Unexpectedly CRF receptor agonist and antagonist
Unexpectedly, CRF2 receptor agonist and antagonist evoked similar effects in the fall in tail skin temperature caused by restraint. However, Ucn3 reduced basal values of tail skin temperature, thus indicating that some degree of basal vasoconstriction caused by BNST treatment with Ucn3 may have contributed to the decrease in restraint-evoked change in tail skin temperature. Also, it has been demonstrated that activation of CRF2 receptors by Ucn3 in the central good intentions decreases sympathetic nerve activity . Therefore, a second possibility is that although activation of BNST CRF2 receptor by physiological release of CRF-like peptides during restraint contribute to cutaneous vasoconstriction (evidenced by reduction in the fall in skin temperature following treatment with antisalvagine-30), exogenous administration of Ucn3 may recruit a neural circuitry that decrease sympathetic nerve activity to cutaneous beds, thus buffering stress-evoked vasoconstriction in cutaneous beds.
In summary, the present results provide evidence that both CRF1 and CRF2 receptors within the BNST modulate the cardiovascular responses during emotional stress. Our data suggest that BSNT CRF1 receptor is involved in the mediation of the pressor and tachycardiac responses induced by restraint stress, whereas local CRF2 receptors control the arterial pressure increase and sympathetic-mediated cutaneous vasoconstriction during restraint. Although the results obtained with the antagonists indicate a specificity of CRF1 (control of arterial pressure and HR responses) and CRF2 (control of arterial pressure and cutaneous vasoconstriction responses) receptors in the control of restraint-evoked cardiovascular responses, treatment with CRF receptor agonists indicated that both receptors are able to modulate arterial pressure, HR, and cutaneous vasoconstriction responses during aversive threats.
Acknowledgments The authors wish to thank Elisabete Lepera and Rosana Silva for technical assistance. This work was supported by FAPESP grants # 2012/14376-0 and 2012/50549-6; and PADC-FCF UNESP.
Transition from drug use to addiction may result, in part, from the need to alleviate dysphoric and anxiety states that emerge during drug abstinence . In animal models, short-term (24–48h) withdrawal from cocaine increases anxiety-like behaviors , , , which are thought to drive drug craving and relapse , . However, an animal model of heightened anxiety states during protracted psychostimulant withdrawal has not been described, but is necessary to examine the neurobiology underlying anxiety during withdrawal. Corticotropin-releasing factor (CRF) is released from the amygdala in response to stressors , and increases anxiety-like behaviors in rodents . Likewise, psychostimulants activate CRF neurons , and alterations to CRF levels throughout the limbic system have been observed during psychostimulant withdrawal . Alterations in CRF systems may represent a compensatory neuroadaptation to restore homeostatic function in response to the presence of the drug, but result in emotional dysfunction in the absence of the drug . In support, intracerebroventricular (icv) administration of CRF antiserum or a CRF receptor antagonist reverses the heightened anxiety behavior observed at 48h after cocaine withdrawal in rats , . The serotonin (5-HT) neurons of the dorsal raphe nucleus (dRN) project throughout the limbic system and 5-HT is important in the regulation of anxiety states . Both CRF and CRF receptors are found in the dRN and have opposing effects on 5-HT release . Activation of CRF receptors in the dRN increases 5-HT release in limbic brain regions , , . Importantly, amphetamine treatment of rats daily for 14 days increased CRF receptors in the dRN, which persisted for at least 6 weeks of withdrawal . While activation of central CRF receptors is associated with increased anxiety-like behavior in animal models, the exact role of CRF receptors has not been clear . Studies of CRF knockout mice suggest that CRF receptor activity may be associated with reduced anxiety-like behaviors . However, icv administration of specific CRF receptor agonists or antagonists increase or decrease rodent anxiety-like behaviors respectively, suggesting an anxiogenic effect of CRF receptor activity . Given that CRF receptors are elevated in the dRN of amphetamine-treated rats during protracted withdrawal , we hypothesized that amphetamine-treated rats would show heightened anxiety-like behavior during long-term withdrawal, and that administration of a specific CRF receptor antagonist into the dRN would reverse this anxiety-like behavior.