Numerous studies have demonstrated that drugs of abuse activate the mesolimbic dopamine reward pathway, and it is widely held that this activation contributes to the motivational and positive ...reinforcing properties of these substances. However, there is evidence that endogenous opioid systems within this brain reward circuit also play a role in drug reinforcement and drug-seeking behavior. Using microdialysis in freely moving rats, we sought to determine whether various drugs of abuse (i.e., ethanol, cocaine, d-amphetamine, and nicotine) would increase neurotransmission of endogenous opioid peptides (i.e., endorphins) in the nucleus accumbens. Drugs were administered intraperitoneally twice at 3 h intervals, and the endorphin content of microdialysates was analyzed by a solid-phase radioimmunoassay. Acute administration of ethanol, cocaine, and d-amphetamine transiently elevated extracellular levels of endorphins in the nucleus accumbens, whereas nicotine and saline were without effect. We hypothesize that this drug-induced release of endorphins may contribute to the positive reinforcing and motivating properties of ethanol and psychostimulants.
There is a substantial amount of evidence indicating control over ethanol intake by steroid hormones, particularly adrenal glucocorticoids. Thus far, however, studies employing pharmacological ...methods have failed to find effects of glucocorticoid receptor blockade on voluntary ethanol consumption. Since length of ethanol access period can influence ethanol consumption levels as well as potential pharmacological effects in such studies, the present study was conducted to determine the effects of acute administration of the glucocorticoid receptor (GR) antagonist mifepristone on voluntary ethanol intake under limited access conditions. Rats were fluid restricted and given concurrent access to 10% ethanol and water in a two-bottle choice paradigm for 1 h/day, 5 days a week. Both fluids were available ad libitum during the remaining 2 days per week. Administration of mifepristone (1, 5 and 20 mg/kg i.p.) immediately prior to the limited access two-bottle access period dose-dependently suppressed ethanol intake (maximum 40% at 20 mg/kg). The mineralcorticoid receptor (MR) antagonist spironolactone (10, 25 and 50 mg/kg i.p.) was without effect on ethanol intake, and neither compound had an effect on water intake. These data confirm an active role of GRs in modulating voluntary ethanol consumption, particularly under conditions of limited access.
Corticotropin-releasing factor (CRF) is widely distributed throughout the brain and has been shown to mediate numerous endocrine and behavioral responses to stressors. During acute ethanol ...withdrawal, CRF release is increased in the central nucleus of the amygdala (CeA), and there is evidence to suggest that this activation of amygdala CRF systems may mediate the anxiogenic properties of the ethanol withdrawal syndrome. The present study was conducted to determine if another CRF-containing limbic structure, the bed nucleus of the stria terminalis (BNST), we would exhibit similar increases in CRF neurotransmission during ethanol withdrawal. Rats were administered an ethanol-containing (6.7% v/v) or control liquid diet for 2 weeks and subsequently implanted with microdialysis probes into the lateral BNST. A 50–75% increase in dialysate CRF levels was observed following removal of the ethanol-containing diet, while no changes were observed in control animals. When ethanol-withdrawn animals were given subsequent access to the ethanol-containing diet, dialysate CRF levels returned to basal levels. However, when ethanol-withdrawn animals were given subsequent access to the control diet, dialysate CRF levels increased further to 101% above basal levels. These data demonstrate that extracellular CRF levels are increased in the BNST during ethanol withdrawal, and that these increases are reduced by subsequent ethanol intake.
Corticotropin-releasing factor (CRF) plays an integral role in mediating stress responses and anxiety. However, little is known regarding the role of CRF in ethanol consumption, a behavior often ...associated with stress and anxiety in humans.
The present study sought to determine the role of CRF in ethanol consumption, locomotor sensitivity and reward by examining these behaviors in C57BL/6J x 129S mice with a targeted disruption in the gene encoding the CRF prohormone.
Male wild-type and CRF-deficient mice were given concurrent access to ethanol and water in both limited and unlimited-access two-bottle choice paradigms. Taste reactivity (saccharin or quinine vs water) was examined in a similar manner under continuous-access conditions. Blood ethanol levels and clearance were measured following limited ethanol access as well as a 4-g/kg i.p. injection of ethanol. Locomotor stimulant effects of ethanol were measured in an open-field testing chamber, and the rewarding effects of ethanol were examined using the conditioned place preference paradigm.
CRF-deficient mice displayed normal body weight, total fluid intake, taste reactivity and blood ethanol clearance, but consumed approximately twice as much ethanol as wild types in both continuous- and limited-access paradigms. CRF-deficient mice failed to demonstrate a locomotor stimulant effect following acute administration of ethanol (2 g/kg i.p.), and also failed to demonstrate a conditioned place preference to ethanol at 2 g/kg i.p., but did display such a preference at 3 g/kg i.p.
CRF deficiency may lead to excessive ethanol consumption by reducing sensitivity to the locomotor stimulant and rewarding effects of ethanol.
The purpose of the present study was to determine the acute effects of the anticraving compound acamprosate (calcium acetylhomotaurinate) and the closely related compound homotaurine on ethanol ...intake and ethanol-stimulated dopamine release in the nucleus accumbens. Male rats were treated with acamprosate (200 or 400 mg/kg intraperitoneally, i.p.) or homotaurine (10, 50, or 100 mg/kg i.p.) 15 min prior to access to 10% ethanol and water for 1 h in a two-bottle choice restricted access paradigm. A separate group of rats was implanted with microdialysis probes in the nucleus accumbens and given an acute injection of ethanol (1.5 g/kg i.p.) that was preceded by saline, acamprosate, or homotaurine. Acamprosate and homotaurine dose-dependently reduced ethanol intake and preference. These compounds also delayed or suppressed ethanol-stimulated increases in nucleus accumbens dopamine release, suggesting that acamprosate and homotaurine may reduce ethanol intake by interfering with the ability of ethanol to activate the mesolimbic dopamine reward system.
There is a great deal of evidence suggesting that endogenous opioid systems are involved in the control of ethanol-seeking behavior and reward. To ascertain the role of the enkephalinergic opioid ...peptide system in these processes, we examined voluntary ethanol consumption patterns in mice lacking the preproenkephalin (Penk) gene using a two-bottle choice paradigm with free access to water and increasing concentrations of ethanol (2, 4, 8, and 10% v/v). We also examined the ability of ethanol (2 g/kg i.p.) to establish a conditioned place preference in these mice. No differences in ethanol consumption or preference were observed between wildtypes and Penk null mutant mice. In addition, both genotypes displayed a similar conditioned place preference to ethanol. These data suggest that the preproenkephalin system is not involved in voluntary ethanol consumption patterns or ethanol reward.
This article represents the proceedings of a symposium at the RSA meeting in Montreal, Canada. The organizer was Andrey E. Ryabinin, and the chair was George F. Koob. The presentations were (1) ...Introduction, by Stephen C. Heinrichs; (2) Role of CRF and its receptors in the hypothalamic-pituitary-adrenal response to alcohol, by Soon Lee and Catherine Rivier; (3) A role for CRF in the allostasis of alcohol dependence, by George F. Koob and Amanda J. Roberts; (4) CRF and alcohol: Lessons from knockouts, microinjections, and microdialysis, by M. Foster Olive, Kristin K. Mehmert, R. Camarini, Joseph A. Kim, Heather N. Koenig, Michelle A. Nannini, and Clyde W. Hodge; and (5) Selective sensitivity of urocortin-containing neurons to alcohol self-administration, by Andrey E. Ryabinin and Ryan K. Bachtell.
This article represents the proceedings of a symposium at the RSA meeting in Montreal, Canada. The organizer was Andrey E. Ryabinin, and the chair was George F. Koob. The presentations were (1) ...Introduction, by Stephen C. Heinrichs; (2) Role of CRF and its receptors in the hypothalamic‐pituitary‐adrenal response to alcohol, by Soon Lee and Catherine Rivier; (3) A role for CRF in the allostasis of alcohol dependence, by George F. Koob and Amanda J. Roberts; (4) CRF and alcohol: Lessons from knockouts, microinjections, and microdialysis, by M. Foster Olive, Kristin K. Mehmert, R. Camarini, Joseph A. Kim, Heather N. Koenig, Michelle A. Nannini, and Clyde W. Hodge; and (5) Selective sensitivity of urocortin‐containing neurons to alcohol self‐administration, by Andrey E. Ryabinin and Ryan K. Bachtell.
Arrhythmogenic cardiomyopathy (ACM) is an inherited disorder characterized by fibro-fatty infiltration with an increased propensity for ventricular arrhythmias and sudden death. Genetic variants in ...desmosomal genes are associated with ACM. Incomplete penetrance is a common feature in ACM families, complicating the understanding of how external stressors contribute towards disease development. To analyze the dual role of genetics and external stressors on ACM progression, we developed one of the first mouse models of ACM that recapitulates a human variant by introducing the murine equivalent of the human R451G variant into endogenous desmoplakin (
. Mice homozygous for this variant displayed embryonic lethality. While
mice were viable with reduced expression of DSP, no presentable arrhythmogenic or structural phenotypes were identified at baseline. However, increased afterload resulted in reduced cardiac performance, increased chamber dilation, and accelerated progression to heart failure. In addition, following catecholaminergic challenge,
mice displayed frequent and prolonged arrhythmic events. Finally, aberrant localization of connexin-43 was noted in the
mice at baseline, becoming more apparent following cardiac stress via pressure overload. In summary, cardiovascular stress is a key trigger for unmasking both electrical and structural phenotypes in one of the first humanized ACM mouse models.
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