Higher anhedonia during withdrawal from initial opioid exposure is protective against subsequent opioid self-administration in rats

Understanding factors contributing to individual differences in vulnerability to opioid addiction is essential for developing more effective preventions and treatments, yet few reliable behavioral predictors of subsequent opioid self-administration have been identified in rodents. Sensitivity to the acute effects of initial drug exposure predicts later addiction vulnerability in both humans and animals, but the relationship of sensitivity to withdrawal from initial drug exposure and later drug use vulnerability is unclear. The goal of the current study was to evaluate whether the degree of anhedonia experienced during withdrawal from early opioid exposure predicts subsequent vulnerability to opioid addiction. Rats were first tested for withdrawal sensitivity following acute injections of morphine (i.e., “acute dependence”), measured as elevations in intracranial self-stimulation (ICSS) thresholds (anhedonia-like behavior) during naloxone-precipitated and spontaneous withdrawal. Rats were then tested for addiction vulnerability using various measures of i.v. morphine self-administration (MSA) including acquisition, demand, extinction, and reinstatement induced by morphine, stress, and/or drug-associated cues. Greater naloxone-precipitated withdrawal across repeated morphine injections and greater peak spontaneous withdrawal severity following a single morphine injection were associated with lower addiction vulnerability on multiple MSA measures. Withdrawal-induced anhedonia predicted a wider range of MSA measures than did any individual measure of MSA itself. These data suggest that high anhedonia during withdrawal from initial opioid exposure is protective against subsequent opioid addiction vulnerability in rodents, thereby establishing one of the first behavioral measures to predict individual differences in opioid SA. This model promises to be useful for furthering our understanding of behavioral and neurobiological mechanisms underlying vulnerability to opioid addiction.