Elsevier

Neuropharmacology

Volume 38, Issue 2, February 1999, Pages 217-222
Neuropharmacology

The selective mGlu2/3 receptor agonist LY354740 attenuates morphine-withdrawal-induced activation of locus coeruleus neurons and behavioral signs of morphine withdrawal

https://doi.org/10.1016/S0028-3908(98)00196-8Get rights and content

Abstract

Naltrexone-precipitated morphine withdrawal induces hyperactivity of locus coeruleus (LC) neurons, as well as a plethora of behavioral withdrawal signs. Previous research has demonstrated that an increased release of glutamate and activation of AMPA receptors, particularly in the LC, play an important role in opiate withdrawal. LY354740 is a novel Group II metabotropic glutamate mGlu2/3 receptor agonist that decreases the release of glutamate. Therefore, we investigated the effect of LY354740 on naltrexone-precipitated morphine-withdrawal-induced activation of LC neurons and behavioral signs of morphine withdrawal. In in vivo recordings from anesthetized rats, pretreatment with LY354740 (3–30 mg/kg, s.c.) dose-dependently attenuated the morphine-withdrawal-induced activation of LC neurons. In unanesthetized, morphine-dependent animals, pretreatment with LY354740 (3–30 mg/kg, s.c.) dose-dependently suppressed the severity and occurrence of many naltrexone-precipitated morphine-withdrawal signs. These results indicate mGlu2/3 receptor agonists: (1) can attenuate the morphine-withdrawal-induced activation of LC neurons and many behavioral signs of morphine withdrawal; and (2) may have therapeutic effects in man for the treatment of opiate withdrawal.

Introduction

The locus coeruleus (LC) is the largest grouping of noradrenergic neurons in the mammalian brain (Dahlstrom and Fuxe, 1965). The cell bodies of the LC are confined to a small area of the pons, but these neurons send extensive projections throughout the neuraxis (Jones and Moore, 1977). These wide ranging projections put the LC in a position to simultaneously influence the activity of a number of brain areas. Hence, the LC has been hypothesized to play a role in a wide variety of behaviors, physiological processes, and brain diseases. In particular, the LC has been shown to play an important role in the expression of opiate withdrawal (Aghajanian, 1978, Rasmussen et al., 1990, Maldonado et al., 1992, Maldonado and Koob, 1993, Rasmussen, 1995). Specifically, the increased release of glutamate and subsequent activation of AMPA receptors is critically involved in opiate withdrawal-induced activation of LC neurons and the behavioral signs of opiate withdrawal (Akaoka and Aston-Jones, 1991, Aghajanian et al., 1994, Rasmussen et al., 1996).

Glutamate receptors have been divided into two broad categories: iontotropic and metabotropic. Iontotropic glutamate receptors contain cation-specific ion channels as a component of their protein complex, while metabotropic glutamate receptors are coupled to G-proteins and modulate intracellular second messenger systems. Thus far, eight different clones for metabotropic glutamate (mGlu) receptors have been isolated (mGlu1-8). Based on agonist interactions, sequence homology, and second messenger coupling, the eight mGlu receptors have been grouped into three large families (Conn and Pin, 1997). Group I mGlu receptors include mGlu1 and mGlu5, Group II mGlu receptors include mGlu2 and mGlu3, and Group III mGlu receptors include mGlu4, 6, 7, and 8. mGlu receptors can differentially modulate synaptic function through both pre- and post-synaptic sites (Schoepp and Conn, 1993, O’Leary et al., 1997). Activation of presynaptic Group II and III mGlu receptors decrease the release of glutamate (Pin and Duvoisin, 1994), while activation of presynaptic Group I mGlu receptors can enhance or depress the release of glutamate (Herrero et al., 1992, Gereau and Conn, 1995). Dube and Marshall (1997) demonstrated that mGlu2/3 receptors inhibit excitatory synaptic transmission in LC neurons, possibly by functioning as autoreceptors for excitatory amino acids. In addition to their presynaptic modulation, activation of postsynaptic mGlu1 and 5 receptors stimulate phosphoinositide hydrolysis, while activation of mGlu2, 3, 4, 6, 7 and 8 receptors inhibit cAMP production (Nakanishi, 1992, Schoepp and Conn, 1993). Therefore, mGlu2/3 receptors can influence a variety of glutamatergic dependent processes by either suppressing postsynaptic neuronal activity or inhibiting presynaptic release of glutamate (Nakanishi, 1992, Pin and Duvoisin, 1994).

Recently, it has been shown that i.c.v. administration of the mGlu2/3 receptor agonist DCG-IV and the non-selective mGlu agonist ACPD attenuate some opiate withdrawal signs in rats (Fundytus and Coderre, 1997). However, a limited number of withdrawal symptoms were examined in this study and ACPD and DCG-IV are not systemically active. Further, DCG-IV is not only an mGlu2/3 agonist, but it is also an agonist for mGlu8 and NMDA receptors, as well as an mGlu7 receptor antagonist (Uyama et al., 1997, Breakwell et al., 1997). Thus, the role of mGlu2/3 receptors in morphine withdrawal and the potential therapeutic uses of mGlu receptor ligands in opiate withdrawal has not been fully explored.

LY354740 is a recently discovered selective mGlu2/3 receptor agonist, which shows no significant iontotropic (iGluR4 and iGluR6) nor mGlu1 and 5 or mGlu4, 6, 7 and 8 receptor activities (Monn et al., 1997, Schoepp et al., 1997). LY354740 is systemically active and highly efficacious in animal models of anxiety and nicotine withdrawal (Helton et al., 1997, Helton et al., 1998). In addition, LY354740 has been shown to decrease the evoked release of glutamate in the striatum (Battaglia et al., 1997). Since increased release of glutamate has been shown to play a critical role in the opiate withdrawal, we examined the effect of LY354740, and its inactive enantiomer LY317207, on the opiate withdrawal-induced activation of LC neurons and behavioral signs of opiate withdrawal.

Section snippets

Opiate dependence and withdrawal

Opiate dependence was induced in male Sprague–Dawley rats (Charles River, 250–350 g) by the subcutaneous pellet implantation method (Way et al., 1969, Blasig et al., 1973). While under halothane anesthesia, animals were implanted with either morphine pellets (NIDA; 75 mg morphine base, 68.5 mg microcrystalline cellulose, 1.5 mg magnesium stearate, 2.5 mg colloidal silicon dioxide) or placebo pellets (NIDA; 150 mg Avicel PH-102, 1.5 mg magnesium stearate, 0.75 mg colloidal silicon dioxide, 1.75

Electrophysiological recordings

Pretreatment with LY354740, but not LY317207, significantly attenuated the morphine-withdrawal-induced activation of LC neurons (ANOVA; F=7.45, P<0.0001; Fig. 1). The basal firing rates of LC cells in animals implanted with morphine pellets were significantly lower than in animals receiving placebo pellets (P<0.05), indicating an incomplete development of tolerance to morphine at the time of testing (Fig. 1; baseline). Pretreatment with LY354740 did not alter the firing rates of LC neurons in

Discussion

The results of this study demonstrate that activation of mGlu2/3 receptors can have a strong influence on opiate withdrawal. In morphine dependent rats, LY354740, but not its inactive isomer LY317207, significantly reduced naltrexone-precipitated activation of LC neurons. The typical 5 to 6-fold increase in LC neuronal firing rates seen during morphine withdrawal was dose-dependently suppressed by acute pretreatment with LY354740. This finding is consistent with previous research demonstrating

Acknowledgements

We would like to thank Brian Eastwood for his help with the statistical analysis of the data.

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