POTENTIATION OF RESPONSES TO ADRENERGIC-NERVE STIMULATION IN ISOLATED RAT ATRIA DURING CHRONIC TRICYCLIC ANTI-DEPRESSANT ADMINISTRATION

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  • 1 January 1980
    • journal article
    • research article
    • Vol. 215  (1) , 143-149
Abstract
Several weeks of tricyclic antidepressant administration are required to effectively reverse depression. To determine whether there are adaptive changes in adrenergic nerve function which correspond to the clinical onset of antidepressant action, the endogenous norepinephrine [NE] content, [3H]NE uptake and retention, responses to exogenous NE and the release of NE during field stimulation were studied using left atrial strips isolated from rats treated acutely or chronically with tricyclic antidepressants. Desipramine, nortriptyline, chlorimipramine and iprindole were administered to rats, 10 mg/kg i.p., twice daily. After 14 days of drug administration, the responses to field stimulation were potentiated markedly by all 4 tricyclics. In contrast, 1 day of tricyclic treatment had only slight potentiating effects. When phenoxybenzamine, 10-7 M, was added to the organ bath in order to block the inhibitory presynaptic .alpha.-receptor, the responses of control atria and atria from rats treated for 1 day with desipramine were potentiated but those of atria treated for 21 days with desipramine were not potentiated. The development of presynaptic .alpha.-receptor subsensitivity during chronic tricyclic administration would explain these findings. The uptake and retention of [3H]NE was markedly inhibited to a similar degree after 1 or 14 days of desipramine or nortriptyline administration. A day of chlorimipramine treatment decreased the amount of [3H]NE taken up and retained by left atrial strips, and after 14 days of treatment decreased the amount further. Iprindole administration 1 or 14 days did not effect the uptake and retention of [3H]NE. The potentiation of the responses to field stimulation cannot be explained by the inhibition of NE uptake. The inotropic response to exogenous NE was not altered by any duration of administration of any of the 4 tricyclics studied. The endogenous NE content of atria did not change after as many as 21 days of desipramine administration. The potentiation of the effects of adrenergic nerve transmission during chronic tricyclic administration is due to an increase in NE release which occurs due to the development of presynaptic .alpha.-receptor subsensitivity. The time course of development of presynaptic receptor subsensitivity corresponds well with the onset of clinical activity of these drugs.