Age-dependent effects of kappa-opioid receptor stimulation on cocaine-induced stereotyped behaviors and dopamine overflow in the caudate-putamen: an in vivo microdialysis study

Abstract

kappa-Opioid receptor stimulation attenuates psychostimulant-induced increases in extracellular dopamine in the caudate-putamen (CPu) and nucleus accumbens of adult rats, while reducing cocaine-induced locomotor activity and stereotyped behaviors. Because kappa-opioid receptor agonists (e.g., U50,488 or U69,593) often affect the behavior of preweanling rats in a paradoxical manner, the purpose of the present study was to determine whether kappa-opioid receptor stimulation differentially affects dopaminergic functioning in the CPu depending on age. In vivo microdialysis was used to determine whether U50,488 (5 mg/kg) attenuates cocaine-induced dopamine overflow in the dorsal CPu on postnatal day (PD) 17 and PD 85. In the microinjection experiment, cocaine-induced stereotyped behaviors were assessed in adult and preweanling rats after bilateral infusions of vehicle or U50,488 (1.6 or 6.4 microg per side) into the CPu. Results showed that U50,488 attenuated the cocaine-induced increases in CPu dopamine overflow on PD 85, while the same dose of U50,488 did not alter dopamine dialysate levels on PD 17. Cocaine also increased stereotyped behaviors (repetitive motor movements, behavioral intensity scores, and discrete behaviors) at both ages, but adult rats appeared to exhibit more intense stereotypic responses than the younger animals. Consistent with the microdialysis findings, bilateral infusions of U50,488 into the dorsal CPu decreased the cocaine-induced stereotypies of adult rats, while leaving the behaviors of preweanling rats unaffected. These results suggest that the neural mechanisms underlying kappa-opioid/dopamine interactions in the CPu are not fully mature during the preweanling period. This lack of functional maturity may explain why kappa-opioid receptor agonists frequently induce different behavioral effects in young and adult rats.

Fig. 1

Mean (±SEM) dopamine dialysate levels in the dorsal CPu following administration of saline or cocaine (25 mg/kg, IP) on PD 85 (n = 7 per group). Adult rats were injected with saline or U50,488 (5 mg/kg, IP) 20 min prior to cocaine treatment. Dopamine overflow was measured using in vivo microdialysis in freely moving rats. Data are expressed as percent of baseline dopamine levels. †Significant difference between the cocaine- and saline-treated rats at the same time point (Cocaine × Time interaction, P<0.001). *Significant difference between the Saline-Cocaine group and all other groups when collapsed across the 8 time points (Cocaine × Kappa interaction, P<0.05).

Fig. 2

Mean (±SEM) dopamine dialysate levels in the dorsal CPu following administration of saline or cocaine (25 mg/kg, IP) on PD 17 (n = 8 per group). Preweanling rats were treated the same as described in Fig. 1. †Significant difference between the cocaine- and saline-treated rats at the same time point (Cocaine × Time interaction, P<0.001).

Fig. 3

Mean (±SEM) dopamine dialysate levels in the dorsal CPu following administration of saline or U50,488 (5 mg/kg, IP) on PD 85 (i.e., after a 90-min recovery period) or on PD 89 (i.e., after a 5-day recovery period). Dopamine overflow was measured using in vivo microdialysis in freely moving adult rats (n = 6 per group). †Significant difference between the saline- and U-50,488-treated rats when collapsed across the 8 time points (Kappa main effect, P<0.01). *Significant difference between the short and long recovery groups when collapsed across the 4 or 8 time points (Recovery main effects, P<0.001).

Fig. 4

Mean time (s) engaged in repetitive motor movements (±SEM) during the 80-min behavioral testing session on PD 85 (n = 8 per group). Adult rats were habituated to the apparatus on time blocks 1–4. At the conclusion of time block 4 (indicated by the first dashed line), rats received bilateral infusions of vehicle or U50,488 (1.6 or 6.4 µg) into the dorsal CPu. At the conclusion of time block 8 (indicated by the second dashed line), rats were injected with cocaine (25 mg/kg, IP). *Significantly different from the 0 µg U50,488-cocaine group when collapsed across time blocks 9–16 (Cocaine × Kappa interaction, P<0.05).

Fig. 5

Mean (s) time engaged in repetitive motor movements (±SEM) during the 80-min behavioral testing session on PD 17 (n = 7–8 per group). Preweanling rats were treated the same as described in Fig. 4. *Significantly different from the saline condition (lower graph) when collapsed across time blocks 9–16 (Cocaine main effect, P<0.01).

Fig. 6

Mean behavioral intensity scores (±SEM) of adult rats during the final 40 min of the behavioral testing session (i.e., only the eight time blocks occurring after cocaine administration are shown). Subjects were a subset of the adult rats (n = 5–6 per group) described in Fig. 4. *Significantly different from the 0 µg U50,488-cocaine group when collapsed across time blocks 9–16 (Cocaine × Kappa interaction, P<0.05).

Fig. 7

Mean behavioral intensity scores (±SEM) of preweanling rats during the final 40 min of the behavioral testing session (i.e., only the eight time blocks occurring after cocaine administration are shown). Subjects were a subset of the preweanling rats (n = 5–7 per group) described in Fig. 5. †Significantly different from the 0 µg U50,488-saline group at the same time point (Cocaine × Kappa × Time block interaction, P<0.01).