Abstract

Although the exact mechanism of interaction of ethanol (EtOH) with its neuronal targets is not yet understood, there is evidence that EtOH interacts with specific neuronal membrane receptor proteins to alter their normal function. Examples of receptors for which evidence supports a direct interaction with EtOH include; GABA-A, glutamate and several serotonin receptors. Newly developed methods for targeted alteration of gene function offer the possibility of establishing a cause and effect relationship between an action of EtOH on a molecular target and an EtOH-induced behavioral change. The current proposal focuses on the function of one such protein hitherto unexplored, namely cannabinoid (CB1) receptor in EtOH drinking and EtOH-related behaviors. Studies have indicated that there are genetic differences in the density and affinity of CB1 receptors in the brains of two strains of mouse found to differ in their preferences for EtOH. It has been demonstrated that administration of CB1 receptor antagonists reduced EtOH intake in EtOH-preferring mice. Based on these findings it is hypothesized that the genetically based differences in the brain levels and distribution of endocannabinoid ANA and CB1 receptors influence EtOH drinking behavior, and genetic manipulation through disruption of the gene for CB1 receptor protein will modulate the CB1-ergic system and the behavioral effects of EtOH.
The Specific Aims are: (1) to generate CBI receptor knockout mice with two different genetic backgrounds (2) study the effect of gene disruption on (2) the levels and distribution of anandamide and its receptor (CB1) in various brain regions, EtOH drinking, and other EtOH-related behaviors, (4) the effects of CB1 receptor agonist and antagonist on EtOH drinking and other EtOH-related behaviors, and (5) to investigate the dopamine release in nucleus accumbens. The long-term goal is to develop medication for treatment of problems associated with alcohol abuse and alcoholism, which would be comparable to medical use of marijuana. Studies with synthetic analogues of ANA or other agonists and antagonists will open up new avenues in alcohol research.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA013003-02
Application #
6509418
Study Section
Special Emphasis Panel (ZAA1-DD (02))
Program Officer
Egli, Mark
Project Start
2001-08-01
Project End
2005-04-30
Budget Start
2002-05-01
Budget End
2003-04-30
Support Year
2
Fiscal Year
2002
Total Cost
$252,262
Indirect Cost

  Institution

Name
Nathan Kline Institute for Psychiatric Research
Department
Type
DUNS #
167204762
City
Orangeburg
State
NY
Country
United States
Zip Code
10962

  Publications

Vinod, K Yaragudri; Yalamanchili, Ratnakumar; Thanos, Panayotis K et al. (2008) Genetic and pharmacological manipulations of the CB(1) receptor alter ethanol preference and dependence in ethanol preferring and nonpreferring mice. Synapse 62:574-81
Vinod, K Yaragudri; Sanguino, Elena; Yalamanchili, Ratnakumar et al. (2008) Manipulation of fatty acid amide hydrolase functional activity alters sensitivity and dependence to ethanol. J Neurochem 104:233-43
Vinod, K Yaragudri; Yalamanchili, Ratnakumar; Xie, Shan et al. (2006) Effect of chronic ethanol exposure and its withdrawal on the endocannabinoid system. Neurochem Int 49:619-25
Basavarajappa, Balapal S; Yalamanchili, Ratnakumar; Cravatt, Benjamin F et al. (2006) Increased ethanol consumption and preference and decreased ethanol sensitivity in female FAAH knockout mice. Neuropharmacology 50:834-44
Carai, Mauro A M; Colombo, Giancarlo; Gessa, Gian Luigi et al. (2006) Investigation on the relationship between cannabinoid CB1 and opioid receptors in gastrointestinal motility in mice. Br J Pharmacol 148:1043-50
Vinod, K Yaragudri; Hungund, Basalingappa L (2006) Cannabinoid-1 receptor: a novel target for the treatment of neuropsychiatric disorders. Expert Opin Ther Targets 10:203-10
Nowak, Karen L; Vinod, K Yaragudri; Hungund, Basalingappa L (2006) Pharmacological manipulation of CB1 receptor function alters development of tolerance to alcohol. Alcohol Alcohol 41:24-32
Baslow, Morris H; Dyakin, Victor V; Nowak, Karen L et al. (2005) 2-PMPA, a NAAG peptidase inhibitor, attenuates magnetic resonance BOLD signals in brain of anesthetized mice: evidence of a link between neuron NAAG release and hyperemia. J Mol Neurosci 26:1-15
Basavarajappa, Balapal S; Hungund, Basalingappa L (2005) Role of the endocannabinoid system in the development of tolerance to alcohol. Alcohol Alcohol 40:15-24
Vinod, K Yaragudri; Arango, Victoria; Xie, Shan et al. (2005) Elevated levels of endocannabinoids and CB1 receptor-mediated G-protein signaling in the prefrontal cortex of alcoholic suicide victims. Biol Psychiatry 57:480-6

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