J Neurosci.

2013 Feb 20;33(8):3434-3442.


Pitchers KK, Vialou V, Nestler EJ, Laviolette SR, Lehman MN, Coolen LM.

Source: Department of Anatomy & Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario N6A 3K7, Canada, Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, Michigan 48109, Fishberg Department of Neuroscience and Friedman Brain Institute, Mount Sinai School of Medicine, New York, New York 10029, and Departments of Neurobiology and Anatomical Sciences and Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi 39216.


Drugs of abuse induce neuroplasticity in the natural reward pathway, specifically the nucleus accumbens (NAc), thereby causing development and expression of addictive behavior. Recent evidence suggests that natural rewards may cause similar changes in the NAc, suggesting that drugs may activate mechanisms of plasticity shared with natural rewards, and allowing for unique interplay between natural and drug rewards.

In this study, we demonstrate that sexual experience in male rats when followed by short or prolonged periods of loss of sex reward causes enhanced amphetamine reward, indicated by sensitized conditioned place preference for low-dose (0.5 mg/kg) amphetamine. Moreover, the onset, but not the longer-term expression, of enhanced amphetamine reward was correlated with a transient increase in dendritic spines in the NAc. Next, a critical role for the transcription factor ΔFosB in sex experience-induced enhanced amphetamine reward and associated increases in dendritic spines on NAc neurons was established using viral vector gene transfer of the dominant-negative binding partner ΔJunD. Moreover, it was demonstrated that sexual experience-induced enhanced drug reward, ΔFosB, and spinogenesis are dependent on mating-induced dopamine D1 receptor activation in the NAc. Pharmacological blockade of D1 receptor, but not D2 receptor, in the NAc during sexual behavior attenuated ΔFosB induction and prevented increased spinogenesis and sensitized amphetamine reward.

Together, these findings demonstrate that drugs of abuse and natural reward behaviors act on common molecular and cellular mechanisms of plasticity that control vulnerability to drug addiction, and that this increased vulnerability is mediated by ΔFosB and its downstream transcriptional targets.


In the current study, we demonstrated cross-sensitization between natural and drug reward, when the natural reward is followed by a period of abstinence. Specifically, we showed that experience with sexual behavior, followed by 7 or 28 d of abstinence, causes enhanced Amph reward.

In conclusion, the current study highlights the cross-sensitization of drug reward by a natural reward (sex) and its dependence on a reward abstinence period. Moreover, this behavioral plasticity was mediated by ΔFosB via D1R activation in the NAc. Therefore, data suggest that loss of a natural reward after reward experience may make individuals vulnerable to development of drug addiction and that one mediator of this increased vulnerability is ΔFosB and its downstream transcriptional targets.