Evidence that imipramine activates 5-HT1C receptor function.

Area of Science:

• Neuroscience
• Pharmacology
• Behavioral Science

Background:

• Imipramine is a widely used antidepressant.
• The exact mechanism of imipramine's anti-immobility effect in the forced swimming test is not fully understood.
• Serotonin (5-HT) and dopamine pathways are implicated in depression and antidepressant action.

Purpose of the Study:

• To investigate the specific receptor mechanisms underlying imipramine's anti-immobility effect in mice.
• To determine the role of serotonin (5-HT) receptor subtypes and dopamine D2 receptors in imipramine's antidepressant-like action.

Main Methods:

• Mice were treated with imipramine and various receptor antagonists (metitepine, mesulergine, d,l-sulpiride, ritanserin, l-propranolol, DAU 6215, GR 38032F).
• Behavioral effects were assessed using the forced swimming test and open-field test.
• Brain imipramine levels were measured, and receptor binding assays were performed.

Main Results:

• The anti-immobility effect of imipramine was antagonized by metitepine (non-selective 5-HT antagonist), mesulergine (5-HT1C/5-HT2 antagonist), and d,l-sulpiride (dopamine D2 antagonist).
• Other tested antagonists (ritanserin, l-propranolol, DAU 6215, GR 38032F) did not reduce imipramine's effect.
• Imipramine inhibited [3H]mesulergine binding to 5-HT1C receptors at concentrations relevant to in vivo administration.

Conclusions:

• The findings suggest a significant contribution of 5-HT1C receptors in mediating the antidepressant-like effect of imipramine.
• Dopamine D2 receptors may also play a role, as indicated by d,l-sulpiride's antagonism of imipramine's effect.
• This study elucidates the receptor pharmacology of imipramine, highlighting 5-HT1C receptor involvement.