Sex-dependent changes in ketamine-induced locomotor activity and ketamine pharmacokinetics in preweanling, adolescent, and adult rats

Abstract

Although ketamine has long been known to increase locomotor activity, only recently was it realized that this behavioral effect varies according to both sex and age. The purpose of the present study was threefold: first, to measure the locomotor activating effects of ketamine in male and female rats across early ontogeny and into adulthood; second, to assess ketamine and norketamine pharmacokinetics in the dorsal striatum and hippocampus of the same age groups; and, third, to use curvilinear regression to determine the relationship between locomotor activity and dorsal striatal concentrations of ketamine and norketamine. A high dose of ketamine (80 mg/kg, i.p.) was administered in order to examine the complete cycle of locomotor responsiveness across a 280-min testing session. In separate groups of rats, the dorsal striata and hippocampi were removed at 10 time points (0-360 min) after ketamine administration and samples were assayed for ketamine, norketamine, and dopamine using HPLC. In female rats, ketamine produced high levels of locomotor activity that varied only slightly among age groups. Male preweanling rats responded like females, but adolescent and adult male rats exhibited lesser amounts of ketamine-induced locomotor activity. Ketamine and norketamine pharmacokinetics, especially peak values and area under the curve, generally mirrored age- and sex-dependent differences in locomotor activity. Among male rats and younger female rats, dorsal striatal ketamine and norketamine levels accounted for a large proportion of the variance in locomotor activity. In adult female rats, however, an additional factor, perhaps involving other ketamine and norketamine metabolites, was influencing locomotor activity.

Keywords: Ketamine; Locomotor activity; Ontogeny; Pharmacokinetics.

Fig. 1

Mean (±SEM) distance traveled scores of male and female rats (n = 8 rats per group) on the test day. Preweanling (PD 20), adolescent (PD 30 and PD 40), and adult rats (PD 80) were injected with saline or ketamine (80 mg/kg, i.p.) immediately before testing. The inset shows data collapsed across the 28 10-min time blocks. ‘a’ Significantly different from same-age rats given saline; ‘b’ Significantly different from same-age/same-sex rats given saline; ‘c’ Significantly different from same-age/opposite-sex rats given 80 mg/kg ketamine; ‘d’ Significantly different from male adult (PD 80) rats given 80 mg/kg ketamine; ‘e’ Significantly different from female adult (PD 80) rats given 80 mg/kg ketamine.

Fig. 2

Mean (±SEM) DA levels in the dorsal striatum of preweanling (PD 20, n = 8 per group), adolescent (PD 30 and PD 40) and adult rats (PD 80). Brains were removed 0–360 min after ketamine (80 mg/kg, i.p.) treatment. ‘a’ Significantly different from all other age groups. ‘b’ Significantly different from PD 80 rats.

Fig. 3

Nonlinear regression showing the ketamine concentration-time curves for male and female rats injected with ketamine (80 mg/kg, i.p.) at different postnatal ages. Discontinuation of the concentration-time curves indicates that ketamine levels were zero at subsequent time points.

Fig. 4

Nonlinear regression showing the norketamine concentration-time curves for male and female rats injected with ketamine (80 mg/kg, i.p.) at different postnatal ages.

Fig. 5

Scatterplots representing the relationship between dorsal striatal ketamine concentrations and the distance traveled scores of male and female rats on PD 20, PD 30, PD 40, and PD 80. Each point represents the mean scores of separate groups of male and female rats tested 5, 10, 20, 40, 70, 120, 240, and 360 min after ketamine (80 mg/kg, i.p.) treatment. The regression line was determined using the model with the best fit. Filled circles = 5 min; open circles = 10 min; filled triangles = 20 min; open triangle = 40 min; filled inverted triangles = 70 min; open inverted triangles = 120 min; filled squares = 240 min; and open squares = 360 min.

Fig. 6

Scatterplots representing the relationship between dorsal striatal norketamine concentrations and distance traveled scores of male and female rats on PD 20, PD 30, PD 40, and PD 80. Characteristics of the scatterplot are the same as described for Fig. 5.