Imipramine - Mechanism of Action

Mechanism of Action

Imipramine, a tertiary amine, affects numerous neurotransmitter systems known to be involved in the etiology of depression, anxiety, ADHD, enuresis and numerous other mental and physical conditions. Imipramine is similar in structure to some muscle relaxants, and has a significant analgesic effect and, thus, is very useful in some pain conditions.

The mechanisms of Imipramine's medicinal action include, but are not limited to, effects on:

• Serotonin (5-HT): Moderate to strong reuptake inhibition. Imipramine's serotonin reuptake inhibition is almost comparable but still less than its reuptake inhibition of norepinephrine. When compared to other tricyclic antidepressants (with the exception of clomipramine)iImipramine's strong serotonin reuptake inhibition make it more akin to the SSRI class of antidepressants than its metabolite desipramine, which has almost purely noradrenergic effects.

• Norepinephrine (NE): Strong reuptake inhibition.

• Dopamine (DA): Reuptake and release at D₁ and D₂ receptors. Similar but less potent than psychostimulants, dopamine agonists, and the atypical antidepressant bupropion on dopaminergic mechanisms (increase in release and blockade of reuptake inhibition). While this effect is much less than the primary effects on NE, SER and ACh, it is nonetheless significant and is partially responsible for the therapeutic benefits of treatment with Imipramine. Enhancement of brain dopamine activity has been implicated in Imipramine's ability to stimulate motor activity and prolong time spent in escape in mice. Regarding dopamine uptake, imipramine is far less potent than most other antidepressants (for example, it has only 5% of the potency of amitryptiline or paroxetine, see the table below).

• Acetylcholine (ACh): Imipramine is an anticholinergic. Thus, it is prescribed with caution to the elderly and with extreme caution to those with psychosis, as the general brain activity enhancement in combination with the "dementing" effects of anticholinergics increases the potential of Imipramine to cause hallucinations, confusion and delirium in this population. Imipramine is an antagonist at M₂ muscarinic acetylcholine receptors (see external links). The blockade of cholinergic (muscarine) receptors is known to cause euphoria, potentially contributing to the mood lifting effects of Imipramine as well. Antimuscarinic effect is also responsible for rapid heart rate (tachycardia).

• Epinephrine: Imipramine antagonizes adreno-receptors (II), thus sometimes causing increased heart rate (contributed to by other effects as well), orthostatic hypotension, and a general decrease in the responsiveness of the central nervous system (hence, a contribution to its potent anti-anxiety properties).

• σ receptor and Enkephalinase: Activity on σ-receptors is present, but it is very low (Ki of 520 nM on σ-receptors, see references) and it is about half the power of amitryptiline (300 nM).

• Histamine: Imipramine is an antagonist at histamine H₁ receptors. This contributes to the acute sedative effect that it has in most people. In turn, its anti-histaminergic and general calming effects take place immediately, and, thus, Imipramine is sometimes prescribed as a sleep aid in low doses.

• BDNF: BDNF is implicated in neurogenesis in the hippocampus, and studies suggest that depressed patients have decreased levels of BDNF and reduced hippocampal neurogenesis. It is not clear how neurogenesis restores mood, as ablation of hippocampal neurogenesis in murine models do not show anxiety related or depression related behaviours. Chronic Imipramine administration results in increased histone acetylation (which is associated with transcriptional activation and decondensed chromatin) at the hippocampal BDNF promotor, and also reduced expression of hippocampal HDAC5.

• μ receptor: Imipramine has been shown to increase the expression of μ-opioid receptors in rat forebrain.