ly-341495 and Substance-Withdrawal-Syndrome

Withdrawal from chronic treatment with a psychostimulant precipitates behavioral and physiological conditions similar to the symptoms of major depressive disorder (MDD). Accumulated studies have indicated that withdrawal from a psychostimulant in rodents elicits depressive phenotypes including despair and anhedonia. Recently, the modulation of the group II metabotropic glutamate (mGlu2/3) receptor has been proposed as a novel therapeutic approach to MDD. In the present study, we investigated the effect of an mGlu2/3 receptor antagonist, LY341495, on the depressive behavior induced by withdrawal from chronic treatment with a psychostimulant, methamphetamine (MAP) (5.0mg/kg/day×5 days). The rats were then tested for depressive behavior using the forced swimming test. Withdrawal from chronic treatment with MAP increased the immobility time during the forced swimming test, indicating increased depressive behavior. Systemically administered LY341495 counteracted the depressive behavior induced by withdrawal from chronic treatment with MAP. Moreover, we found that the microinjection of LY341495 into the nucleus accumbens (NAc) also counteracted the increase in the immobility time caused by withdrawal from chronic treatment with MAP. Taken together, the present results suggested that the blockade of the mGlu2/3 receptor may prevent the depressive symptoms induced by withdrawal from a psychostimulant and that the blockade of the mGlu2/3 receptor in the NAc may contribute to the antidepressant-like effects of the mGlu2/3 receptor antagonist in this test.

Topics: Amino Acids; Analysis of Variance; Animals; Central Nervous System Stimulants; Depression; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Delivery Systems; Drug Interactions; Excitatory Amino Acid Antagonists; Immobility Response, Tonic; Male; Methamphetamine; Motor Activity; Rats; Rats, Sprague-Dawley; Substance Withdrawal Syndrome; Swimming; Xanthenes

Stimulatory actions of nicotine on mesocorticolimbic dopamine transmission are partly mediated by nicotine-induced glutamate release acting on ionotropic and metabotropic glutamate (mGlu) receptors. Because both presynaptic inhibitory mGlu2/3 and postsynaptic excitatory mGlu5 receptors provide potential targets for treatment of aspects of nicotine dependence, we examined interacting effects of mGlu5 (2-methyl-6-(phenylethynyl)-pyridine, MPEP) and mGlu2/3 (LY341495) receptor antagonists on nicotine self-administration and brain reward threshold elevations associated with spontaneous nicotine withdrawal in rats. We hypothesized that increasing glutamate transmission by blocking presynaptic inhibitory mGlu2/3 autoreceptors would antagonize MPEP-induced decreases in nicotine self-administration. We also hypothesized that blocking postsynaptic actions of glutamate on mGlu5 receptors would exacerbate nicotine withdrawal-induced reward deficits, and that this effect would be attenuated by co-administration of the mGlu2/3 receptor antagonist LY341495. MPEP selectively decreased nicotine, but not food, self-administration in rats. LY341495 slightly decreased both nicotine and food self-administration. Co-administration of LY341495 with MPEP attenuated the effectiveness of MPEP in decreasing nicotine intake, although MPEP was still effective. Spontaneous nicotine withdrawal induced somatic signs of withdrawal and reward threshold elevations indicating reward deficits. MPEP increased somatic signs and reward deficits in both nicotine- and saline-withdrawing rats. Thus, while mGlu5 receptor antagonists may be therapeutically useful in decreasing tobacco smoking, they worsen nicotine withdrawal. Co-administration of LY341495 reduced MPEP-induced reward deficits in both nicotine- and saline-withdrawing rats. Thus, increasing glutamate transmission via mGlu2/3 autoreceptor blockade reduces the effects of mGlu5 receptor blockade on nicotine self-administration and MPEP-induced exacerbation of brain reward deficits associated with nicotine withdrawal.

Topics: Amino Acids; Animals; Dose-Response Relationship, Drug; Drug Interactions; Eating; Excitatory Amino Acid Antagonists; Ganglionic Stimulants; Infusions, Intravenous; Injections, Intraperitoneal; Male; Nicotine; Pyridines; Rats; Rats, Wistar; Receptor, Metabotropic Glutamate 5; Receptors, Metabotropic Glutamate; Reinforcement Schedule; Reward; Self Administration; Substance Withdrawal Syndrome; Time Factors; Xanthenes

Previous research has demonstrated that mGlu2/3 agonists can decrease many behavioral signs and the activation of locus coeruleus (LC) neurons observed during morphine withdrawal. However, it is not known if mGlu2/3 receptors are activated during morphine withdrawal by endogenous glutamate. Therefore, we investigated the effect of a novel metabotropic glutamate 2, 3 (mGlu2/3) receptor antagonist (LY341495) on naltrexone-precipitated behavioral signs of morphine withdrawal and withdrawal-induced activation of LC neurons. Three levels of severity of morphine withdrawal (mild, moderate, and strong) were operationally defined by varying the exposure to morphine. Pretreatment with LY341495 (1 mg/kg, s.c.) had no affect on behavioral signs at the mild level of withdrawal, but significantly increased behavioral signs at the moderate level of withdrawal. At the strong level of withdrawal, 3 and 10 mg/kg, but not 1 mg/kg, LY341495 significantly increased the behavioral signs of withdrawal. In in vivo recordings from anesthetized rats, pretreatment with 1 mg/kg LY341495 did not affect the morphine-withdrawal-induced activation of LC neurons at the mild level of withdrawal. At the moderate level of withdrawal, 1 and 10 mg/kg LY341495 did not affect morphine-withdrawal-induced activation of LC neurons. At the strong level of withdrawal, both 1 and 10 mg/kg LY341495 significantly increased morphine-withdrawal-induced activation of LC neurons. These results indicate that endogenous activation of mGlu2/3 receptors during morphine withdrawal acts to reduce the severity of morphine withdrawal and demonstrates that mGlu2/3 receptors are activated under a physiologically relevant, pathological condition.

Topics: Action Potentials; Amino Acids; Animals; Excitatory Amino Acid Antagonists; Locus Coeruleus; Male; Morphine Dependence; Neurons; Rats; Rats, Sprague-Dawley; Receptors, Metabotropic Glutamate; Substance Withdrawal Syndrome; Xanthenes