Neuropharmacology. 2016 Aug;107:122-30. doi: 10.1016/j.neuropharm.2016.03.002
Natural rewards and psychostimulants cause similar neural plasticity in the nucleus accumbens (NAc). In addition, sexual experience in male rats causes increased locomotor activity and conditioned place preference (CPP) induced by d-Amphetamine (amph). The latter is dependent on a period of abstinence from sexual reward. In this study, the role of mGluR5 activation in the NAc for expression of mating and the cross-sensitizing effects of sexual experience was tested. First, intra-NAc infusions of mGluR5 antagonists MPEP (1 or 10 μg/μL) or MTEP (1 μg/μL) 15 min prior to mating during 4 daily sessions had no effect on male rat sexual behavior. Subsequently, these sexually experienced males were tested for amph-induced locomotor activity and CPP after one week of abstinence from sexual reward. In addition, sexually naïve males that received MPEP, MTEP or vehicle infusions prior to 4 daily handling sessions were included. Cross-sensitization of locomotion or CPP was not prevented by NAc mGluR5 antagonism during acquisition of sexual experience. Instead, sexually naive animals that received NAc mGluR5 antagonists without mating demonstrated sensitized amph-induced locomotor responses and enhanced CPP on par with sexually experienced males. Finally, we showed that sexual experience caused prolonged down-regulation of mGluR5 protein in the NAc, dependent on abstinence from sexual behavior. Together, these findings suggest that mGluR5 activation in the NAc is not essential for the expression of mating, but that experience-induced reduction in mGluR5 protein may contribute to the cross-sensitization of amph responses by sexual experience and abstinence.
KEYWORDS: Amphetamine; Behavioral sensitization; Conditioned place preference; Glutamate; Reward; mGluR protein
Drugs of abuse and natural rewards, including male rat sexual behavior, have been shown to not only activate overlapping brain regions (Balfour et al., 2004; Frohmader et al., 2010b) but also utilize similar neuroplasticity mediators and mechanisms to cause neuroplasticity underlying behavioral changes (Pitchers et al., 2010a, 2012, 2013, 2014, Beloate et al., 2016). Administration of a psychostimulant causes an acute increase in extracellular glutamate in the NAc (Del Arco et al., 1999; Gray et al., 1999; Reid and Berger, 1996), whereas repeated cocaine causes a reduction in basal glutamate levels (Baker et al., 2003; Madayag et al., 2007; McFarland et al., 2003).
Glutamate or mGluR5 agonists activate mGluR5 and trigger a marked and rapid desensitization of mGluR5 involving down-regulation of mGluR5 (Dhami and Ferguson, 2006; Gereau and Heinemann, 1998). Repeated cocaine plus an extended abstinence period (but not after only 1 day) causes a decrease in mGluR5 expression in the striatum, and as a result, diminishing group 1 mGluR-mediated increases in extracellular glutamate
It has been suggested that lowered glutamate levels represent a compensatory response to repeated reward exposure and that lowered mGluR5 activity would attenuate effects of drug-induced glutamate release that might otherwise produce stimulus induced sensitized responses (Kalivas et al., 2009). There seems to be a similarity among sex experience and repeated psychostimulants causing a potentially compensatory, abstinence dependent decrease in mGluR5 levels in the NAc. Moreover, this decrease in mGluR5 receptors with sexual experience is correlated temporally with the sensitized responses to psychostimulants and sexual stimuli (Pitchers et al., 2010a, 2010b, 2012, 2013). In particular, the effects of sexual experience on the sensitization of amph-CPP and on mGluR5 levels are both dependent on a period of abstinence and persist with prolonged abstinence (Pitchers et al., 2010a).
In contrast, the effects of sexual experience on locomotor sensitization is not dependent on a period of abstinence and is observed within one day after sexual experience. Hence, mGluR5 protein reduction may contribute to the maintenance of sex induced locomotor sensitization, but is unlikely an initial causal factor. Future studies are required to further investigate the functional significance of the down-regulation of mGluR5 expression following sexual experience on receptor activity and glutamate levels.
The glutamatergic projection from the mPFC to the NAc, and mGluR5 have been implicated in drug reinstatement and extinction learning Ghasemzadeh et al., 2009; Kalivas et al., 2005; Knackstedt et al., 2014). mGluR5 have been shown to be critical for cocainerelated responses through the use of mGluR5 KO mice. mGluR5 KO mice do not self-administer cocaine, nor do they demonstrate any cocaine-induced changes in locomotor activity (Chiamulera et al., 2001). Systemic administration of the mGluR5 antagonist MPEP decreases cocaine, morphine and nicotine self administration and subsequent drug-seeking behavior (Aoki et al., 2004; Chiamulera et al., 2001; Kumaresan et al., 2009; Popik and Wrobel, 2002; Tessari et al., 2004). Moreover, by stimulating mGluR5 in the NAc, cue-induced reinstatement is potentiated
In contrast, MPEP does not affect the development or expression of food CPP (Herzig et al., 2005). Here, we did not test mGluR5 antagonism at the time of expression of sensitized amph-induced locomotor activity or amph reward. The current study demonstrates that mGluR5 antagonism during sexual experience did not block the effects of sexual experience on amph responses. A manipulation of receptor activity at the time of testing amph responses, rather than during development, would better parallel most of the experiments with drugs of abuse and might show an effect in sexually experienced animals.
In summary, our results suggest that antagonism of mGluR5 activity in the NAc neither disrupts sexual behavior nor blocks the long-term effects of sexual experience and abstinence on sensitized amph responses. However, administration of an mGluR5 antagonist alone without sexual behavior causes sensitized amph-induced locomotor activity and enhanced conditioned amph reward, mimicking the effects of sexual experience. Finally, it was shown that sexual experience followed by prolonged abstinence from sex reward caused significant down regulation of mGluR5 protein levels in NAc, which in turn potentially contributes to the cross-sensitizing effects of sexual experience and abstinence.