The endogenous sulfonated amino acid taurine has numerous functions in the nervous system, including osmoregulation, neuroprotection and neuromodulation. However, the recent successful of the taurine analogue acamprosate (calcium acetylhomotaurinate) in reducing alcohol consumption in both rodents and humans suggests that taurine-related systems may be involved in the neurobiological mechanisms mediating alcohol self-administration.. Thus, taurine-related compounds may provide to be successful therapeutics for the treatment of alcohol abuse. Originally, we demonstrated that mutant mice lacking PKCepsilon, which exhibit reduced operant ethanol self-administration, showed elevated basal extracellular levels of taurine in the nucleus accumbens as compared to wild-type controls. This led us to the hypothesis that taurine may exert an inhibitory control over ethanol-seeking behavior. We now present preliminary data that acute peripheral injections of taurine, its metabolic precursor hypotaurine, as well as the taurine analogs homotaurine and acamprosate suppress voluntary ethanol consumption in the rat in a two-bottle choice paradigm. Of these compounds, homotaurine and acamprosate were the most effective in suppressing ethanol intake (i.e., > 50%). Moreover, only homotaurine was able to significantly suppress ethanol intake and preference in this acute administration paradigm. These data indicate that pharmacological compounds related to homotaurine may be of potential benefit in the treatment of excessive ethanol consumption. The following Specific Aims describe two sets of experiments designed to further study the ability of homotaurine and acamprosate to suppress alcohol self-administration. To date, no studies have been conducted regarding the neuroanatomical site(s) at which acamprosate or homotaurine suppress ethanol consumption. Thus, the first specific aim uses site-specific microinjection procedures to examine the neuroanatomical basis for homotaurine- and acamprosate-induced suppression of ethanol intake in ethanol-dependent and non-dependent animals. These studies will test the hypothesis that homotaurine and acamprosate act within the mesolimbic reward circuitry to reduce ethanol self-administration behavior in non-dependent animals, while homotaurine and acamprosate act within the extended amygdala to reduce ethanol self-administration behavior in ethanol-dependent animals. Thus, we hypothesize that the transition to ethanol dependency shifts the neuroanatomical locus of ethanol reinforcement from the mesolimbic system to structures in the extended amygdala, providing noel information regarding neurobiological changes that occur during the development of alcohol addiction. The second specific aim will use microdialysis to determine brain extracellular concentrations of acamprosate and homotaurine following acute and repeated oral administration. These studies will provide important and novel information regarding the bioavailability of these compounds in the central nervous system following peripheral administration. In addition, these studies will allow us to correlate the concentrations of these compounds in the brain following oral administration with he concentrations microinjected in Specific Aim 1 that are effect in reducing ethanol consumption in dependent and non-dependent animals.
|Burattini, Costanza; McGeehan, Andrew J; Griffin 3rd, William C et al. (2008) A microdialysis study of extracellular levels of acamprosate and naltrexone in the rat brain following acute and repeated administration. Addict Biol 13:70-9|
|Sahuque, Lacey L; Kullberg, Erika F; Mcgeehan, Andrew J et al. (2006) Anxiogenic and aversive effects of corticotropin-releasing factor (CRF) in the bed nucleus of the stria terminalis in the rat: role of CRF receptor subtypes. Psychopharmacology (Berl) 186:122-32|
|Mcgeehan, Andrew J; Olive, Michael Foster (2006) Attenuation of cocaine-induced reinstatement of cocaine conditioned place preference by acamprosate. Behav Pharmacol 17:363-7|
|Olive, M Foster; McGeehan, Andrew J; Kinder, Jennifer R et al. (2005) The mGluR5 antagonist 6-methyl-2-(phenylethynyl)pyridine decreases ethanol consumption via a protein kinase C epsilon-dependent mechanism. Mol Pharmacol 67:349-55|
|Olive, M Foster; Messing, Robert O (2004) Protein kinase C isozymes and addiction. Mol Neurobiol 29:139-54|
|McGeehan, Andrew J; Olive, M Foster (2003) The anti-relapse compound acamprosate inhibits the development of a conditioned place preference to ethanol and cocaine but not morphine. Br J Pharmacol 138:9-12|