Increased anxiety-like behavior of rats during amphetamine withdrawal is reversed by CRF2 receptor antagonism

Abstract

Withdrawal from psychostimulants increases anxiety states, and amphetamine-treated rats show increased CRF2 receptors in the serotonergic cell body region, the dorsal raphe nucleus (dRN). In the current study, amphetamine (2.5 mg/kg, ip, 14 days) pre-treated rats spent less time in open arms of the elevated plus maze compared saline pre-treated rats at both 24 hours or 2 weeks of withdrawal, and CRF2 receptor antagonism (ASV-30; 2 μg/0.5 μl) within the dRN reversed the effects of amphetamine withdrawal on anxiety-like behavior. Overall, results suggest that CRF2 receptor antagonism may be a novel pharmacological target for anxiety states during drug withdrawal.

The Role of the Amygdala in Anxiety Disorders

“…However, one can argue that experimental manipulations (such as earlylife stress or amphetamine withdrawal) that drive a group of animals towards greater fearand anxiety-like phenotypes also examine the underlying basis of trait fear or anxiety [e.g. 11,12]. As noted by Sylver et al [1] clinical studies most often examine trait anxiety, whereas experiments involving animal models most often focus on state anxiety and fear, and then relate these findings to concepts associated with trait anxiety.…”

“…A strong body of evidence implicates central CRF in mediating fear and anxiety [12,[121][122][123][124][125][126][127][128], and recent clinical studies suggest an important role for CRF in anxiety disorders [129]. Like anxiogenic and fearful stimuli, central infusion of CRF or CRF receptor agonists increases 5-HT, NE and DA levels in the amygdala [130][131][132][133], and stress-induced increases in monoamine levels in the amygdala are prevented by CRF receptor antagonists [108,111].…”

“…Importantly, increased neuronal surface expression of CRF2 receptors occurs in the dRN as a result of stress [142], and increased expression of CRF2 receptors in the dRN has been observed in rat models of high anxiety [11,128,137,143]. Furthermore, CRF2 receptor antagonists infused directly into the dRN reduce heightened anxiety-like behavior in rat models of amphetamine withdrawal or early life stress [12,128]. Combined, these findings suggest that CRF2 receptor modulation of 5-HT activity in the amygdala may play an important role in heightened anxiety.…”

“…The role of 5-HT or 5-HT receptors has not been well studied in the CeA. However, rats undergoing amphetamine withdrawal that exhibit greater anxiety-like behavior have greater 5-HT release in the CeA [12,133], suggesting a similar anxiogenic relationship between 5-HT and anxiety as for the BLA. Future work should determine whether 5-HT in the CeA reduces anxiety-like behaviors as is suggestive for the MeA, or in contrast, increases anxiety-like behaviors as appears to be the case for the BLA.…”

“…Furthermore, CRF and its receptors (CRF1 and CRF2) are implicated in fear and anxiety within animal models and in the development of anxiety disorders [12,[121][122][123][124][125][126][127][128][129]. Upon the development of non-peptide CRF1 receptor antagonists that cross the blood-brain barrier, there was great interest in the use of CRF1 receptor antagonist in the treatment of anxiety disorders.…”