Buprenorphine and a CRF1 Antagonist Block the Acquisition of Opiate Withdrawal-Induced Conditioned Place Aversion in Rats

Abstract

Conditioned place aversion in rats has face validity as a measure of the aversive stimulus effects of opiate withdrawal that reflects an important motivational component of opiate dependence. The purpose of the present study was to validate conditioned place aversion as sensitive to medications that will alleviate the aversive stimulus effects of opiate withdrawal in humans, and to extend this model to the exploration of the neuropharmacological basis of the motivational effects of opiate withdrawal. Male Sprague-Dawley rats were implanted with two subcutaneous morphine pellets and 5 days later began place conditioning training following subcutaneous administration of a low dose of naloxone. Animals were subjected to three pairings of a low dose of naloxone (15 mg/kg, s.c.) to one arm of a three-chambered place conditioning apparatus. Buprenorphine administered prior to each pairing dose-dependently blocked the place aversion produced by precipitated opiate withdrawal. A corticotropin-releasing factor-1 (CRF 1 ) receptor antagonist (antalarmin) also reversed the place aversion produced by precipitated opiate withdrawal. Antalarmin did not produce a place preference or place aversion by itself in morphine-dependent rats. No effect was observed with pretreatment of the dopamine partial agonist terguride or the selective serotonin reuptake inhibitor fluoxetine. Also, chronic pretreatment with acamprosate (a glutamate receptor modulator used to prevent relapse in alcohol dependence) did not alter naloxone-induced place aversion. Buprenorphine by itself in dependent rats produced a mild place preference at low doses and a mild place aversion at higher doses. These results suggest that buprenorphine blocks the aversive stimulus effects of precipitated opiate withdrawal in rats and provides some validity for the use of place conditioning as a measure that is sensitive to potential opiate-dependence medications. In addition, these results suggest that CRF 1 antagonists can block the aversive stimulus effects of opiate withdrawal and may be potential therapeutic targets for opiate dependence.

Effects of Corticotropin-Releasing Factor Receptor-1 Antagonists on the Brain Stress System Responses to Morphine Withdrawal

“…Several studies have shown that increased CRF release contributes to the anxiety and aversive states produced by drug withdrawal (Zorrilla and Koob, 2004;Gallagher et al, 2008), and recruitment of the CRF system has been hypothesized to be involved in drug dependence (Koob, 2008). Accordingly, antagonism of CRF neurotransmission attenuated the anxiety-like and aversive effects of drug withdrawal (Stinus et al, 2005). In addition, previous findings have shown anxiolytic-like action of CRF1R antagonists (Contarino and Papaleo, 2005).…”

Erratum: Neurocircuitry of Addiction

“…Systemic administration of a CRF 1 receptor antagonist and direct intracerebral administration of a peptide CRF 1 /CRF 2 antagonist also decreased opioid withdrawal-induced place aversions (Stinus et al, 2005;Heinrichs et al, 1995). Functional noradrenergic antagonists administered directly into the BNST blocked opioid withdrawal-induced place aversion, implicating the importance of noradrenergic stimulation in the stress responses that follow acute drug withdrawal (Delfs et al, 2000).…”

Antagonism of CRF Receptors Prevents the Deficit in Brain Reward Function Associated with Precipitated Nicotine Withdrawal in Rats

“…Although the role of CRF in negative mood states associated with nicotine withdrawal had not been investigated, experimental evidence indicates that a hyperactivity of brain CRF systems may play a role in negative emotional states associated with withdrawal from other drugs of abuse. For example, antagonism of CRF receptors has been shown to prevent the development of opioid withdrawal-induced conditioned place aversion (Heinrichs et al, 1995;Stinus et al, 2005). It has been suggested that an increased release of CRF in extrahypothalamic brain sites mediates the negative affective state of drug withdrawal (Koob and Le Moal, 2005).…”