Reverse Pharmacogenetic Modulation of the Nucleus Accumbens Reduces Ethanol Consumption in a Limited Access Paradigm

Bilateral stereotactic lesioning of the nucleus accumbens (NAc) core reduces relapse rates in alcohol-dependent patients but may cause irreversible cognitive deficits. Deep brain stimulation has similar effects but requires costly implanted hardware and regular surgical maintenance. Therefore, there is considerable interest in refining these approaches to develop reversible, minimally invasive treatments for alcohol dependence. Toward this end, we evaluated the feasibility of a reverse pharmacogenetic approach in a preclinical mouse model. We first assessed the predictive validity of a limited access ethanol consumption paradigm by confirming that electrolytic lesions of the NAc core decreased ethanol consumption, recapitulating the effects of similar lesions in humans. We then used this paradigm to test the effect of modulating activity in the NAc using the Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) hM3Dq and hM4Di. We found that increasing activity with hM3Dq had no effect, but suppressing activity with hM4Di reduced alcohol consumption to a similar extent as lesioning without affecting consumption of water or sucrose. These results may represent early steps toward a novel neurosurgical treatment modality for alcohol dependence that is reversible and externally titratable, yet highly targetable and less invasive than current approaches such as lesioning or deep brain stimulation.

[1]  M. Souweidane,et al.  Gene therapy for late infantile neuronal ceroid lipofuscinosis: neurosurgical considerations. , 2010, Journal of neurosurgery. Pediatrics.

[2]  Robert D Brewer,et al.  Economic costs of excessive alcohol consumption in the U.S., 2006. , 2011, American journal of preventive medicine.

[3]  J. Neumaier,et al.  Increased expression of 5-HT1B receptors in rat nucleus accumbens via virally mediated gene transfer increases voluntary alcohol consumption. , 2006, Alcohol.

[4]  N. Volkow,et al.  Overexpression of dopamine D2 receptors reduces alcohol self‐administration , 2001, Journal of neurochemistry.

[5]  V. Dole,et al.  Toward an analogue of alcoholism in mice: scale factors in the model. , 1984, Proceedings of the National Academy of Sciences of the United States of America.

[6]  J. Crabbe,et al.  Evaluation of a simple model of ethanol drinking to intoxication in C57BL/6J mice , 2005, Physiology & Behavior.

[7]  M. Ford,et al.  Assessment of GABA-B, metabotropic glutamate, and opioid receptor involvement in an animal model of binge drinking. , 2011, Alcohol.

[8]  R. Hitzemann,et al.  Electrolytic lesions of the medial nucleus accumbens shell selectively decrease ethanol consumption without altering preference in a limited access procedure in C57BL/6J mice , 2009, Pharmacology Biochemistry and Behavior.

[9]  J. Tepper,et al.  Heterogeneity and Diversity of Striatal GABAergic Interneurons , 2010, Front. Neuroanat..

[10]  Russell S. Ray,et al.  Impaired Respiratory and Body Temperature Control Upon Acute Serotonergic Neuron Inhibition , 2011, Science.

[11]  M. Jann,et al.  Reversible metabolism of clozapine and clozapine N-oxide in schizophrenic patients , 1998, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[12]  B. Bynum.  Consumption , 1897, The Lancet.

[13]  Wei Zhao,et al.  Preliminary findings in ablating the nucleus accumbens using stereotactic surgery for alleviating psychological dependence on alcohol , 2010, Neuroscience Letters.

[14]  Nora D Volkow,et al.  Neurocircuitry of Addiction , 2010, Neuropsychopharmacology.

[15]  Lief E. Fenno,et al.  The development and application of optogenetics. , 2011, Annual review of neuroscience.

[16]  B. Roth,et al.  Rapid, reversible activation of AgRP neurons drives feeding behavior in mice. , 2011, The Journal of clinical investigation.

[17]  P. Janak,et al.  Separable Roles of the Nucleus Accumbens Core and Shell in Context- and Cue-Induced Alcohol-Seeking , 2010, Neuropsychopharmacology.

[18]  A. Rezai,et al.  AAV2-GAD gene therapy for advanced Parkinson's disease: a double-blind, sham-surgery controlled, randomised trial , 2011, The Lancet Neurology.

[19]  G. Mcclearn,et al.  Mouse strain differences in preference for various concentrations of alcohol. , 1962, Quarterly journal of studies on alcohol.

[20]  B. Roth,et al.  Evolving the lock to fit the key to create a family of G protein-coupled receptors potently activated by an inert ligand , 2007, Proceedings of the National Academy of Sciences.

[21]  B. Bogerts,et al.  Deep brain stimulation surgery for alcohol addiction. , 2013, World neurosurgery.

[22]  V. Sturm,et al.  Successful deep brain stimulation of the nucleus accumbens in severe alcohol dependence is associated with changed performance monitoring , 2011, Addiction biology.

[23]  N. Volkow,et al.  DRD2 gene transfer into the nucleus accumbens core of the alcohol preferring and nonpreferring rats attenuates alcohol drinking. , 2004, Alcoholism, clinical and experimental research.

[24]  J. Neumaier,et al.  Overexpression of 5-HT(1B) mRNA in nucleus accumbens shell projection neurons differentially affects microarchitecture of initiation and maintenance of ethanol consumption. , 2011, Alcohol.

[25]  V. Sturm,et al.  Counteracting Incentive Sensitization in Severe Alcohol Dependence using Deep Brain Stimulation of the Nucleus Accumbens: Clinical and Basic Science Aspects , 2009, Front. Hum. Neurosci..

[26]  M. Nicolelis,et al.  Remote Control of Neuronal Activity in Transgenic Mice Expressing Evolved G Protein-Coupled Receptors , 2009, Neuron.

[27]  E. Nestler,et al.  The Striatal Balancing Act in Drug Addiction: Distinct Roles of Direct and Indirect Pathway Medium Spiny Neurons , 2011, Front. Neuroanat..

[28]  N. Volkow,et al.  Dopamine D2R DNA transfer in dopamine D2 receptor-deficient mice: effects on ethanol drinking. , 2005, Life sciences.

[29]  C. Fahlke,et al.  Effects of ibotenic acid lesions of the ventral striatum and the medial prefrontal cortex on ethanol consumption in the rat. , 1995, Alcohol.

[30]  W. Jagust,et al.  Safety and tolerability of putaminal AADC gene therapy for Parkinson disease , 2009, Neurology.

[31]  A. Grace,et al.  Identifying the neural circuitry of alcohol craving and relapse vulnerability , 2009, Addiction biology.

[32]  S. Hansen,et al.  Increased alcohol intake and behavioral disinhibition in rats with ventral striatal neuron loss , 2000, Physiology & Behavior.

[33]  B. Roth,et al.  Remote Control of Neuronal Signaling , 2011, Pharmacological Reviews.

[34]  G. Miesenböck,et al.  Photocontrol of neural activity: biophysical mechanisms and performance in vivo. , 2008, Chemical reviews.

[35]  D. Miao,et al.  Evaluation of Short-Term Psychological Functions in Opiate Addicts after Ablating the Nucleus Accumbens via Stereotactic Surgery , 2008, Stereotactic and Functional Neurosurgery.

[36]  C. Gremel,et al.  Roles of the Nucleus Accumbens and Amygdala in the Acquisition and Expression of Ethanol-Conditioned Behavior in Mice , 2008, The Journal of Neuroscience.