Long-term D1-dopamine receptor sensitization in neonatal 6-OHDA-lesioned rats is blocked by an NMDA antagonist

Abstract

Repeated administration of the D1-dopamine agonist SKF-38393 to adult rats having had dopaminergic neurons destroyed early in development results in an increasing enhancement of the behavioral response to SKF-38393 with each dose until a maximum is reached. This increased sensitivity lasts for at least 6 months. In the present study, this long-lasting change in behavioral responsiveness to repeated treatment with SKF-38393, referred to as D1-dopamine receptor priming, was shown to be dose dependent with smaller doses requiring an increased number of administrations to produce a maximal response when compared to higher doses. In addition, priming occurred equally well when treatment intervals ranged from 1 day to 14 days. These latter data reinforced the view that activation of D1-dopamine receptors results in a prolonged change in neural function. In subsequent experiments, D1-dopamine receptor priming was blocked by pretreatment with the NMDA-receptor antagonist MK-801. This antagonism of priming could not be attributed to a blockade of D1-dopamine receptors by MK-801 or to the induction of interfering behaviors. Because an NMDA antagonist interfered with D1-receptor priming as it does with other long-term neural messages, a common requirement for these diverse forms of neuronal plasticity appears to involve activation of the NMDA receptor. This functional link between NMDA receptors and dopaminergic function and its relationship to neuronal plasticity could have relevance to the biochemical mechanisms involved in learning and to symptoms in central disorders during development that worsen over time, particularly those proposed to involve malfunctioning dopaminergic mechanisms.

Fig. 1

Activity following repeated administration of SKF-38393 at varying time intervals to neonatal 6-OHDA-lesioned rats with destruction of both dopaminergic and noradrenergic neurons. Rats received 4 consecutive 3 mg/kg i.p. injections of SKF-38393 at injection intervals of 1, 2, 7 or 14 days. Rats were habituated to the testing chamber for 50 min immediately prior to testing and total counts are shown for a 150 min period. D₁-dopamine receptor priming occurred at similar rates and reached a similar final sensitivity for all groups (P > 0.1 for time interval by dose number interaction). *P < 0.05 when compared to dose 1 for that group.

Fig. 2

Effect of varying doses of SKF-38393 on D₁-dopamine receptor priming. All rats received multiple i.p. doses of SKF-38393 at 4 day intervals. Data for the 3 mg/kg naive group was obtained after the first 3 mg/kg dose of SKF-38393. The 1.5 mg/kg group received six 1.5 mg/kg doses, the 3.0 mg/kg group received three 3 mg/kg doses and the 9 mg/kg group received one 9 mg/kg dose of SKF-38393. The responses shown under ‘after 9 mg/kg’ is the response to an additional 3 mg/kg dose after an accumulated 9 mg/kg of SKF-38393 had been administered to all groups. Asymptote represents the activity scores from the 3rd additional 3 mg/kg dose after the rats had previously received the cumulative dose of 9 mg/kg. Table I can be consulted in order to see the response to intervening treatments with SKF-38393 (i.e. dose 7 for the 1.5 mg/kg group and doses 4 and 2 for the 3 and 9 mg/kg groups, respectively). * P < 0.05 when compared to the 3 mg/kg naive group.

Fig. 3

Priming of D₁-dopamine receptor responses during and after 0.3 mg/kg MK-801 treatment. The lines below the illustration indicate the course of the drug treatments. Neonatal 6-OHDA-lesioned rats received MK-801 (0.3 mg/kg) 30 min prior to the injection of SKF-38393 (3 mg/kg) for four treatments (MS1 to MS4). Beginning one week after the last treatment combination, the rats received 5 treatments (S5 to S9) of SKF-38393 (3 mg/kg) in the absence of MK-801. The response to the seventh dose of SKF-38393 for the 0.1 mg/kg MK-801 pretreatment groups (S-7; see Fig. 4) was 17,379 ± 3,732 activity counts/150 min ± S.E.M. (n = 4). The response for the seventh dose of SKF-38393 for the 1.0 mg/kg MK-801 treatment groups was 24,514 ± 4,935 activity counts/150 min ± S.E.M. These values are significantly greater (P < 0.01) than the response for the fifth dose of SKF-38393 (see 4B) indicating that priming occurred in these animals. *P < 0.05 compared to S5 SKF-38393 treatment.

Fig. 4

Effect of varying doses of MK-801 on priming of SKF-38393-induced activity in neonatal 6-OHDA-lesioned rats. (A) illustrates the response to the first dose of SKF-38393 (3 mg/kg) in the absence and presence of MK-801 pretreatment. (B) illustrates the response to the fifth dose of SKF-38393 in the groups in (A) given doses 1–4 of SKF-38393 in the presence of MK-801. The groups in (B) received only SKF-38393 (3 mg/kg). Responses for the first 4 doses of SKF-38393 and subsequent doses of SKF-38393 (i.e., in absence of MK-801) for the 0.3 mg/kg MK-801 group are presented in Fig. 3. Data indicating that priming of D₁-dopamine receptor responses occurred when SKF-38393 was administered alone following 0.1 and 0.3 mg/kg MK-801/SKF-38393 treatment are presented in Fig. 3 legend. (0 mg/kg) is a saline-treated group. *P < 0.05 when compared to 0 mg/kg group. *P < 0.01 when compared to 0 mg/kg group.