Doxepin and imipramine: Effect on catecholamine inhibition of ganglionic transmission

Life Sciences Vol. 17, pp . Printed in the U .S .A .

257-262

Pergamon Press

DOXEPIN AND IMIPRAMINE : EFFECT ON CATECHOLAMINE INHIBITION OF GANGLIONIC TRANSMISSION* Jamshid B . Tehrani, G . Victor Rossi and Frederick J . Goldstein Department of Biological Sciences Philadelphia College of Pharmacy and Science Philadelphia, Pennsylvania 19104 (Received in final form June 10, 1975)

Summary Doxepin (DOX) and imipramine (IM) administered by close intra-arterial injection (25, 40 and 60 ug/kg) potentiated the inhibitory effect of norepinephrine (NE) on electricallyevoked postganglionic potentials in the superior cervical ganglion of the cat . Dose-response relationships indicated no significant difference between DOX and IM with regard to their effect on NE activity . Potentiation of dopamine (DA)-induced suppression of ganglionic transmission by DOX and IM (25, 40 and 60 ug/kg) was not as pronounced as the potentiation of NE activity by these two antidepressants . Significant potentiation of DA was evident only at the 40 and 60 ug/kg dose levels of DOX and IM . Dose-response relationships indicated that potentiation of DA by DOX was significantly greater than that produced by IM . A major hypothesis proposes that perturbations of central monoaminergic processes may be related etiologically to certain affective disorders (1) . Further, substantial evidence suggests that drugs effective in the treatment of depressive disorders may modify the availability or activity of biogenic amines at receptor sites in the brain (2,3) . Inhibition of central norepinephrine (NE) uptake is regarded as a possible factor in the antidepressant mechanism of imipramine (IM) and related tricyclic compounds (3) . Although there is little documentation in support of substantial differences in clinical antidepressant efficacy among various tricyclic derivatives, several investigators have noted that, in addition to antidepressant activity, doxepin (DOX) possesses notable anxiolytic properties (4-7) . Differential effects on the metabolism of biogenic amines other than NE may possibly account for relative differences in the antidepressant and anxiolytic spectrums of the individual tricyclic compounds . This investigation was intended to compare the effects of IM and DOX on NE and dopamine (DA) inhibition of synaptic transmission in an attempt to explore possible biochemical bases for the *- Aspects o t is study were reported at the Fifth Pahlavi Medical Congress, Shiraz, Iran, April, 1974 . 257

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clinical differences between these two psychoactive tricyclics . Based on its relative simplicity and accessibility, coupled with fundamental similarities in the peripheral ganglionic and central neural metabolism of catecholamines (8,9), the superior cervical ganglion was utilized as a limited model for central synaptic systems . Methods Cats of either sex, weighing 1 .6 - 2 .9 kg , were anesthetized with urethane, 1 .2 g/kg, i .p . The procedure for monitoring transmission in the superior cervical ganglion has been described in previous publications from this laboratory (10-12) . Modification of monoamine-induced changea in evoked postganglionic potentials was determined following administration of IM or DOX . The monoamines were dissolved in 0 .9% saline con taining 0 .17 sodium bisulfite to retard oxidation . Injections in volumes not exceeding 0 .1 ml, were made rapidly through a 27-gauge needle inserted into the ipsilateral common carotid artery . Graded doses of either NE or DA were administered every 10 min until an approximate 25% reduction in the postganglionic potential was observed with a given dose of either monoamine . This dose, once established for each animal, was administered 5 min before saline, DOX or IM and repeated 5, 15, 30, 60, 120 and 180 min after treatment . At each time period, the postganglionic potentials (evoked via preganglionic supramaximal stimulation at a rate of 0 .5 shock per sec) were recorded at the point of maximum depression (0-12 sec) and at 12, 30 and 60 sec thereafter . Responses of the potential to either NE~or DA after administration of tricyclic antidepressant (dissolved in 0 .97 saline and infused slowly via the carotid cannula) were compared to control . All doses were calculated in terms of the free base . Data are reported in terms of maximum per cent reduction of the postganglionic potential . Neither DOX nor IM, as employed in this investigation, affected electrically-evoked ganglionic transmission . Results Close intra-arterial infusion of IM, in doses of 25, 40 and 60 ug/kg, significantly (P < 0 .05) potentiated the ganglionic inhibitory effect of NE . At identical dosage levels (i .e ., 25, 40 and 60 ug/kg), a fundamentally similar pattern of NE facilitation was observed with DOX (Table 1) . Comparison of dose-response relationships derived for IM and DOX indicated that, at the dose levels tested, there was no significant difference between these two tricyclic compounds with regard to the facilitation of NE activity . One mg of IM was estimated to be equivalent to 1 .2 mg of DOX, with 95% confidence limits of 0 .8 and 1 .6 mg . Since the molecular weights of these two compounds are similar (IM - 280 .40 ; DOX - 279 .37) the potency relationship is valid on a molar as well as a weight basis . Potentiation of DA activity by IM and DOX, also in doses of 25, 40 and 60 ug/kg, was not as pronounced as the enhancement of NE by these two tricyclic derivatives (Table 2) . Facilitation of

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DA-induced suppression of ganglionic transmission was significant (P < 0 .05) only at the two higher (40 and 60 ug/kg) doses of IM and DOX . A comparison of dose-response relationships indicated that, at the dose levels tested, the potentiation of DA activity by DOX was significantly (P < 0 .01) greater than the potentiation of DA by IM . One mg of IM was estimated to be equivalent to 0 .62 mg of DOX, with 957 confidence limits of 0 .35 and 0 .85 mg . Discussion Clinical studies have indicated that IM and DOX, a more recently introduced member of the tricyclic aeries, are essentially of equal effectiveness in the treatment of depressive states (13,14) . Alleviation of such syndromes by tricyclic compounds has been explained on the basis of increased availability of NE at central noradrenergic receptor sites as a consequence of inhibition of NE uptake by neural tissues (2,3) . A previous investigation from this laboratory indicated that DOX potentiated the ganglionic inhibitory effect of NE (12) . In the present study, dose-response analyses demonstrated an approximately equivalent potentiation of the inhibitory effect of NE on ganglionic transmission by IM and DOX . Although these data were derived with a peripheral rather than a central synaptic system, it is interesting that IM and DOX, tricyclic derivatives reputed to possess equivalent antidepressant efficacy, both potentiated the synaptic inhibitory effect of NE to an equal extent . Several investigators (15-17) have reported that DA exerts an inhibitory effect when applied to single neurons of the brain . Although less potent than NE, DA also suppressed electrically evoked postganglionic potentials in our test system . Both IM and DOX enhanced the synaptic inhibitory effect of DA ; however, DOX appears to be the more active agent in this respect . It has been observed clinically that, in addition to antidepressive effectiveness, DOX possesses considerable anxiolytic activity (4-7) . Although the biochemical basis for differences in the pharmacotherapeutic spectrums of different tricyclic compounds has not been elucidated, the present investigation indicates a quantitative selectivity between DOX and IM with regard to interaction with DA, a biogenic amine which apparently serves a neurotransmitter or neuromodulator function in central synaptic processes . References 1.

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Acknowled ements . The authors wish to thank Pfizer, Inc ., for t e supp y o oxepin and Geigy Pharmaceuticals for the supply of imipramine .