Effects of binge pattern cocaine administration on dopamine D1 and D2 receptors in the rat brain: an in vivo study using positron emission tomography

Abstract

The aim of the present study was to determine the effect of "binge" pattern cocaine administration on dopamine D1 and D2 receptors in the rat brain. Male Sprague Dawley rats were injected three times at 1 hr intervals with saline or cocaine (15 mg/kg) each day for 2, 7, or 14 d. The in vivo binding of [11C]SCH23390 (dopamine D1 receptor antagonist) and [11C]N-methylspiperone (NMSP; dopamine D2 receptor antagonist) in the striatal region was measured by a high-resolution positron emission tomography at 1 and 3.5 hr, respectively, after the last cocaine or saline injection. Acute (2 d) binge cocaine administration did not change the in vivo binding potential of [11C]SCH23390 or the binding of [11C]NMSP in the striatum. After 7 d of binge cocaine administration, a significant decrease in the binding potential of [11C]SCH23390 was observed, whereas no change in the binding of [11C]NMSP was found. After 14 d of binge cocaine administration, the in vivo binding was significantly reduced for both [11C]SCH23390 and [11C]NMSP. Separate saturation experiments indicated that the observed alterations of in vivo binding were attributable mainly to apparent alterations in the affinity and not the number of binding sites. These results suggest that both dopamine D1 and D2 receptors may have altered physiologically available binding sites after binge pattern cocaine administration.

Fig. 1.

PET Images of [¹¹C]SCH23390 and [¹¹C] N-methylspiperone (NMSP) in the rat brain. During the scan, the rat was fixed in a stereotaxic frame under anesthesia with a continuous infusion of chloral hydrate (100 mg · kg⁻¹ · hr⁻¹, i.v.). ROIs were identified on striatum and cerebellum according to the rat brain atlas (Paxinos and Watson, 1986), as shown by red circles. ROIs were placed on corresponding PET images to obtain the time activity curves.

Fig. 2.

Typical time activity curves in the striatum and cerebellum of the rat brain after intravenous injection of [¹¹C]SCH23390. Rats were administered saline or cocaine (15 mg/kg × 3) in a binge pattern for 2 (A), 7 (B), and 14 (C) d. On the day of the PET scan, the final injection was performed 1 hr before the scan. ROIs were identified according to the rat brain atlas (Paxinos and Watson, 1986). Radioactivity is indicated in the striatum (○) or cerebellum (▵) in saline-treated rats, and in the striatum (•) or cerebellum (▴) in cocaine-treated rats.

Fig. 3.

Typical time activity curves in the striatum and cerebellum of the rat brain after intravenous injection of [¹¹C]NMSP. Rats were administered saline or cocaine (15 mg/kg × 3) in a binge pattern for 2 (A), 7 (B), and 14 (C) d. On the day of the PET scan, the final injection was performed 1 hr before the scan. ROIs were identified according to the rat brain atlas (Paxinos and Watson, 1986). Radioactivity is indicated in the striatum (○) or cerebellum (▵) in saline-treated rats, and in the striatum (•) or cerebellum (▴) in cocaine-treated rats.

Fig. 4.

Effect of cocaine on binding potential of [¹¹C]SCH23390 in the striatum of rat brain. Rats were administered saline or cocaine (15 mg/kg × 3) in a binge pattern for 2, 7, and 14 d. On the day of the PET scan, the final injection was performed 1 hr before the scan. The total radioactivity in the cerebellum was used as an estimate of the free and nonspecific binding radioligand concentration in the striatum; the three-compartment model was fitted to the time activity curve of specific binding in the striatum. The binding potential was calculated by the ratio of association rate (k₃) to dissociation rate (k₄). Data are expressed as mean ± SD for six animals per treatment group.

Fig. 5.

Effect of cocaine on binding of [¹¹C]NMSP in the striatum of rat brain. Rats were administered saline or cocaine (15 mg/kg × 3) in a binge pattern for 2, 7, and 14 d. On the day of the PET scan, the final injection was performed 1 hr before the scan. The total radioactivity in the cerebellum was used as an estimate of the free and nonspecific binding radioligand concentration in the striatum;k₃ value was calculated with a graphical analysis method. Data are expressed as mean ± SD for six animals per treatment group.

Fig. 6.

Saturation studies of in vivobinding of [¹¹C]SCH23390 (A) and [¹¹C]NMSP (B) in rat brain. Rats were administered saline or cocaine (15 mg/kg × 3) in a binge pattern for 14 d. On the day of the PET scan, the final injection was performed 1 hr before the scan. Rats were injected with [¹¹C]SCH23390 or [¹¹C]NMSP, with various doses of each carrier ligand ranging from 3 to 300 μg/kg. The radioactivities in striatum and cerebellum at 33 min for [¹¹C]SCH23390 and 45 min for [¹¹C]NMSP after tracer injection were expressed as percent of dose/gm. Data are expressed as mean ± SD for three animals per treatment group. Radioactivity is indicated in the striatum (○) or cerebellum (▵) in saline-treated rats, and in the striatum (•) or cerebellum (▴) in cocaine-treated rats.

Fig. 7.

Scatchard plot analysis of saturation studies of the in vivo binding of [¹¹C]SCH23390 (A) and [¹¹C]NMSP (B) in saline- (○) and cocaine-treated (•) rats. The total radioligand concentration in the cerebellum was used as the free radioligand concentration (F) in the striatum. Specific binding (B) was defined as radioactivity in the striatum reduced with F. The values for B andF at 33 min for [¹¹C]SCH23390 and 45 min for [¹¹C]NMSP after tracer injection were used in a Scatchard analysis in which the ratios B/F were plotted against B.