Urocortin 1 microinjection into the mouse lateral septum regulates the acquisition and expression of alcohol consumption

Abstract

Previous studies using genetic and lesion approaches have shown that the neuropeptide Urocortin 1 (Ucn1) is involved in regulating alcohol consumption. Ucn1 is a corticotropin releasing factor (CRF)-like peptide that binds CRF1 and CRF2 receptors. Perioculomotor urocortin-containing neurons (pIIIu), also known as the non-preganglionic Edinger-Westphal nucleus, are the major source of Ucn1 in the brain and are known to innervate the lateral septum. Thus, the present study tested whether Ucn1 could regulate alcohol consumption through the lateral septum. In a series of experiments Ucn1 or CRF were bilaterally injected at various doses into the lateral septum of male C57BL/6J mice. Consumption of 20% v/v ethanol or water was tested immediately after the injections using a modification of a 2-hour limited access sweetener-free "drinking-in-the-dark" procedure. Ucn1 significantly suppressed ethanol consumption when administered prior to the third ethanol drinking session (the expression phase of ethanol drinking) at doses as low as 6 pmol. Ethanol intake was differentially sensitive to Ucn1, as equivalent doses of this peptide did not suppress water consumption. In contrast, CRF suppressed both ethanol and water intake at 40 and 60 pmol, but not at lower doses. Repeated administration of Ucn1 during the acquisition of alcohol consumption showed that 40 pmol (but not 2 or 0.1 pmol) significantly attenuated ethanol intake. Repeated administration of Ucn1 also resulted in a decrease of ethanol intake in sham-injected animals, a finding suggesting that the suppressive effect of Ucn1 on ethanol intake can be conditioned. Taken together, these studies confirm the importance of lateral septum innervation by Ucn1 in the regulation of alcohol consumption.A variety of evidence has suggested that the neuropeptide corticotropin releasing factor (CRF) plays an important role in the development of alcoholism (Koob and Le Moal, 2001). CRF is known as the prototypical ligand acting on CRF receptors (Vale et al., 1981). However, recent studies indicate that CRF is not the sole ligand of CRF receptors, and that the endogenous neuropeptides urocortin 1 (Ucn1), urocortin 2 (Ucn2, also known as stresscopin-related peptide) and urocortin 3 (Ucn3, also known as stresscopin) also bind these receptors (Vaughan et al., 1995, Hsu and Hsueh, 2001. Moreover, these studies show that all three urocortins have higher affinity than CRF at CRF2 receptors, and that Ucn1 has higher or equal affinity than CRF at CRF1 receptors. The complexity of the CRF system requires that the potential role of each of the CRF-like peptides be considered in studying the pathogenesis of alcoholism. corresponding authorPublisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that d...

Neurogenetic studies of alcohol addiction

“…A similar effect is seen when a CRF-1 receptor antagonist is administered to normal mice , and, as noted above, an antagonist also attenuates ethanol DID (Sparta et al 2008). Also as noted above, intra-septal CRF and urocortin 1 both reduce DID (Ryabinin et al 2008). Ethanol intake can also be potentiated following induction of physical dependence ( Lopez & Becker 2005), and these increases are also blocked by CRF 1 antagonists (Chu et al 2007;Finn et al 2007;Richardson et al 2008) or are absent in the knockout (Chu et al 2007).…”

Turning the Clock Ahead: Potential Preclinical and Clinical Neuropharmacological Targets for Alcohol Dependence

“…The authors used a limited access procedure, which takes advantage of higher levels of activity, fluid and alcohol consumption that are observed in mice during early hours into the dark portion of the circadian cycle. Injection of Ucn1 into the LS of C57 mice significantly attenuated ethanol consumption both in the expression phase of ethanol drinking and during the acquisition phase of alcohol consumption [134].…”

“…The hypothalamus is a long-proposed integrator of consummatory responses, but hypothalamic subregions affected by ethanol have not been mapped in sufficient detail [133]. A recent study by Ryabinin et al [134] confirmed the importance of Ucn1 innervation and in particular of the LS in the regulation of alcohol consumption. In a series of experiments the authors injected Ucn1 or CRF bilaterally at various doses into the lateral septum of male C57BL/6J mice and immediately after the injection tested ethanol consumption.…”

“…As an alternative explanation, since pIIIu neurons contain other peptides besides Ucn1 as potential regulators of the rewarding properties of drugs of abuse, it is possible that synergistic actions of these peptides are needed to increase the rewarding properties of alcohol [134]. It is important to note that Ucn3 innervates the same brain structures and alcohol consumption may also be regulated by this peptide.…”

Neurochemical and Neurostructural Plasticity in Alcoholism

“…71 Regions of the extended amygdala as well as the lateral septum appear to mediate CRF involvement in alcohol intake. 67,72 Alcohol consumption is also attenuated in CRF 1 knockout mice when compared to that of littermate controls. 73 These findings suggest that alcohol dependence engages the brain's stress systems by either altering CRF release or up-regulating CRF 1 receptors in limbic regions such as the amygdala.…”