Effects of age and sex on ketamine-induced hyperactivity in rats
Introduction
Subanesthetic doses of dissociative anesthetics such as ketamine, MK-801, and phencyclidine (PCP) can produce behavioral symptoms ranging from psychotic episodes, mood alterations, cognitive disturbances, and hallucinations in humans (see [1] for review, [2], [3]) to hyperactivity in mice [4], [5] and rats [6] and stereotypy, and ataxia in mice and rats [5].
While dissociative anesthetics block N-methyl-d-aspartate (NMDA) receptors [7], other neural systems appear to be activated with administration of these drugs (for review see [8]). For example, ketamine and ketamine-like drugs have been shown to stimulate ventral tegmental area dopamine (DA) neurons [9] and PCP has been shown to block DA uptake in striatal synaptosomes [10]. Behaviorally, stereotypies induced by subanesthetic doses of PCP in various species are similar to those induced by amphetamine and can be antagonized by administration of neuroleptics such as pimozide ([11], [12], respectively). Additionally, Yamamoto et al. [13] reported hyperactivity with subanesthetic doses of ketamine, an effect that was reversed with administration of neuroleptics. Thus, DA systems appear inherently involved in behavioral effects seen with dissociative anesthetic administration.
As altricial animals mature, the behavioral sensitivity to DA agonists apparently changes. For example, Spear and Brake [14] suggested that periadolescent (approximately 40 days of age) rats are hyposensitive to catecholaminergic agonists, as compared with either younger or older animals. In addition, several authors have reported a subsensitivity to the behavioral effects of cocaine [15], amphetamine [16], and quinpirole [17] in periadolescent rats when compared to rats at other ages. Interestingly, both Laviola et al. [15] and Frantz and Van Hartesveldt [17] reported gender differences with respect to sensitivity to DA agonists during periadolescence with female rats showing greater responsiveness to these agents than males.
With the apparent involvement of DA in ketamine/PCP-induced behavioral changes and age- and sex-related variations in DA sensitivity in mind, we speculated that administration of the abused drug ketamine might have differential effects on behaviors in animals as a function of age and/or sex. In support of this notion, as for sex differences of NMDA blockers, Honack and Loscher [18] reported that administration of low doses (0.1 mg/kg) of MK-801 produced ataxia, hyperlocomotion, and head weaving in adult female, but not male, Wistar rats. Larger doses (0.3 mg/kg) resulted in behavioral alterations in both sexes but with decreased intensity and duration of effects in males, compared with females. Therefore, it appears that female rats are more responsive to NMDA blockade than are male rats.
As for age effects of NMDA blockers, Scalzo and Burge [19] reported high levels of PCP-induced wall-climbing in 5- and 12-day-old rats, after which little or no effect was observed. Similarly, Jacobs et al. [20] reported significantly higher locomotor levels with PCP in prepubertal (21 days of age) male rats, compared with older (37, 50, and 90 days of age) animals. Interestingly, MK-801 administration did not produce this ontogenetic effect, with a higher dose (0.2 mg/kg) stimulating locomotion equally regardless of age. Thus, it appears that activity levels resulting from NMDA blockade, at least with the antagonist PCP, are age dependent.
Based upon the aforementioned studies, we tested the hypothesis that ketamine administration to weanling, i.e., 22 days of age, rats would produce increments in activity in both males and females with little difference between the sexes. We also hypothesized that ketamine administration near or during periadolescence, i.e., 35 or 50 days of age, would differentially affect male and female rats, with the females showing greater increments in activity than the males. To get a better indication of other effects of ketamine with respect to age and sex, we also chose to measure levels of rearing, turning, reverse locomotion, and head weaving, behaviors that have been shown to be related to ketamine administration [21].
Section snippets
Animals
Subjects were 144 (24 litters) male and female Sprague–Dawley albino rats, 22, 35, or 50 days of age at the time of testing. Rats were derived from an established breeding colony at Sam Houston State University and housed in groups of 8 to 10 in Plexiglas breeding cages. Subjects were maintained on a 12:12 h light:dark schedule with lights on at 0700 h with food and water available ad libitum. All testing occurred between 1200 h and 1400 h (light phase) under normal ambient light conditions
Data analyses
Data in this experiment were analyzed using standard parametric procedures, i.e., 2 (drug dose) × 2 (sex) × 3 (age) analyses of variance (ANOVAs). Differences among individual groups were assessed using Newman–Keuls a posteriori procedures with alpha set at 0.05.
Open-field activity
Data for open-field activity are presented in Fig. 1. An ANOVA on these data yielded a significant drug effect, F(1,132) = 63.53, P < 0.05, a significant sex effect, F(1,132) = 11.53, P < 0.05, and a significant age effect, F(2,132) = 4.88, P < 0.05. Also, the drug × age interaction was significant, F(2,132) = 32.75, P < 0.05, as was the sex × age interaction, F(2,132) = 7.40, P < 0.05. Finally, the drug × sex × age triple interaction effect was significant, F(2,132) = 5.52, P < 0.05.
Post hoc tests on the open-field data
Discussion
In the present study, we investigated the effects of ketamine administration on open-field activity, turning, reverse locomotion, head weaving, and rearing in rats with respect to sex and age. Ketamine administration resulted in large increases in open-field activity in both males and females at 22 days of age and in females at 35 days of age. By 50 days of age, the difference in activity levels between females that had received ketamine and control females was not statistically significant.
References (36)
- et al.
The neuropsychopharmacology of phencyclidine: from NMDA receptor hypofunction to the dopamine hypothesis of schizophrenia
Neuropsychopharmacology
(1999) - et al.
Effects of (S)ketamine on striatal dopamine: a [-sup-1-sup-1C] raclopride PET study of a model psychosis in humans
J Psychiat Res
(2000) - et al.
Involvement of dopamine receptors in the antipsychotic profile of (−)eticlopride
Physiol Behav
(1997) - et al.
The behavioural effects of MK-801: a comparison with antagonists acting non-competitively and competitively at the NMDA receptor
Eur J Pharmacol
(1989) - et al.
Increases in extracellular dopamine levels and locomotor activity after direct infusion of phencyclidine into the nucleus accumbens
Brain Res
(1992) - et al.
Non-competitive N-methyl-d-aspartate antagonists are potent activators of ventral tegmental A10 dopamine neurons
Neurosci Lett
(1990) - et al.
Phencyclidine-induced stereotyped behavior in monkeys: antagonism by pimozide
Eur J Pharmacol
(1978) - et al.
Effects of dopamine antagonists on changes in spontaneous EEG and locomotor activity in ketamine-treated rats
Pharmacol Biochem Behav
(1997) - et al.
Subsensitivity to dopaminergic drugs in periadolescent rats: a behavioral and neurochemical analysis
Dev Brain Res
(1998) - et al.
The locomotor effects of quinpirole in rats depend on age and gender
Pharmacol Biochem Behav
(1999)
Sex differences in NMDA receptor mediated responses in rats
Brain Res
Maturation of locomotor and Fos responses to the NMDA antagonists, PCP and MK801
Dev Brain Res
Naloxone increases ketamine-induced hyperactivity in the open field in female rats
Pharmacol Biochem Behav
The N-methyl-d-aspartate antagonist, 2-amino-7-phosphonoheptanoate, produces phencyclidine-like behavioral effects in rats
Eur J Pharmacol
Locomotion elicited by MK801 in developing and adult rats: temporal, environmental, and gender effects
Eur J Pharmacol
Physiological and pathophysiological roles of excitatory amino acids during central nervous system development
Brain Res Revs
Sex-dependent differences in the pharmacological actions and pharmacokinetics of phencyclidine in rats
Eur J Pharmacol
Effects of mecamylamine, nicotine, atropine and physostigmine on the phencyclidine-induced behavioral toxicity
Pharmacol Biochem Beh
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