Acknowledgements br Introduction Addiction is

Acknowledgements
Introduction Addiction is a life-long condition in which individuals show an intense drug craving and a high risk of relapse even after years of drug abstinence [1], [2]. A major goal of successful treatment of addiction is being able to prevent craving, seeking and relapse [3], [4]. Persistent molecular changes, associated with chronic drug consumption and abstinence, are believed to mediate craving and relapse to drug use [5], [6]. In both human addicts and in animal models of addictive behaviour the relapse to drug seeking has been shown to be precipitated by the exposure to three distinct types of stimuli: (a) stress; (b) environmental cues associated with the drug experience and (c) the drug itself [7]. Over the last few years there have been promising advances in the understanding of addiction; however, the mechanisms by which stress enhances drug use and triggers relapse remain elusive [8], [9]. On one hand, drug addiction is related to the reward system which is centered in dopaminergic neurons located in the ventral tegmental area (VTA) that innervate several interconnected nuclei such as the nucleus accumbens (NAcc), lateral septum, bed nucleus of the stria terminalis (BNST), amygdala, lateral hypothalamus (LH) and prefrontal cortex (PFC). All drugs of abuse activate, directly or indirectly, the dopaminergic neurons and increase the release of dopamine in the NAcc [10]. On the other hand, the stress response is related to the BMS 777607 corticotropin releasing factor (CRF) system. At present, the mammalian CRF system is composed of four peptides, CRF, urocortin-1, urocortin-2 and urocortin-3, originated from independent genes; a binding protein with high affinity for CRF (CRF-BP) and urocortin-1, and two receptors CRF1 and CRF2 [reviewed in 11]. CRF and urocortin-1 have high affinity for both CRF receptors. In contrast, urocortin-2 and urocortin-3 have high affinity only for CRF2 receptors. Anatomically, there is significant overlap between brain nuclei involved in stress response and in addiction [8], [12], [13]. Compelling evidence indicates that the CRF system is responsible for connecting stress and addiction [8], [14], [15]. Even though several studies have focussed on understanding the molecular and neurochemical mechanisms by which the CRF system determines stress-induced relapse to drug seeking, these phenomena are still only partially understood [9], [16], [17], [18].
Role of CRF1 receptors in the BNST in stress-induced relapse to cocaine seeking The seminal work of Stewart and co-workers [19] showed that rats that have extinguished their auto-administration of different drugs of abuse relapse to drug-seeking behaviour when exposed to footshock, even after a 4–6 week drug-free period and this relapse depends on the CRF system. The CRF-dependence of stress-induced relapse to drug seeking was shown by administering systemically CP-154,526, a selective CRF1 receptor antagonist or intra cerebroventricularly D-Phe CRF12-41, a non-selective CRF1/CRF2 antagonist [20]. Both antagonists blocked the relapse induced by exposure to footshock. However, the same treatment only attenuated relapse to cocaine seeking induced by a priming dose of cocaine suggesting that different or partially different mechanisms underlie drug priming and stress-induced relapse to drug seeking, consistent with the different brain subcircuits related to these distinct types of relapse initiators [13]. In addition, by infusing D-Phe CRF12-41 directly into the BNST, Erb and Stewart [21] showed the critical role of this nucleus in stress-induced relapse to drug seeking behaviour. Other groups have added valuable information showing that CRF/CRF1 receptors in the BNST mediate stress-induced relapse to other drugs of abuse as well [22], [23], [24], [25].