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 reflexa measure of anxiety induced by opiate withdrawalwas 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 sensitizationa 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.
Bibliographical noteFunding Information:
We thank Bonnie LaCroix, Jonathan Ehrich, Armin Jewell, Mihir Pendurkar, Michael Smet, and Bobby Wasem for technical assistance; Gail Towers for diligent animal husbandry; and members of the Thomas and Gewirtz labs for stimulating discussions. This work was supported by funding from the University of Minnesota Graduate School (to PER) and grants from NIDA (DA007234 and DA023750 to PER, DA019666 to MJT, and DA018784 to JCG), the Whitehall Foundation (to MJT), and NARSAD (to JCG).
- acoustic startle
- individual differences