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Introductory Remarks
Introductory Remarks W. L. M. PERRY Uepnrtiizeiit of Pknrvuzcology nud M.R.C. ll/rit for Research i n Brain Metobolism, IJiiiverxity of Ediiiburgh Mediccrl School, Ediitburgh, Scothiad
There is no doubt that both mood and behavior can be influenced by drugs. Indeed, one of the more terrifying aspects of modern pharmacology is the power that it places in the hands of a physician to modify the emotional and rational reactions of a patient. Were this power ever to be put to political ends, the results would savour of the worst of nightmares. On the other hand, in this power rests the main hope of those of us whose preoccupation is the provision of a rational basis for the therapy of psychoses and whose faith is that psychotic disease is the outward manifestation of a biochemical or physiologic dysfunction of the brain. The great problem, still an insuperable barrier to real understanding, is the utter lack of any links that relate precise changes in behavior to precise changes in physiologic or biochemical activity. I use the word “precise” advisedly. If we measure a change in a conditioned avoidance response in animals treated with a drug which, in the same animals, causes a depletion of an indole derivative in the caudate nucleus, we can certainly claim to have shown a link between behavior and biochemistry; but our degree of precision is lamentably inadequate. We must learn what are the mechanisms of synaptic transmission in that pathway; and we must learn whether and how the metabolism of an indole derivative is involved in the activity of the pathway. Only then will we be able to obtain any insight into the real nature of the link. This is, I am aware, the characteristic outlook of a physiologist; but we can only look a t our common problem from the background and with the outlook that was engendered by our very varied original training; and the common problem is seen very differently by those who started as psychiatrists or, indeed, as biochemists. Nevertheless, as a physiologist, I am impressed by the difficulties that have arisen in determining the precise mode of action of drugs that affect catechols a t the peripheral sympathetic nerve endings, where we have a readily isolated and essentially simple neural situation, and where the amines are located in one known cell. Yet the complexity of the various storage pools is such that it has taken several years to elucidate, even partially, how drugs like reserpine, guanethidine, bretylium, tyramine, and cocaine exerted their effects. Even now there are aspects that are far from clear. Yet we are proposing to try to explain the actions of similar drugs 209
210
W . L. M. PERRY
upon the CNS where we know little of the storage sites or of the transmission mechanisms and where isolation of any particular neuronal pathway is extremely difficult. I can only admire the courage with which these appalling difficulties have been faced. Let me look a t certain specific problems that have arisen in the course of our work in Edinburgh. I n cases of endogenous depression there is a considerable drop in the concentration of 5-HIAA in the cerebrospinal fluid (CSF). It is tempting to claim that this is a link, however crude, established between this particular abnormality of behavior and the metabolism of tryptophan. Yet, in the course of this work, we established that there was a very considerable gradient between the high concentrations of 5-HIAA found in the lateral ventricles and the much lower concentrations found in the lumbar CSF (Table I). TABLE I CONCENTRATIONS
(mpg/ml)
OF
HOMOVANILLIC ACID A N D 5-HYDROXYINDOLYLACETIC ACIDIN Doc CSF 5-HIAA
Control Ventricular CSF (v) Cisternal CSF ( c ) Mean of ratios (v/c) No. of ratios
291 41 7.23 8
HVA
Probenecid 434 274 1.63 9
Control
Probenecid
1309 51 28.80 5
1995 424 4.90 9
This concentration gradient was due to removal of the 5-HIAA from the fourth ventricle, probably by an active transport mechanism for organic acids similar to that in the nephron. Transport could be blocked by p aminohippuric acid or by probenecid. Thus a hyperactivity of this system in depression could have accounted for our results, with no change in tryptophan metabolism. Furthermore, we have no knowledge of how the acid gains access to the CSF. It does not enter from blood since large intravenous loads of the acid do not increase the CSF concentration. It may reach the CSF by simple diffusion, but if so it can only come from neurons in close proximity to the ventricular ependyma. Thus, even if we have established a link between depressive symptoms and tryptophan metabolism, we do not know whether this is a general defect of tryptophan metabolism or a defect limited to some specific area of the brain in close proximity to the ventricular ependyma. And, even if we knew this answer, we still have no idea of what the functional role of the tryptophan metabolites really is; and
211
INTRODUCTORY REMARKS
how i t is related to the behavioral pattern. Nevertheless, I believe that studies of the CSF in psychotic patients now offer a better chance of finding out than do studies of, for instance, excretory levels. Similar studies of the ventricular CSF, taken a t operation from cases of parkinsonism and from nonparkinsonian controls by Dr. Gillingham and his colleagues, have shown significant reductions in the concentrations of both HVA and 5-HIAA (Table 11). TABLE I1 HOMOVANILLIC ACIDAND 5-HYDROXYINDOLYLACETIC CSF ACIDIN VENTRICULAR ~~
mpglml
HVA 5-HIAA a
Parkinsonism
186 f 105a (37) 59 f 27 (32)
Control
447 f 153 (15) 111 f 50 (17)
Mean f SD (No. of cases).
I well remember the excitement of the early experiments of Feldberg and Sherwood when they first demonstrated the dramatic behavioral changes in cats injected intraventrically with small doses of the amines. It was almost irresistible to see in this system a possible explanation of behavioral abnormality. We have made great strides since then, but I doubt whether our understanding has advanced in parallel with our knowledge. Nevertheless speculation is just as irresistibly attractive.
There is no doubt that both mood and behavior can be influenced by drugs. Indeed, one of the more terrifying aspects of modern pharmacology is the power that it places in the hands of a physician to modify the emotional and rational reactions of a patient. Were this power ever to be put to political ends, the results would savour of the worst of nightmares. On the other hand, in this power rests the main hope of those of us whose preoccupation is the provision of a rational basis for the therapy of psychoses and whose faith is that psychotic disease is the outward manifestation of a biochemical or physiologic dysfunction of the brain. The great problem, still an insuperable barrier to real understanding, is the utter lack of any links that relate precise changes in behavior to precise changes in physiologic or biochemical activity. I use the word “precise” advisedly. If we measure a change in a conditioned avoidance response in animals treated with a drug which, in the same animals, causes a depletion of an indole derivative in the caudate nucleus, we can certainly claim to have shown a link between behavior and biochemistry; but our degree of precision is lamentably inadequate. We must learn what are the mechanisms of synaptic transmission in that pathway; and we must learn whether and how the metabolism of an indole derivative is involved in the activity of the pathway. Only then will we be able to obtain any insight into the real nature of the link. This is, I am aware, the characteristic outlook of a physiologist; but we can only look a t our common problem from the background and with the outlook that was engendered by our very varied original training; and the common problem is seen very differently by those who started as psychiatrists or, indeed, as biochemists. Nevertheless, as a physiologist, I am impressed by the difficulties that have arisen in determining the precise mode of action of drugs that affect catechols a t the peripheral sympathetic nerve endings, where we have a readily isolated and essentially simple neural situation, and where the amines are located in one known cell. Yet the complexity of the various storage pools is such that it has taken several years to elucidate, even partially, how drugs like reserpine, guanethidine, bretylium, tyramine, and cocaine exerted their effects. Even now there are aspects that are far from clear. Yet we are proposing to try to explain the actions of similar drugs 209
210
W . L. M. PERRY
upon the CNS where we know little of the storage sites or of the transmission mechanisms and where isolation of any particular neuronal pathway is extremely difficult. I can only admire the courage with which these appalling difficulties have been faced. Let me look a t certain specific problems that have arisen in the course of our work in Edinburgh. I n cases of endogenous depression there is a considerable drop in the concentration of 5-HIAA in the cerebrospinal fluid (CSF). It is tempting to claim that this is a link, however crude, established between this particular abnormality of behavior and the metabolism of tryptophan. Yet, in the course of this work, we established that there was a very considerable gradient between the high concentrations of 5-HIAA found in the lateral ventricles and the much lower concentrations found in the lumbar CSF (Table I). TABLE I CONCENTRATIONS
(mpg/ml)
OF
HOMOVANILLIC ACID A N D 5-HYDROXYINDOLYLACETIC ACIDIN Doc CSF 5-HIAA
Control Ventricular CSF (v) Cisternal CSF ( c ) Mean of ratios (v/c) No. of ratios
291 41 7.23 8
HVA
Probenecid 434 274 1.63 9
Control
Probenecid
1309 51 28.80 5
1995 424 4.90 9
This concentration gradient was due to removal of the 5-HIAA from the fourth ventricle, probably by an active transport mechanism for organic acids similar to that in the nephron. Transport could be blocked by p aminohippuric acid or by probenecid. Thus a hyperactivity of this system in depression could have accounted for our results, with no change in tryptophan metabolism. Furthermore, we have no knowledge of how the acid gains access to the CSF. It does not enter from blood since large intravenous loads of the acid do not increase the CSF concentration. It may reach the CSF by simple diffusion, but if so it can only come from neurons in close proximity to the ventricular ependyma. Thus, even if we have established a link between depressive symptoms and tryptophan metabolism, we do not know whether this is a general defect of tryptophan metabolism or a defect limited to some specific area of the brain in close proximity to the ventricular ependyma. And, even if we knew this answer, we still have no idea of what the functional role of the tryptophan metabolites really is; and
211
INTRODUCTORY REMARKS
how i t is related to the behavioral pattern. Nevertheless, I believe that studies of the CSF in psychotic patients now offer a better chance of finding out than do studies of, for instance, excretory levels. Similar studies of the ventricular CSF, taken a t operation from cases of parkinsonism and from nonparkinsonian controls by Dr. Gillingham and his colleagues, have shown significant reductions in the concentrations of both HVA and 5-HIAA (Table 11). TABLE I1 HOMOVANILLIC ACIDAND 5-HYDROXYINDOLYLACETIC CSF ACIDIN VENTRICULAR ~~
mpglml
HVA 5-HIAA a
Parkinsonism
186 f 105a (37) 59 f 27 (32)
Control
447 f 153 (15) 111 f 50 (17)
Mean f SD (No. of cases).
I well remember the excitement of the early experiments of Feldberg and Sherwood when they first demonstrated the dramatic behavioral changes in cats injected intraventrically with small doses of the amines. It was almost irresistible to see in this system a possible explanation of behavioral abnormality. We have made great strides since then, but I doubt whether our understanding has advanced in parallel with our knowledge. Nevertheless speculation is just as irresistibly attractive.