Localizations and Projections of Brain Antistress Systems?Neuropeptide Y

NPY administered intracerebroventricularly blocked ethanol withdrawal (Woldbye et al., 2002). Subsequent studies using animal models of dependence-induced drinking in rodents showed that NPY administered intracerebroventricularly reduced limited-access alcohol intake in Wistar rats if they had a history of alcohol dependence produced by chronic intermittent exposure to alcohol vapor (Thorsell et al., 2005). Intracerebroventricularly administered NPY also suppressed alcohol intake in rats selectively bred for high alcohol preference but did not alter alcohol intake in their low alcohol-preferring counterparts (Badia-Elder et al., 2001, 2003). The suppressive effects of intracerebroventricularly administered NPY on ethanol drinking in P rats is enhanced and prolonged following periods of imposed alcohol abstinence (Gilpin et al., 2003). Intracerebroventricular administration of NPY did not affect limited-access nondependent alcohol intake by Wistar rats (Badia-Elder et al., 2001).

Given the evidence that the anti-anxiety-like effects of NPY are mediated by the central or basolateral amygdala complex (Heilig et al., 1994), a logical site for exploring the NPY-induced decrease in excessive ethanol intake is the central nucleus of the amygdala. Ethanol withdrawal decreased NPY protein in the central and medial nuclei of the amygdala (Roy and Pandey, 2002). Infusion of a viral vector encoding prepro-NPY directly into the central nucleus of the amygdala reduced continuous-access alcohol drinking by Long-Evans rats that exhibited anxiety-like behavior in the elevated plus maze (Primeaux et al., 2006). In Wistar rats with a history of dependence and multiple abstinence periods, viral vector-induced amygdala NPY overexpression reduced anxiety-like behavior and produced long-term suppression of alcohol drinking (Thorsell et al., 2007). In P rats with a long history of alcohol consumption, infusions of NPY directly into the central nucleus of the amygdala suppressed alcohol drinking only in P rats that were subjected to periods of imposed alcohol abstinence (Gilpin et al., 2008). P rats have been shown to have lower basal levels of NPY in the central nucleus of the amygdala and correlationally higher anxiety-like behavior compared with alcohol-nonpreferring rats (Suzuki et al., 2004; Pandey et al., 2005). Increases in NPY activity in the central nucleus of the amygdala, produced via alterations in CREB function or direct administration of NPY, decreased ethanol intake and anxiety-like behavior in P rats with a short history of self-administration (Pandey et al. 2005). Exogenous NPY administered into the central nucleus of the amygdala also significantly decreased alcohol drinking by alcohol-dependent rats but not in nondependent controls (Gilpin et al., 2008), confirming the results observed with viral vector-induced induction of NPY activity (Thorsell et al., 2007).

Both Y₁ and Y₂ receptor subtypes are involved in the excessive drinking associated with alcohol dependence. Y₁ receptor knockout mice show increased alcohol consumption (Thiele et al., 2002). In contrast, Y₂ receptor knockout mice drink significantly less alcohol (Thiele et al., 2004). Pharmacological studies have confirmed that blockade of Y₁ receptors increases ethanol intake in C57BL/6 high-drinking mice (Sparta et al., 2004) and blockade of Y₂ receptors decreases ethanol intake in dependent animals (Rimondini et al., 2005) and in animals responding for ethanol in a sweet solution (Thorsell et al., 2002). Y₁ knockout mice and Y₁ antagonists show an anxiogenic-like profile, and Y₂ knockout mice and Y₂ antagonists show an anxiolytic-like profile, thus providing an important link between the NPY system, anxiety-like responses, and alcohol intake in dependent animals (Valdez and Koob, 2004). Combined with the extensive work in dependent animals, these studies suggest that the NPY system may change its impact on drinking during the transition from nondependent to dependent drinking.

These studies suggest that both constitutive and alcohol-induced changes in NPY activity in the amygdala may be involved not only in mediating anxiety-like responses but also in the motivational effects of ethanol dependence. One hypothesis is that decreased activity of NPY, parallel to increased activity of CRF, may provide a motivational basis for increased alcohol self-administration during alcohol withdrawal or protracted abstinence that drives excessive alcohol consumption (Heilig et al., 1994).

NPY has been implicated in dependence on other drugs of abuse, but the extant literature is not as extensive. Chronic heroin treatment increased NPY neuron activity measured by immunohistochemistry in the thalamic paraventricular nucleus and bed nucleus of the stria terminalis (D?Este et al., 2006). NPY administered intracerebroventricularly blocked the somatic signs of withdrawal from morphine precipitated by the opioid antagonist naloxone, and these behavioral changes were accompanied by decreases in c-fos expression in the locus coeruleus, lateral septal nucleus, periaqueductal gray, cingulate and frontal cortices, and septohippocampal nucleus (Clausen et al., 2001). NPY and NPY peptide analogs administered intracerebroventricularly decreased naloxone-precipitated withdrawal in rats (Woldbye et al., 1998).

Date: 2016-06-12; view: 363