Poster
# 86
Poster |
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6th Internet World Congress for Biomedical Sciences |
Kirsten Culver(1), Henry Szechtman(2)
(1)(2)McMaster University - Hamilton. Canada
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[Neuroscience] |
Repeated administration of the D2/D3 receptor agonist, quinpirole (QNP), results in behavioral sensitization(5); a progressive augmentation of the locomotor response to subsequent injections of the drug(4). Recent studies have shown that monoamine oxidase inhibitors (MAOIs) such as clorgyline (CLG), inhibit the binding of quinpirole, but not that of the D2 receptor antagonist, spiperone, in rat striatal membranes(2,3). These findings suggest that monoamine oxidase inhibitors posses a unique affinity for a MAOI displaceable quinpirole binding site (MQB) that is either labeled by quinpirole, or which modulates quinpirole binding at D2-like receptors(2,3).
Behavioral studies have shown that continuous infusion of clorgyline blocks the induction of quinpirole-induced locomotor sensitization by a mechanism other than inhibition of the MAO enzyme, suggesting that the MQB site may be involved in sensitization to quinpirole (1,6,7).
The purpose of the present study was to determine whether intermittent injections of clorgyline would block quinpirole-induced locomotor sensitization as effectively as did the continuous infusion of clorgyline via osmotic mini-pump.
To induce locomotor sensitization, 30 male rats were injected twice weekly with quinpirole (0.5 mg/kg, s.c.) for a total of 8 injections, while 10 control rats were similarly injected with saline. Quinpirole-treated rats were assigned, at random, into 3 groups (n=10 per group): a chronic clorgyline group that received clorgyline (1 mg/kg/day) via osmotic mini-pump (QNP+CLG), a chronic clorgyline group that received a subcutaneous injection of clorgyline (1 mg/kg) 90 minutes prior to each quinpirole injection (QNP+CLGinj), and a quinpirole control group that received a subcutaneous injection of saline 90 minutes prior to each quinpirole injection (QNP+SAL). Saline control rats received a subcutaneous injection of saline 90 minutes prior to each of the 8 injections of saline (SAL Control).
Immediately following each injection of quinpirole, rats were placed in activity monitors and their locomotor activity was recorded for 90 minutes. During the first and last 15 minutes of the testing period, mouthing activity was recorded for 30 seconds every 3-3.5 minutes for a total of 4 minutes using a hand-held timer.
To determine whether chronic clorgyline blocked the induction of locomotor sensitization to quinpirole, or merely blocked its expression, clorgyline treatment was discontinued after the 8th quinpirole injection, and all groups received a test injection of quinpirole (0.5 mg/kg, s.c.) one week later.
As shown in Figure 1, quinpirole produced a robust sensitization in the QNP+SAL group, as evidenced by a 5-fold increase in locomotor activity on Injection 8, compared to Injection 1 (p<0.001, paired t-test). Clorgyline, regardless of whether administered via osmotic mini-pump or subcutaneous injection, blocked the induction of locomotor sensitization (Injection 1 vs Injection 8; p>0.05, paired t-test). Both groups of clorgyline treated rats (QNP+CLG and QNP+CLGinj) displayed an acute locomotor response to the test injection of quinpirole, no different from that of the SAL Control group (p>0.05), and significantly lower than the QNP sensitized group (p<0.05, Duncan multiple range test). This finding shows that clorgyline, regardless of whether it is administered continuously or intermittently, blocks the induction, rather than merely the expression of quinpirole-induced locomotor sensitization.
As shown in Figure 2, repeated injections of quinpirole reduced the percentage of time spent engaged in mouthing activity in the QNP+SAL group on Injection 8, compared to Injection 1 (p<0.05, paired t-test). In contrast, regardless of whether administered via osmotic mini-pump or subcutaneous injection, clorgyline significantly increased the percentage of time spent mouthing (Injection 1vs Injection 8; p<0.05, paired t-test). Both groups of clorgyline treated rats (QNP+CLG and QNP+CLGinj), engaged in significantly more mouthing activity on the test injection of quinpirole compared to the SAL Control and QNP+SAL groups (p<0.05, Duncan multiple range test). Mouthing activity occurred predominantly in the last 15 minutes of the testing period, and consisted primarily of self-directed behaviors such as nibbling of the tail and paws, and licking of the fur around the neck and chest (data not shown).
1. Results show that regardless of whether it is administered continuously or intermittently, clorgyline A) blocks the induction of locomotor sensitization to repeated injections of quinpirole, and B) induces sensitization of mouthing.
2. To the extent that the process of sensitization involves 4 discrete stages (trigger, induction, expression and maintenance), the finding that intermittent and continuous clorgyline administration have equal effects on locomotion and mouthing suggests that clorgyline acts early in the process of sensitization, that is, at the stage of triggering the sensitization process.
3. The finding that clorgyline treatment shifts sensitization from locomotion to mouthing suggests that clorgyline exerts its action at a “switch” that selects which motor pathway (locomotion or mouthing) is to be sensitized by repeated injections of quinpirole. Since clorgyline has a high affinity for the MQB site, we suggest that it is the MQB site which acts as this “switch”(7).
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[Neuroscience] |
