biie-0246 and Alcoholism

Neuropeptide Y (NPY), the prototypical member of the NPY-like peptide family, antagonizes behavioral consequences of stress through actions within the brain. This was initially indicated by microinjection studies with NPY receptor ligands, suggesting that NPY Y1 receptors mediate the anti-stress effects of NPY. Behavioral anti-stress actions of NPY are note-worthy in that 1) their magnitude surpasses that of other endogenous compounds; 2) they are produced across a wide range of animal models, normally thought to reflect different aspects of emotionality. These findings suggest that NPY acts with a high potency on a common core mechanism of emotionality and behavioral stress responses. This hypothesis is supported by behavioral studies in genetically modified animals. Increased emotionality, as well as increased alcohol intake, has been reported in mice with a homologous recombination knockout of the preproNPY gene. More detailed studies have been made possible by a transgenic rat system, in which NPY is selectively overexpressed within the hippocampus. These subjects display no overt phenotype under baseline conditions and have a normal endocrine stress response, but lack behavioral responses to stress. These findings point to the potential of the NPY system for developing novel pharmacological treatments of stress-related disorders, including anxiety and depression. Recent data additionally point to a role of NPY in the regulation of alcohol intake, and alcohol dependence emerges as a novel potential indication for compounds targeting the NPY system.

Topics: Alcoholism; Animals; Anxiety; Arginine; Behavior, Animal; Benzazepines; Brain; Depression; Disease Models, Animal; DNA-Binding Proteins; Gene Expression; Genetic Heterogeneity; Humans; Neuropeptide Y; Receptors, Neuropeptide Y; Stress, Physiological

Electrophysiological data suggest a dual role of Y2 receptors (Y2 Rs) as autoreceptors regulating neuropeptide Y release and heteroceptors regulating gamma-aminobutyric acid release in the central amygdala (CeA). Here, we report that neither systemic (JNJ-31020028) nor intra-CeA (BIIE0246) Y2 R antagonism altered operant alcohol responding by alcohol-dependent or non-dependent rats. Conversely, BIIE0246 in the CeA reduced anxiety-like behavior in alcohol-dependent and alcohol-naïve rats. The finding that Y2 R antagonism reduces anxiety-like behavior but not alcohol drinking suggests that these two effects may occur via different functions of the Y2 R (e.g. autoreceptor versus heteroceptor function).

Topics: Alcohol Drinking; Alcoholism; Animals; Anti-Anxiety Agents; Anxiety; Arginine; Benzamides; Benzazepines; Central Amygdaloid Nucleus; Central Nervous System Depressants; Ethanol; Male; Piperazines; Rats, Wistar; Receptors, Neuropeptide Y; Reinforcement Schedule; Reinforcement, Psychology

Evidence from genetically modified mice suggests a role for NPY in regulation of ethanol intake, but results of pharmacological studies have been more variable. We have previously shown that potentiation of NPY signaling through antagonism at NPY-Y2 receptors decreases operant responding for ethanol in Wistar rats without a history of dependence. Here, we examined the effects of Y2-antagonism in animals with a history of dependence induced by long-term intermittent exposure to ethanol vapor. The Y2-receptor antagonist BIIE0246 suppressed operant responding for ethanol (approximately 50%, p=0.01), at a dose (0.5 nmol i.c.v.) which was ineffective in subjects without a history of dependence. Responding for the ethanol-free control solution was unaffected. These data confirm that antagonism at central NPY-Y2 receptors selectively suppresses motivation to self-administer ethanol, and indicate that the NPY system is sensitized in animals with a history of dependence. This may render the NPY system, and Y2 receptors in particular, an attractive target for treatment of alcohol dependence.

Topics: Alcoholism; Animals; Arginine; Benzazepines; Brain; Brain Chemistry; Disease Models, Animal; Ethanol; Male; Neuropeptide Y; Rats; Rats, Wistar; Receptors, Neuropeptide Y; Self Administration