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17 décembre 2006
Eur J Pharmacol.
Effects of age on behavioral responses
to dopamine agonists in the rat
Ushijima I, Mizuki Y, Soeda K, Kishimoto O, Hara T, Yamada M
Depart Psychiatry. Yamaguchi University. Japan


Abstract :
This study served to examine the differential effects of age (rats aged 2 or 12 months) on behavioral responses induced by bromocriptine and apomorphine. Intraperitoneal (i.p.) injection of bromocriptine or apomorphine produced a lower frequency of yawning responses, in 12-month-old rats than in 2-month-old rats. Apomorphine produced a more pronounced stereotyped behavior in 12-month-old rats than in 2-month-old rats. Apomorphine, at 0.1 mg/kg administered after bromocriptine (1.0-20 mg/kg) potentiated yawning behavior. The frequency of yawning in 2-month-old rats was pronounced at 2.5 mg/kg of bromocriptine but only at 5 mg/kg 12-month-old rats. Apomorphine (0.1 mg/kg) did not produce perioral behavior in 2-month-old rats but did in 12-month-old rats. The apomorphine (1.0 mg/kg)-induced stereotypy was stimulated dose dependently by bromocriptine in 2-month-old-rats but not in 12-month-old rats. Bromocriptine did not produce this behavior when administered alone. Pretreatment of 2-month-old rats with reserpine, a catecholamine depletor, plus alpha-methyl-p-tyrosine, a tyrosine hydroxylase inhibitor, inhibited the yawning induced by bromocriptine but potentiated that induced by apomorphine. Such treatment did not significantly alter either bromocriptine or apomorphine-induced yawning responses in 12-month-old rats. The apomorphine-induced stereotypy in 2-month-old rats was markedly potentiated by catecholamine depletion but was not affected in 12-month-old rats. These results suggest that the increasing effect on stereotypy and decreasing effects on yawning in the 12-month-old rats seem to result in an alteration of potency and of the ratio of D-2 versus D-1 receptor activity.
It has been reported that the behavioral, stereotypy-inducing actions of apomorphine are increased in aging rats. These authors also observed that the duration of action of apomorphine greater in rats aged 20-24 months than in rats aged 2 months suggesting that either increased levels in brain or decreased elimination of apomorphine may be important factors contributing to the marked ircrease in behavioral sensitivity to apomorphine with increasing age in the rat. On the other hand, direct binding studies with 3H-ligands indicate an age-related decline in the density of dopamine receptors in rat striata and human striata. The decline of 3H-antagonist binding is progressive with age and losses in receptor density can be detected at midlife. Dopamine agonist binding in striatum declines more rapidly with age than does antagonist binding. The major part of the decline of 3H-agonist binding appears to occur before midlife in rats. The total D-2 receptor population, as defined by [3 H]spiperone binding, declined progressively from 3 to 24 months, and age-related changes were restricted to D-2 receptor density in mice. We found that pretreatment with reserpine plus a-methyl-p-tyrosine markedly potentiated the yawning and stereotyped behaviors induced by apomorphine, a dopamine receptor (both D-1 and D-2 receptors) agonist, whereas this treatment inhibited the yawning induced by bromocriptine, a selective dopamine D-2 agonist. Apomorphine-induced stereotypy was stimulated by bromocriptine, which does not produce this behavior when administered alone. Jenkins and Jackson (1985) also reported that bromocriptine has no behavioral efficacy per se at the postsynaptic dopamine receptor and that it requires either dopamine or the administration of an exogenous agonist such as apomorphine for the expression of its effects. The purpose of the present study was to demonstrate the effects of age on yawning and stereotyped behaviors which are mediated mainly by D-2 and D-1 dopainine receptors in rats. This study was also designed to investigate whether age-related changes in these behaviors were primarily determined by dopamine D-1 or D-2 receptor activity, or by dopamine synthesis (tyrosine hydroxylase activity).
The study showed that the yawning behavior induced by bromocriptine and apomorphine decreased in 12-month-old rats whereas the apomorphine-induced stereotypy was incr eased, as compared with that of 2-month-old rats. Apomorphine exerts biphasic effects on bahavior i.e. yawning and hypomotility at low doses and stereotypy and hyperlocomotion at higher doses. This, bahavior has been suggested to be mediated by cholinergic activation secondary to the inhibition of dopamine transmission by activation of presynaptic autoreceptors. Furthermore, there is evidence suggesting that acetylcholine release is controlled by the dopamine D-2-receptor. Recently, we found that bromocriptine-induced yawning was inhibited by sulpiride, a selective dopamine D-2 receptor antagonist. The yawing was characterized by the head moving downward similarly to the effects produced by apomorphine. The fact that apomorphine-induced yawning responses are also inhibited by sulpiride suggests that presynaptic dopamine autoreceptors may be similar to presynaptic D2 receptors. Most recently, SCH 23390, a selective D1 receptor blocker, prevented apomorphine-induced yawning. Increasing D-1 receptor activity intact adult rat with the selective agonist SK&F an potentiate stereotyped responses to the selective D-2 agonist RU 24213. It was suggested that dopamine receptors mediating yawning and stereotypy may include not only D-2 but probably also D-1 receptors. However, it appears from this study that since the frequency of yawning induced by bromociptine was more pronounced than that induced by apomorphine, the yawning behavior is mainly mediated via D-2 receptor activity. Furthermore, apomorphine-induced stereotypy was stimulated in a dose-dependent manner by bromocriptine which did not produce this behavior when administered alone. Bromocriptine-induced yawning was also potentiated by a low dose of apomorphine. Bromocriptine but not apomorphine appears to require another dopamine receptor agonist for the induction of stereotypy. This suggests a dissimilarity in the mode of action of bromocriptine and apomorphine. The ability of dopamine agonists to induce yawning and stereotyped behaviors seems to depend upon the ratio and potency of D-2 versus D-1 receptor activity.
The yawning behaviors induced by bromocriptine and by lower doses of apomorphine were decreased with increasing age. The frequency of apomorphine (0.1 mg/kg)-induced yawning as potentiated by the combination with bromocriptine was pronounced in 2-month-old rats at the 2,5mg/kg dose of bromocriptine but at the 5 mg/kg dose in 12-month-old rats, suggesting that dopamine D-2 receptor activity may be attenuated in 12-month old rats. Conversely, despite the age associated loss of striatal dopamine receptors, apomorphine-induced stereotypy in rats which is mediated by stimulation of post-synaptic dopamine receptors (including D-1 and D-2) was potentiated with increasing age and appeared as perioral movement. Apomorphine (0.1mg/kg) did not produce stereotypy in 2- or in 12 month-old rats but when combined with bromocriptine it increased the stereotypy shownas discontinuous sniffing, the cumulated scores for stereotypy of 12-month-old being higher than those 2-month-old rats. The stereotypy induced by apomorphine (1.0 mg/kg) in 2-month-old rats was potentiated by bromocriptine in a dose-dependent manner, but was unaltered in 12-month-old rats, suggesting that the activity of postsynaptic dopamine D-2 receptors mediating stereotypy was also attenuated with advancing age.
Rosengarten et al. (1983) have shown that abnormal mouth movements in rats can be induced by selective D-1 receptor stimulation by SKF 38393 or by selective blockade of the D-2 receptor with sulpiride or spiroperidol. It appears, therefore, that these perioral movements are mediated by the D-1 receptor and by an imbalance in D-1 and D-2 responsiveness. Moreover, these authors found that whereas rats treated with apomorphine alone displayed stereotypy, the rats pretreated with sulpiride showed perioral movements. The apomorphine-induced perioral behavior that we observed in 12-month-old rats may have been due to a relative increase of dopamine D-1 receptor activity secondary to the attenuation of dopamine D-2 receptor activity.
Combined pretreatment with reserpine and a methyl-p-tyrosine in 2-month-old rats inhibited bromocriptine-induced yawning and potentiated apomorphine-induced yawning, as compared with their respective control groups. This was consistent with the results of our previous experiments. Catecholamine depletion in 12-month-old rats did not produce a significant difference from the control group. The apomorphine-induced stereotyped behavior of 12-month-old rats was less pronounced than that of 2-month-old rats if the rats were pretreated with reserpine plus a-methylp-tyrosine. The inhibitory effect of reserpine plus a-methyl-p-tyrosine on bromocriptine-induced yawning behavior may have been due to the lack of endogenous dopamine, whereas the stimulatory effect of these drugs on apomorphine-induced yawning and stereotypy may be due to dopamine depletion based on the inhibition of dopamine synthesis and stimulation of presynaptic dopamine D-2 receptor activity. Furthermore, important factors in the occurrence of yawning include not only dopamine D-2 receptor stimulation but also stimulation of D-1 receptors. The increasing effect on stereotypy and decreasing effect on yawning in 12-month-old rats seem to result from an alteration of the potency and the ratio of D-2 versus D-1 receptor activity.
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