The selective mGlu2/3 receptor agonist LY354740 attenuates morphine-withdrawal-induced activation of locus coeruleus neurons and behavioral signs of morphine 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.
References (44)
- et al.
Effects of β-flu-naltrexamine (β-FNA) on morphine dependence in rats and monkeys
Eur. J. Pharmacol.
(1986) - et al.
Opiate withdrawal increases glutamate and aspartate efflux in the locus coeruleus: an in vivo microdialysis study
Brain Res.
(1994) - et al.
In vivo inhibition of veratridine-evoked release of striatal excitatory amino acids by the group II metabotropic glutamate receptor agonist LY354740 in rats
Neurosci. Lett.
(1997) - et al.
DCG-IV inhibits synaptic transmission by activation of NMDA receptors in area CA1 of rat hippocampus
Eur. J. Pharmacol.
(1997) - et al.
Modulation of excitatory synaptic transmission in locus coeruleus by multiple presynaptic metabotropic glutamate receptors
Neuroscience
(1997) - et al.
Potent inhibitory input to locus coeruleus from the nucleus prepositus hypoglossi
Brain Res. Bull.
(1989) - et al.
Ascending projections of the locus coeruleus in the rat. II. Autoradiographic study
Brain Res.
(1977) - et al.
Destruction of the locus coeruleus decreases physical signs of opiate withdrawal
Brain Res.
(1993) Under siege: the brain on opiates
Neuron
(1996)- et al.
Distribution of the mRNA for a metabotropic glutamate receptor, mGluR2, in the central nervous system of the rat
Neuroscience
(1993)