Metabotropic glutamate receptors and neuroadaptation to antidepressants: imipramine-induced down-regulation of beta-adrenergic receptors in mice treated with metabotropic glutamate 2/3 receptor ligands.
Antidepressant drugs have a clinical latency that correlates with the development of neuroadaptive changes, including down-regulation of beta-adrenergic receptors in different brain regions. The identification of drugs that shorten this latency will have a great impact on the treatment of major depressive disorders. We report that the time required for the antidepressant imipramine to reduce the expression of beta-adrenergic receptors in the hippocampus is reduced by a co-administration with centrally active ligands of type 2/3 metabotropic glutamate (mGlu2/3) receptors. Daily treatment of mice with imipramine alone (10 mg/kg, i.p.) reduced the expression of beta-adrenergic receptors in the hippocampus after 21 days, but not at shorter times, as assessed by western blot analysis of beta1-adrenergic receptors and by the amount of specifically bound [3H]CGP-12177, a selective beta-adrenergic receptor ligand. Down-regulation of beta-adrenergic receptors occurred at shorter times (i.e. after 14 days) when imipramine was combined with low doses (0.5 mg/kg, i.p.) of the selective mGlu2/3 receptor agonist LY379268, or with the preferential mGlu2/3 receptor antagonist LY341495 (1 mg/kg, i.p.). Higher doses of LY379268 (2 mg/kg, i.p.) were inactive. This intriguing finding suggests that neuroadaptation to imipramine--at least as assessed by changes in the expression of beta1-adrenergic receptors--is influenced by drugs that interact with mGlu2/3 receptors and stimulates further research aimed at establishing whether any of these drugs can shorten the clinical latency of classical antidepressants.
Matrisciano
F
F
Department of Human Physiology and Pharmacology, University of Rome La Sapienza, Rome, Italy.
Scaccianoce
S
S
Del Bianco
P
P
Panaccione
I
I
Canudas
A M
AM
Battaglia
G
G
Riozzi
B
B
Ngomba
R T
RT
Molinaro
G
G
Tatarelli
R
R
Melchiorri
D
D
Nicoletti
F
F
D000222:Adaptation, Physiological; D000596:Amino Acids / Q000494:pharmacology; D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D015536:Down-Regulation; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D006624:Hippocampus / Q000378:metabolism; D007099:Imipramine / Q000494:pharmacology*; D008024:Ligands; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009424:Nervous System Physiological Phenomena; D011930:Reaction Time / Q000187:drug effects; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D018094:Receptors, Metabotropic Glutamate / Q000008:administration & dosage / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014966:Xanthenes / Q000494:pharmacology
D000596:Amino Acids; D000929:Antidepressive Agents, Tricyclic; D019086:Bridged Bicyclo Compounds, Heterocyclic; D018691:Excitatory Amino Acid Antagonists; C114624:LY 341495; C118218:LY 379268; D008024:Ligands; D011943:Receptors, Adrenergic, beta; D018094:Receptors, Metabotropic Glutamate; D014966:Xanthenes; C108822:metabotropic glutamate receptor 2; C102718:metabotropic glutamate receptor 3; D007099:Imipramine