Opiate withdrawal-induced place aversion lasts for up to 16 weeks

The relative intermittency or continuity of drug delivery is a major determinant of addictive liability, and also influences the impact of drug exposure on brain function and behavior. Events that occur during the offset of drug action (ie, acute withdrawal) may have an important role in the consequences of intermittent drug exposure. We assessed whether recurrent episodes of acute withdrawal contribute to the development of psychomotor sensitization in rodents during daily morphine exposure. The acoustic startle reflexFa measure of anxiety induced by opiate withdrawalFwas used to resolve and quantify discrete withdrawal episodes, and pharmacological interventions were used to manipulate withdrawal severity. Startle potentiation was observed during spontaneous withdrawal from a single morphine exposure, and individual differences in initial withdrawal severity positively predicted the subsequent development of sensitization. Manipulations that reduce or exacerbate withdrawal severity also produced parallel changes in the degree of sensitization. These results demonstrate that the episodic experience of withdrawal during daily drug exposure has a novel role in promoting the development of psychomotor sensitizationFa prominent model of drug-induced neurobehavioral plasticity. Episodic withdrawal may have a pervasive role in many effects of intermittent drug exposure and contribute to the development of addiction.

Section: Discussionmentioning

confidence: 98%

Episodic Withdrawal Promotes Psychomotor Sensitization to Morphine

Rothwell

Gewirtz

Thomas

2010

“…The apparatus and procedure used to produce a reliable conditioned place aversion have been described in detail elsewhere (Stinus et al, 2000. Briefly, the apparatus consisted of three identical rectan-5-HT/NA interaction in opiate dependence S Caillé et al gular boxes (A, B, C) (40 Â 33 Â 34 cm) arranged radially (1201 to each other) and accessible from a triangular central compartment.…”

Section: Place Aversion Conditioningmentioning

confidence: 99%

Inhibition of 5-HT Neurotransmission Increases Clonidine Protective Effects on Naloxone-induced Conditioned Place Aversion in Morphine-dependent Rats

Caillé

Stinus

Fernández-Espejo

et al. 2002

Previous pharmacological studies have implicated serotonergic brain systems in opiate-withdrawal-precipitated conditioned place aversion. To assess this hypothesis, we tested the effects of either (i) a near-total 5,7-dihydroxytryptamine-induced lesion (90% depletion) or (ii) an acute serotonin (5-HT) inhibition induced by the specific stimulation of 5-HT1A autoreceptors (8-OHDPAT 5-100 mg/kg), on naloxone-induced conditioned place aversion in morphine-dependent rats. Morphine dependence was induced by the implantation of morphine slow-release pellets. The protective properties of clonidine (an alpha-2 adrenergic agonist classically given for opiate detoxification) were also tested after inhibition of 5-HT transmission. Serotonergic lesions in morphine-dependent rats failed to alter naloxone-induced conditioned place aversion but increased the sensitivity to the protective effects of clonidine. Acute neuropharmacological blockade of serotonin transmission also potentiated the clonidine effects on naloxone-induced conditioned place aversion. When combined with the 5-HT1A agonist 8-OHDPAT, clonidine was also found to be more potent. Further understanding of this serotonin/noradrenaline interaction might help devise new therapeutic treatments for the acute opiate withdrawal syndrome.

“…The doses of naloxone required to precipitate a place aversion are below those that produce overt physical or somatic signs of opiate withdrawal (Schulteis et al, 1994). The place aversion response does not require maintenance of opiate dependence because its manifestation continues to be present weeks after animals are 'detoxified' (eg up to 16 weeks after the morphine pellets are removed; see Baldwin and Koob, 1993;Hand et al, 1988;Stinus et al, 1990Stinus et al, , 2000, which clearly indicates that the memory of withdrawal can have long-lasting effects on behavioral responses.…”

Section: Introductionmentioning

confidence: 99%

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

Stinus

Cador

Zorrilla

et al. 2004

127

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.