CLINICAL
AND
RESEARCH
REPORTS
those interested in linguistic and paralinguistic of psychiatric phenomena.
aspects
REFERENCES 1. Qranacher R, Baldessanni R: Physostigmine. Arch Gen Psychiatry 32:375-380, 1975 2. Peck E: The relationship of disease and other stress to second language. Int J Soc Psychiatry 20:128-133, 1973 3. Kalinowsky LB: Clinical observations in ECT (ltr to ed). Am J
Do
Tricyclic
BY
ALAN
Antidepressants FRAZER,
PH.D.,
AND
Enhance JOE
Adrenergic
,
Dr. Frazer is Associate Professor of Pharmacology in Psychiatry, University of Pennsylvania and Veterans Administration Hospital, Philadelphia, Pa. Dr. Mendels is Professor ofPsychiatry, University of Pennsylvania, and Chief, Affective Diseases Research Unit, Veterans Administration Hospital, Philadelphia, Pa. Address reprint requests to Dr. Frazer at the Veterans Administration Hospital, University and Woodland Avenues, Philadelphia, Pa. 19104. This work was supported by research funds from the Veterans ministration and by Alcohol, Drug Abuse, and Mental Health ministration grant RO1-MH-29094 from the National Institute Mental Health.
Am
J Psychiatry
/34:9,
September
Transmission?
M.D.
MENDELS,
It has been suggested repeatedly that the tricyclic antidepressants exert their effects by blocking the neuronal reuptake of biogenic amines (norepinephrine and/or serotonin), thereby increasing the amount of neurotransmitter available to act at postsynaptic receptors and overcoming a hypothesized amine deficiency. Most of the evidence for this theory has been derived from studies of the acute pharmacological actions ofthese drugs, either after a single injection or by examination of in vitro effects. Since it is widely believed that the tricyclic compounds do not exert a significant therapeutic effect until they have been administered for 10-14 days or longer, it is surprising that relatively little attention has been directed toward their pharmacological actions after chronic administration. The available information suggests that tricyclics initiate effects that are different from, and perhaps opposite to, their acute effects. As is discussed below, such effects may be compensatory changes to the acute pharmacological actions of tricyclics. In the course of a continuing series of studies dealing with this question (1), we have noted a late-deveboping pharmacological action of desmethylimipramine (DM1) that is relevant to the functional activity of the noradrenergic system. Male Sprague-Dawley rats (200-300 g) were given intraperitoneal injections of DM1 (5 mg/kg) once daily for either 4, 1 1 or 18 days. Control animals received intraperitoneal injections of isotonic saline solution for
1040
Psychiatry 132:878, 1975 4. Rosenbaum J, Gelenberg A: Clinical observations in ECT (ltr to ed). Ibid, p 878 5. Lopez M, Hicks R, Young R: Retroactive inhibition in a bilingual A-B, A-B’ paradigm. J Exp Psychol 103:85-90, 1974 6. Brown R: Schizophrenia, language and reality. Am Psychol 28:395-403, 1973 7. Hemphill R: Auditory hallucinations in polyglots. S Afr Med J 18:1391-1394, 1971 8. Marcos L, Urcuyo L, Kesselman M, et al: The language barrier in evaluating Spanish American patients. Arch Gen Psychiatry 29:655-659, 1973
/977
AdAdof
corresponding time periods. Twenty-four hours after the last injection of the series, the rats were decapitated. Procedures used for preparation of cerebral cortical slices, labeling with 3H-adenine (l0Ci/ml), and determination of 3H-adenosine 3 ,5 ‘-monophosphate (cAMP) in the slices have been reported previousby (1). Data from cortical slices of the three groups of saline-injected rats were not significantly different and have therefore been combined to form a single control group. From table 1 it can be seen that DM1 treatment did not significantly alter the basal accumulation of cAMP in cerebral cortical slices. In contrast, DM1 treatment significantly reduced the net synthesis of cAMP stimubated by norepinephrine (NE) when the treatment lasted for more than 4 days. As noted above, enhancement of adrenergic or serotonergic neuronal activity, as a consequence of tncyclic-induced blockade of amine reuptake (2), is the pharmacological effect to which the therapeutic effect oftricyclics is most often ascribed. Based on this idea, we explored initially the effect of treatment with imipramine given for 5 days on NE-stimulated cAMP net synthesis in cerebral cortical slices (1). The expectation was that blocking amine reuptake would cause an exaggerated response (i.e. stimulation ofcAMP) to NE. However, the response to NE was reduced. Similan observations have been reported by others (3, 4), and it is apparent the administration oftricyclics does, over time, produce a diminished responsiveness to NE. This diminished response produced by exogenous NE after chronic tricyclic treatment is the opposite of the effect that would be predicted on the basis of blockade of amine reuptake. There are several other pharmacological effects of chronic tnicyclic treatment that might attenuate the postulated enhancement of adrenergic transmission produced by these drugs. Segal and associates (5) reported that in rats treated with DM1 for 8 days and ‘
,
,
killed 24 hours
after the final injection, the activity of
CLINICAL
TABLE 1 Influence of DM1 on Accumulation
of cAMP
in Cerebral
Cortical
AND
RESEARCH
REPORTS
Slices’ In Vitro Drug Addition Norepinephrine (2xl0M)
None Treatment
N
Mean
SE
0.9% NaCI DM1. 4 days DM1, 11 days DM1, l8days
IS 5 5 6
0.58 0.65 0.45 0.49
0.04 0.09 0.03 0.04
Drug
#{149}Resultsare expressed as the percent conversion of radioactivity **Student’s t test (two-tailed) for comparisons with results from
into cAMP. saline-injected
brain tyrosine hydroxylase, the rate-limiting enzyme in catecholamine biosynthesis, was reduced significantly. This may account for the reports that chronic treatment with tnicyclic drugs lowers brain concentrations of NE, whereas acute treatment has no such effect (6). It would be incorrect to assume that the lowered concentration of brain NE observed after chronic treatment with tnicyclic drugs necessarily indicates diminished activity of NE-containing neuronab systems, as there need not be a correlation between amine concentrations and functional effects. Therefore, studies of the effect of tnicyclic treatment on the “turnover” of NE may provide a better correlation with activity in NE neurons. Acute administration of tnicyclic drugs reduces amine turnover, but chronic treatment with imipramine in rats accelerated the disappearance of radioactive NE from brain (6). Schildkraut and associates (6) speculated that enhanced turnover of NE after chronic treatment with imipramine might result in greater availability of NE to adrenergic receptors despite reduced brain NE concentration. In other words, chronic tricyclic treatment would still result in enhanced adrenergic transmission. An alternative interpretation of data on NE turnover arises from our studies of the effects of chronic tncyclic treatment on NE-induced responses in brain tissue. The diminished effects produced by NE in rats given tnicyclic drugs chronically may be due to the devebopment of adrenergic receptor subsensitivity. The development of receptor subsensitivity may be viewed as a compensatory change to the presence of sustained elevated concentrations of NE in the synaptic cleft-a consequence of DM1 blocking amine reuptake. It is possible decreases in adrenergic receptor sensitivity lead to a second compensatory change, namely, an increase in amine turnover, in much the same way that drug-induced blockade of adrenergic receptors produces an enhancement of turnover in adrenergic neurons (7). Ifthis interpretation is correct, then tricyclicinduced alterations in presynaptic neurotransmitter metabolism would be rebated inversely to activity at the postsynaptic receptor site. The point to be emphasized is how difficult it may be to distinguish primary
p
Mean
>
>.2
p
0.20 0.34 0.28 0.17
2.96 2.73 2.00 2.10
.4 .05
>
SE
.5
AND
RESEARCH
REPORTS
those interested in linguistic and paralinguistic of psychiatric phenomena.
aspects
REFERENCES 1. Qranacher R, Baldessanni R: Physostigmine. Arch Gen Psychiatry 32:375-380, 1975 2. Peck E: The relationship of disease and other stress to second language. Int J Soc Psychiatry 20:128-133, 1973 3. Kalinowsky LB: Clinical observations in ECT (ltr to ed). Am J
Do
Tricyclic
BY
ALAN
Antidepressants FRAZER,
PH.D.,
AND
Enhance JOE
Adrenergic
,
Dr. Frazer is Associate Professor of Pharmacology in Psychiatry, University of Pennsylvania and Veterans Administration Hospital, Philadelphia, Pa. Dr. Mendels is Professor ofPsychiatry, University of Pennsylvania, and Chief, Affective Diseases Research Unit, Veterans Administration Hospital, Philadelphia, Pa. Address reprint requests to Dr. Frazer at the Veterans Administration Hospital, University and Woodland Avenues, Philadelphia, Pa. 19104. This work was supported by research funds from the Veterans ministration and by Alcohol, Drug Abuse, and Mental Health ministration grant RO1-MH-29094 from the National Institute Mental Health.
Am
J Psychiatry
/34:9,
September
Transmission?
M.D.
MENDELS,
It has been suggested repeatedly that the tricyclic antidepressants exert their effects by blocking the neuronal reuptake of biogenic amines (norepinephrine and/or serotonin), thereby increasing the amount of neurotransmitter available to act at postsynaptic receptors and overcoming a hypothesized amine deficiency. Most of the evidence for this theory has been derived from studies of the acute pharmacological actions ofthese drugs, either after a single injection or by examination of in vitro effects. Since it is widely believed that the tricyclic compounds do not exert a significant therapeutic effect until they have been administered for 10-14 days or longer, it is surprising that relatively little attention has been directed toward their pharmacological actions after chronic administration. The available information suggests that tricyclics initiate effects that are different from, and perhaps opposite to, their acute effects. As is discussed below, such effects may be compensatory changes to the acute pharmacological actions of tricyclics. In the course of a continuing series of studies dealing with this question (1), we have noted a late-deveboping pharmacological action of desmethylimipramine (DM1) that is relevant to the functional activity of the noradrenergic system. Male Sprague-Dawley rats (200-300 g) were given intraperitoneal injections of DM1 (5 mg/kg) once daily for either 4, 1 1 or 18 days. Control animals received intraperitoneal injections of isotonic saline solution for
1040
Psychiatry 132:878, 1975 4. Rosenbaum J, Gelenberg A: Clinical observations in ECT (ltr to ed). Ibid, p 878 5. Lopez M, Hicks R, Young R: Retroactive inhibition in a bilingual A-B, A-B’ paradigm. J Exp Psychol 103:85-90, 1974 6. Brown R: Schizophrenia, language and reality. Am Psychol 28:395-403, 1973 7. Hemphill R: Auditory hallucinations in polyglots. S Afr Med J 18:1391-1394, 1971 8. Marcos L, Urcuyo L, Kesselman M, et al: The language barrier in evaluating Spanish American patients. Arch Gen Psychiatry 29:655-659, 1973
/977
AdAdof
corresponding time periods. Twenty-four hours after the last injection of the series, the rats were decapitated. Procedures used for preparation of cerebral cortical slices, labeling with 3H-adenine (l0Ci/ml), and determination of 3H-adenosine 3 ,5 ‘-monophosphate (cAMP) in the slices have been reported previousby (1). Data from cortical slices of the three groups of saline-injected rats were not significantly different and have therefore been combined to form a single control group. From table 1 it can be seen that DM1 treatment did not significantly alter the basal accumulation of cAMP in cerebral cortical slices. In contrast, DM1 treatment significantly reduced the net synthesis of cAMP stimubated by norepinephrine (NE) when the treatment lasted for more than 4 days. As noted above, enhancement of adrenergic or serotonergic neuronal activity, as a consequence of tncyclic-induced blockade of amine reuptake (2), is the pharmacological effect to which the therapeutic effect oftricyclics is most often ascribed. Based on this idea, we explored initially the effect of treatment with imipramine given for 5 days on NE-stimulated cAMP net synthesis in cerebral cortical slices (1). The expectation was that blocking amine reuptake would cause an exaggerated response (i.e. stimulation ofcAMP) to NE. However, the response to NE was reduced. Similan observations have been reported by others (3, 4), and it is apparent the administration oftricyclics does, over time, produce a diminished responsiveness to NE. This diminished response produced by exogenous NE after chronic tricyclic treatment is the opposite of the effect that would be predicted on the basis of blockade of amine reuptake. There are several other pharmacological effects of chronic tnicyclic treatment that might attenuate the postulated enhancement of adrenergic transmission produced by these drugs. Segal and associates (5) reported that in rats treated with DM1 for 8 days and ‘
,
,
killed 24 hours
after the final injection, the activity of
CLINICAL
TABLE 1 Influence of DM1 on Accumulation
of cAMP
in Cerebral
Cortical
AND
RESEARCH
REPORTS
Slices’ In Vitro Drug Addition Norepinephrine (2xl0M)
None Treatment
N
Mean
SE
0.9% NaCI DM1. 4 days DM1, 11 days DM1, l8days
IS 5 5 6
0.58 0.65 0.45 0.49
0.04 0.09 0.03 0.04
Drug
#{149}Resultsare expressed as the percent conversion of radioactivity **Student’s t test (two-tailed) for comparisons with results from
into cAMP. saline-injected
brain tyrosine hydroxylase, the rate-limiting enzyme in catecholamine biosynthesis, was reduced significantly. This may account for the reports that chronic treatment with tnicyclic drugs lowers brain concentrations of NE, whereas acute treatment has no such effect (6). It would be incorrect to assume that the lowered concentration of brain NE observed after chronic treatment with tnicyclic drugs necessarily indicates diminished activity of NE-containing neuronab systems, as there need not be a correlation between amine concentrations and functional effects. Therefore, studies of the effect of tnicyclic treatment on the “turnover” of NE may provide a better correlation with activity in NE neurons. Acute administration of tnicyclic drugs reduces amine turnover, but chronic treatment with imipramine in rats accelerated the disappearance of radioactive NE from brain (6). Schildkraut and associates (6) speculated that enhanced turnover of NE after chronic treatment with imipramine might result in greater availability of NE to adrenergic receptors despite reduced brain NE concentration. In other words, chronic tricyclic treatment would still result in enhanced adrenergic transmission. An alternative interpretation of data on NE turnover arises from our studies of the effects of chronic tncyclic treatment on NE-induced responses in brain tissue. The diminished effects produced by NE in rats given tnicyclic drugs chronically may be due to the devebopment of adrenergic receptor subsensitivity. The development of receptor subsensitivity may be viewed as a compensatory change to the presence of sustained elevated concentrations of NE in the synaptic cleft-a consequence of DM1 blocking amine reuptake. It is possible decreases in adrenergic receptor sensitivity lead to a second compensatory change, namely, an increase in amine turnover, in much the same way that drug-induced blockade of adrenergic receptors produces an enhancement of turnover in adrenergic neurons (7). Ifthis interpretation is correct, then tricyclicinduced alterations in presynaptic neurotransmitter metabolism would be rebated inversely to activity at the postsynaptic receptor site. The point to be emphasized is how difficult it may be to distinguish primary
p
Mean
>
>.2
p
0.20 0.34 0.28 0.17
2.96 2.73 2.00 2.10
.4 .05
>
SE
.5
