Effects of monoamine depletion on the ketamine-induced locomotor activity of preweanling, adolescent, and adult rats: Sex and age differences

Abstract

Ketamine significantly increases the locomotor activity of rodents, however this effect varies according to the sex and age of the animal being tested. To determine the role monoamine systems play in ketamine's locomotor activating effects: (a) male and female preweanling, adolescent, and adult rats were pretreated with vehicle or the monoamine depleting agent reserpine (1 or 5 mg/kg), and (b) the behavioral actions of ketamine (20 or 40 mg/kg) were then compared to d-amphetamine (2 mg/kg) and cocaine (10 or 15 mg/kg). The ability of reserpine to deplete dorsal striatal dopamine (DA) and serotonin (5-HT) in male and female rats was determined using HPLC. Ketamine caused substantial increases in the locomotion of preweanling rats and older female rats (adolescents and adults), but had only small stimulatory effects on adolescent and adult male rats. When compared to cocaine and d-amphetamine, ketamine was especially sensitive to the locomotor-inhibiting effects of monoamine depletion. Ketamine-induced locomotion is at least partially mediated by monoamine systems, since depleting DA and 5-HT levels by 87-96% significantly attenuated the locomotor activating effects of ketamine in male and female rats from all three age groups. When administered to reserpine-pretreated rats, ketamine produced a different pattern of behavioral effects than either psychostimulant, suggesting that ketamine does not stimulate locomotor activity via actions at the presynaptic terminal. Instead, our results are consistent with the hypothesis that ketamine increases locomotor activity through a down-stream mechanism, possibly involving ascending DA and/or 5-HT projection neurons.

Keywords: Cocaine; Ketamine; Locomotor activity; Ontogeny; Reserpine; d-Amphetamine.

Figure 1.

Mean distance traveled scores (±SEM) of male and female preweanling, adolescent, and adult rats during the habituation phase. The right panel represents total distance traveled collapsed across the testing session. a = Significantly different from preweanling (PD 20) rats.

Figure 2.

Mean distance traveled scores (±SEM) of male and female preweanling rats pretreated with vehicle (upper graph) or 1 mg/kg reserpine (lower graph) and then tested after saline or ketamine (5–40 mg/kg) treatment on PD 21. The right panels represent total distance traveled collapsed across the testing session. a = Significantly different from saline-treated rats from the same pretreatment condition; b = Significantly different from reserpine-pretreated rats given the same dose of ketamine.

Figure 3.

Mean distance traveled scores (±SEM) of male and female preweanling rats pretreated with vehicle (upper graph) or 1 mg/kg reserpine (lower graph) and then tested after saline, cocaine (10 mg/kg), or _D-amphetamine (2 mg/kg) treatment on PD 21. The right panels represent total distance traveled collapsed across the testing session. a = Significantly different from saline-treated rats from the same pretreatment condition; b = Significantly different from reserpine-pretreated rats given the same agonist.

Figure 4.

Mean distance traveled scores (±SEM) of male and female preweanling rats pretreated with vehicle (upper graph) or 5 mg/kg reserpine (lower graph) and then tested after saline, ketamine (20 or 40 mg/kg), cocaine (15 mg/kg), or _D-amphetamine (2 mg/kg) treatment on PD 21. The right panels represent total distance traveled collapsed across the testing session, a = Significantly different from saline-treated rats from the same pretreatment condition; b = Significantly different from reserpine-pretreated rats given the same agonist.

Figure 5.

Mean distance traveled scores (±SEM) of male adolescent rats pretreated with vehicle (upper graphs), 1 mg/kg (middle graphs), or 5 mg/kg reserpine (lower graphs) and then tested after saline, ketamine (20 or 40 mg/kg), cocaine (15 mg/kg), or _D-amphetamine (2 mg/kg) treatment on PD 41. The right panels represent total distance traveled collapsed across the testing session, a = Significantly different from saline-treated rats from the same pretreatment condition; b = Significantly different from vehicle-pretreated rats tested with the same drug.

Figure 6.

Mean distance traveled scores (±SEM) of female adolescent rats pretreated with vehicle (upper graphs), 1 mg/kg (middle graphs), or 5 mg/kg reserpine (lower graphs) and then tested after saline, ketamine (20 or 40 mg/kg), cocaine (15 mg/kg), or _D-amphetamine (2 mg/kg) treatment on PD 41. The right panels represent total distance traveled collapsed across the testing session, a = Significantly different from saline-treated rats from the same pretreatment condition; b = Significantly different from vehicle-pretreated rats tested with the same drug, c = Significantly different from vehicle-pretreated male rats given 40 mg/kg ketamine.

Figure 7.

Total distance traveled (mean, ±SEM) of male and female adolescent rats pretreated with vehicle (upper graph), 1 mg/kg (middle graph), or 5 mg/kg reserpine (lower graph) and then tested after saline, ketamine (20 or 40 mg/kg), cocaine (15 mg/kg), or _D-amphetamine (2 mg/kg) treatment on PD 41. a = Significantly different from male rats given the same drug treatment.

Figure 8.

Mean distance traveled scores (±SEM) of male and female adult rats pretreated with vehicle (upper graphs), 1 mg/kg (middle graphs), or 5 mg/kg reserpine (lower graphs) and then tested after saline or ketamine (40 mg/kg) treatment on PD 81. The right panels represent total distance traveled collapsed across the testing session. a = Significantly different from saline-treated same-sex rats from the same pretreatment condition; b = Significantly different from same-sex rats pretreated with 5 mg/kg reserpine; c = Significantly different from ketamine-treated male rats from the same pretreatment condition.

Figure 9.

Mean dorsal striatal DA and 5-HT content (±SEM) of male and female preweanling (PD 21), adolescent (PD 41), and adult (PD 81) rats pretreated with reserpine (1 or 5 mg/kg) or vehicle (represented by the dashed line). Data are expressed as percent of same age vehicle controls. Males and females did not differ, so data are collapsed over the sex variable, a = Significantly different from same-age vehicle-pretreated rats; b = Significantly different from adolescent and adult rats pretreated with 1 mg/kg reserpine.