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Natural and drug rewards act on common neural plasticity mechanisms with ΔFosB as a key mediator - PubMed

  • ️Tue Jan 01 2013

Natural and drug rewards act on common neural plasticity mechanisms with ΔFosB as a key mediator

Kyle K Pitchers et al. J Neurosci. 2013.

Abstract

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.

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Figures

Figure 1.
Figure 1.

Sexual experience caused an immediate and persistent increase in number of ΔFosB-IR cells. Fold change of number of ΔFosB-IR cells in the NAc shell (A) and core (B) in sexually experienced (black) animals compared with sexually naive (white) controls (n = 4 each group). Data are group mean ± SEM. *p < 0.05, significant difference compared with naive controls. Representative of images of Naive 1 d (C), Exp 1 d (D), Exp 7 d (E), and Exp 28 d (F). ac, Anterior commissure. Scale bar, 100 μm.

Figure 2.
Figure 2.

Sexual experience caused an increase in number of dendritic spines in the NAc and sensitized Amph reward. A, B, The number of dendritic spines in the NAc shell and core of 7 d (A) or 28 d (DB of sexually naive [white] and experienced [black] animals; n = 4 or 5). Data are group mean ± SEM. #p < 0.05, significant difference compared with naive controls. C, Representative dendritic segments from Naive 7 d and Exp 7 d groups used to quantify spine density. Scale bar, 3 μm. D, The amount of time spent in the paired chamber (Amph or saline) during the post-test minus the pretest (CPP score) for sexually naive (white) or experienced (black) animals tested either 7 d or 28 d after final mating or handling session: Naive-Sal (7 d after handling; n = 8), Naive Amph (7 d after handling; n = 9), Exp-Sal (combined groups of animals tested either 7 d or 28 d after mating; n = 7), 7 d Exp Amph (7 d after mating; n = 9), and 28 d Exp Amph (28 d after mating; n = 11). Sal groups received Sal paired with both chambers. *p < 0.05, significant difference compared with sexually experienced saline controls.

Figure 3.
Figure 3.

Attenuating ΔFosB activity in the NAc blocked sensitized AMPH reward and increase in number of NAc spines in sexually experienced animals. A, Representative images of GFP expression in three animals receiving an injection of recombinant adeno-associated viral-ΔJunD directed at the nucleus accumbens, illustrating small (left), intermediate (middle), and large (right) injection sites. ac, Anterior commissure; LV, lateral ventricle. Scale bar, 250 μm. B, Schematic illustration of most prominent locations and patterns of spread of virus. In all animals, GFP was detected in the shell, but spread to the core was variable. C, The amount of time spent in the Amph-paired chamber during the post-test minus the pretest (CPP score) for sexually naive (white) and experienced (black) animals that either received an injection of GFP control vector (Naive, n = 9; Exp, n = 10) or ΔJunD vector (Naive, n = 9; Exp, n = 9). D, Representative images of dendritic segments from sexually experienced GFP and ΔJunD used to quantify spine density. Scale bar, 3 μm. E, The number of dendritic spines in the NAc of sexually naive (white) and experienced (black) animals that either received an injection of GFP control vector or ΔJunD vector. Data are group mean ± SEM. *p < 0.05, significant difference compared with naive controls. #p < 0.05, significant difference from GFP experienced controls.

Figure 4.
Figure 4.

Dopamine receptor antagonists infused into the NAc did not affect sexual behavior. Coronal NAc sections (A, +2.2; B, +1.7; C, +1.2 from bregma) indicating intra-NAc injection sites for all animals. Cannulas were bilateral but are represented unilaterally for ease of presentation of all animals (Naive-Sal, white, n = 7; Exp-Saline; dark gray, n = 9; Exp D1R Ant, light gray, n = 9; Exp D2R Ant, black, n = 8). ac, Anterior commissure; LV, lateral ventricle; CPu, caudate-putamen. Mount latency (D), intromission latency (E), and ejaculation latency (F) for all sexually experienced groups (Saline, white; D1R Ant, gray; D2R Ant, black). Data represent mean ± SEM. *p < 0.05, significant difference between day 1 and day 4 within treatment.

Figure 5.
Figure 5.

Blocking D1R in the NAc attenuates the increase in number of ΔFosB-IR cells in the NAc of sexually experienced animals. Fold change of number of ΔFosB-IR cells in the NAc shell (A) and core (B) in sexually experienced (black) animals compared with sexually naive (white) controls (Naive-Sal, n = 6; Exp-Saline, n = 7; Exp D1R Ant, n = 9; Exp D2R Ant, n = 8). Data are group mean ± SEM. *p < 0.05, significant difference compared with naive controls. #p < 0.05, significant difference compared with saline and D2R Ant experienced animals. Representative of images of Naive Sal (C), Exp Sal (D), Exp D1R Ant (E), and Exp D2R Ant (F). ac, Anterior commissure. Scale bar, 100 μm.

Figure 6.
Figure 6.

Blocking D1 receptors in the NAc abolishes sensitized Amph reward and increased dendritic spines in sexually experienced animals. A, The amount of time spent in the Amph-paired chamber during the post-test minus the pretest (CPP score, seconds) for sexually naive (white, n = 6) and experienced (black) animals that received saline (n = 7), D1R antagonist (n = 9), or D2R antagonist (n = 8). Data are group mean ± SEM. *p < 0.05, significant difference compared with naive saline controls. #p < 0.05, significant difference from D1R Ant experienced animals. B, The number of dendritic spines (per 10 μm) for sexually naive (white, n = 7) and experienced (black) animals that received saline (n = 8), D1R antagonist (n = 8), or D2R antagonist (n = 8). Data are group mean ± SEM. *p < 0.05, significant difference compared with naive saline controls. #p < 0.05, significant difference from experienced saline controls.

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