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Clinical implication of microdialysis findings
TiPS-jtfiy
1993 [Vol. 141
Altered S-IV,, receptor-mediated
263
neurotransmission
ical implic ion of micro Artigas has made a number of interesting observations about the effects of selective 5-HT (serotonin) reuptake inhibitors (SSRIs) in increasing dendritic but not terminal 5-HT release. An important implication is that behavioural effects of single doses of reuptake blockers cannot be assumed to be due to increased 5-HT release. Fenfluramine may be a better probe of 5-HT function since dialysis studies show it induces acute increases in 5-I-IT release, unlike the SSRIs’. Indeed, we have suggested that SSRIs may behave as 5-HT receptor antagonists and prevent activation of 5-HT neurones under aversive conditions2. This prediction could be tested using microdialysis. The new information about release may resolve some experimental contradictions; for example, acute clomipramine administration to volunteers normal increased anxiety in the simulated publicspeaking mode13, but this now seems likely to be due to reduced rather than increased 5-HT release since fenfluramine was recently shown to have anxiolytic effects that are marked and clearly dosedependent4. A clinical corollary may be that SSRIs exacerbate panic symptoms early in treatment by suppressing 5-HT release (as we have previously suggested2) in the periaqueductal grey and other parts of the fight-flight system that may be dysfunctional in panic. Artigas has shown that coadministration of a 5-!-ITtA receptor antagonist with an SSRI allows the SSRI to induce an immediate increase in terminal 5-HT release somatodendritic by blocking autoreceptors. He speculates that this may accelerate the onset of the antidepressant effect. Whether this prediction is upheld depends critically on which postsynaptic antimediate the receptors depressant effect of enhanced 5-HT release. The postsynaptic effect of combined treatment with a SSRI and a 5-HTiA receptor antagonist would be to block postsynaptic 5-HTiA receptors, leaving the enhanced 5-HT release to act
on other subtypes including the 5-HT, receptor family. However, there is little evidence that 5-HTz receptors mediate antidepressant effects; indeed some powerful antidepressants such as clomipramine are effective 5-HTzc receptor antagonists. Deakinsh has argued that blockade or downregulation of 5-HT2 receptor subtypes, located chiefly in frontal cortex and amygdala, mediate anxiolytic effects in conditioned or anticipatory anxiety as in generalized anxiety disorder and depression. subsequent The demonstration that the 5-HT2c receptor agonist nr-chlorophenylpiperazine (m-CPP) has anxiogenic effects is in keeping with this theory. This predicts anxiogenic effects of the combination proposed by Artigas. We and others have suggested that the postsynaptic mechanism involved in the effects of SSRIs is an enhancement of 5-HTiA receptor-mediated neurotransmission2,i Our theory> holds that depression is caused by impaired 5-HTiA receptor mediated neurotransmission since: (1) depression is reproducibly associated with impaired growth hormone and prolactin responses following tryptophan administration, (2) these responses are blocked in animal and human studies by 5-HTt,++ receptor antagonists, (3) impaired 5-HT neuroendocrine function is statedependent, and (4) all effective
antidepressants, in various ways, enhance 5-HTiA receptor mediated neurotransmission in electrophysiological experiments. This would suggest that a 5-HTlA receptor antagonist, by its postsynaptic actions, would block rather than enhance the therapeutic effects of SSRIs. Therefore, determining whether acute administration of a 5-HTiA receptor antagonist causes a temporary relapse in recovered depressives treated with SSRIs is arguably an important priority. Nevertheless, Artigas’s proposed trial of combination therapy would be an important test of the autoreceptor downregulation theory and of our theory.
References 1 Sarkissian, C. F., Wurtman, R. J., Morse, A. N. and Gleason, R. (1990) Ernirt Rcs. 529, 294-301 2 Deakin, J. F. W. and Graeff,
F. G. (1991) 1. Ps~/clroyknr,~ra~a/. 5, 305315 3 Guimaraes, F. S., Zuardi, A. W. and Graeff, F. G. (1987) 1. Ps!/cRoplrnrrrmcol. 1, 184-192 4 Hetern, L. A., de Souza, C. J., Guimaraes, F. S., Zuardi, A. W. and Graeff, F. G. (1993) Pflr World Cotr,qr. Ps~yckinf. 1251 5 Deakin. 1. F. W. and Penneil. I. (19861 Ps?lchodl;R~nrecol~~~~
89 !Suppi.),
6 Deakin, I. F. W. (1988)
24
Phnrmaral.
J. F. W. DEAKIN,
F. G. GRAEFF AND F. S. GUIMARAES
Letters to the Editor TiPS welcomes
letters to the Editor
in response
to recently
pub-
lished articles. Letters relating to other issues of general interest to pharmacologists will also be considered. Letters should be brief, with a minimum
of references,
Bin-
B&v. 29, 819-820 7 Blier, I’., de Montigny, C. and Chaput, Y. (1987) 1. C/iv. Psychoplfn,,t~n~o/. 7 (Suppl.), 24-35 clrern.
and should
be submitted
The Editor, Trends in Phnrrnncologicnl Sciences, Elsevier Trends Journals, 68 Hills Road, Cambridge,
UK CB2 ILA.
to:
1993 [Vol. 141
Altered S-IV,, receptor-mediated
263
neurotransmission
ical implic ion of micro Artigas has made a number of interesting observations about the effects of selective 5-HT (serotonin) reuptake inhibitors (SSRIs) in increasing dendritic but not terminal 5-HT release. An important implication is that behavioural effects of single doses of reuptake blockers cannot be assumed to be due to increased 5-HT release. Fenfluramine may be a better probe of 5-HT function since dialysis studies show it induces acute increases in 5-I-IT release, unlike the SSRIs’. Indeed, we have suggested that SSRIs may behave as 5-HT receptor antagonists and prevent activation of 5-HT neurones under aversive conditions2. This prediction could be tested using microdialysis. The new information about release may resolve some experimental contradictions; for example, acute clomipramine administration to volunteers normal increased anxiety in the simulated publicspeaking mode13, but this now seems likely to be due to reduced rather than increased 5-HT release since fenfluramine was recently shown to have anxiolytic effects that are marked and clearly dosedependent4. A clinical corollary may be that SSRIs exacerbate panic symptoms early in treatment by suppressing 5-HT release (as we have previously suggested2) in the periaqueductal grey and other parts of the fight-flight system that may be dysfunctional in panic. Artigas has shown that coadministration of a 5-!-ITtA receptor antagonist with an SSRI allows the SSRI to induce an immediate increase in terminal 5-HT release somatodendritic by blocking autoreceptors. He speculates that this may accelerate the onset of the antidepressant effect. Whether this prediction is upheld depends critically on which postsynaptic antimediate the receptors depressant effect of enhanced 5-HT release. The postsynaptic effect of combined treatment with a SSRI and a 5-HTiA receptor antagonist would be to block postsynaptic 5-HTiA receptors, leaving the enhanced 5-HT release to act
on other subtypes including the 5-HT, receptor family. However, there is little evidence that 5-HTz receptors mediate antidepressant effects; indeed some powerful antidepressants such as clomipramine are effective 5-HTzc receptor antagonists. Deakinsh has argued that blockade or downregulation of 5-HT2 receptor subtypes, located chiefly in frontal cortex and amygdala, mediate anxiolytic effects in conditioned or anticipatory anxiety as in generalized anxiety disorder and depression. subsequent The demonstration that the 5-HT2c receptor agonist nr-chlorophenylpiperazine (m-CPP) has anxiogenic effects is in keeping with this theory. This predicts anxiogenic effects of the combination proposed by Artigas. We and others have suggested that the postsynaptic mechanism involved in the effects of SSRIs is an enhancement of 5-HTiA receptor-mediated neurotransmission2,i Our theory> holds that depression is caused by impaired 5-HTiA receptor mediated neurotransmission since: (1) depression is reproducibly associated with impaired growth hormone and prolactin responses following tryptophan administration, (2) these responses are blocked in animal and human studies by 5-HTt,++ receptor antagonists, (3) impaired 5-HT neuroendocrine function is statedependent, and (4) all effective
antidepressants, in various ways, enhance 5-HTiA receptor mediated neurotransmission in electrophysiological experiments. This would suggest that a 5-HTlA receptor antagonist, by its postsynaptic actions, would block rather than enhance the therapeutic effects of SSRIs. Therefore, determining whether acute administration of a 5-HTiA receptor antagonist causes a temporary relapse in recovered depressives treated with SSRIs is arguably an important priority. Nevertheless, Artigas’s proposed trial of combination therapy would be an important test of the autoreceptor downregulation theory and of our theory.
References 1 Sarkissian, C. F., Wurtman, R. J., Morse, A. N. and Gleason, R. (1990) Ernirt Rcs. 529, 294-301 2 Deakin, J. F. W. and Graeff,
F. G. (1991) 1. Ps~/clroyknr,~ra~a/. 5, 305315 3 Guimaraes, F. S., Zuardi, A. W. and Graeff, F. G. (1987) 1. Ps!/cRoplrnrrrmcol. 1, 184-192 4 Hetern, L. A., de Souza, C. J., Guimaraes, F. S., Zuardi, A. W. and Graeff, F. G. (1993) Pflr World Cotr,qr. Ps~yckinf. 1251 5 Deakin. 1. F. W. and Penneil. I. (19861 Ps?lchodl;R~nrecol~~~~
89 !Suppi.),
6 Deakin, I. F. W. (1988)
24
Phnrmaral.
J. F. W. DEAKIN,
F. G. GRAEFF AND F. S. GUIMARAES
Letters to the Editor TiPS welcomes
letters to the Editor
in response
to recently
pub-
lished articles. Letters relating to other issues of general interest to pharmacologists will also be considered. Letters should be brief, with a minimum
of references,
Bin-
B&v. 29, 819-820 7 Blier, I’., de Montigny, C. and Chaput, Y. (1987) 1. C/iv. Psychoplfn,,t~n~o/. 7 (Suppl.), 24-35 clrern.
and should
be submitted
The Editor, Trends in Phnrrnncologicnl Sciences, Elsevier Trends Journals, 68 Hills Road, Cambridge,
UK CB2 ILA.
to: