Importance of D1 and D2 receptor stimulation for the induction and expression of cocaine-induced behavioral sensitization in preweanling rats

Abstract

The behavioral manifestations of psychostimulant-induced sensitization vary markedly between young and adult rats, suggesting that the neural mechanisms mediating this phenomenon differ across ontogeny. In this project we examined the importance of D1 and D2 receptors for the induction and expression of cocaine-induced behavioral sensitization during the preweanling period. In the behavioral experiments, rats were injected with reversible D1 and/or D2 antagonists (SCH23390 and/or raclopride) or an irreversible receptor antagonist (EEDQ) either before cocaine administration on the pretreatment day (induction) or before cocaine challenge on the test day (expression). In the EEDQ experiments, receptor specificity was assessed by using selective dopamine antagonists to protect D1 and/or D2 receptors from inactivation. Receptor binding assays showed that EEDQ caused substantial reductions in dorsal striatal D1 and D2 binding sites, while SCH23390 and raclopride fully protected D1 and D2 receptors from EEDQ-induced alkylation. Behavioral results showed that neither D1 nor D2 receptor stimulation was necessary for the induction of cocaine sensitization in preweanling rats. EEDQ disrupted the sensitization process, suggesting that another receptor type sensitive to EEDQ alkylation was necessary for the induction process. Expression of the sensitized response was prevented by an acute injection of a D1 receptor antagonist. The pattern of DA antagonist-induced effects described for preweanling rats is, with few exceptions, similar to what is observed when the same drugs are administered to adult rats. Thus, it appears that maturational changes in D1 and D2 receptor systems are not responsible for ontogenetic differences in the behavioral manifestation of cocaine sensitization.

Keywords: Behavioral sensitization; Cocaine; EEDQ; Ontogeny; Raclopride; SCH23390.

Figure 1

Mean distance traveled (±SEM) on the pretreatment and test day. On the pretreatment day (PD 20), rats were injected with saline alone (0 mg/kg raclopride–Saline) or raclopride and cocaine. Behavioral assessment lasted 30 min. On the test day (PD 21), all rats were challenged with 20 mg/kg cocaine before a 120 min testing session. * Significantly different from the 0 mg/kg Raclopride–Saline group (acute control group; open bars) † Significantly different from the 0 mg/kg Raclopride–Cocaine group (black bars).

Figure 2

Mean distance traveled (±SEM) on the pretreatment and test day. On the pretreatment day (PD 20), rats were injected with raclopride (0 or 0.5 mg/kg) followed by saline or cocaine. Behavioral assessment lasted 30 min. On the test day (PD21), all rats were challenged with 20 mg/kg cocaine before a 120 min testing session. * Significantly different from the 0 mg/kg Raclopride–Saline group (acute control group; open bars) † Significantly different from the 0 mg/kg Raclopride–Cocaine group (cocaine alone group; black bars).

Figure 3

Mean distance traveled (±SEM) on the pretreatment and test day. On the pretreatment day (PD 20), rats were injected with saline alone (0 mg/kg SCH23390+Raclopride–Saline) or a cocktail of SCH23390+Raclopride and cocaine. Behavioral assessment lasted 30 min. On the test day (PD21), all rats were challenged with 20 mg/kg cocaine before a 120 min testing session. * Significantly different from the 0 mg/kg SCH23390+Raclopride–Saline group (acute control group; open bars) † Significantly different from the 0 mg/kg SCH23390+Raclopride–Cocaine group (cocaine alone group; filled circles and black bars).

Figure 4

Mean distance traveled (±SEM) on the pretreatment and test day. On the preinjection day (PD 18), rats were injected with EEDQ (0, 7.5, or 15 mg/kg). On the pretreatment day (PD 19), rats were injected with saline or 30 mg/kg cocaine, with behavioral assessment lasting 30 min. On the test day (PD 21), all rats were challenged with 20 mg/kg cocaine before a 120 min testing session. * Significantly different from the 0 mg/kg EEDQ–Saline group (open bars) † Significantly different from the 0 mg/kg EEDQ–Cocaine group (black bars).

Figure 5

Mean distance traveled (±SEM) on the pretreatment and test day. On the preinjection day (PD 18), rats were injected with saline (nonprotected, NP), SCH23390 (D1 protected), raclopride (D2 protected), or SCH+RAC (D1/D2 protected), followed by an injection of vehicle or 7.5 mg/kg EEDQ. On the pretreatment day (PD 19), rats were injected with saline or 30 mg/kg cocaine, with behavioral assessment lasting 30 min. On the test day (PD 21), all rats were challenged with 20 mg/kg cocaine before a 120 min testing session. * Significantly different from the Nonprotected+Vehicle–Saline group (acute control group; open bars) † Significantly different from the Nonprotected+Vehicle–Cocaine group (cocaine alone group; black bars).

Figure 6

Mean distance traveled (±SEM) on the test day. On the pretreatment day (PD 20), rats were injected with saline or cocaine, with behavioral assessment lasting 30 min. On the test day (PD 21), rats were treated with raclopride (0, 0.1, or 0.5 mg/kg) 15 min before a challenge injection of 20 mg/kg cocaine. The testing session lasted 120 min. * Significantly different from the acute control groups. † Significantly different from the 0 mg/kg Raclopride–Cocaine group (cocaine alone group; black bars). ‡ Significantly different from the 0 mg/kg Raclopride–Saline group (acute control group; open bars)

Figure 7

Mean distance traveled (±SEM) on the test day. On the pretreatment day (PD 20), rats were injected with saline or cocaine, with behavioral assessment lasting 30 min. On the test day (PD 21), rats were treated with SCH23390 (0, 0.1, or 0.5 mg/kg) or a cocktail of SCH23390+Raclopride (S+R, 0.1 or 0.5 mg/kg) 15 min before a challenge injection of 20 mg/kg cocaine. The testing session lasted 120 min. * Significantly different from the 0 mg/kg SCH23390–Saline group (acute control group; open bars) † Significantly different from the 0 mg/kg SCH23390–Cocaine group (cocaine alone group; black bars). ‡ Significantly different from the 0.1 mg/kg SCH23390–Cocaine group.

Figure 8

Mean distance traveled (±SEM) on the test day. On the pretreatment day (PD 19), rats were injected with saline or 30 mg/kg cocaine, with behavioral assessment lasting 30 min (data not shown). On the preinjection day (PD 20), rats were injected with EEDQ (0, 7.5, or 15 mg/kg). On the test day (PD 21), all rats were challenged with 20 mg/kg cocaine. The testing session lasted 120 min. * Significantly different from the 0 mg/kg EEDQ–Saline group (open bars) † Significantly different from the 0 mg/kg EEDQ–Cocaine group (black bars).