Effect of CRF1 Receptor Antagonist on Alcohol and Nicotine Self-Administration in Dependent Rats

Increased expression of CRF₁ receptors is associated with stress-induced ethanol intake in Marchigian Sardinian (msP) alcohol-preferring rats (Hansson et al., 2006) as well as in nongenetically selected animals in a postdependent state (Sommer et al., 2008). In the genetically selected msP rat line, high ethanol preference was correlated with a genetic polymorphism of the crhr1 promoter and an increase in CRF₁ density in the amygdala as well as increased sensitivity to stress and increased sensitivity to a CRF₁ antagonist (Hansson et al., 2006). In nongenetically selected rats exposed to repeated cycles of ethanol intoxication and dependence, a CRF₁ antagonist blocked the increased ethanol intake associated with protracted abstinence, an effect that coincided with upregulation of the CRF₁ gene and downregulation of the CRF₂ gene in the amygdala (Sommer et al., 2008). Adolescents homozygous for the C allele of R1876831 located on an intron that could potentially influence transcription of the CRF₁ receptor gene drank more alcohol per occasion and had higher lifetime rates of heavy drinking in relation to negative life events than subjects carrying the T allele (Blomeyer et al., 2008). These results suggest the exciting possibility that certain single-nucleotide polymorphisms in the human population may predict vulnerability to certain subtypes of excessive drinking syndromes and, perhaps more exciting, may predict responsiveness to the use of CRF receptor antagonists in the treatment of alcoholism.

Similar interactions with CRF have been observed with the dependence associated with cocaine, heroin, and nicotine. Chronic administration of cocaine produces an anxiety-like response that is blocked by intracerebroventricular administration of a CRF₁/CRF₂ antagonist (Sarnyai et al., 1995; Basso et al., 1999). A CRF₁/CRF₂ peptide antagonist injected into the central nucleus of the amygdala and systemic administration of CRF₁ antagonists blocked conditioned place aversion associated with precipitated opiate withdrawal (Heinrichs et al., 1995; Stinus et al., 2005). Opioid withdrawal also increased CRF release in the amygdala, measured by in vivo microdialysis (Weiss et al., 2001). CRF₁ knockout mice failed to show conditioned place aversion to opioid withdrawal and failed to show an opioid-induced increase in dynorphin mRNA in the nucleus accumbens (Contarino and Papaleo, 2005). A CRF antagonist injected intracerebroventricularly blocked the anxiogenic-like effects of withdrawal from bolus injections of nicotine (Tucci et al., 2003). The anxiogenic-like effects of precipitated withdrawal from chronic nicotine also were blocked by a CRF₁ receptor antagonist (George et al., 2007) (Figure 2). A CRF₁/CRF₂ peptide antagonist also blocked the nicotine withdrawal-induced increase in brain reward thresholds (Bruijnzeel et al., 2007). Continuous access to intravenous self-administration of cocaine for 12 hr, precipitated opioid withdrawal, and precipitated nicotine withdrawal increased CRF release in the amygdala during the withdrawal, measured by in vivo microdialysis (Richter and Weiss, 1999; Weiss et al., 2001; George et al., 2007) (Figure 2). Systemic administration of CRF₁ antagonists reversed the increased self-administration of cocaine, heroin, and nicotine associated with extended access (Specio et al., 2008; George et al., 2007; T.N. Greenwell, C.K. Funk, P. Cottone, H.N. Richardson, S.A. Chen, K. Rice, M.J. Lee, E.P. Zorrilla, and G.F.K., unpublished data).

The role of CRF in stress-induced reinstatement of drug seeking follows a pattern of results similar to its role in the anxiety-like effects of acute withdrawal and dependence-induced increases in drug intake (for reviews, see Shaham et al., 2003; Lu et al., 2003) (Figure 1B). Mixed CRF₁/CRF₂ antagonists injected intracerebroventricularly and/or CRF₁ small-molecule antagonists blocked stress-induced reinstatement of cocaine, opiate, alcohol, and nicotine intake (Erb et al., 1998; Lu et al., 2001; Shaham et al., 1997, 1998; Shalev et al., 2006; Le et al., 2000; Liu and Weiss, 2002; Gehlert et al., 2007; Hansson et al., 2006; Zislis et al., 2007). These effects have been replicated with intracerebral injections of a mixed CRF₁/CRF₂ antagonist or small-molecule CRF₁ antagonist into the bed nucleus of the stria terminalis, median raphe, and ventral tegmental area, but not the amygdala or nucleus accumbens (Le et al., 2002; Erb et al., 2001; Erb and Stewart, 1999; Wang et al., 2006, 2007), suggesting that different sites, such as the bed nucleus of the stria terminalis, median raphe, and ventral tegmental area, may be important for stress-induced relapse, in contrast to the role of CRF in dependence-induced drug self-administration that has been localized to the central nucleus of the amygdala (Funk et al., 2006).

In summary, the extrahypothalamic CRF systems play a role in mediating the anxiety-like effects of acute withdrawal, the increase in drug-taking associated with dependence, and stress-induced reinstatement for all major drugs of abuse, including psychostimulants, opioids, ethanol, nicotine, and (with limited studies) cannabinoids. Many of these effects have been localized to the extended amygdala, and acute withdrawal from all major drugs of abuse increased CRF release in the central nucleus of the amygdala, measured by in vivo microdialysis (Figures 1B and ​and2).2). This pattern of results suggests a major role for CRF in mediating the negative emotional states that have motivational significance in maintaining the dependent state (Koob and Le Moal, 2005; Bruijnzeel and Gold, 2005).

Norepinephrine

Norepinephrine is a well established neurotransmitter in the central nervous system with widespread distribution throughout the brain (Figure 4) and has hypothesized functions in arousal, attention, stress, anxiety, and affective disorders (see Supplemental Data). Cell bodies for the brain norepinephrine systems originate in the dorsal pons and brainstem. The locus coeruleus in the dorsal pons is the source of the dorsal noradrenergic pathway to the cortices and hippocampus, and the brainstem projections converge in the ventral noradrenergic bundle to innervate the basal forebrain and hypothalamus.

Figure 4

Date: 2016-06-12; view: 265