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: Dimethyl sulfoxide (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.

Fig. 1

Schematic representations (a), as well as a typical photomicrograph (b), of cannula placements in the dorsal CPu of preweanling and adult rats from Experiments 1–4. In all cases, numbers on the right indicate distance (mm) from Bregma using coordinates from the rat brain atlas of Paxinos and Watson (1998).

Fig. 2

Mean distance traveled (±SEM) of DMSO- and EEDQ-pretreated rats during the habituation (i.e., time blocks 1–8) and testing (i.e., time blocks 9–16) phases on PD 18 (n = 8 per group). On PD 17, rats received no protection, SCH23390 (SCH), sulpiride (Sul), or SCH/Sul protection prior to EEDQ or DMSO infusions. DMSO pretreatment = ⊙; EEDQ pretreatment = ⊗; DMSO–Vehicle group = ○; DMSO–NPA group = □; EEDQ–Vehicle group = ●; EEDQ–NPA group = ■. * Significantly different from all other groups in the same protection condition. ‡ Significantly different from the EEDQ-Vehicle and DMSO-Vehicle groups in the same protection condition. † Significantly different from the DMSO-Vehicle group in the same protection condition. § Significantly different from vehicle-treated rats (circles) in the same protection condition (collapsed across time blocks 9–16). ¶ Significantly different from DMSO-pretreated rats (open symbols) in the same protection condition (collapsed across time blocks 9–16).

Fig. 3

Mean distance traveled (±SEM) during the habituation (i.e., time blocks 1–8) and testing (i.e., time blocks 9–16) phases on PD 18 (n = 8–12 per group). DMSO pretreatment = ⊙; EEDQ pretreatment = ⊗; Vehicle = ○; 5 μg SKF82958 = ●; 10 μg SKF82958 = ▲; 10 μg Quinpirole = ■. * Significantly different from all other groups in the same pretreatment condition. ‡ Significantly different from the SKF82958 (5 μg) and vehicle groups in the same pretreatment condition. † Significantly different from the vehicle group in the same pretreatment condition. § Significantly different from the DMSO-Quinpirole group (collapsed across time blocks 9–16). ¶ Significantly different from the EEDQ-Vehicle group (collapsed across time blocks 9–16).

Fig. 4

Mean distance traveled (±SEM) during the habituation (i.e., time blocks 1–8) and testing (i.e., time blocks 9–16) phases on PD 18 (n = 10–11 per group). DMSO pretreatment = ⊙; EEDQ pretreatment = ⊗; Vehicle = ○; 2.5 μg Haloperidol = ●; 10 μg Terguride = ▲; 20 μg Terguride = ■. * Significantly different from all other groups given EEDQ. ‡ Significantly different from the 10 and 20 μg terguride groups given EEDQ. † Significantly different from the 20 μg terguride group given EEDQ. § Significantly different from the vehicle group given EEDQ (collapsed across time blocks 9–16).

Fig. 5

Mean distance traveled (±SEM) during the habituation (i.e., time blocks 1–8) and testing (i.e., time blocks 9–20) phases on PD 18 (n = 8 per group). DMSO pretreatment = ⊙; EEDQ pretreatment = ⊗; Saline = ○; 0.2 mg/kg MK801 = ▲; 5 mg/kg U50488 = ■. * Significant difference between the U50488 and saline groups. ‡ Significant difference between the MK801 and saline groups. † Significantly different from saline-treated rats (collapsed across time blocks 9–20).

Fig. 6

Mean distance traveled (±SEM) during the habituation (i.e., time blocks 1–8) and testing (i.e., time blocks 9–20) phases on PD 18 (n = 8 per group). DMSO pretreatment = ⊙; EEDQ pretreatment = ⊗; DMSO–Saline group = ○; DMSO–Cocaine group = □; EEDQ–Saline group = ●; EEDQ–Cocaine group = ■. * Significantly different from all other groups (collapsed across time blocks 9–20). ‡ Significantly different from the DMSO-Saline group (collapsed across time blocks 9–20).

Fig. 7

Representative autoradiograms of (a) [³H]-SCH23390 and (b) [³H]-spiperone binding after bilateral infusions of EEDQ into the dorsal CPu on PD 17.