LETTER TO THE EDITOR Group-II metabotropic glutamate receptor ligands as adjunctive drugs in the treatment of depression: a new strategy to shorten the latency of antidepressant medication? Molecular Psychiatry (2007) 12, 704–706; doi:10.1038/sj.mp.4002005 Unipolar depression is a major public health problem and will be the second most prevalent cause of illness-induced disability by the year 2020 according to the World Health Organization. There are several antidepressant drugs that are effective and relatively safe, but they all require a long latency (usually 3–4 weeks) to improve depressive symptoms. This latency seriously complicates the management of severely depressed patients, who are at high risk for suicide during the early phases of treatment. Paradoxically, suicide attempts may even increase during the first days of antidepressant medication because of the shorter latency of drug-induced psychomotor activa- tion. Fast-active drugs or adjunctive drugs that short- en the clinical latency of classical antidepressants will provide a major breakthrough in the treatment of depression. Recent evidence suggests that glutamate receptors are potential targets for antidepressant drugs. 1 These receptors are subdivided into two major classes: (i) ionotropic glutamate receptors (i.e. alpha- amino-3-hydroxy-5-methyl-4-isoxazole propionate, N-Methyl-D-aspartate (NMDA) and kainate receptors), which are ligand-gated ion channels; and (ii) metabo- tropic glutamate (mGlu) receptors, which are coupled to G proteins. NMDA receptor antagonists produce beneficial effects in animal models of depression, 2–4 but their potential use in humans is limited by their strong impact on excitatory synaptic transmission, which results in serious adverse effects, such as sedation, ataxia and impairment of learning and memory. 5 Drugs acting at mGlu receptors should offer a better profile of tolerability because these receptors ‘modulate’ rather than mediate synaptic transmission in the central nervous system. 6,7 mGlu receptors form a family of eight subtypes subdivided into three groups on the basis of their amino-acid sequence, pharmacological profile and transduction mechan- isms. Group-I mGlu receptors (mGlu1 and mGlu5 receptors) are coupled to Gq, and their activation stimulates polyphosphoinositide (PI) hydrolysis lead- ing to mobilization of intracellular Ca 2 þ and activa- tion of protein kinase C. Group-II (mGlu2 and mGlu3) and group-III (mGlu4, mGlu6, mGlu7 and mGlu8) receptors are all coupled to Gi/o proteins. Their activation inhibits cAMP formation and indirectly affects synaptic transmission and neurotransmitter release by modulating membrane Ca 2 þ and K þ channels. 8 Subtype-selective ligands are now avail- able that either bind to the glutamate-binding domain of mGlu receptors or interact with an allosteric site acting as receptor enhancers or negative modulators. 9 Drugs that inhibit group-I mGlu receptors (particu- larly the mGlu5 receptor antagonists, 2-methyl-6- (phenylethynyl)-pyridine and ((2-methyl-1,3-thiazol- 4-yl)ethynyl)pyridine), inhibit group-II mGlu recep- tors (3-(3,4-dichloro-benzyloxy)-2-amino-6-fluorobi- cyclo(hexane-2,6-dicarboxylic acid 6-heptyl ester and 2S-2-amino-2-(1S,2S-2-carboxycyclopropan-1- yl)-3-(xanth-9-yl)propionate (LY341495)) or activate group-III receptors (1S,3R,4S)-1-aminocyclo-pentane- 1,3,4-tricarboxylic acid, (RS)-4-phosphonophenyl- glycine and (N-phenyl-7-(hydroxyimino)cyclo- propane(b)chromen-1-acarboxamide) are effective in animal models of depression, and, in same cases, produce behavioral effects that are consistent with an antidepressant activity. 10,11 We have focused on how mGlu receptors affect neuroadaptive changes induced by classical antide- pressants. Initially, we found that a 21-day treatment with the tricyclic antidepressant imipiramine in- creases the expression of mGlu2/3 receptors in brain regions that are implicated in the pathophysiology of depression, such as the hippocampus and nucleus accumbens. One of the established functions of these receptors, that is their synergistic activity with mGlu1/5 receptors in stimulating PI hydrolysis, was enhanced in hippocampal slices isolated from ani- mals treated with imipramine. 12 We reasoned that the upregulation of mGlu2/3 receptors could contribute to the overall process of neuroadaptation to antide- pressants, and addressed this issue by monitoring the downregulation of b-adrenergic receptors in mice treated with imipramine for up to 21 days. Interest- ingly, the latency required for the downregulation of b-adrenergic receptors in the hippocampus was shortened from 21 to 14 days when imipramine was combined either with low doses of the mGlu2/3 receptor agonist, ()-2-oxa-4-aminobicy-clo(exhane- 4,6-dicarboxylic acid (LY379268) (0.5 mg/kg, intra peritoneally (i.p.)), or with the preferential mGlu2/3 receptor antagonist, LY341495 (1 mg/kg, i.p.). 13 We interpreted these findings by speculating that low doses of LY379268 activated a subset of mGlu2 or Molecular Psychiatry (2007) 12, 704–706 & 2007 Nature Publishing Group All rights reserved 1359-4184/07 $30.00 www.nature.com/mp