Stressful life events are modulators of mood and

Stressful life events are modulators of mood and can trigger a variety of destructive behavior, including drug abuse and relapse in addicts (Association, 2013; Chen et al., 2012; Sinha, 2009). Likewise, drug-associated stimuli evoke a negative affective state in abstinent drug users. Compelling evidence indicates that stress hormones and neurotransmitters, such as glucocorticoids and noradrenaline (NA), respectively, mediate and modulate memory consolidation (Chen et al., 2012; Roozendaal, 2000). In addition, corticotrophin-releasing factor (CRF) is an important mediator not only of the stress response but also of the reinforcing properties of drugs of abuse (Goeders, 2003; Koob, 2008; Li et al., 2011; Mantsch et al., 2016) and drug-associated cues (Sinha et al., 2000), acting as a neuroregulator of behavioral and emotional stimuli associated with drug dependence (Haass-Koffler and Bartlett, 2012). CRF and its receptor subtype CRF1 (CRF1R) are distributed widely in orexin synthesis regions, including the hippocampal DG and the BLA (Chen et al., 2004; Refojo et al., 2005), two regions associated with learning and memory. On the other hand, CPA develops through associative learning and requires synaptic plasticity (Hou et al., 2009). Many neurotransmitters, transcription factors, and protein kinases have been delineated in the regulation of the formation and expression of withdrawal-associated aversive memories. A role for cAMP response element binding protein (CREB) in neuronal plasticity, learning and memory formation is well established (Barco and Marie, 2011; Frank and Greenberg, 1994; Silva et al., 1998). Also, activity-regulated cytoskeletal-associated protein (Arc) is required in long-term memory (Guzowski et al., 2000; Korb and Finkbeiner, 2011), and its expression is increased by a number of tasks involving learning and memory formation and reactivation (Bramham et al., 2008; Carmichael and Henley, 2017; Garcia-Perez et al., 2016a, Garcia-Perez et al., 2016b).
Materials and methods
Results
Discussion Substantial evidence shows that the negative reinforcement resulting from the aversive affective consequences of opiate withdrawal might play a crucial role in drug craving and relapse (Koob, 2009; Ungless et al., 2010). In the present study we have used the CPA paradigm for studying the involvement of CRF-CRF1R pathway in the negative affective component of opiate withdrawal as well as to investigate neural and molecular substrates underlying the aversive memory associated with CPA in morphine-withdrawn rats.
Introduction Animal exposure to aversive stimuli induces fear- and anxiety-like behaviors (e.g., fight, flight, freezing and vocalization) as well as neuroendocrine (e.g., ACTH and corticosterone release) and autonomic (e.g., tachycardia, tachypnea, increased blood pressure and defecation) activations (Blanchard and Blanchard, 2003, Blanchard et al., 1993, Graeff, 1990). These defensive reactions are coordinated by various areas of the brain aversive system (Graeff, 1990). For instance, the midbrain periaqueductal gray, the hypothalamus, and the amygdaloid complex have been implicated in the modulation of behavioral, hormonal, and autonomic responses induced by dangerous and threatening situations (Bandler and Depaulis, 1991, Behbehani, 1995, Brandao et al., 2003, Carrive et al., 1997, Fanselow, 1991, Graeff et al., 1993, Lang et al., 1998, Lovick, 2000, Walker and Carrive, 2003). The amygdaloid complex has been widely investigated as an important modulator site of defensive responses, such as freezing, the startle reflex, antinociception, and heart rate alteration (Rosen and Schulkin, 1998), and its extensive connections to the bed nucleus of the stria terminalis (BNST) have raised substantial interest in the identification of the role of the BNST in the modulation of anxiety-related responses (Alheid, 2003, Davis, 1998, Heimer, 2003, Sahuque et al., 2006, Schulkin et al., 2005, Ventura-Silva et al., 2012). For instance, electrical stimulation of the BNST elicits behavioral and endocrine changes that are similar to those induced by environmental stressors (Casada and Dafny, 1991, Dunn, 1987). In contrast, pharmacological inactivation of the BNST decreases the expression of conditioned or unconditioned responses induced by aversive situations (Sahuque et al., 2006).