mise à jour du
23 juillet 2006
Pharmacol Biochem Behav
1992;43(3): 673-6.
Behavioral effects of dilazep
on cholinergic, dopaminergic,
and purinergic systems in the rat
Ushijima I., Y Mizuki et al.


Abstract : This study examined the effects of 1,4-bis[3-(3,4,5-trimethoxy benzoyloxy)-propyl] perhydro-1,4-diazepine (dilazep; Comelian) on central dopaminergic, cholinergic, and purinergic neuronal systems in rats. Intraperitoneal injections of dilazep (1-5 mg/kg) produced yawning responses, the most effective dose being 2 mg/kg. Dilazep potentiated physostigmine-induced yawning but not pilocarpine- and bromocriptine-induced yawning. Dilazep-induced yawning was not affected by low doses of haloperidol or sulpiride, but was completely inhibited by atropine, a muscarinic M1 receptor antagonist. Dilazep-induced yawning, as well as physostigmine-induced yawning, were markedly inhibited by pretreatment with SK & F 38393, a dopamine D1 receptor agonist, and were potentiated by SCH23390, a dopamine D1 receptor antagonist that alone does not elicit yawning. Caffeine, an adenosine receptor antagonist, inhibited dilazep- and physostigmine-induced yawning responses but N6-cyclohexyl adenosine (CHA) and N6-(L-phenylisopropyl, adenosine (L-PIA), adenosine A1 receptor agonists, were inactive. These results suggest that because the effects of dilazep on central cholinergic neurons are similar to those of physostigmine dilazep may potentiate indirectly the action of endogenous acetylcholine. Cholinergic neurons activated by dilazep may be modulated by postsynaptic dopamine D1 receptor activity but may not be affected by dopamine D2 receptor activity. Furthermore, the stimulatory effects of dilazep on cholinergic neuron may not be due to an inhibition of dopamine D1 receptors via purinergic (adenosine A1 receptor) stimulation by dilazep.

Introduction: DILAZEP (Comelian; 1 ,4-bLs[3-(3,4,5-trimethoxy benzoyloxy)propyl]perhydro- 1 ,4-diazepine) has been proposed to increase coronary blood flow and potentiate the dilating effect of adenosine on coronary vessels. Because dilazep also has a dilating effect on central vessels, probably via inhibiting adenosine uptake, the drug has been proposed as a valuable therapeutic agent in cerebrovascular dementia. Dilazep and N6-(L-phenylisopropyl) adenosine (L-PIA: adenosine A, receptor agonist) inhibit aggressive behaviors induced by high doses of clonidine, which antagonizes adenosine A, receptors. On the other hand, the memory dysfunction associated with senile dementia of the Alzheimer type has been associated with a deficiency and loss of cholinergic neurons. An adenosine receptor antagonist, theophylline, inhibits physostigmine-induced yawning behaviors, which result in activation of central cholinergic neurons.
Yawning behaviors induced by physostigmine, a cholinesterase inhibitor, and pilocarpine, a direct acetylcholine receptor agonist, in rats are essentially mediated through the stimulation of central muscarinic receptors but not nicotinic receptors. On the other hand, yawning can also be elicited by apomorphine, a D1/D2 agonist, and bromocriptine, a D2 agonist, which have been reported to be mediated by cholinergic activation secondary to the inhibition of dopamine transmission. This behavior may be mediated by septal-striatal and hypothalamic D2 receptor activation. In the present study, we found that yawning was induced by IP injection of dilazep to rats. These results were examined more closely to clarify whether the behavioral effects of dilazep involve central cholinergic and dopaminergic or purinergic systems.
In this study, dilazep alone induced yawning and potentiated physostigmine yawning but did not affect pilocarpine and bromocriptine yawning. There was a bell-shaped dose response curve for the effects of dilazep on yawning. This suggests that dilazep yawning may involve an indirect activation of cholinergic neurons, probably by releasing acetylcholine and/or inhibiting acetylcholinesterase. Because dilazep yawning was not affected by (-)-sulpiride, a D2 antagonist, and by a low dose of haloperidol that preferentially inhibits presynaptic dopamine receptors (D2 receptors) but was completely blocked by atropine, a muscarinic receptor antagonist, dilazep yawning appears unlikely to be due to cholinergic neuronal activation secondary to the activation of presynaptic dopamine D2 receptors.
There is some evidence that physostigmine yawning is inhibited by SK&F38393, a D1 agonist but is potentiated by SCH23390, a D1 antagonist, whereas pilocarpine yawning is not affected by SK&F38393, suggesting that activation of D1 receptors may inhibit cholinergic neurons activated by cholinesterase inhibition, that is, endogenous acetylcholine, but may not affect the stimulation of cholinergic neurons to a direct acetylcholine agonist (muscarinic M1 receptor agonist). In this study, the effects of SK&F38393 and SCH23390 on dilazep yawning were compatible with those observed on physostigmine yawning. Pretreatment with SK&F38393 markedly inhibited dilazep yawning and physostigmine yawning whereas SCH23390 potentiated them. Pilocarpine yawning was unaffected by either SK&F38393 or SCH23390. From these results, it is suggested that dilazep as well as physostigmine yawning may be mediated by dopamine D1 receptor activity. The inhibitory effects of high doses of apomorphine on dilazep and physostigmine yawning appear to be due to the activation of dopamine D1 receptors. D1 and D2 dopamine receptors that exist in the striatum stimulate and inhibit, respectively, the formation of striatal cyclic adenosine monophosphate. The striatum contains the highest concentration of acetyicholine in the brain and dopamine receptors have a regulatory role on striatal acetylcholine.
The opposing effects of D1 and D2 receptors on striatal cholinergic neurons have also been shown in biochemical studies.
On the other hand, dilazep has an adenosine action as mentioned in the introductory section. Adenosine receptors have also been classified into two different types, called A1 and A2 receptors on the basis of inhibitory and stimulatory effects, respectively, of adenosine on rat brain adenylate cyclase activity. An adenosine A1/A2 receptor antagonist, theophylline, inhibits physostigmine yawning. In this study, the adenosine A1/A2 receptor antagonist, caffeine, also inhibited dilazep as well as physostigmine yawning. However, only dilazep and not L-PIA or CHA (adenosine A1 receptor agonists) potentiated physostigmine yawning. These results suggest that the stimulatory effect of dilazep on physostigmine yawning may not be due to an inhibition of dopamine D, receptors via stimulation of adenosine A1 receptors but rather may be due to an activation of cholinergic neuron by endogenous acetylcholine. The mode of action of dilazep is similar to that of physostigmine, which indirectly stimulates cholinergic neurons.
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