Behavioral effects of dopamine receptor inactivation in the caudate-putamen of preweanling rats: role of the D2 receptor

Abstract

Rationale Inactivating dopamine (DA) receptors in the caudate-putamen (CPu) attenuates basal and DA agonist-induced behaviors of adult rats, while paradoxically increasing the locomotor activity of preweanling rats. Objective The purpose of this study was to determine (a) whether D1 or D2 receptor inactivation is responsible for the elevated locomotion shown by preweanling rats and (b) whether DA receptor inactivation produces a general state in which any locomotor-activating drug will cause a potentiated behavioral response. Methods DMSO or N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) was bilaterally infused into the CPu on postnatal day (PD) 17. In Experiment 1, DA receptors were selectively protected from EEDQ-induced alkylation by pretreating rats with D1 and/or D2 antagonists. On PD 18, rats received bilateral microinjections of the DA agonist R(–)-propylnorapomorphine into the dorsal CPu and locomotor activity was measured for 40 min. In subsequent experiments, the locomotion of DMSO- and EEDQ-pretreated rats was assessed after intraCPu infusions of the selective DA agonists SKF82958 and quinpirole, the partial agonist terguride, or after systemic administration of nonDAergic compounds. Results Experiment 1 showed that EEDQ's ability to enhance the locomotor activity of preweanling rats was primarily due to the inactivation of D2 receptors. Consistent with this finding, only drugs that directly or indirectly stimulated D2 receptors produced a potentiated locomotor response in EEDQ-treated rats. Conclusions These results show that DA receptor inactivation causes dramatically different behavioral effects in preweanling and adult rats, thus providing additional evidence that the D2 receptor system is not functionally mature by the end of the preweanling period.

Age-dependent changes in cocaine sensitivity across early ontogeny in male and female rats: possible role of dorsal striatal D2High receptors

“…In adolescent and adult rats, EEDQ minimally elevates the percentage of D2 High receptors while attenuating DA agonist-induced behaviors (Der Ghazarian et al 2012; McDougall et al 2014b). Microinjecting EEDQ into the striatum of preweanling rats, on the other hand, significantly reduces D2 receptor densities, increases the percentage of D2 High receptors, and potentiates cocaine-induced locomotor activity (Der Ghazarian et al 2012, 2014; McDougall et al 2014b). Thus, EEDQ-induced increases in D2 High receptors appear to enhance behavioral sensitivity to cocaine and other DA agonists.…”

Sex differences, learning flexibility, and striatal dopamine D1 and D2 following adolescent drug exposure in rats

“…Ontogenetic changes in D2 receptors may be partially responsible for differences in psychostimulant sensitivity (McDougall et al 2015) since functionality of the D2 receptor continues to mature beyond the preweanling period (Der-Ghazarian et al 2014) and likely through adolescence. Other groups, assessing D2 density via autoradiography after early MPH exposure (PND 21) do not report enduring effects of the drug on either D1 or D2 density (Gill et al 2013).…”

Behavioral effects of dopamine receptor inactivation during the adolescent period: age-dependent changes in dorsal striatal D2High receptors

“…Irreversible receptor antagonists, on the other hand, induce qualitatively different behavioral effects in young and adult rats. Specifically, systemic and intrastriatal injections of N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) attenuate the DA agonist-induced behaviors of adult rats (Arnt et al 1988; Bordi et al 1989; Meller et al 1989; Giorgi and Biggio 1990a,b; McDougall et al 1992; Der-Ghazarian et al 2012), whereas EEDQ potentiates R-propylnorapomorphine- (NPA) and quinpirole-induced locomotor activity in preweanling rats (McDougall et al 1992, 1993; Der-Ghazarian et al 2012, 2013). These behavioral differences are apparent even though EEDQ causes a substantial reduction in the D1 and D2 receptor levels of both age groups (Leff et al 1984; Crawford et al 1992, 1994; Kula et al 1992; Der-Ghazarian et al 2012, 2013).…”

“…Stimulation of these high affinity receptors is hypothesized to produce the potentiated locomotor response exhibited by young rats. Evidence that EEDQ causes DA supersensitivity is sparse, but includes the following findings: (a) intrastriatal infusions of EEDQ increase the basal locomotor activity of preweanling rats (Der-Ghazarian 2012, 2013); (b) very low doses of EEDQ (0.8 mg/kg) cause D1 receptor supersensitivity in the prefrontal cortex of adult rats (Trovero et al 1992); and (c) EEDQ decreases DA levels in the dorsal striatum (Crawford et al 1992, 1994), thus producing a state often associated with DA supersensitivity (Arnt and Hyttel 1984; Farley et al 2006; Carvalho et al 2009). Unfortunately, there is no direct evidence showing that EEDQ alters the percentage of high affinity receptors or that such an effect might vary according to the age of the animal being tested.…”