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False neurochemical transmitters and disordered function of the CNS
J. psychial. Res.1974, Vol. 10,pp.315-324. Pergamon Press.Printed in GreatBritain.
ABSTRACTS OF PAPERS PRESENTED AT THE PSYCHIATRIC RESEARCH SOCIETY [OCTOBER 19 AND 20, 1973, IN VALLEY FORGE, PENNSYLVANIA] Denervation and reinnervation of skeletal muscle in psychotic patients JOHN W.
Department
CRAYTON
HERBERT Y.
and
MELTZER
of Psychiatry, Pritzker School of Medicine, University of Chicago, Chicago, Illinois, U.S.A.
Previous studies from this laboratory (Mellzer, Arch. gen. P.sychiatry. 27: 125, 1972) have indicated that acutely psychotic patients have elevations of serum creatine phosphokinase and pathological lesions of muscle such as scattered atrophic fibres and Z-band streaming which, taken together, are suggestive of a “neuropathic” neuromuscular disorder as opposed to a primary defect of muscle tissue. Such a process ought to be reflecteq in the pattern of distribution of intra-muscular motor neurons (Coers and Woolf, The Innervation of Muscle, 1959). We have therefore studied the appearance of intramuscular nerve endings in muscle biopsies of peroneus brevis from 24 psychotic patients and seven normal volunteers. The extent of denervation and reinnervation occurring in the subjects was assessed by determining the Absolute and Functional Terminal Innervation Ratios (ATIR and FTIR, respectively). Values for ATIR and FTIR exceeded the 95 per cent upper limit of normal based on the volunteer group in 16 of the 24 psychotic patients. The pattern of innervation could also be correlated with histochemical and phase microscopic results. The correlation between ATIR and the number of scattered atrophic fibres was highly significant (r = 0.733, p < 0.01). The ATIR for 7 patients with both histochemical and phase microscopic pathology was significantly greater (p < 0.05) than that of 6 psychotic patients with neither type of pathology. There was no evidence that acute vs chronic, paranoid vs nonparanoid, or good vs poor prognosis factors were related to the degree of abnormality of the innervation ratios. The results suggest that psychotic illness can be associated with a peripheral neuropathic process resulting in denervation and reinnervation of skeletal muscle.
False neorocbemical transmitters and disordered function of the CN§* Ross
Departments
J. BALDESSARIM~
and
JQSEF E. FISCHER
of Psychiatry and General Surgery, Massachusetts Harvard Medical School, Boston, Massachusetts,
General Hospital and U.S.A.
The accumulation of relatively inactive structural analogs of normal synaptic neurotransmitters may in certain circumstances have profound behavioral and neurological consequences. Such analbgs are called “false neurotransmitters”. Our clinical and laboratory experimental findings suggest that abnormalities in the metabolism of biogenic amines and amino acids may explain certain behavioral, neurological and peripheral abnormalities which occur in patients with hepatic failure. *This work was supported in part by General Research Support Grant FR-05486, NIAMD Grant ROI-AM 15347-01 PHRA (JF) and Grant MH-16674 (RB). f Recipient of Research Scientist Development Award Type II, National Institute of Mental Health MH-74370. 315
316
AssTi3.4c~
For example, we propose that when portal blood is shunted around the liver into the systemic circulation and when hepatic function is impaired, amines or their amino-acid precursors accumulate in both the central and peripheral adrenergic nervous systems to interfere with the function of the normal synaptic transmitters, norepinephrine and dopamine. Such compounds can arise from the breakdown of protein in the gut and are normally metabolized in the liver. Their accumulation in the brain may account for the altered consciousness and coma, and perhaps the tremor (aster&is) and even the psychoses which occur during hepatic failure; in the peripheral sympathetic nervous system, the metabolic abnormality may account for the states of high cardiac output, low peripheral vascular resistance and decreased renal function associated with hepatic failure. We have also found evidence that indoleamines and glutamine may accumulate during hepatic failure at the expense of other stimulatory neurotrausmitters. Our hypothesis also offers an explanation of the clinical efficacy of newer methods of pharmacotherapy which we have reported to be useful in the management of the complications of hepatic failure. These treatments include the arousal of patients from hepatic coma with L-dihydroxyphenylalanine @-Dopa), and the treatment of the circulatory and renal abnormalities with alpha-adrenergic agents. We suggest further that the accumulation of false neurotransmitters might also mediate a variety of other neuropsychiatric phenomena which occur in states of inborn or acquired metabolic error or after the administration of certain drugs which are sometimes associated with psychotic phenomena. Thus, we would suggest that the study of relationships between neuropsychiatric disorders and the metabolism of neurotransmitters could include as a novel approach, the search for accumulations of inactive analogs of the various molecules known or suspected to function as physiological synaptic transmitters in the central nervous system.
Conditioning aspects of narcotics addiction
Department
C. P. O’BRIEN of Psychiatry, University of Pennsylvania, Philadelphia,
Pennsylvania,
U.S.A.
The importance of conditioning factors in narcotic addiction and relapse has been established in animal studies and has been suggested by clinical experience. Wikler has developed a theoretical system which involves both classical and operant conditioning, but systematic studies in humans are lacking. Stimuli which precipitate either “craving” or “sickness” were elicited from 8 former addicts, drug-free at least 6 months and 100 addicts currently undergoing methadone treatment. The subjects were able to arrange the stimuli in a hierarchy from most to least potent. Addicts were able to clearly distinguish between the symptoms of “cravings” and “sickness”, but the stimuli which provoke each of these overlap. Various desensitization paradigms were utilized to extinguish the responses to these stimuli using both psychophysiological and subjective dependent variables. One series of extinction trials involved the use of the narcotic antagonist cyclazocine. Previous studies with antagonists have assumed random experimentation with narcotics by the addict in his environment. In this study systematic extinction trials were conducted in the clinic. Heroin addicts were detoxified and permitted to inject themselves with the narcotic hydromorphone (Dilaudid) under double-blind saline controlled conditions, while maintaining their usual rituals. Baseline responses were obtained. After a blocking dose of cyclazocine was achieved, thrice weekly extinction trials were conducted consisting of self-injections of either saline or hydromorphone under double-blind conditions. Results with 15 patients to date indicate that, (1) the procedure is acceptable to patients; (2) all injections even saline, are pleasurable initially, but after 10-15 trials they have become neutral and continued injections become increasingly aversive; (3) self injections in the clinic are generalized to other environments according to patient reports (supported by frequent urine tests); (4) pupillometry is the best measure of pharmacological “high”, but conditioned constriction to the injection of saline may occur; (5) video tapes and slides of addicts “shooting up” are potent stimuli for most addicts and post-addicts, but not for individuals who have undergone extinction trials. This treatment technique is still in a preliminary stage of development. The drop-out rate due to cyclazocine side effects is high (up to 50 per cent), but this should be reduced by naltrexone, an antagonist with few side effects. It remains to be seen whether relapse occurs after termination of antagonist when the patients know that getting narcotic effects is again possible.
ABSTRACTS OF PAPERS PRESENTED AT THE PSYCHIATRIC RESEARCH SOCIETY [OCTOBER 19 AND 20, 1973, IN VALLEY FORGE, PENNSYLVANIA] Denervation and reinnervation of skeletal muscle in psychotic patients JOHN W.
Department
CRAYTON
HERBERT Y.
and
MELTZER
of Psychiatry, Pritzker School of Medicine, University of Chicago, Chicago, Illinois, U.S.A.
Previous studies from this laboratory (Mellzer, Arch. gen. P.sychiatry. 27: 125, 1972) have indicated that acutely psychotic patients have elevations of serum creatine phosphokinase and pathological lesions of muscle such as scattered atrophic fibres and Z-band streaming which, taken together, are suggestive of a “neuropathic” neuromuscular disorder as opposed to a primary defect of muscle tissue. Such a process ought to be reflecteq in the pattern of distribution of intra-muscular motor neurons (Coers and Woolf, The Innervation of Muscle, 1959). We have therefore studied the appearance of intramuscular nerve endings in muscle biopsies of peroneus brevis from 24 psychotic patients and seven normal volunteers. The extent of denervation and reinnervation occurring in the subjects was assessed by determining the Absolute and Functional Terminal Innervation Ratios (ATIR and FTIR, respectively). Values for ATIR and FTIR exceeded the 95 per cent upper limit of normal based on the volunteer group in 16 of the 24 psychotic patients. The pattern of innervation could also be correlated with histochemical and phase microscopic results. The correlation between ATIR and the number of scattered atrophic fibres was highly significant (r = 0.733, p < 0.01). The ATIR for 7 patients with both histochemical and phase microscopic pathology was significantly greater (p < 0.05) than that of 6 psychotic patients with neither type of pathology. There was no evidence that acute vs chronic, paranoid vs nonparanoid, or good vs poor prognosis factors were related to the degree of abnormality of the innervation ratios. The results suggest that psychotic illness can be associated with a peripheral neuropathic process resulting in denervation and reinnervation of skeletal muscle.
False neorocbemical transmitters and disordered function of the CN§* Ross
Departments
J. BALDESSARIM~
and
JQSEF E. FISCHER
of Psychiatry and General Surgery, Massachusetts Harvard Medical School, Boston, Massachusetts,
General Hospital and U.S.A.
The accumulation of relatively inactive structural analogs of normal synaptic neurotransmitters may in certain circumstances have profound behavioral and neurological consequences. Such analbgs are called “false neurotransmitters”. Our clinical and laboratory experimental findings suggest that abnormalities in the metabolism of biogenic amines and amino acids may explain certain behavioral, neurological and peripheral abnormalities which occur in patients with hepatic failure. *This work was supported in part by General Research Support Grant FR-05486, NIAMD Grant ROI-AM 15347-01 PHRA (JF) and Grant MH-16674 (RB). f Recipient of Research Scientist Development Award Type II, National Institute of Mental Health MH-74370. 315
316
AssTi3.4c~
For example, we propose that when portal blood is shunted around the liver into the systemic circulation and when hepatic function is impaired, amines or their amino-acid precursors accumulate in both the central and peripheral adrenergic nervous systems to interfere with the function of the normal synaptic transmitters, norepinephrine and dopamine. Such compounds can arise from the breakdown of protein in the gut and are normally metabolized in the liver. Their accumulation in the brain may account for the altered consciousness and coma, and perhaps the tremor (aster&is) and even the psychoses which occur during hepatic failure; in the peripheral sympathetic nervous system, the metabolic abnormality may account for the states of high cardiac output, low peripheral vascular resistance and decreased renal function associated with hepatic failure. We have also found evidence that indoleamines and glutamine may accumulate during hepatic failure at the expense of other stimulatory neurotrausmitters. Our hypothesis also offers an explanation of the clinical efficacy of newer methods of pharmacotherapy which we have reported to be useful in the management of the complications of hepatic failure. These treatments include the arousal of patients from hepatic coma with L-dihydroxyphenylalanine @-Dopa), and the treatment of the circulatory and renal abnormalities with alpha-adrenergic agents. We suggest further that the accumulation of false neurotransmitters might also mediate a variety of other neuropsychiatric phenomena which occur in states of inborn or acquired metabolic error or after the administration of certain drugs which are sometimes associated with psychotic phenomena. Thus, we would suggest that the study of relationships between neuropsychiatric disorders and the metabolism of neurotransmitters could include as a novel approach, the search for accumulations of inactive analogs of the various molecules known or suspected to function as physiological synaptic transmitters in the central nervous system.
Conditioning aspects of narcotics addiction
Department
C. P. O’BRIEN of Psychiatry, University of Pennsylvania, Philadelphia,
Pennsylvania,
U.S.A.
The importance of conditioning factors in narcotic addiction and relapse has been established in animal studies and has been suggested by clinical experience. Wikler has developed a theoretical system which involves both classical and operant conditioning, but systematic studies in humans are lacking. Stimuli which precipitate either “craving” or “sickness” were elicited from 8 former addicts, drug-free at least 6 months and 100 addicts currently undergoing methadone treatment. The subjects were able to arrange the stimuli in a hierarchy from most to least potent. Addicts were able to clearly distinguish between the symptoms of “cravings” and “sickness”, but the stimuli which provoke each of these overlap. Various desensitization paradigms were utilized to extinguish the responses to these stimuli using both psychophysiological and subjective dependent variables. One series of extinction trials involved the use of the narcotic antagonist cyclazocine. Previous studies with antagonists have assumed random experimentation with narcotics by the addict in his environment. In this study systematic extinction trials were conducted in the clinic. Heroin addicts were detoxified and permitted to inject themselves with the narcotic hydromorphone (Dilaudid) under double-blind saline controlled conditions, while maintaining their usual rituals. Baseline responses were obtained. After a blocking dose of cyclazocine was achieved, thrice weekly extinction trials were conducted consisting of self-injections of either saline or hydromorphone under double-blind conditions. Results with 15 patients to date indicate that, (1) the procedure is acceptable to patients; (2) all injections even saline, are pleasurable initially, but after 10-15 trials they have become neutral and continued injections become increasingly aversive; (3) self injections in the clinic are generalized to other environments according to patient reports (supported by frequent urine tests); (4) pupillometry is the best measure of pharmacological “high”, but conditioned constriction to the injection of saline may occur; (5) video tapes and slides of addicts “shooting up” are potent stimuli for most addicts and post-addicts, but not for individuals who have undergone extinction trials. This treatment technique is still in a preliminary stage of development. The drop-out rate due to cyclazocine side effects is high (up to 50 per cent), but this should be reduced by naltrexone, an antagonist with few side effects. It remains to be seen whether relapse occurs after termination of antagonist when the patients know that getting narcotic effects is again possible.