Xia Li1, Manoranjan S D'Souza1, Ana M Niño1, James Doherty2, Alan Cross3, Athina Markou4. 1. Department of Psychiatry, M/C 0603, School of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0603, USA. 2. Present address: Sage Therapeutics, Cambridge, MA, 02142, USA. 3. AstraZeneca Neuroscience Innovative Medicines, Cambridge, MA, 02139, USA. 4. Department of Psychiatry, M/C 0603, School of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0603, USA. amarkou@ucsd.edu.
Abstract
RATIONALE: Numerous medication development strategies seek to decrease nicotine consumption and prevent relapse to tobacco smoking by blocking glutamate transmission. Decreasing glutamate release by activating presynaptic inhibitory metabotropic glutamate (mGlu)2/3 receptors inhibits the reinforcing effects of nicotine and blocks cue-induced reinstatement of nicotine-seeking behavior in rats. However, the relative contribution of mGlu2 receptors in nicotine dependence is still unknown. OBJECTIVES: The present study evaluated the role of mGlu2 receptors in nicotine-taking and nicotine-seeking behavior using the novel, relatively selective mGlu2 positive allosteric modulators (PAMs) AZD8418 and AZD8529. RESULTS: Acute treatment with AZD8418 (0.37, 1.12, 3.73, 7.46, and 14.92 mg/kg) and AZD8529 (1.75, 5.83, 17.5, and 58.3 mg/kg) deceased nicotine self-administration and had no effect on food-maintained responding. Chronic treatment with AZD8418 attenuated nicotine self-administration, but tolerance to this effect developed quickly. The inhibition of nicotine self-administration by chronic AZD8529 administration persisted throughout the 14 days of treatment. Chronic treatment with either PAMs inhibited food self-administration. AZD8418 (acute) and AZD8529 (acute and subchronic) blocked cue-induced reinstatement of nicotine- and food-seeking behavior. CONCLUSIONS: These findings indicate an important role for mGlu2 receptors in the reinforcing properties of self-administered nicotine and the motivational impact of cues that were previously associated with nicotine administration (i.e., cue-induced reinstatement of nicotine-seeking behavior). Thus, mGlu2 PAMs may be useful medications to assist people to quit tobacco smoking and prevent relapse.
RATIONALE: Numerous medication development strategies seek to decrease nicotine consumption and prevent relapse to tobacco smoking by blocking glutamate transmission. Decreasing glutamate release by activating presynaptic inhibitory metabotropic glutamate (mGlu)2/3 receptors inhibits the reinforcing effects of nicotine and blocks cue-induced reinstatement of nicotine-seeking behavior in rats. However, the relative contribution of mGlu2 receptors in nicotine dependence is still unknown. OBJECTIVES: The present study evaluated the role of mGlu2 receptors in nicotine-taking and nicotine-seeking behavior using the novel, relatively selective mGlu2 positive allosteric modulators (PAMs) AZD8418 and AZD8529. RESULTS: Acute treatment with AZD8418 (0.37, 1.12, 3.73, 7.46, and 14.92 mg/kg) and AZD8529 (1.75, 5.83, 17.5, and 58.3 mg/kg) deceased nicotine self-administration and had no effect on food-maintained responding. Chronic treatment with AZD8418 attenuated nicotine self-administration, but tolerance to this effect developed quickly. The inhibition of nicotine self-administration by chronic AZD8529 administration persisted throughout the 14 days of treatment. Chronic treatment with either PAMs inhibited food self-administration. AZD8418 (acute) and AZD8529 (acute and subchronic) blocked cue-induced reinstatement of nicotine- and food-seeking behavior. CONCLUSIONS: These findings indicate an important role for mGlu2 receptors in the reinforcing properties of self-administered nicotine and the motivational impact of cues that were previously associated with nicotine administration (i.e., cue-induced reinstatement of nicotine-seeking behavior). Thus, mGlu2 PAMs may be useful medications to assist people to quit tobacco smoking and prevent relapse.
Authors: Manoranjan S D'Souza; Matthias E Liechti; Ana M Ramirez-Niño; Ronald Kuczenski; Athina Markou Journal: Neuropsychopharmacology Date: 2011-06-08 Impact factor: 7.853
Authors: Zuzana Justinova; Leigh V Panlilio; Maria E Secci; Godfrey H Redhi; Charles W Schindler; Alan J Cross; Ladislav Mrzljak; Amy Medd; Yavin Shaham; Steven R Goldberg Journal: Biol Psychiatry Date: 2015-02-07 Impact factor: 13.382
Authors: Kari A Johnson; Lucas Voyvodic; Gabriel C Loewinger; Yolanda Mateo; David M Lovinger Journal: Neuropsychopharmacology Date: 2020-01-29 Impact factor: 7.853