The Preclinical Properties of a Novel Group II Metabotropic Glutamate Receptor Agonist LY379268

Metabotropic glutamate receptor subtypes (mGlu2/3) regulate a variety of alcohol-associated behaviors, including alcohol reinforcement, and relapse-like behavior. To date, the role of mGlu2/3 receptors in modulating the discriminative stimulus effects of alcohol has not been examined. Given that the discriminative stimulus effects of drugs are determinants of abuse liability and can influence drug seeking, we examined the contributions of mGlu2/3 receptors in modulating the discriminative stimulus effects of alcohol. In male Long-Evans rats trained to discriminate between alcohol (1 g/kg, IG) and water, the mGlu2/3 agonist LY379268 (0.3-10 mg/kg) did not produce alcohollike stimulus effects. However, pretreatment with LY379268 (1 and 3 mg/kg; in combination with alcohol) inhibited the stimulus effects of alcohol (1 g/kg). Systemic LY379268 (3 mg/kg, i.p.) was associated with increases in neuronal activity within the amygdala, but not the nucleus accumbens, as assessed by c-Fos immunoreactivity. Intra-amygdala activation of mGlu2/3 receptors by LY379268 (6 mg) inhibited the discriminative stimulus effects of alcohol, without altering response rate. In contrast, intra-accumbens LY379268 (3 mg) profoundly reduced response rate; however, at lower LY379268 doses (0.3, 1 mg), the discriminative stimulus effects of alcohol and response rate were not altered. These data suggest that amygdala mGlu2/3 receptors have a functional role in modulating the discriminative stimulus properties of alcohol and demonstrate differential motor sensitivity to activation of mGlu2/3 receptors in the amygdala and the accumbens. Understanding the neuronal mechanisms that underlie the discriminative stimulus effects of alcohol may prove to be important for future development of pharmacotherapies for treating alcoholism.

Section: Discussionmentioning

confidence: 99%

Activation of Group II Metabotropic Glutamate Receptors Inhibits the Discriminative Stimulus Effects of Alcohol via Selective Activity Within the Amygdala

Cannady

Grondin

Fisher

et al. 2011

“…Because LY379268 administration (3 mg/kg) blocked both nicotine and food self-administration , indicating a lack of reinforcer selectivity at this dose and impairment of locomotor activity at higher doses (6-10 mg/ kg; Imre, 2007), we did not assess the effects of 3 mg/kg or higher doses of LY379268 beyond Experiment 1. Importantly, LY379268 (1 mg/kg) selectively attenuated nicotine, but not food, self-administration and had no effect on locomotor activity (Imre, 2007;; therefore, this dose was used in all subsequent experiments.…”

Section: Discussionmentioning

confidence: 99%

The Metabotropic Glutamate 2/3 Receptor Agonist LY379268 Blocked Nicotine-Induced Increases in Nucleus Accumbens Shell Dopamine only in the Presence of a Nicotine-Associated Context in Rats

D’Souza

Liechti

Ramirez-Niño

et al. 2011

The metabotropic glutamate 2/3 (mGlu2/3) receptor agonist LY379268 ([À]-2-oxa-4-aminobicyclo [3.1.0] hexane-4,6-dicarboxylate) attenuates both nicotine self-administration and cue-induced nicotine seeking in rats. In this study, the effects of LY379268 (1 mg/kg) or saline pretreatment on nicotine-induced increases in nucleus accumbens (NAcc) shell dopamine were evaluated using in vivo microdialysis under different experimental conditions: (i) nicotine (0.4 mg/kg, base) was experimenter-administered subcutaneously to nicotine-naïve rats; (ii) nicotine was experimenter-administered either subcutaneously (0.4 mg/kg) or by a single experimenteradministered infusion (0.06 mg/kg, base) in rats with a history of nicotine self-administration (nicotine experienced) in the absence of a nicotine-associated context (ie, context and cues associated with nicotine self-administration); (iii) nicotine (0.06 mg/kg) was selfadministered or experimenter-administered in nicotine-experienced rats in the presence of a nicotine-associated context. In salinepretreated nicotine-naïve and nicotine-experienced rats, nicotine increased NAcc shell dopamine regardless of the context used for testing. Interestingly, LY379268 pretreatment blocked nicotine-induced increases in NAcc shell dopamine in nicotine-experienced rats only when tested in the presence of a nicotine-associated context. LY379268 did not block nicotine-induced increases in NAcc shell dopamine in nicotine-naïve or -experienced rats tested in the absence of a nicotine-associated context. These intriguing findings suggest that activation of mGlu2/3 receptors negatively modulates the combined effects of nicotine and nicotine-associated contexts/cues on NAcc dopamine. Thus, these data highlight a critical role for mGlu2/3 receptors in context/cue-induced drug-seeking behavior and suggest a neurochemical mechanism by which mGlu2/3 receptor agonists may promote smoking cessation by preventing relapse induced by the combination of nicotine and nicotine-associated contexts and cues.

“…In this paper, we showed that LY379268, a compound effective in animal models of schizophrenia (Cartmell et al, 1999(Cartmell et al, , 2000Clark et al, 2002;Imre et al, 2006;Imre, 2007), blocked PPI impairment associated with GLT-1 upregulation. Although the present findings do not allow predictions about clinical efficacy of LY379268, it is worth noting that the better assimilated analog LY404039 ameliorates both positive and negative symptoms in schizophrenia patients (Patil et al, 2007;Harrison, 2008).…”

Section: Ly379268 Blocks Cef-induced Ppi Impairment M Bellesi and F Cmentioning

confidence: 99%

“…The selective mGluR2/3 agonist LY379268 attenuates behavioral abnormalities in animal models of schizophrenia, and its analog LY404039 is effective in a schizophrenia phase 2 clinical trial (Cartmell et al, 1999(Cartmell et al, , 2000Clark et al, 2002;Imre et al, 2006;Imre, 2007;Patil et al, 2007;Harrison, 2008). Recently, we have shown that ceftriaxone (CEF)-induced GLT-1 upregulation impairs hippocampal long-term depression (LTD) in a DHK-reversible manner by limiting activation of mGluR2/3, thus indicating that a reduced function of mGluR2/3 mediates the effects of GLT-1 upregulation (Omrani et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

The mGluR2/3 Agonist LY379268 Blocks the Effects of GLT-1 Upregulation on Prepulse Inhibition of the Startle Reflex in Adult Rats

Bellesi

Conti

2010

The main glutamate transporter GLT-1 is responsible for clearing synaptically released glutamate from the extracellular space and contributes to the shaping of glutamatergic transmission. Recently, it has been shown that ceftriaxone (CEF)-induced GLT-1 upregulation is associated with an impairment of the prepulse inhibition (PPI) of the startle reflex, a simple form of information processing that is reduced in schizophrenia, and determines a strong reduction in hippocampal metabotropic glutamate receptor (mGluR)2/3-dependent long-term depression. In this study, we tested the hypothesis that administration of the mGluR2/3 agonist LY379268 blocks the effect of GLT-1 upregulation on PPI of the startle. We showed that administration of LY379268 (1 mg/kg) prevented PPI alterations associated with GLT-1 upregulation, suggesting that CEF-induced PPI impairment was mGluR2/3 dependent. In addition, we showed that CEF-induced GLT-1 upregulaton did not alter the expression of mGluR2/3, and also that it occurred at sites of mGluR2/3 expression. These results indicate a novel mechanism by which GLT-1 upregulation modulates PPI of the startle.