Metabotropic glutamate 2/3 receptor activation induced reward deficits but did not aggravate brain reward deficits associated with spontaneous nicotine withdrawal in rats
Introduction
Nicotine withdrawal produces negative affective symptoms in humans, including depressed mood, irritability, craving, and anxiety [1], [2], [3]. This aversive abstinence syndrome in smokers is thought to contribute to the persistence of the tobacco smoking habit and relapse during abstinence [4], [5]. In animals, nicotine withdrawal precipitates a deficit in brain reward function, as measured by elevations in reward thresholds for intracranial self-stimulation (ICSS), similar to those observed in rats undergoing withdrawal from other major drugs of abuse [6]. In addition, a somatic nicotine withdrawal syndrome has been characterized in rats, including somatic signs such as abdominal constrictions (writhes), gasps, foot licks, and eyeblinks [6], [7], [8].
Metabotropic glutamate (mGlu) 2/3 receptors are presynaptic inhibitory autoreceptors that negatively modulate excitatory glutamate transmission [9]. LY379268 is a heterobicyclic amino acid and selective mGlu2/3 receptor agonist. LY379268 is highly selective for the presynaptic mGlu2 and mGlu3 receptor subtypes as compared to other glutamate receptors including N-methyl-d-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA), kainate, and other mGlu receptors [10].
mGlu2/3 receptor agonists reduce brain glutamate transmission, thereby indirectly reducing dopamine levels in the nucleus accumbens [11]. Both reduced glutamate and dopamine transmission play a role in depression and withdrawal from drugs of abuse [12], [13], [14]. Accordingly, mGlu2/3 receptor antagonists that increase glutamate and dopamine neurotransmission have been suggested as potential treatments for depression and depressive symptoms associated with drug-withdrawal [13], [14]. Consistent with this hypothesis, mGlu2/3 receptor antagonists had antidepressant-like effects in the rat forced swim test [15], the mouse tail suspension test [15], and the learned helplessness procedure in rats [16], prevented stress-induced autonomic hyperactivity [17], and attenuated reward deficits associated with spontaneous nicotine withdrawal in rats [18]. In contrast, the mGlu2/3 receptor agonist LY314582 precipitated withdrawal-like reward deficits in nicotine-dependent rats while nicotine was on board [18]. Taken together, these data suggest that mGlu2/3 receptor antagonists may be used to treat depression and depressive symptoms during nicotine withdrawal.
However, mGlu2/3 receptor agonists have also been suggested for the treatment of drug dependence based on their well-documented potential to reduce drug reward and reinstatement of drug-seeking behavior that was previously extinguished. In particular, the mGlu2/3 receptor agonist LY379268 reduced self-administration of cocaine, ethanol, and nicotine and prevented reinstatement of drug-seeking behavior for cocaine, ethanol, heroin, and nicotine [19], [20], [21], [22], [23], [24], [25]. While many recent studies have assessed the beneficial effects of the mGlu2/3 receptor agonist LY379268 in decreasing drug reward and drug-seeking behavior, little if any work has assessed whether mGlu2/3 receptor stimulation may have adverse effects on the reward system during spontaneous drug withdrawal. Because the mGlu2/3 receptor antagonist LY341495 reversed brain reward deficits associated with nicotine withdrawal and the mGlu2/3 agonist LY314582 precipitated nicotine withdrawal-like reward deficits in rats under chronic nicotine treatment, we hypothesized that the mGlu2/3 receptor agonist LY379268 would increase reward deficits associated with spontaneous nicotine withdrawal in rats.
Section snippets
Subjects
Male Wistar rats (Charles River, Raleigh, NC) weighing 300–350 g upon arrival in the laboratory were group housed (two per cage throughout the duration of the study) in a temperature- and humidity-controlled vivarium on a 12 h reverse light–dark cycle (lights off at 8 a.m.). All behavioral testing took place during the dark phase of the light–dark cycle. After arrival in the vivarium, animals were allowed to habituate to their new environment for 1 week and were handled twice during that time.
Effect of LY379268 on brain reward thresholds under baseline conditions
Mean ± S.E.M. baseline thresholds during Session 1 were 106 ± 7 μA. LY379268 elevated intracranial self-stimulation thresholds [F(2,22) = 4.8, p < 0.02]. The dose of 3 mg/kg LY379268 significantly elevated reward thresholds (p < 0.001), while the 1 mg/kg dose induced a non-significant elevation (Fig. 1). Mean ± S.E.M. baseline response latencies during Session 1 were 3.36 ± 0.13 s before vehicle injection, 3.14 ± 0.12 s before the 1 mg/kg LY379268 dose injection, and 3.14 ± 0.15 s before the 3 mg/kg LY379268 dose
Discussion
Spontaneous nicotine withdrawal elevated ICSS thresholds, indicating a deficit in reward function consistent with previous findings [6]. Elevations in ICSS reward thresholds observed in rats during nicotine withdrawal are considered a model of the affective depression-like aspects of nicotine withdrawal in humans, and more specifically of the symptom of anhedonia [4], [6], [31]. Contrary to our hypothesis that the mGlu2/3 receptor agonist would aggravate this reward deficit, LY379268 did not
Acknowledgements
This work was supported by National Institute on Drug Abuse grant DA11946 to AM. M.E.L was supported by fellowship awards from the Swiss National Science Foundation (SNF-PBZHB-108501, SSMBS 1246 and F. Hofmann-La Roche Ltd., Basel, Switzerland). The authors would like to thank Dr. Neil E. Paterson for comments on the manuscript, Ms. Jessica Benedict for technical assistance, and Mr. Mike Arends for editorial assistance.
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