ly-341495 and Alcoholism

Alcohol use disorders are associated with deficits in adaptive behavior. While some behavioral impairments that are associated with alcohol use disorders may predate exposure to drugs of abuse, others may result directly from exposure to drugs of abuse, including alcohol. Identifying a causal role for how alcohol exposure leads to these impairments will enable further investigation of the neurobiological mechanisms by which it acts to dysregulate adaptive behavior.. In the present study, we examined the effects of chronic intermittent ethanol exposure (CIE) on the use of reward-paired cues to guide consummatory behaviors in a mouse model, and further, how manipulations of mGluR2/3 signaling-known to be dysregulated after chronic alcohol exposure-may alter the expression of this behavior.. Adult male C57B/6J mice were trained to self-administer 10 % ethanol and exposed to CIE via vapor inhalation. After CIE exposure, mice were trained in a Pavlovian task wherein a cue (tone) was paired with the delivery of a 10 % sucrose unconditioned stimulus. The use of the reward-paired cue to guide licking behavior was determined across training. The effect of systemic mGluR2/3 manipulation on discrimination between cue-on and cue-off intervals was assessed by administration of the mGluR2/3 agonist LY379268 or the antagonist LY341495 prior to a testing session.. Exposure to CIE resulted in reductions in discrimination between cue-on and cue-off intervals, with CIE-exposed mice exhibiting significantly lower consummatory behavior during reward-paired cues than air controls. In addition, systemic administration of an mGluR2/3 agonist restored the use of reward-paired cues in CIE-exposed animals without impacting behavior in air controls. Conversely, administration of an mGluR2/3 antagonist mimicked the effects of CIE on cue-guided licking behavior, indicating that mGluR2/3 signaling can bidirectionally regulate the ability to use reward-paired cues to guide behavior.. Together, these data suggest that chronic ethanol exposure drives impairments in the ability to use reward-paired cues to adaptively regulate behavior and that mGluR2/3 receptors represent a therapeutic target for restoration of these deficits in behavioral control in the alcoholic.

Topics: Adaptation, Psychological; Alcoholism; Amino Acids; Animals; Bridged Bicyclo Compounds, Heterocyclic; Conditioning, Operant; Consummatory Behavior; Cues; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Male; Mice; Mice, Inbred C57BL; Psychomotor Performance; Receptors, AMPA; Reward; Self Administration; Signal Transduction; Xanthenes

Metabotropic glutamate receptors 2 and 3 (mGluR2/3) contribute to control the level of glutamate in the synapse. In rodents, mGluR2/3 agonists attenuate the reinstatement of alcohol-seeking behavior. Linking possible alterations of the mGluR2/3 system to the etiology and type of alcoholism could provide valuable information for the development of novel mGluR2/3 function modulating therapies in addiction treatment. To date, mGluR2/3 binding density has not been studied in human alcoholics. We aimed to investigate the possible differences in mGluR2/3 binding between Cloninger type 1 anxiety-prone and type 2 impulsive alcoholics and controls.. We performed a post-mortem whole-hemisphere autoradiography to study the mGluR2/3 binding density of 9 type 1 alcoholics, 8 type 2 alcoholics and 10 controls. [(3)H]LY341495, a potent group II metabotropic glutamate receptor antagonist, was used as the radio-ligand with l-glutamate as a displacer.. [(3)H]LY341495 binding density was statistically significantly increased (P = 0.046) in the perigenual anterior cingulate cortex (pACC) of type 2 alcoholics when compared with controls. In other brain areas, no significant difference between the groups was found.. This preliminary study suggests that impulsive type 2 alcoholics might have alterations in the mGluR2/3 function in the pACC, a brain area presumed to be involved in the control of drug-seeking behaviors and self-control.

Topics: Adolescent; Adult; Aged; Alcoholism; Amino Acids; Autoradiography; Brain; Case-Control Studies; Female; Gyrus Cinguli; Humans; Male; Middle Aged; Receptors, Metabotropic Glutamate; Xanthenes; Young Adult