Stressful life events are associated with increased alcohol intake and relapse in humans. We have studied, using animal models, the brain mechanisms underlying such reinstatement for many years and have recently found that prazosin, an alpha-1 adrenoceptor antagonist, blocks reinstatement induced by the stressors intermittent footshock and yohimbine. Both of these stressors have been extensively used in studies on stress-induced alcohol seeking. In the present proposal, we wish to extend these findings to the kappa opioid receptor agonist U50,488 (U50), a compound that also induced stress-like effects, and that can induce reinstatement of alcohol, nicotine and other drugs. Since alcohol dependence affects responses to stressors and to the drugs used to treat alcoholism, we will assess in Aim 1 the effects of alcohol dependence on footshock- and U50-induced reinstatement and then if dependence affects blockade of footshock and U50-induced reinstatement by prazosin.
In Aim 2 we will determine the effects of prazosin on neuronal activation (assessed by induction of the immediate early gene protein product Fos) induced by these stressors in a mapping study. The Fos data will be used as a guide for studies with intracranial injections of prazosin to determine the brain sites in which it blocks stress-induced relapse.
In Aim 3 we will use a novel neuropharmacogenetic approach (the Daun02 inactivation method) to identify activated neurons in specific brain areas that play causal roles in footshock- and U50-induced reinstatement of alcohol seeking. These studies will provide information on the neuronal mechanisms that underlie stress-induced alcohol seeking. Such data will be useful in two major ways: 1) understanding the mechanisms by which footshock and U50 produce relapse to alcohol seeking and 2) guiding the development of treatment strategies for the prevention of relapse.
About 2% of North American adults are dependent on alcohol, and another 8.5% misuse alcohol. This results in harm to the individual, as well as great costs to society in terms of increased accidents, health care costs and lost productivity. Stress i a major factor in increased drinking and in abstinent alcoholics, relapse. We reported that the alpha-1 noradrenergic receptor blocking agent prazosin, a drug that has anti-stress effects, reduces stress-induced relapse to alcohol in rats. Alcohol dependence changes how animals and humans respond to stress as well as their response to drugs used to treat alcoholism, so we will determine if alcohol dependent rats show greater stress-induced relapse, and whether dependence changes the effects of prazosin on this relapse. Then we will find the brain areas in which prazosin acts to reduce relapse induced by stress. Our proposal will provide important, timely data on the brain mechanisms involved in stress-induced relapse that will help refine relapse prevention treatments currently used, or indicate potential new treatments.
| Lê, A D; Funk, Douglas; Coen, Kathleen et al. (2018) Role of ?-Opioid Receptors in the Bed Nucleus of Stria Terminalis in Reinstatement of Alcohol Seeking. Neuropsychopharmacology 43:838-850 |
| Russo, Melissa; Funk, Douglas; Loughlin, Andrew et al. (2018) Effects of alcohol dependence on discrete choice between alcohol and saccharin. Neuropsychopharmacology 43:1859-1866 |
| Lê, Anh D; Kalant, Harold (2017) Intravenous self-administration of alcohol in rats-problems with translation to humans. Addict Biol 22:1665-1681 |
