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Published on: January 28, 2019
Presynaptic alpha-receptor subsensitivity after long-term antidepressant treatment
Science (New York, N.Y.)
|October 20, 1978
Summary
Tricyclic antidepressants like desipramine enhance norepinephrine release by desensitizing presynaptic alpha receptors over time. This gradual receptor sensitivity decrease explains the delayed clinical effects of these antidepressants.
Area of Science:
- Neuropharmacology
- Cardiovascular Physiology
Background:
- Tricyclic antidepressants (TCAs) are widely used for treating depression.
- The precise mechanisms underlying the delayed onset of clinical efficacy for TCAs are not fully understood.
Purpose of the Study:
- To investigate the time-dependent effects of desipramine on adrenergic neurotransmission in rat atrial preparations.
- To elucidate the role of presynaptic alpha-adrenergic receptors in mediating the delayed therapeutic effects of TCAs.
Main Methods:
- Administration of desipramine to rats for varying durations (1 day and 3 weeks).
- Assessment of adrenergic neuron function using field stimulation of isolated left atrial strips.
- Measurement of [3H]norepinephrine efflux and analysis of frequency-response curves.
- Pharmacological blockade of alpha-adrenergic receptors using phenoxybenzamine.
Main Results:
- Chronic desipramine treatment (3 weeks) significantly enhanced norepinephrine efflux and shifted the frequency-response curve leftward.
- Acute desipramine treatment (1 day) showed minimal effects on the frequency-response curve despite maximal norepinephrine uptake inhibition.
- Phenoxybenzamine mimicked the effect of chronic desipramine, causing a significant leftward shift in the frequency-response curve.
Conclusions:
- A gradual decrease in presynaptic alpha-receptor sensitivity contributes to the delayed onset of clinical effects observed with tricyclic antidepressants.
- Desipramine's long-term administration leads to adaptive changes in adrenergic neuron function, impacting norepinephrine release.
- Presynaptic alpha-adrenergic receptor modulation is a key factor in the therapeutic response to TCAs.
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