. Decreased anxiety-like behavior, reduced stress hormones, and neurosteroid supersensitivity in mice lacking protein kinase Cepsilon. J Clin Invest. 2002 Oct;110(7):1003-10. PubMed PMID: 12370278; PubMed Central PMCID: PMC151152.
    • Kash SF, Tecott LH, Hodge C, Baekkeskov S. Increased anxiety and altered responses to anxiolytics in mice deficient in the 65-kDa isoform of glutamic acid decarboxylase. Proc Natl Acad Sci U S A. 1999 Feb 16;96(4):1698-703. PubMed PMID: 9990087; PubMed Central PMCID: PMC15565.