Nucleus accumbens NMDA receptor activation regulates amphetamine cross-sensitization and deltaFosB expression following sexual experience in male rats
Introduction
Drugs of abuse cause neural plasticity within the mesolimbic pathway, which in turn, contributes to the development and maintenance of addiction (Chen et al., 2010, Koob and Volkow, 2010, Mameli and Luscher, 2011, Feltenstein and See, 2013, Grueter et al., 2013, Gipson et al., 2014). The mesolimbic pathway regulates natural reward behaviors (Frohmader et al., 2010, Olsen, 2011, Volkow et al., 2011, Volman 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., 2010b, Pitchers et al., 2013, Pitchers et al., 2014, Olsen, 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. For example, pair bonding and environmental enrichment can serve as a protective component to drug-seeking behavior (Aragona et al., 2007, Solinas et al., 2008, Gipson et al., 2011, Liu et al., 2011, Burkett and Young, 2012, Puhl et al., 2012). Conversely, social isolation or the removal of environmental enrichment can cause an increased vulnerability to drug seeking (Lu et al., 2003, Raz and Berger, 2010, Nader et al., 2012, Neisewander et al., 2012).
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 long-lasting (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., 2013, Staffend 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., 2010b, Pitchers 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.
Glutamate is a key mediator of drug-induced neural plasticity in the NAc (Kalivas and Volkow, 2011, Loweth et al., 2014, Pomierny-Chamiolo et al., 2014, van Huijstee and Mansvelder, 2014). The NAc receives multiple glutamatergic inputs, including those from the medial prefrontal cortex (mPFC), basolateral amygdala (BLA) and hippocampus (Britt et al., 2012, Papp et al., 2012, Tye, 2012), but a role for glutamate in the regulation of sexual behavior or for the effects of sexual experience on neural and behavioral plasticity has not been established. 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). These results suggest an initial activation and increase in NMDA receptors during sexual experience, followed by increased synthesis and trafficking of AMPA receptors during the abstinence period. However, the functional relevance of NMDA receptor activation during sexual behavior for experience-induced neuroplasticity and cross-sensitization to Amph reward remains unknown and will be the focus of the current set of studies.
As mentioned above, sexual experience causes long-lasting expression of deltaFosB in the NAc (Meisel and Mullins, 2006, Pitchers et al., 2010b, Pitchers et al., 2013). DeltafosB is also persistently expressed in reward-related brain regions, including the NAc, in response to drugs of abuse (Perrotti et al., 2008, Robison and Nestler, 2011) and natural rewards, such as food (Teegarden et al., 2009) and sucrose consumption (Wallace et al., 2008, Christiansen et al., 2011), wheel running (Werme et al., 2002, Greenwood et al., 2011) and environmental enrichment (Solinas et al., 2008). DeltaFosB expression in the NAc has been shown to play a causal role in the sensitivity to drugs of abuse, particularly psychostimulants (Kelz et al., 1999, Nestler, 2008, Grueter et al., 2012, Robison et al., 2013). In addition, deltaFosB expression in the NAc is essential for the effects of sex experience on cross-sensitization of Amph reward (Pitchers et al., 2010b, Pitchers et al., 2013) and facilitation of sexual behavior (Pitchers et al., 2012). In the NAc, dopamine plays a major role in the induction of deltaFosB. It is induced in D1 receptor neurons in response to drugs of abuse (Lee et al., 2006, Kim et al., 2009, Lobo et al., 2013), and drug- and sex-induced deltaFosB induction is prevented by D1 receptor antagonism (Muller and Unterwald, 2005, Pitchers et al., 2013) and absent in D1 receptor mutant mice (Zhang et al., 2002). Besides the role for dopamine in activation of deltaFosB, there is also limited evidence that NMDA receptor activation may play a role, as treatment with NMDA receptor agonists increases striatal deltaFosB (Hollen et al., 1997). However, the involvement of NMDA receptor activation in induction of this transcription factor by natural or drug rewards is largely unexplored. Therefore, here we examine the role of NMDA receptor activation in sex-induced deltaFosB in the NAc.
In conclusion, the current study had four objectives. First, we tested the role of NMDA receptor activation in the NAc for the initiation, facilitation and reward of sexual behavior in male rats. Next, we tested the hypothesis that sex experience-induced Amph reward cross-sensitization is dependent on NMDA receptor activation in the NAc during mating. And third, the contribution of NMDA receptor activation for sexual experience-induced deltaFosB was examined. In particular, the effects of intra-NAc infusions of the NMDA receptor antagonist, MK 801, on sex behavior, experience-induced Amph CPP and NAc deltaFosB expression were determined. Finally, as NMDA receptor activation also contributes to the induction of cFos in the NAc by drugs of abuse (Liu et al., 1994, Hussain et al., 2001, Yanahashi et al., 2004) and in the medial preoptic nucleus (MPN) by sex behavior (Dominguez et al., 2007), we tested the hypothesis that NAc NMDA receptor activity regulates mating-induced cFos expression in the NAc.
Section snippets
Animals
Young adult male Sprague Dawley rats (Charles River, Wilmington, MA; 225–250 g) were housed in same sex pairs (of identical treatment groups) in standard Plexiglas cages. Food and water were provided ad libitum, and animals were maintained in temperature and humidity-controlled rooms on a 12/12 h dark–light cycle with lights off at 6–8 am. Female Sprague Dawley rats (Charles River; 210–225 g) were bilaterally ovariectomized and implanted with subcutaneous (s.c.) capsules (Dow Corning tubing,
Experiment 1: effects of intra-NAc MK 801 on sexual behavior and experience-induced Amph CPP and NAc deltaFosB expression
The main goals of this study were to investigate if intra-NAc MK 801 during mating experience would prevent experience-induced Amph CPP sensitization and NAc deltaFosB expression.
Sexually experienced and naïve groups of males received intra-NAc MK 801 (1 μg in 0.5 μl or 1 μl saline) or saline 15 (1 μl) min prior to each of the four daily mating or handling sessions. Latencies to first mount, intromission and ejaculation were analyzed between days 1 and 4 for all groups using a two-way analysis
Intra-NAc MK 801 did not disrupt sexual behavior
In the first experiment, intra-NAc infusions of MK 801 did not affect sexual behavior on any of the four daily mating tests, and no differences between groups were detected. Moreover, animals in all groups showed facilitation of sexual behavior with experience (mount latencies: F(2,92) = 5.413, p = 0.022; intromission latencies: F(2,91) = 6.742, p = 0.011; ejaculation latencies: F(2,91) = 8.565, p = 0.004), evidenced by significantly lower latencies or trends in the fourth mating session
Discussion
The current study demonstrates that NMDA receptor activation in the NAc during sexual behavior is critical for the cross-sensitizing effects of sexual experience on Amph reward as intra-NAc MK 801 injections during sexual experience prevented increased CPP for Amph. Moreover, NAc NMDA receptor activation during sexual behavior contributes to mating-induced cFos and deltaFosB expression but not to sexual behavior or reward. In summary, NAc NMDA receptor activation during sexual behavior
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2018, International Review of NeurobiologyCitation Excerpt :Males will typically reduce the numbers of mounts prior to ejaculation and thus increase copulation efficiency, and latencies to ejaculation are reduced (Beloate, Omrani, et al., 2016; Pitchers et al., 2014, 2012). This effect of sexual experience on decreased latency to mount, intromission and ejaculation, i.e., facilitation of sexual behavior, is evident even after only one mating experience, but typically requires several sessions to reach reliable detection of statistically significant differences (Beloate, Omrani, et al., 2016; Beloate, Weems, et al., 2016; Pitchers et al., 2014, 2012, 2013; Pitchers, Di Sebastiano, & Coolen, 2016; Pitchers, Frohmader, et al., 2010). Finally, experience-induced facilitation of sexual behavior is expressed in a long-term manner, as it is maintained for at least a month after the last mating session (Pitchers et al., 2014, 2012).
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2017, Cell ReportsCitation Excerpt :Moreover, we have demonstrated that D1R blockage in the NAcc during the conditioning phase reduced the olfactory preference of males toward female chemosignals more than 10 days later. The reinforcing effects of sexual stimuli are mediated by long-lasting neuroplasticity changes in the NAc (Beloate et al., 2016; Pitchers et al., 2012; Staffend et al., 2014), which are dependent on D1R signaling and its down-stream effects (Pitchers et al., 2013; Staffend et al., 2014). Our results suggest that blocking D1R signaling during the initial interactions with female chemosignals prevented the occurrence of female-induced neuroplasticity in the NAcc, and this altered the olfactory preference of males days later.
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2017, Neuroscience and Biobehavioral ReviewsCitation Excerpt :Indeed, NAc NMDA receptor activation during sexual experience is important for sexual experience-induced neuroplasticity and cross-sensitization to psychostimulant preference, as intra-NAc NMDA antagonism prior to each 4 days of sexual behavior prevents experience-induced Amph CPP (Beloate et al., 2016c). Furthermore, intra-NAc NMDA antagonism blocks mating-induced neural activation in the NAc, as measured by cFos immunoreactivity, but does not block sexual behavior or CPP (Beloate et al., 2016c). However, the functional role of other glutamate receptor changes throughout the abstinence period and the source of glutamate acting in the NAc during sexual activity remain unknown.
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