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The reduction of the unpleasant state of the withdrawal symptoms becomes the major drive in continued drug use.In a simplified view of the (Wise, 1978, 2008; Berridge and Robinson, 1998; Everitt and Robbins, 2005; Diana, 2011), the acute euphoric process obtained by binge-intoxication represents the activation of the dopaminergic system, while the negative component resulting from the withdrawal period is marked by the reduction of dopamine function (Tomkins and Sellers, 2001).Corticotropin releasing factor (CRF) has been shown to induce various behavioral changes related to adaptation to stress.Dysregulation of the CRF system at any point can lead to a variety of psychiatric disorders, including substance use disorders (SUDs).Following chronic drug use, the compulsive seeking and uncontrollable use leads to long-lasting alterations in synaptic plasticity, such as changes in synaptic strength.Human studies (Gawin and Kleber, 1986; Wallace, 1989) and experiments with preclinical models (Thatcher-Britton and Koob, 1986; Piazza et al., 1990; Goeders and Guerin, 1994; Kreibich et al., 2009) have identified stress as a critical factor in the drug addiction process, including triggering relapse.Although substances of abuse have different mechanisms of action, repeated exposure has been shown to lead to similar neural adaptations.

This review will attempt to examine recent research on the role of CRF and its interaction with drug-mediated synaptic plasticity.The introduction of CRF, also known as corticotropin releasing hormone (CRH), has been shown to induce various behavioral changes related to adaptation to stress.Dysregulation of the CRF system at any point can lead to a variety of psychiatric disorders such as depression, obsessive compulsive disorder, post-traumatic stress disorder and SUDs (Cole et al., 1990; Sarnyai et al., 1992, 2001; Cador et al., 1993; Koob and Kreek, 2007; Koob and Le Moal, 2008a).Footshock-induced stress has been shown to be effective in inducing reinstatement of alcohol (Le et al., 1998, 2000; Gass and Olive, 2007; Richards et al., 2008), nicotine (Buczek et al., 1999), cocaine (Erb et al., 1996), opiate and psycostimulants (Lu et al., 2003) and heroin (Shaham et al., 1997) seeking.Specifically CRF has been associated with drug reinstatement (Shaham et al., 1997; Le et al., 2002; Liu and Weiss, 2002; Funk et al., 2006).

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It was originally identified as a hypothalamic factor responsible for stimulating adrenocorticotropic hormone (ACTH) secretion from the anterior pituitary (Guillemin and Rosenberg, 1955; Saffran et al., 1955) where it stimulates glucocorticoid synthesis and secretion form the adrenal cortex (Turnbull and Rivier, 1997).

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