Potentiation of responses to adrenergic nerve stimulation in isolated rat atria during chronic tricyclic antidepressant administration.

Several weeks of tricyclic antidepressant administration are required to effectively reverse depression. To determine whether there are adaptive changes in andrenergic nerve function which correspond to the clinical onset of antidepressant action, the endogenous norepinephrine content, [3H]norepinephrine uptake and retention, responses to exogenous norepinephrine and the release of norepinephrine during field stimulation were studied using left atrial strips isolated from rats treated with either 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 four 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. Other possible explanations were also investigated. The uptake and retention of [3H]norepinephrine was markedly inhibited to a similar degree of either 1 or 14 days of desipramine or nortriptyline administration. One day of chlorimipramine treatment decreased the amount of [3H]norepinephrine taken up and retained by left atrial strips, and after 14 days of treatment decreased the amount further. In contrast, neither 1 nor 14 days of iprindole administration had any effect on the uptake and retention of [3H]norepinephrine. These data indicate that the potentiation of the responses to field stimulation cannot be explained by the inhibition of norepinephrine uptake. The inotropic response to exogenous norepinephrine was not altered by any duration of administration of any of the four tricyclics studied. Furthermore, the endogenous norepinephrine content of atria did not change after as many as 21 days of desipramine administration. The present results indicate that the potentiation of the effects of adrenergic nerve transmission during chronic tricyclic administration is the result of an increase in norepinephrine 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.