Abstract
Stress induces the release of the peptide corticotropin-releasing factor (CRF) into the ventral tegmental area (VTA), and also increases dopamine (DA) levels in brain regions receiving dense VTA input. Since the role of stress in drug addiction is well established, the present study examined the possible involvement of CRF1 receptor in the interaction between morphine withdrawal and catecholaminergic pathways in the reward system. The effects of naloxone-precipitated morphine withdrawal on signs of withdrawal, hypothalamo-pituitary-adrenocortical (HPA) axis activity, dopamine (DA) and noradrenaline (NA) turnover in the nucleus accumbens (NAc) and activation of VTA dopaminergic neurons, were investigated in rats pretreated with vehicle or CP-154,526 (selective CRF1R antagonist). CP-154,526 attenuated the increases in body weight loss and suppressed some of withdrawal signs. Pretreatment with CRF1 receptor antagonist resulted in no significant modification of the increased NA turnover at NAc or plasma corticosterone levels that were seen during morphine withdrawal. However, blockade of CRF1 receptor significantly reduced morphine withdrawal-induced increases in plasma adrenocorticotropin (ACTH) levels, DA turnover and TH phosphorylation at Ser40 in the NAc. In addition, CP-154,526 reduced the number of TH containing neurons expressing c-Fos in the VTA after naloxone-precipitated morphine withdrawal. Altogether, these results support the idea that VTA dopaminergic neurons are activated in response to naloxone-precipitated morphine withdrawal and suggest that CRF1 receptors are involved in the activation of dopaminergic pathways which project to NAc.
Highlights
Addiction research has traditionally focused on dopamine (DA) and positive reinforcement-based behaviours
CRF1 binding sites have been demonstrated in several key brain areas involved in the addictive processes [e.g., cerebral cortex, hippocampus, hypothalamus, amygdala, nucleus of tractus solitarius (NTS), ventral tegmental area (VTA) and nucleus accumbens (NAc) that are involved in reward, reinforcement, craving and aversive effects of drugs of abuse [9]
A significant decrease (p,0.001) in body weight loss was seen in morphine withdrawn rats pretreated with the CRF1 receptor antagonist CP-154,526 (20, 30 mg/kg i.p.) compared with morphine withdrawn rats receiving vehicle instead of CP-154,526
Summary
Addiction research has traditionally focused on dopamine (DA) and positive reinforcement-based behaviours. Noradrenergic and corticotropin-releasing factor (CRF) signalling systems have been heavily implicated in negative reinforcement [1,2,3]. Both noradrenaline (NA) and CRF are critical in behavioural aspects of addiction, including the reinforcing properties of drugs [4,5] and anxiogenic effects of drug withdrawal [6,7]. CRF1 binding sites have been demonstrated in several key brain areas involved in the addictive processes [e.g., cerebral cortex, hippocampus, hypothalamus, amygdala, nucleus of tractus solitarius (NTS), ventral tegmental area (VTA) and nucleus accumbens (NAc) that are involved in reward, reinforcement, craving and aversive effects of drugs of abuse [9]. The decreased brain reward function associated with drug withdrawal is CRF1 receptor-dependent [10]
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