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Possible subsensitization of alpha2-adrenergic receptors by chronic monoamine oxidase inhibitor treatment in psychiatric patients
Psychiarrp
Research,
293
6, 293-302 (1982)
Elsevier Biomedical Press
Possible Subsensitization of Alpha,-Adrenergic Receptors by Chronic Monoamine Oxidase Treatment in Psychiatric Patients Larry J. Siever, Thomas W. Uhde, and Dennis
Inhibitor
L. Murphy
Received September 25. 198l;$rst revised version received January version received January 21. 1982; accepted March 22, 1982.
II, 1982; second revised
Abstract. Clonidine was administered to nine psychiatric patients before and after chronic treatment (3 to 4 weeks) with clorgyline, a selective monoamine oxidase type A inhibitor with antidepressant efficacy. The hypotensive response to clonidine, believed to be mediated by brain a,-adrenergic receptors, was significantly attenuated by chronic but not acute (2 to 3 days) clorgyline treatment, with a time course similar to the onset of its clinical efficacy. This study supports the hypothesis that subsensitization of a,-adrenergic receptors plays an important role in clorgyline’s antidepressant effects and may constitute a key contribution to the mode of action of other antidepressant treatments as well. Key Words. Clonidine,
monoamine
oxidase
inhibitors,
adrenergic
receptors.
Recent models of the somatic antidepressant therapies suggest that the clinical efficacy of these agents may depend on neurotransmitter receptor alterations (Sulser et al., 1978; Chiodo and Antelman, 1980; Peroutka and Snyder, 19804. One intriguing hypothesis suggests that central cY,-adrenergic autoreceptor subsensitivity may be a crucial step in the establishment of the increased noradrenergic activity required for an antidepressant response (Crews and Smith, 1978; Cohen et al., 1980; Langer, 1980; Siever et al., 1981a). However, this hypothesis is based primarily on animal studies, with little supporting clinical evidence yet available. The lack of clinical studies for any receptor model of antidepressant action is largely due to methodological difficulties in assessing brain receptor function in man. To examine this hypothesis in the clinical arena, we have studied the hypotensive response to clonidine in psychiatric patients before and during treatment with clorgyline, a new, clinically effective monoamine oxidase (MAO) inhibitor selective for the noradrenergic system (Lipper et al., 1979). This paradigm represents a potentially powerful approach to central receptor evaluation, the pharmacological challenge strategy, which examines physiologic or biochemical responses to specific agonists that have been demonstrated to be mediated by particular neurotransmitter receptors (Siever et al. 198 lb). For example, the hypotensive response to clonidine appears to be mediated by central cr,-adrenergic receptors, similar to the peripheral a,-adrenergic
Larry J. Siever, M.D., is in the Clinical Neuropharmacology Branch, and Thomas W. Uhde, M.D., is in the Section on Psychobiology, Biological Psychiatry Branch, National Institute of Mental Health (NIMH). Dennis L. Murphy, M.D., is Chief, Clinical Neuropharmacology Branch, NIMH, Bethesda, MD, USA. (Reprint 20205.)
requests
to Dr. L.J. Siever, NIMH,
0165-1781~ 82:0000-0000/$02.75
Bldg. 10, Rm. 3D-41,
@ Elsevier Biomedical
Press
9000 Rockville
Pike, Bethesda,
MD
294 autoreceptors which inhibit the release of norepinephrine (Starke, 1981). Thus, the magnitude of this response provides a possible indication of central cr,-adrenergic responsiveness. If the hypothesized a,-adrenergic autoreceptor subsensitivity developed with chronic antidepressant treatment, one would expect an attenuated hypotensive response to clonidine during chronic treatment. We had, in fact, observed a blunted hypotensive response to oral clonidine in two subjects after chronic (but not acute) antidepressant treatment (Siever et al., 198 la) and were encouraged to study a larger series of patients before and after clorgyline administration with intravenous clonidine as a challenge. We also studied the hypothermic response to clonidine, which also may be noradrenergically mediated (Tangri et al., 1974). To investigate the time course of this change, we examined the responses of several patients after both acute and intermediate duration treatment with clorgyline. Methods Nine psychiatric patients (age range 20-58 years, mean age 38.6 t- SD 13.6 years) were studied while receiving a double-blind therapeutic trial of clorgyline on a clinical research ward of the National Institute of Mental Health. All subjects were tested (1) while on placebo as part of the double-blind study after being free of medication for at least 3 weeks and (2) again after clorgyline treatment for at least 21 days. Three subjects were also tested 2 to 3 days after clorgyline treatment began, when MAO is at least 90% inhibited in both animals and humans (Murphy, unpublished data) to distinguish its acute and chronic effects. These three patients were tested again after 10 to 15days of clorgyline treatment. Clonidine at a dose of 2 pg/ kg body weight dissolved in 10 ml of normal saline was administered intravenously over 5 minutes in eight subjects. In one subject, reported previously (Siever et al., 198la), clonidine was administered orally at a dose of 4 pg/ kg. Blood pressure was monitored by an ultrasonic blood pressure monitor at 5-minute intervals for at least 20 minutes before the infusion and for 3 hours after the infusion. The hypotensive response was assessed by subtracting the average of the blood pressure readings obtained at the 5-minute intervals between 45 minutes and 1 hour, when the peak response has been achieved, from the average of those obtained from the 5-minute interval readings averaged for the 20 minutes before the infusion. The response to clonidine during chronic clorgyline treatment was compared to the response during placebo treatment by Student’s t test.
Results The hypotensive response (expressed as percent of baseline blood pressure) to clonidine was significantly decreased (p < 0.05, Student’s t test) after chronic clorgyline treatment regardless of whether the subject receiving oral clonidine was included or excluded from the analysis (Figs. 1 and 2). The hypotensive response was unchanged in the three subjects tested after 2 to 3 days and was modestly decreased after 10 to 15 days of clorgyline treatment, but not to the extent observed after more chronic treatment. There was also a trend for a decrease in the hypothermic response to clonidine (see Fig. 3), although this effect did not reach significance. Discussion The significant decrement in the a,-adrenoreceptor-mediated hypotensive response to clonidine after chronic but not acute clorgyline treatment lends support to hypotheses proposing autoreceptor subsensitization to be an important step in the mechanism of
295 action of the antidepressants et al., 1981~).
(Crews and Smith,
1978, 1980, Cohenet
al., 1980; Siever
Fig. 1. Decrease in mean arterial pressure (MAP) 1 hour after clonidine administration, expressed as percerlage of baseline blood pressure, in patients treated with placebo or clorgyline 0 Placebo
-30
n Clorgyline q Clorgyline
-25
&j Clorgyline + 30 days
+ 3 days + 10 days
-20 -15
IL
-10 -5 0
5 f
Pt. 1 Pt. 2
Pt. 3
Pt. 4
Pt. 5
Pt. 6
Pt. 7
Pt. 6
Pt. 9’
for all Patients
L
t Admmistered oral clonidine. * Significantly decreased from placebo day up < 0.05, Student’s Error bars represent standard error of the mean.
t test]
This blunting of the clonidine hypotensive effect appears to develop over time with chronic clorgyline treatment rather than to represent an acute effect of clorgyline. The lack of an acute effect of clorgyline, in conjuction with the lack of antagonism of cr,-adrenergic binding by clorgyline at comparable doses (Cohen et al., in press), makes it unlikely that the decreased responses to clonidine are due to direct (Y*adrenergic blockade. Although no definite conclusions can be reached regarding receptor sensitivity in this paradigm, clonidine’s selective action on (Yeadrenoreceptors suggests that the decreased hypotensive response may reflect a decrement in functional a,-adrenergic responsiveness. As clorgyline has effects on other amine systems which may play a role in blood pressure regulation, an indirect interaction with clonidine’s action cannot be excluded. The pharmacologic similarity between central a,-adrenergic receptors and peripheral a,-adrenergic autoreceptors decreasing noradrenergic release (Langer, 1980) and the inhibition of locus ceruleus firing observed in response to iontophoretically administered clonidine centrally (Svensson et al., 1975) make it tempting to speculate that this phenomenon may reflect central a,-adrenergic autoreceptor sensitivity changes. However, central (Yeadrenergic receptors may also be present postsynaptically (UPrichard et al., 1977), and, while clonidine can lower blood pressure by acting on presynaptic autoreceptors in the locus ceruleus (Zandberg et al., 1979), its hypotensive effects may be mediated in
296 part by postsynaptic receptors as well (Kobinger and Pichler, 1976). These postsynaptic receptors may or may not be pharmacologically identical to autoreceptors and thus cannot be assumed with certainty to be regulated in the same fashion as are the autoreceptors on nerve terminals or cell bodies. Fig. 2. Mean arterial pressure (MAP) following clonidine patients receiving treatment with placebo or clorgyline 115
-
administration
in
Placebo n=9
- - - Clorgyline + 3 days n=3
-- Cbrgyhe+ 10 days n =3 T 110
.
Clorgyline + 30 days n=9
105
100 % zz 95
90
65 I
60
I 1
I
I
I,
0
15
30
45
I
I
60
75
I
I
I
I
I
I
I
90 105 120 135 150 165 160
MINUTES POST-INFUSION Error bars represent
standard
error of the mean
The fact that the decrease in the hypothermic response to clonidine after chronic clorgyline did not reach significance in this study may reflect the small magnitude of the decrease and the large variance in this small sample. Resistance to clonidine’s hypothermic effects after chronic antidepressant treatment has, however, been demonstrated in animal studies (Von Voigtlander et al., 1978). As noradrenergic enhancresponse to ing agents increase temperature (Tangri et al., 1974), the hypothermic clonidine also seems likely to be mediated by a,-adrenergic autoreceptors which inhibit noradrenergic activity. The a,-adrenergic autoreceptors mediate the feedback inhibitory effect of norepinephrine on its own release from nerve terminals (Starke, 198 1) and on the firing rate
297 of these of noradrenergic neurons (Svensson et al., 1975). Thus down-regulation autoreceptors may permit sustained increases in noradrenergic activity by attenuating excessive feedback inhibition of the system induced by the initial acute increments of intrasynaptic noradrenergic availability, secondary to MAO inhibition or amine uptake blockade. This model is consistent with animal studies indicating that acutely administered antidepressants decrease levels of brain norepinephrine and noradrenergic metabolites, apparently due to a decrease in noradrenergic firing rates, while these effects return toward pretreatment or, in some studies, higher than pretreatment levels after chronic treatment (Schildkraut et al., 1970; Nielson and Braestrup, 1977; Bareggi et al., 1978; McMillen et al., 1980). The decreased firing is blocked by phenoxybenzamine, indicating this effect is mediated by a-adrenoreceptors (Bareggi et al., 1978). Its return toward normal may represent subsensitization of a,-adrenoreceptors after chronic antidepressant treatment.
Fig. 3. Percent fall in temperature 1 hour after clonidine administration patients receiving placebo or chronic clorgyline treatment 2.0
in
r
1.8 1.6 1.4 1.2 1.0 .8 .6 .4 .2 0
-.6 L Error bars represent
standard
error of the mean
Alternatively, cY,-adrenoreceptor desensitization may enhance the ratio of specifically stimulated noradrenergic activity to baseline activity rather than uniformly increasing noradrenergic activity. The unstimulated firing rate of the locus ceruleus is decreased by chronic desipramine (DMI) and imipramine (Svensson and Usdin, 1978; McMillen et al., 1980) and chronic clorgyline (Campbell et al., 1979) treatment.
298 However, evidence suggests an increase in norepinephrine release per nerve impulse secondary to the induced a,-adrenergic receptor desensitization following chronic antidepressant treatment (McMillen et al., 1980). Thus, more norepinephrine may be released in response to specific stimulation which enhances the rate of nerve impulses. Consistent with such a model, Huang (1979) has found that hippocampal neurons, which are inhibited by the activity of the locus ceruleus in the rat, increase their firing after chronic treatment with DMI, but there is no difference in hippocampal firing in the treated animals compared to controls following electrical stimulation of the locus ceruleus. Since the hippocampal inhibition is mediated by /3-adrenergic receptors, which are known to become subsensitive following chronic DMI treatment, presynaptic noradrenergic activity in response to stimulation would have to be enhanced to offset the decreased receptor responsiveness. While, in rodents, DMI decreases the brain accumulation of the norepinephrine metabolite, 3-methoxy-4-hydroxyphenylglycol-sulfate (MHPG-SO,), acutely but not chronically, it does not acutely antagonize the increases in MHPG-SO, in the cortex-hippocampus following locus ceruleus stimulation (Bareggi et al., 1978). Again, the suggestion is of a relative decrease in baseline noradrenergic activity in comparison to stimulated activity. Although speculative, this model is consistent with animal studies, and suggests a way in which cY,-adrenergic desensitization may alter noradrenergic function in the direction of greater efficiency. There is also evidence for the induction of decreased cY,-adrenergic responsiveness by other antidepressants. Reduction of the hypotensive response to clonidine has now also been reported following chronic DMI treatment in depressed patients (Charney et al., 198 1; Checkley et al., 198 1). The decreased hypotensive response to clonidine after tricyclic antidepressant administration has been hypothesized to represent direct blockade of cY-adrenergic receptors (Svensson et al., 1975; von Zwieten, 1976), and clinical studies have not ruled out an acute effect of DMI on the clonidine response. However, physiologic and binding studies suggest that tricyclics do not have significant a,-adrenergic antagonist properties at clinically relevant doses (Harper and Hughes, 1979; Maggi et al., 1980). In a quite different approach to testing this hypothesis in humans, peripheral platelet cY,-adrenoreceptors have been measured in depressed patients and have been shown to decrease in number with chronic DMI treatment (Garcia-Sevilla et al., 198 1). Subsensitivity of ol,-adrenergic autoreceptors in animal studies has also been demonstrated after chronic but not acute administration of imipramine or DMI using a variety of methodologies (Crews and Smith, 1978; Svensson and Usdin, 1978; Tang et al., 1978; Crews and Smith, 1980). However, there is conflicting evidence with regard to other antidepressants. Chronic treatment with the atypical antidepressants nisoxetine, iprindole, or mianserin failed to block the clonidine-induced MHPG decrease that has been demonstrated with imipramine and DMI (Sugrue, 1981). Recent electrophysiologic studies also fail to show functional subsensitivity of autoreceptors on the locus ceruleus after treatment with iprindole, mianserin, and chlomipramine, although these effects could be confirmed for desipramine, imipramine, and zimelidine (Svensson and Scuvee-Moreau, in press). Although az-receptor subsensitization therefore seems unlikely to be a necessary concomitant of all antidepressant treatments, this effect may be of heuristic value in understanding the final common pathways of the antidepressants’ mechanism of
299
action. For example, a,-receptor subsensitization could be a prerequisite for an increase in stimulated noradrenergic release after treatment with many of the typical antidepressants. Other antidepressants may achieve the same effect via a different pharmacologic route. For example, mianserin blocks presynaptic availability by directly antagonizing feedback inhibition of noradrenergic neuronal activity (Engberg and Svensson, 1980). Thus, in the case of mianserin, the direct blockade of oZadrenoreceptors would be expected to protect receptors from down-regulation by increased concentrations of norepinephrine, although leading to the same end-point of increased release of norepinephrine per nerve impulse. Although we are not suggesting that this is necessarily the ultimate mechanism of the antidepressant action of mianserin, it serves as an example of how common biochemical effects might be achieved through different pharmacological actions. The relationship between changes in a-adrenergic receptors and other receptor changes induced by antidepressant administration such as P-adrenergic subsensitization, which appears to be a more regular consequence of antidepressant treatment than a,-adrenoreceptor subsensitization, is of potential importance. In the case of clorgyline, reductions in a,-adrenergic binding precede reductions in P-adrenergic binding in animal studies (Cohen et al., in press), suggesting that P-adrenergic subsensitization may require sustained increases of noradrenergic availability. In the case of the tricyclics, the interpretation of current studies becomes more problematic: 3- to 4-day treatment with DMI or iprindole increases [3H] clonidine or [jH]aminoclonidine binding in the rat brain (Johnson et al., 1980; Reisine et al., 1980), but decreases or no changes in these ligands’ binding in rat brain have been reported after chronic treatment with amitriptyline (Peroutka and Snyder, 1980b; Smith et al., 1981). As [3H] clonidine appears to label predominantly postsynaptic a,-adrenergic sites in rat brain (UPrichard et al., 1977), these results might not be expected necessarily to parallel desensitization of presynaptic a,-adrenergic responsiveness or attenuation of the hypotensive responses in human subjects after antidepressant treatment. Furthermore, time course considerations may also be important in the process of cr,-adrenergic desensitization, (U’Prichard et al., in press), so that effects after 3 to 4 days of antidepressant administration may not be the same as those observed after chronic treatment. It is, however, interesting to note that concurrent administration of phenoxybenzamine, a direct cY-adrenergic antagonist, with DMI accelerates the onset of B-adrenergic sensitivity in rodents (Paul and Crews, 1980; Crews et al., 1981). Because intact presynaptic neurons are required for /3-adrenergic subsensitization to be achieved (Wolfe et al., 1978; Schweitzer et al., 1979) it seems plausible that decreased sensitivity of presynaptic a-adrenoreceptors permits enhanced intrasynaptic noradrenergic availability, which in turn down-regulates postsynaptic P-adrenergic receptors. The pathway described may not be the only means by which noradrenergic function may be enhanced, but we might speculate such autoreceptor subsensitization could be a necessary step in maintaining increases in noradrenergic efficiency induced by the MAO inhibitors and classical tricyclic antidepressants. Acknowledgments.
Beverly Mucciardi,
We wish to acknowledge the assistance of Mr. Joseph Aloi, Ms. Mrs. Gloria Goldsmith, Mrs. Irene Bellesky, Dr. Thomas Insel,
300 Dr. Benjamin during
Roy, Dr. Robert
the course
of this study
Cohen, and
Dr. Jean preparation
Hamilton,
and the nursing
staff of 6D
of this manuscript.
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Maggi, A., UPrichard, D.C., and Enna, S.J. PAdrenergic regulation of cr,-adrenergic receptors in the central nervous system. Science, 207, 645 (1980a). Maggi, A., UPrichard, D.C., and Enna, S.J. Differential effects of antidepressant treatment on brain monoaminergic receptors. European Journal of Pharmacology, 61, 91 (1980b). McMillen, B.A., Warnack, W., German, D.C., and Shore, P.A. Effects of chronicdesipramine treatment on rat brain noradrenergic responses to cY-adrenergic drugs. European Journal of Pharmacology, 671, 239 (1980). Nielson, M., and Braestrup, C. Chronic treatment with desipramine caused a sustained decrease of 3,4 dihydroxyphenylglycol sulfate and total 3-methoxy-4-hydroxyphenylglycol in the rat brain. Naunyn-Schmiedeberg’s Archives of Pharmacology, 300, 87 (1977). Paul, SM., and Crews, F.T. Rapid desensitization of cerebral cortical Padrenergic receptors induced by desmethylimipramine and phenoxybenzamine. European Journal of Pharmacology, 62, 349 (1980). Peroutka, S.J., and Snyder, S.H. Long-term antidepressant treatment decreases spiroperidollabeled serotonin receptor binding. Science, 210, 88 (1980~). Peroutka, S.J., and Snyder, S.H. Regulation of serotonin, (5-HTz) receptors labelled with 3Hspiroperidol by chronic treatment with the antidepressant amitriptyline. Journalof Pharrnacology and Experimental Therapeutics, 215, 587 (1980b). Reisine, T., UPrichard, D., Wiech, N., Ursillo, R., and Yamamura, H.1. The effects of combined administration of amphetamine and iprindole on brain adrenergic receptors. Brain Research, 188, 587 (1980). Schildkraut, J.J., Winokur, A., and Applegate, C.W. Norepinephrine turnover and metabolism in rat brain after long-term administration of imipramine. Science, 168, 867 (1970). Schweitzer, J.W., Schwartz, R.,and Friedhoff, A.J. Intact presynaptic terminals required for beta-adrenergic receptor regulation by desipramine. Journal of Neurochemistry, 33, 377 (1979). Siever, L.J., Cohen, R.M., and Murphy, D.L. Antidepressants and cY,-adrenergic subsensitivity in man. American Journal of Psychiatry, 138, 681 (1981a). Siever, L.J., Insel, T., and Uhde, T. Noradrenergic challenges in the affective disorders. Journal of Clinical Psychopharmacology, 1, 193 (198 1b). Smith, C.B., Garcia-Sevilla, J.A., and Hollingsworth, P.J. cY,-Adrenoreceptors in rat brain are decreased after long-term tricyclic antidepressant drug treatment. Brain Research, 210, 413 (1981). Starke, K. Presynaptic receptors. In: George, R., Okun, R., and Cho, A.K., eds. Annual Review of Pharmacology and Toxicology. Annual Reviews, Inc., Palo Alto, CA (1981). Sugrue, M.F. Effects of acutely and chronically administered antidepressants on the clonidine induced decrease in rat brain 3-methoxy-4hydroxyphenylethyleneglycol sulphate content. Life Sciences, 28, 327 (198 1). Sulser, F., Vetulani, J., and Mobley, P. Mode of action of antidepressant drugs. Biochemical Pharmacology, 27, 257 (1978). Svensson, T.H., Bunney, B.S., and Aghajanian, G.K. Inhibition of both noradrenergic and serotonergic neurons in brain by the a-adrenergic agonist clonidine. Brain Research, 92, 291 (1975). Svensson, T.H., and Scuvee-Moreau, J. Sensitivity in vivo of central oZ- and opiate receptors after chronic treatment with various antidepressants. Psychopharmacology Bulletin (in press). Svensson, T.H., and Usdin, T. Feedback inhibition of brain noradrenaline neurons by tricyclic antidepressant: Alpha-receptor mediation. Science, 202, 1089 (1978). Tang, S.W., Helmeste, D.M., and Stancer, H.C. The effect of acute and chronic desipramine and amitriptyline treatment on rat brain total 3-methoxy-4-hydroxyphenylglycol. Nuunyn Schmiedeberg S Archives of Pharmacology, 305, 207 ( 1978). Tangri, K.K., Bhargava, A.K., and Bhargava, K.P. Interrelation between monoaminergic and cholinergc mechanisms in the hypothalamic thermoregulatory centre of rabbits. Neuropharmacology, 13, 333 (1974).
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Research,
293
6, 293-302 (1982)
Elsevier Biomedical Press
Possible Subsensitization of Alpha,-Adrenergic Receptors by Chronic Monoamine Oxidase Treatment in Psychiatric Patients Larry J. Siever, Thomas W. Uhde, and Dennis
Inhibitor
L. Murphy
Received September 25. 198l;$rst revised version received January version received January 21. 1982; accepted March 22, 1982.
II, 1982; second revised
Abstract. Clonidine was administered to nine psychiatric patients before and after chronic treatment (3 to 4 weeks) with clorgyline, a selective monoamine oxidase type A inhibitor with antidepressant efficacy. The hypotensive response to clonidine, believed to be mediated by brain a,-adrenergic receptors, was significantly attenuated by chronic but not acute (2 to 3 days) clorgyline treatment, with a time course similar to the onset of its clinical efficacy. This study supports the hypothesis that subsensitization of a,-adrenergic receptors plays an important role in clorgyline’s antidepressant effects and may constitute a key contribution to the mode of action of other antidepressant treatments as well. Key Words. Clonidine,
monoamine
oxidase
inhibitors,
adrenergic
receptors.
Recent models of the somatic antidepressant therapies suggest that the clinical efficacy of these agents may depend on neurotransmitter receptor alterations (Sulser et al., 1978; Chiodo and Antelman, 1980; Peroutka and Snyder, 19804. One intriguing hypothesis suggests that central cY,-adrenergic autoreceptor subsensitivity may be a crucial step in the establishment of the increased noradrenergic activity required for an antidepressant response (Crews and Smith, 1978; Cohen et al., 1980; Langer, 1980; Siever et al., 1981a). However, this hypothesis is based primarily on animal studies, with little supporting clinical evidence yet available. The lack of clinical studies for any receptor model of antidepressant action is largely due to methodological difficulties in assessing brain receptor function in man. To examine this hypothesis in the clinical arena, we have studied the hypotensive response to clonidine in psychiatric patients before and during treatment with clorgyline, a new, clinically effective monoamine oxidase (MAO) inhibitor selective for the noradrenergic system (Lipper et al., 1979). This paradigm represents a potentially powerful approach to central receptor evaluation, the pharmacological challenge strategy, which examines physiologic or biochemical responses to specific agonists that have been demonstrated to be mediated by particular neurotransmitter receptors (Siever et al. 198 lb). For example, the hypotensive response to clonidine appears to be mediated by central cr,-adrenergic receptors, similar to the peripheral a,-adrenergic
Larry J. Siever, M.D., is in the Clinical Neuropharmacology Branch, and Thomas W. Uhde, M.D., is in the Section on Psychobiology, Biological Psychiatry Branch, National Institute of Mental Health (NIMH). Dennis L. Murphy, M.D., is Chief, Clinical Neuropharmacology Branch, NIMH, Bethesda, MD, USA. (Reprint 20205.)
requests
to Dr. L.J. Siever, NIMH,
0165-1781~ 82:0000-0000/$02.75
Bldg. 10, Rm. 3D-41,
@ Elsevier Biomedical
Press
9000 Rockville
Pike, Bethesda,
MD
294 autoreceptors which inhibit the release of norepinephrine (Starke, 1981). Thus, the magnitude of this response provides a possible indication of central cr,-adrenergic responsiveness. If the hypothesized a,-adrenergic autoreceptor subsensitivity developed with chronic antidepressant treatment, one would expect an attenuated hypotensive response to clonidine during chronic treatment. We had, in fact, observed a blunted hypotensive response to oral clonidine in two subjects after chronic (but not acute) antidepressant treatment (Siever et al., 198 la) and were encouraged to study a larger series of patients before and after clorgyline administration with intravenous clonidine as a challenge. We also studied the hypothermic response to clonidine, which also may be noradrenergically mediated (Tangri et al., 1974). To investigate the time course of this change, we examined the responses of several patients after both acute and intermediate duration treatment with clorgyline. Methods Nine psychiatric patients (age range 20-58 years, mean age 38.6 t- SD 13.6 years) were studied while receiving a double-blind therapeutic trial of clorgyline on a clinical research ward of the National Institute of Mental Health. All subjects were tested (1) while on placebo as part of the double-blind study after being free of medication for at least 3 weeks and (2) again after clorgyline treatment for at least 21 days. Three subjects were also tested 2 to 3 days after clorgyline treatment began, when MAO is at least 90% inhibited in both animals and humans (Murphy, unpublished data) to distinguish its acute and chronic effects. These three patients were tested again after 10 to 15days of clorgyline treatment. Clonidine at a dose of 2 pg/ kg body weight dissolved in 10 ml of normal saline was administered intravenously over 5 minutes in eight subjects. In one subject, reported previously (Siever et al., 198la), clonidine was administered orally at a dose of 4 pg/ kg. Blood pressure was monitored by an ultrasonic blood pressure monitor at 5-minute intervals for at least 20 minutes before the infusion and for 3 hours after the infusion. The hypotensive response was assessed by subtracting the average of the blood pressure readings obtained at the 5-minute intervals between 45 minutes and 1 hour, when the peak response has been achieved, from the average of those obtained from the 5-minute interval readings averaged for the 20 minutes before the infusion. The response to clonidine during chronic clorgyline treatment was compared to the response during placebo treatment by Student’s t test.
Results The hypotensive response (expressed as percent of baseline blood pressure) to clonidine was significantly decreased (p < 0.05, Student’s t test) after chronic clorgyline treatment regardless of whether the subject receiving oral clonidine was included or excluded from the analysis (Figs. 1 and 2). The hypotensive response was unchanged in the three subjects tested after 2 to 3 days and was modestly decreased after 10 to 15 days of clorgyline treatment, but not to the extent observed after more chronic treatment. There was also a trend for a decrease in the hypothermic response to clonidine (see Fig. 3), although this effect did not reach significance. Discussion The significant decrement in the a,-adrenoreceptor-mediated hypotensive response to clonidine after chronic but not acute clorgyline treatment lends support to hypotheses proposing autoreceptor subsensitization to be an important step in the mechanism of
295 action of the antidepressants et al., 1981~).
(Crews and Smith,
1978, 1980, Cohenet
al., 1980; Siever
Fig. 1. Decrease in mean arterial pressure (MAP) 1 hour after clonidine administration, expressed as percerlage of baseline blood pressure, in patients treated with placebo or clorgyline 0 Placebo
-30
n Clorgyline q Clorgyline
-25
&j Clorgyline + 30 days
+ 3 days + 10 days
-20 -15
IL
-10 -5 0
5 f
Pt. 1 Pt. 2
Pt. 3
Pt. 4
Pt. 5
Pt. 6
Pt. 7
Pt. 6
Pt. 9’
for all Patients
L
t Admmistered oral clonidine. * Significantly decreased from placebo day up < 0.05, Student’s Error bars represent standard error of the mean.
t test]
This blunting of the clonidine hypotensive effect appears to develop over time with chronic clorgyline treatment rather than to represent an acute effect of clorgyline. The lack of an acute effect of clorgyline, in conjuction with the lack of antagonism of cr,-adrenergic binding by clorgyline at comparable doses (Cohen et al., in press), makes it unlikely that the decreased responses to clonidine are due to direct (Y*adrenergic blockade. Although no definite conclusions can be reached regarding receptor sensitivity in this paradigm, clonidine’s selective action on (Yeadrenoreceptors suggests that the decreased hypotensive response may reflect a decrement in functional a,-adrenergic responsiveness. As clorgyline has effects on other amine systems which may play a role in blood pressure regulation, an indirect interaction with clonidine’s action cannot be excluded. The pharmacologic similarity between central a,-adrenergic receptors and peripheral a,-adrenergic autoreceptors decreasing noradrenergic release (Langer, 1980) and the inhibition of locus ceruleus firing observed in response to iontophoretically administered clonidine centrally (Svensson et al., 1975) make it tempting to speculate that this phenomenon may reflect central a,-adrenergic autoreceptor sensitivity changes. However, central (Yeadrenergic receptors may also be present postsynaptically (UPrichard et al., 1977), and, while clonidine can lower blood pressure by acting on presynaptic autoreceptors in the locus ceruleus (Zandberg et al., 1979), its hypotensive effects may be mediated in
296 part by postsynaptic receptors as well (Kobinger and Pichler, 1976). These postsynaptic receptors may or may not be pharmacologically identical to autoreceptors and thus cannot be assumed with certainty to be regulated in the same fashion as are the autoreceptors on nerve terminals or cell bodies. Fig. 2. Mean arterial pressure (MAP) following clonidine patients receiving treatment with placebo or clorgyline 115
-
administration
in
Placebo n=9
- - - Clorgyline + 3 days n=3
-- Cbrgyhe+ 10 days n =3 T 110
.
Clorgyline + 30 days n=9
105
100 % zz 95
90
65 I
60
I 1
I
I
I,
0
15
30
45
I
I
60
75
I
I
I
I
I
I
I
90 105 120 135 150 165 160
MINUTES POST-INFUSION Error bars represent
standard
error of the mean
The fact that the decrease in the hypothermic response to clonidine after chronic clorgyline did not reach significance in this study may reflect the small magnitude of the decrease and the large variance in this small sample. Resistance to clonidine’s hypothermic effects after chronic antidepressant treatment has, however, been demonstrated in animal studies (Von Voigtlander et al., 1978). As noradrenergic enhancresponse to ing agents increase temperature (Tangri et al., 1974), the hypothermic clonidine also seems likely to be mediated by a,-adrenergic autoreceptors which inhibit noradrenergic activity. The a,-adrenergic autoreceptors mediate the feedback inhibitory effect of norepinephrine on its own release from nerve terminals (Starke, 198 1) and on the firing rate
297 of these of noradrenergic neurons (Svensson et al., 1975). Thus down-regulation autoreceptors may permit sustained increases in noradrenergic activity by attenuating excessive feedback inhibition of the system induced by the initial acute increments of intrasynaptic noradrenergic availability, secondary to MAO inhibition or amine uptake blockade. This model is consistent with animal studies indicating that acutely administered antidepressants decrease levels of brain norepinephrine and noradrenergic metabolites, apparently due to a decrease in noradrenergic firing rates, while these effects return toward pretreatment or, in some studies, higher than pretreatment levels after chronic treatment (Schildkraut et al., 1970; Nielson and Braestrup, 1977; Bareggi et al., 1978; McMillen et al., 1980). The decreased firing is blocked by phenoxybenzamine, indicating this effect is mediated by a-adrenoreceptors (Bareggi et al., 1978). Its return toward normal may represent subsensitization of a,-adrenoreceptors after chronic antidepressant treatment.
Fig. 3. Percent fall in temperature 1 hour after clonidine administration patients receiving placebo or chronic clorgyline treatment 2.0
in
r
1.8 1.6 1.4 1.2 1.0 .8 .6 .4 .2 0
-.6 L Error bars represent
standard
error of the mean
Alternatively, cY,-adrenoreceptor desensitization may enhance the ratio of specifically stimulated noradrenergic activity to baseline activity rather than uniformly increasing noradrenergic activity. The unstimulated firing rate of the locus ceruleus is decreased by chronic desipramine (DMI) and imipramine (Svensson and Usdin, 1978; McMillen et al., 1980) and chronic clorgyline (Campbell et al., 1979) treatment.
298 However, evidence suggests an increase in norepinephrine release per nerve impulse secondary to the induced a,-adrenergic receptor desensitization following chronic antidepressant treatment (McMillen et al., 1980). Thus, more norepinephrine may be released in response to specific stimulation which enhances the rate of nerve impulses. Consistent with such a model, Huang (1979) has found that hippocampal neurons, which are inhibited by the activity of the locus ceruleus in the rat, increase their firing after chronic treatment with DMI, but there is no difference in hippocampal firing in the treated animals compared to controls following electrical stimulation of the locus ceruleus. Since the hippocampal inhibition is mediated by /3-adrenergic receptors, which are known to become subsensitive following chronic DMI treatment, presynaptic noradrenergic activity in response to stimulation would have to be enhanced to offset the decreased receptor responsiveness. While, in rodents, DMI decreases the brain accumulation of the norepinephrine metabolite, 3-methoxy-4-hydroxyphenylglycol-sulfate (MHPG-SO,), acutely but not chronically, it does not acutely antagonize the increases in MHPG-SO, in the cortex-hippocampus following locus ceruleus stimulation (Bareggi et al., 1978). Again, the suggestion is of a relative decrease in baseline noradrenergic activity in comparison to stimulated activity. Although speculative, this model is consistent with animal studies, and suggests a way in which cY,-adrenergic desensitization may alter noradrenergic function in the direction of greater efficiency. There is also evidence for the induction of decreased cY,-adrenergic responsiveness by other antidepressants. Reduction of the hypotensive response to clonidine has now also been reported following chronic DMI treatment in depressed patients (Charney et al., 198 1; Checkley et al., 198 1). The decreased hypotensive response to clonidine after tricyclic antidepressant administration has been hypothesized to represent direct blockade of cY-adrenergic receptors (Svensson et al., 1975; von Zwieten, 1976), and clinical studies have not ruled out an acute effect of DMI on the clonidine response. However, physiologic and binding studies suggest that tricyclics do not have significant a,-adrenergic antagonist properties at clinically relevant doses (Harper and Hughes, 1979; Maggi et al., 1980). In a quite different approach to testing this hypothesis in humans, peripheral platelet cY,-adrenoreceptors have been measured in depressed patients and have been shown to decrease in number with chronic DMI treatment (Garcia-Sevilla et al., 198 1). Subsensitivity of ol,-adrenergic autoreceptors in animal studies has also been demonstrated after chronic but not acute administration of imipramine or DMI using a variety of methodologies (Crews and Smith, 1978; Svensson and Usdin, 1978; Tang et al., 1978; Crews and Smith, 1980). However, there is conflicting evidence with regard to other antidepressants. Chronic treatment with the atypical antidepressants nisoxetine, iprindole, or mianserin failed to block the clonidine-induced MHPG decrease that has been demonstrated with imipramine and DMI (Sugrue, 1981). Recent electrophysiologic studies also fail to show functional subsensitivity of autoreceptors on the locus ceruleus after treatment with iprindole, mianserin, and chlomipramine, although these effects could be confirmed for desipramine, imipramine, and zimelidine (Svensson and Scuvee-Moreau, in press). Although az-receptor subsensitization therefore seems unlikely to be a necessary concomitant of all antidepressant treatments, this effect may be of heuristic value in understanding the final common pathways of the antidepressants’ mechanism of
299
action. For example, a,-receptor subsensitization could be a prerequisite for an increase in stimulated noradrenergic release after treatment with many of the typical antidepressants. Other antidepressants may achieve the same effect via a different pharmacologic route. For example, mianserin blocks presynaptic availability by directly antagonizing feedback inhibition of noradrenergic neuronal activity (Engberg and Svensson, 1980). Thus, in the case of mianserin, the direct blockade of oZadrenoreceptors would be expected to protect receptors from down-regulation by increased concentrations of norepinephrine, although leading to the same end-point of increased release of norepinephrine per nerve impulse. Although we are not suggesting that this is necessarily the ultimate mechanism of the antidepressant action of mianserin, it serves as an example of how common biochemical effects might be achieved through different pharmacological actions. The relationship between changes in a-adrenergic receptors and other receptor changes induced by antidepressant administration such as P-adrenergic subsensitization, which appears to be a more regular consequence of antidepressant treatment than a,-adrenoreceptor subsensitization, is of potential importance. In the case of clorgyline, reductions in a,-adrenergic binding precede reductions in P-adrenergic binding in animal studies (Cohen et al., in press), suggesting that P-adrenergic subsensitization may require sustained increases of noradrenergic availability. In the case of the tricyclics, the interpretation of current studies becomes more problematic: 3- to 4-day treatment with DMI or iprindole increases [3H] clonidine or [jH]aminoclonidine binding in the rat brain (Johnson et al., 1980; Reisine et al., 1980), but decreases or no changes in these ligands’ binding in rat brain have been reported after chronic treatment with amitriptyline (Peroutka and Snyder, 1980b; Smith et al., 1981). As [3H] clonidine appears to label predominantly postsynaptic a,-adrenergic sites in rat brain (UPrichard et al., 1977), these results might not be expected necessarily to parallel desensitization of presynaptic a,-adrenergic responsiveness or attenuation of the hypotensive responses in human subjects after antidepressant treatment. Furthermore, time course considerations may also be important in the process of cr,-adrenergic desensitization, (U’Prichard et al., in press), so that effects after 3 to 4 days of antidepressant administration may not be the same as those observed after chronic treatment. It is, however, interesting to note that concurrent administration of phenoxybenzamine, a direct cY-adrenergic antagonist, with DMI accelerates the onset of B-adrenergic sensitivity in rodents (Paul and Crews, 1980; Crews et al., 1981). Because intact presynaptic neurons are required for /3-adrenergic subsensitization to be achieved (Wolfe et al., 1978; Schweitzer et al., 1979) it seems plausible that decreased sensitivity of presynaptic a-adrenoreceptors permits enhanced intrasynaptic noradrenergic availability, which in turn down-regulates postsynaptic P-adrenergic receptors. The pathway described may not be the only means by which noradrenergic function may be enhanced, but we might speculate such autoreceptor subsensitization could be a necessary step in maintaining increases in noradrenergic efficiency induced by the MAO inhibitors and classical tricyclic antidepressants. Acknowledgments.
Beverly Mucciardi,
We wish to acknowledge the assistance of Mr. Joseph Aloi, Ms. Mrs. Gloria Goldsmith, Mrs. Irene Bellesky, Dr. Thomas Insel,
300 Dr. Benjamin during
Roy, Dr. Robert
the course
of this study
Cohen, and
Dr. Jean preparation
Hamilton,
and the nursing
staff of 6D
of this manuscript.
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