Natural Reward Experience Alters AMPA and NMDA Receptor Distribution and Function in the Nucleus Accumbens

Abstract

Natural reward and drugs of abuse converge upon the mesolimbic system which mediates motivation and reward behaviors. Drugs induce neural adaptations in this system, including transcriptional, morphological, and synaptic changes, which contribute to the development and expression of drug-related memories and addiction. Previously, it has been reported that sexual experience in male rats, a natural reward behavior, induces similar neuroplasticity in the mesolimbic system and affects natural reward and drug-related behavior. The current study determined whether sexual experience causes long-lasting changes in mating, or ionotropic glutamate receptor trafficking or function in the nucleus accumbens (NAc), following 3 different reward abstinence periods: 1 day, 1 week, or 1 month after final mating session. Male Sprague Dawley rats mated during 5 consecutive days (sexual experience) or remained sexually naïve to serve as controls. Sexually experienced males displayed facilitation of initiation and performance of mating at each time point. Next, intracellular and membrane surface expression of N-methyl-D-aspartate (NMDA: NR1 subunit) and α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA: GluA1, GluA2 subunits) receptors in the NAc was determined using a bis(sulfosuccinimidyl)suberate (BS3) protein cross-linking assay followed by Western Blot analysis. NR1 expression was increased at 1 day abstinence both at surface and intracellular, but decreased at surface at 1 week of abstinence. GluA2 was increased intracellularly at 1 week and increased at the surface after 1 month of abstinence. Finally, whole-cell patch clamp electrophysiological recordings determined reduced AMPA/NMDA ratio of synaptic currents in NAc shell neurons following stimulation of cortical afferents in sexually experienced males after all reward abstinence periods. Together, these data show that sexual experience causes long-term alterations in glutamate receptor expression and function in the NAc. Although not identical, this sex experience-induced neuroplasticity has similarities to that caused by psychostimulants, suggesting common mechanisms for reinforcement of natural and drug reward.

The Nucleus Accumbens: A Comprehensive Review

“…While a number of the other neurotransmitters, including norepinephrine [266], serotonin [267,268], and GABA [269], are likely involved, the role of glutamate is perhaps the most well studied [251,252,270,271,272,273,274,275,276]. On a molecular level, these changes are likely mediated by a host of transcription factors, but three in particular - the cyclic-AMP response element-binding protein (CREB) [277,278,279,280,281], ΔFosBand [282,283,284,285,286,287], and CaMKII [288,289,290,291,292] - have often been implicated in addiction (for review, see [293,294]).…”

Nucleus accumbens NMDA receptor activation regulates amphetamine cross-sensitization and deltaFosB expression following sexual experience in male rats

“…The mesolimbic pathway regulates natural reward behaviors (Frohmader et al, 2010;Olsen, 2011;Volkow et al, 2011Volkow et al, , 2013, and repeated exposure to natural rewards causes neural plasticity similar to that induced by drugs of abuse (Solinas et al, 2008;Pitchers et al, 2010bPitchers et al, , 2013Pitchers et al, , 2014Olsen, 2011;Nader et al, 2012;Adams et al, 2013;Bardo et al, 2013), suggesting that drugs of abuse act on the same plasticity mechanisms that regulate natural reward learning (Pitchers et al, 2013(Pitchers et al, , 2014. Indeed, natural reward experience influences subsequent drug-seeking behavior in rodent models.…”

“…Repeated experience with sexual behavior causes subsequent sensitization of drug-induced locomotor activity in female hamsters (Bradley and Meisel, 2001) and male rats (Pitchers et al, 2010a(Pitchers et al, , 2012. Moreover, in male rats sexual experience causes sensitized conditioned place preference (CPP) for low doses of the psychostimulant, D-Amphetamine (Amph) (Pitchers et al, 2010a), which is dependent on a period of sexual abstinence and is longlasting (Pitchers et al, 2010a(Pitchers et al, , 2013.…”

“…Moreover, in male rats sexual experience causes sensitized conditioned place preference (CPP) for low doses of the psychostimulant, D-Amphetamine (Amph) (Pitchers et al, 2010a), which is dependent on a period of sexual abstinence and is longlasting (Pitchers et al, 2010a(Pitchers et al, , 2013. Sexual experience also causes neural alterations in the nucleus accumbens (NAc) and ventral tegmental area (VTA), including increased dendritic arborization and spine density in NAc medium spiny neurons (Pitchers et al, 2010a(Pitchers et al, , 2013Staffend et al, 2014), reduction of VTA dopamine cell soma size (Pitchers et al, 2014), and upregulation of the transcription factor deltaFosB, in both NAc and VTA (Meisel and Mullins, 2006;Pitchers et al, 2010bPitchers et al, , 2013. Hence, our laboratory has proposed that these neural alterations contribute to the effects of sexual experience on cross-sensitization to Amph reward.…”

“…We have previously demonstrated that sexual experience influences the function, expression and distribution of glutamate receptors in the NAc of male rats. In particular, patch clamp studies showed reduced AMPA/NMDA ratios in the postsynaptic response to frontal cortex inputs, with no alterations in presynaptic inputs (Pitchers et al, 2012). Moreover, biochemical analysis showed that expression of the NMDA receptor NR1 subunit was upregulated shortly following sexual behavior, whereas AMPA receptor GluA1 and 2 subunits were upregulated following prolonged periods of reward abstinence (Pitchers et al, 2012).…”