Neuroplasticity in the mesolimbic system induced by natural reward and subsequent reward abstinence

Abstract

Background: Natural reward and drugs of abuse converge on the mesolimbic system, where drugs of abuse induce neuronal alterations. Here, we tested plasticity in this system after natural reward and the subsequent impact on drug responses.

Methods: Effects of sexual experience in male rats on behavioral sensitization and conditioned place preference associated with d-amphetamine (AMPH) and Golgi-impregnated dendrites and spines of nucleus accumbens (NAc) cells were determined. Moreover, the impact of abstinence from sexual behavior in experienced males on these parameters was tested.

Results: First, repeated sexual behavior induced a sensitized locomotor response to AMPH compared with sexually naive control subjects observed 1, 7, and 28 days after last mating session. Second, sexually experienced animals formed a conditioned place preference for lower doses of AMPH than sexually naive males, indicative of enhanced reward value of AMPH. Finally, Golgi-Cox analysis demonstrated increased numbers of dendrites and spines in the NAc core and shell with sexual experience. The latter two alterations were dependent on a period of abstinence of 7-10 days.

Conclusions: Sexual experience induces functional and morphological alterations in the mesolimbic system similar to repeated exposure to psychostimulants. Moreover, abstinence from sexual behavior after repeated mating was essential for increased reward for drugs and dendritic arbors of NAc neurons, suggesting that the loss of sexual reward might also contribute to neuroplasticity of the mesolimbic system. These results suggest that some alterations in the mesolimbic system are common for natural and drug reward and might play a role in general reinforcement.

Figure 1

Locomotor response of sexually experienced and naïve animals to saline or amphetamine administration. A is a schematic diagram of the zone map used to measure locomotor activity. A crossover is recorded each time the animal enters one of the black zones. Mean +/− SEM of total number of crossovers over 90 minutes (B) and in 30-minute intervals (C-E; C, 0–30 minutes. D, 31–60 minutes. E, 61–90 minutes). * indicates a statistically significant difference between AMPH and saline. # indicates a statistically significant difference between experience and naive groups (p < 0.05). F displays crossovers per 3-minute interval over 90-minutes (statistical differences are not indicated) (p-values: B, NA vs. NS, p = 0.0422; EA vs. ES, p < 0.0001, EA vs. NA; p < 0.0001; C–E, EA vs. NA; p < 0.001, EA vs. ES; p < 0.001; E, NA vs. NS; p = 0.0024).

Figure 2

Locomotor response of sexually experienced and naïve animals to saline or amphetamine administered one day (Day 8; A,B), one week (Day 14; C,D) or one month (Day 35; E,F) following the last mating session. Mean +/− SEM of total number of crossovers over the last 60 minutes divided into 30-minute intervals (31–60 minutes; A,C,E. 61–90 minutes; B,D,E). * indicates a statistically significant difference between AMPH and saline (NA vs NS: A; 0.0009, B; 0.0190, C; < 0.0001, D; 0.0002. EA vs ES: A; < 0.0001, B; 0.0002, C; < 0.0001, D; < 0.0001). # indicates a statistically significant difference between experience and naïve groups (p-values: EA vs NA: A; 0.0154, B; 0.0170, C; = 0.05, D; = 0.05, E; 0.0014, F; 0.0400).

Figure 3

Conditioned place preference of sexually experienced and naive animals in response to amphetamine either 10 days following (A) or during (B) mating sessions. Mean +/− SEM of CPP score, defined as the time spent in the AMPH-paired chamber in the post-test minus the pre-test (seconds). * indicates a statistically significant difference from males receiving saline (E0) (p < 0.05). (p-values: A, E0.5 p = 0.014; E1.0 p = 0.017; N2.5 p = 0.016, N5.0 p = 0.022; B, E0.5 p = 0.014, E2.5 p = 0.005, E5.0 p = 0.001; N2.5 p = 0.007, N5.0 p = 0.037)

Figure 4

Dendritic morphology in the NAc of sexually experienced and naïve animals. Sexual experience caused an increase in numbers of dendrites and dendritic spines, illustrated by images (A,B) and camera lucida drawings (C,D) of representative NAc shell neurons as well as spine density on second order dendrites (E,F) in NAc shell of naïve (A,C,E) or experienced (B,D,F) animals, 7 days following last treatment. Scale bar indicates 50 (A,B) or 10 (E,F) μm. Quantitative analysis shows significant increases of numbers of dendrites per centrifugal order (G–J) and numbers of spines (K,L) in NAc core (G,H) and shell (I,J) in sexually experienced males (black bars) compared to naïve males (white bars), but only 7 days following last mating (H,J,I). * indicates a statistically significant difference from naïve males (p-values: G: 0: 0.013 1: < 0.001; 2: <0.001; 3: <0.0001; 4: < 0.001; 5: < 0.001; I: 0: 0.002; 1: < 0.0001; 2: < 0.001; 3: < 0.001; 4: < 0.001; 5: < 0.001; L: core: 0.001; shell: < 0.001).