Nucleus accumbens dopamine mediates amphetamine-induced impairment of social bonding in a monogamous rodent species

Abstract

The prairie vole (Microtus ochrogaster) is a socially monogamous rodent species that forms pair bonds after mating, a behavior in which central dopamine (DA) has been implicated. Here, we used male prairie voles to examine the effects of drug exposure on pair bonding and related neural circuitry. In our first experiment, amphetamine (AMPH) motivated behavior was examined using a conditioned place preference (CPP) paradigm and was shown to be mediated by activation of D1-like DA receptors. Next, we examined the effects of repeated AMPH exposure on pair bonding. Intact and saline pretreated control males displayed mating-induced partner preferences, whereas males pretreated with AMPH at the doses effective to induce CPP failed to show mating-induced partner preferences. Such AMPH treatment also enhanced D1, but not D2, DA receptor expression in the nucleus accumbens (NAcc). Furthermore, pharmacological blockade of D1-like DA receptors in the NAcc rescued mating-induced partner preferences in AMPH-treated males. Together, our data indicate that repeated AMPH exposure may narrow the behavioral repertoire of male prairie voles via a DA receptor-specific mechanism in the NAcc, resulting in the impairment of pair bond formation.

Fig. 1.

(A) Males that received i.p. injections of saline or the low doses of AMPH (0.1 or 0.5 mg/kg) during 3 days of conditioning did not show CPP. However, males conditioned with AMPH at higher doses (1.0, 3.0, and 5.0 mg/kg) spent significantly more time in the conditioned cage during the posttest than the pretest. (B) To test the role of DA receptors in AMPH-induced CPP, males were pretreated with either saline or different doses of a nonselective DA receptor antagonist (haloperidol), D1-like receptor antagonist (SCH23390), or D2-like receptor antagonist (eticlopride) before AMPH injections during 3 days of conditioning. Injections of saline or low doses of haloperidol did not alter AMPH-induced CPP. However, haloperidol injected at 5.0 mg/kg blocked AMPH-induced CPP, demonstrating an involvement of DA receptors in AMPH-induced CPP. Furthermore, injections of the D1-like antagonist at both the low and high doses, but not the D2-like antagonist, blocked AMPH-induced CPP, demonstrating a receptor-specific DA regulation of AMPH-induced CPP. *P < 0.05, **P < 0.01.

Fig. 2.

(A) After 24 h of mating, intact males displayed partner preferences by spending significantly more time in side-by-side contact with a familiar mate versus a strange female. This mating-induced partner preference was also displayed by males that received 3 days of pretreatment with saline. However, 3 days of pretreatment with AMPH at 1.0 or 5.0 mg/kg (doses of AMPH that induced CPP) blocked mating-induced partner preferences. No group differences were found in the frequency of mating bouts during the first 6 h of mating (B) or in the number of cage crossings during the partner preference test (C). **P < 0.01.

Fig. 3.

Photo images showing in situ labeling of D1R (A) and D2R (B) mRNA in the NAcc and caudate putamen (CP) of male prairie voles that received i.p. injections of saline or AMPH (1.0 mg/kg) for 3 days. AMPH treatment significantly increased the density of D1R, but not D2R, mRNA in the NAcc. Because this increase was equivalent across the NAcc core and shell, data were collapsed across subregions (C). Photo images illustrating mRNA labeling of tyrosine TH (D), DAT (E), and D2Rs (F) in the VTA of the prairie vole brains. AMPH treatment did not affect the density of those DA marker mRNAs in the VTA (G). In the NAcc, AMPH treatment significantly increased the protein density of D1Rs, but not D2Rs, as measured by Western blotting (H and I). *P < 0.05, **P < 0.01. (Scale bar, 1 mm.)

Fig. 4.

(A) A photo image and schematic drawing illustrating the injection site in the NAcc of the male prairie vole brain. We focused on the NAcc shell because this specific subregion mediates mating-induced partner preferences. (B) Males that received intra-NAcc injections of CSF or a low dose of D1 receptor antagonist (SCH23390; 0.4 ng/side) before AMPH injections displayed AMPH-impairment of partner preferences. However, intra-NAcc injections of a high dose of SCH23390 (100 ng/side) rescued mating-induced partner preferences in AMPH-treated males. *P < 0.05.