NeuroscienceandBiobehavioralReviews,Vol. 16, pp. 365-369, 1992
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Substance P and Neuropsychiatric Disorders: An Overview PARVIZ MALEK-AHMADI
Department o f Psychiatry, School o f Medicine, Texas Tech University Health Sciences Center, Lubbock, T X 79430 Received 27 D e c e m b e r 1990 MALEK-AHMADI, P. Substance P and neuropsychiatric disorders: An overview. NEUROSCI BIOBEHAV REV 16(3) 365-369, 1992.- Substance P (SP) is a naturally-occurring tachykinin peptide isolated from brain tissues and gastrointestinal tract. In the brain, substantia nigra and basal ganglia contain relatively high amounts of substance P. There is evidence suggesting that substance P functions as a neurotransmitter. It has been implicated in the pathophysiology of several neuropsychiatric disorders. Substance P may also serve as a useful tool in studying the effects of antidepressant drugs and electroconvulsive therapy. However, the contribution of substance P to the understanding of neuropsychiatric disorders is far from clear. Future studies should focus on the interactions and coexistence of substance P with other neurotransmitters and neuropeptides. Tachykinins
Substance P
Central nervous system
Neurotransmitter
Neuropsychiatricdisorders
studies have shown the presence of several SP pathways in the brain. SP-containing neurons from striato-nigral, pallidonigral, septo-hippocampal, amygdalo-hypothalamic, habenulo-interpenduncularand tegmento-frontal pathways interacting with other neurotransmitters [for review (52)].
IN the past decade a number of neuropeptides have been implicated in the pathophysiology of some neuropsychiatric disorders. One of these peptides, substance P, is now considered a neurotransmitter and has received particular attention. It is the purpose of this article to review the possible role of substance P in neuropsychiatric disorders. It is not an exhaustive review, only an attempt to highlight some areas of psychiatric research pertinent to substance P.
SP Receptors A large number of studies have focused on identification and characterization of SP receptors in the brain. Autoradiographic studies have demonstrated the presence of SP receptors in the various regions of the central nervous system. SP receptors are not evenly distributed in the brain. For example, the substantia nigra contains the highest level of SP immunoreactivity, with almost no detectable SP receptors. On the other hand, high levels of SP receptors have been found in other areas of the brain, with very low concentrations of SP immunoreactivity. It has been suggested the SP/SP receptors' "mismatch" may indicate the presence of multiple receptors (57). Indeed, recent studies have provided evidence for the presence of at least three distinct postsynaptic neurokinin receptors (NK-I, 2, and 3), all of which are coupled to phosphatidylinositol cycle [for review (53)]. In the rat brain, high desities of NK-1 have been demonstrated in the striatum, while the substantia nigra apparently lacks NK-I receptors. The issue of transmitter/receptor "mismatch" has recently been reviewed. With respect to SP, technical limitations, the presence of occupied, low affinity receptors, and nonsynaptic transmission may explain the "mismatch" [for review (27)]. The possibility of nonsynaptic transmission suggests that the role of SP in physiological and pathological conditions is not always confined to the synapse. Low receptor density in synaptic area
SUBSTANCE P Substance P (SP) is a naturally-occurring and pharmacologically-active undecanopeptide (13). It is a member of a family of peptides, known as the tachykinins [for review (41)]. SP and neurokinin A (NKA), another tachykinin, are derived from three precursors termed alpha, beta, and gamma-preprotachykinins (49). Alpha-preprotachykinin generates only SP, the other two precursors give rise to both SP and NKA (38). It has been demonstrated that SP and NKA are colocalized in striato-nigral neurons (40). There is evidence suggesting that SP is an excitatory neurotransmitter. SP is synthesized by neurons and transported to synaptic vesicles. It is released by a calcium-dependent mechanism and has a depolarizing action [for review (52)1. The presence of a highly specific membrane-bound-SP-degrading enzyme in the human brain has been demonstrated (39). SP-positive cells have been identified in the brain, spinal cord, and gastrointestinal tract. In human subjects, the substantia nigra (pars compacta and pars reticulata), basal ganglia, (caudate nucleus, putamen and globus pallidus), hypothalamus, temporal cortex, and dorsal horns of the spinal cord contain SP-positive neurons (21,22,28,42). Immunohistochemical 365
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Animal studies indicate that the intestine is the main source of SP in plasma (25). In vitro studies indicate that human plasma SP is inactivated by a metalloendopeptidase (8). However, a recent study has demonstrated the endogenous plasma SP is bound to proteins and is more stable (16). It is not known to what extent (if any) brain SP reaches the circulation. However, in vitro studies also indicate that circulating SP penetrates the blood-brain barrier (4). The levels of SP in human cerebrospinal fluid (CSF) are much lower than those of plasma. In infants, children, and adults, CSF SP levels are inversely related to age (19,64). The levels are not affected by sex, body weight, or body height (2). Here again, the contribution of brain SP to its levels in the CSF is not known.
system, leading to clinical depression (12). There are only a few studies on the possible role of SP in the pathophysiology of mood disorders. In a postmortem study, there was not a significant difference between suicide victims and control subjects, with respect to SP content of the caudate nucleus (36). However, a review of the available data suggests that SP is a potential research tool in studying the effects of antidepressant agents and electroconvulsive therapy (ECT). Some studies have indicated increased cortical neuronal sensitivity to SP in rats following chronic (but not acute) administration of antidepressant agents (33,34). Opposite findings are seen after repeated electroconvulsive shock (ECS) (34). The contrasting results may be explained by the increased SP content of the brain (induced by ECS) causing reduced receptor sensitivity. The effects of ECS and ECT on SP have also been investigated in just a few studies. It has been reported that repeated ECS and antidepressant drugs increase the SP levels in rat cerebral cortex (10, l 1). A pilot study did not show any elevation of plasma SP immunoreactivity in depressed patients during the 30 minute period after bilateral ECT. It was suggested that changes in the brain SP induced by ECT might not have been detected in the periphery (62). In one study, it was found that patients with depressive and schizophrenic disorders had higher levels of SP immunoreactivity in their CSF when compared to normal volunteers (54). However, these finding were not confirmed in a later study involving bipolar patients (lithium treated and unmedicated) and control subjects (9). It should be pointed out that ECT increases the permeability of the blood-brain barrier. There is also evidence suggesting that blood-brain barrier permeability is altered in patients with mood disorders (47). Therefore, the possibility that SP changes in plasma may reflect changes in brain SP levels in ECT-treated patients cannot be dismissed and warrants further investigations. However, in a recent study ECT had no significant effect on the concentration of SP in the cerebrospinal fluids of four patients with schizophrenic disorders (15).
SP and Schizophrenic Disorders
SP and Neurologic Disorders
does not necessarily indicate that SPergic system lacks a functional significance. SP and Neuropsychiatric Disorders As stated earlier, there is growing evidence that SP is a neurotransmitter and plays a role in the pathophysiology of some neuropsychiatric disorders. SP receptors also interact with a number of other neurotransmitters. For example, it has been demonstrated that SP and NKA stimulate the release of serotonin in the rat cerebral cortex (32). There is also evidence suggesting that SP enhances desensitization of acetylcholine receptors via a second messenger (59). Perhaps the strongest evidence supporting the role of SP in the pathophysiology of neuropsychiatric disorders is based on the experimental data indicating that biosynthesis of tachykinins is controlled by dopamine receptors. It has been demonstrated that chronic administration of dopamine antagonists decreases the levels of SP in the basal ganglia (5). On the other hand, indirect dopamine agonists increase the SP levels of these structures (5). SP in Biological Fluids
The stimulating effect of SP on the dopaminergic system and the high density of the SP-containing neurons in some of the limbic structures have led to the hypothesis that "hyperfunction" of SP is of etiological importance in schizophrenia (63). A number of postmortem studies have focused on the SP changes in the brain tissues of schizophrenic patients [for review (63)]. Some studies have reported no difference in SP immunoreactivity in the brain tissues of schizophrenic patients when compared with control subjects. However, increased SP immunoreactivity has been reported in other studies. Since schizophrenia is considered a heterogeneous disorder, the possibility that SP is of etiological importance in a subgroup of schizophrenia cannot be totally ruled out. It has been demonstrated that SP and NKA differentially "modulate" dopaminergic neurons of the mesocortical and mesolimbic pathways (23). It has been postulated that SP is involved in the positive symptoms (e.g., delusions and hallucinations) of schizophrenia, while NKA is associated with the negative symptoms (e.g., apathy and flat affect). Stress, clinically associated with worsening of positive symptoms, induces the release of SP in the ventral tegmental area (23). SP and Mood Disorders It has been suggested that the "deficiency" of substance P in the brain results in underactivity of the monoaminergic
SP content of basal ganglia is altered by a number of centrally-acting pharmacological agents. A recent study has shown that L-dihydroxphenylalanine enhances SP synthesis in the neonatal dopaminergic denervated rats (60). Haloperidol and other antipsychotic agents, which induce parkinsonian symptoms, reduce SP content of the substantia nigra in laboratory animals (5). These observations have led to the hypothesis that reduced brain SP levels mediate the pathophysiology of the disorders of extrapyramidal system. Indeed, several controlled postmortem studies have consistently demonstrated decreased SP immunoreactivity in substantia nigra and globus pallidus in patients with Parkinson's and Huntington's diseases [for review (7,67)]. However, the studies on CSF SP immunoreactivity have produced inconsistent results. In one study, CSF SP immunoreactivity was significantly lower in patients with neuropathy and multiple system atrophy (48). In the same study, patients with parkinsonism, Huntington's disease, supranuclear palsy, amyotrophic lateral sclerosis, and dyskinesias did not differ in their CSF SP immunoreactivity from normal adults (48). On the other hand, another controlled study demonstrated a decreased CSF SP immunoreactivity in patients with parkinsonism (20). Increased CSF SP immunoreactivity has also been reported in patients with polyneuropathy and spinal cord disease (18). It seems that CSF SP changes reflect intraspinal pathology
NEUROPSYCHIATRIC DISORDERS rather than intracranial degenerative diseases (vide infra). In a more recent study, CSF SP immunoreactivity was measured in patients with "senile" parkinsonism and control "senile" subjects. The two groups did not differ in their CSF SP immunoreactivity (19). However, SP immunoreactivity has been reported to be low in the CSF and limbic structures of patients with Alzheimer's disease (14,17). In other studies no changes were reported [for review (56)]. The role of SP in memory functions has been extensively reviewed. Injections o f SP into the hypothalarnus and septum facilitate learning, whereas injections into the amygdala and substantia nigra impair memory tasks [for review (31)]. There is also evidence suggesting that subcutaneous administration of SP in mice counteracts the amnestic effects of ECS (58). These findings may have important clinical implications in that they suggest a possible role for SP in dementing disorders. In a recent study, the neurotoxic effects of amyloid beta protein of senile plaques on rat hippocampal ceils were "mimicked" by tachykinin antagonists. The study suggests that SP inhibits the effects of amyloid beta protein (69). Furthermore, it has been suggested that SP plays a protective role by counteracting the effects o f beta amyloid in the brain (37). The significance of the changes in the brain SP content in degenerative neurological disorders is not known. However, in the case of Parkinson's disease, the SP content of the brain may have some pathophysiological significance. Recent studies suggest that ECT has an ameliorating effect on the symptoms of Parkinson's disease (3). Animal studies indicate that repeated ECS increases SP content of the brain (11). These findings suggest that SP changes in the brain may mediate the therapeutic effects of ECT in Parkinson's disease. In neonatal animals, dopaminergic denervation is associated with decreased SP content of striatonigral neurons (60,61). The question of whether the SP changes are preceded or followed by degenerative processes certainly deserves further investigation.
SP and Chronic Pain Syndrome There is an abundance of animal data suggesting that SP is involved in transmission of pain [for review (44)]. However, the literature contains only a few studies on the possible role of SP in acute pain and chronic pain syndrome. In patients suffering from familial dysautonomia, sensitivity to pain is reduced. In a controlled study, a reduction of SP immunoreactivity in the spinal cord of five patients with familial dysautonomia was reported (51). On the other hand low CSF SP levels have been reported in patients with chronic pain syndromes as compared to healthy subjects (2). In a clinical study, the changes in CSF SP correlated with the CSF level of pethidine in patient-controlled analgesia (65). Increased CSF SP immunoreactivity has been reported in pain patients following treatment with dorsal column, intracerebral, and transcutaneous nerve stimulations (1,45).
36"l measured levels in a group of depressed patients. The study failed to detect SP, but "an N-terminally extended form of SP" was measured (43,66). Even with the aid of a highly sensitive and specific assay, CSF SP levels are not necessarily indicative of pathological changes in the brain. The lack of a rostrocaudal concentration gradient for SP in CSF suggests that the spinal cord and dorsal root ganglia are probably the main source of SP in the human CSF (48). In a recent study, CSF SP was measured in patients with multiple sclerosis and inflammatory diseases of the central nervous system. There was no significant difference between the patients and controls in their CSF SP immunoreactivity (55). Another complicating factor is the effect of ECT and various pharmacological agents, particularly psychoactive drugs, on the SP levels (35). In one postmortem study, antipsychotic drugs had no effect on brain SP levels (36). However, animal studies indicate that brain SP levels are affected by a number of centrally-acting drugs (Table 1). There is also evidence suggesting that CSF SP levels are altered by opioid drugs. Reduced CSF SP levels by systemic administration of morphine in arachnoiditis has been reported (30). Low CSF SP immunoreactivity has been reported in patients treated with levodopa (19). Clinical research on SP is further complicated by its close relationship with other peptides and the classical neurotransmitters. The link between SP and nonpeptide neurotransmitters also emphasizes the importance of studies in which SP and other neurotransmitters are simultaneously investigated. Immunohistochemical studies have demonstrated that in some areas of the brain SP coexists with several classical and peptide neurotransmitters. The implications of coexistence of SP with other neurotransmitters in the brain are not completely understood. It has been suggested that one of the functions of the neuropeptides is to potentiate the effect of their coexisting classical neurotransmitters (52). There is also the possibility of coexisting peptides functioning both as transmitter and modulator. The modulating effect may have important clinical implications in that it may extend to the effects of exogenous compounds. Receptor studies have addressed the modulating effects of SP on the action of antidepressant drugs on serotonin synapses. It has been demonstrated that chronic imipramine treatment increases the affinity of serotonin binding sites and this effect is counteracted when SP is added to the binding assay (24). It has been suggested that one of the action antidepressant drugs is to regulate the effect of SP on serotonin receptors (24). Antidepressant drugs lower the firing rate of serotonin and serotonin/SP-containing neurons as a result of which the release of serotonin is decreased but the release of SP is increased (6). It has been suggested that the effects of serotonin-uptake inhibitor antidepressant drugs are
TABLE 1 EFFECTS OF PSYCHOTROPIC AGENTS ON BRAIN (BASAL GANGLIA) SUBSTANCE P CONTENT
DISCUSSION
While the literature is replete with animal research publications on SP, there is a paucity of clinical psychiatric research on possible involvement of this peptide in neuropsychiatric disorders. This may have been due to complex issues associated with this type of clinical research. One particular problem is related to the measurement of SP in biological fluids and brain tissues. The concentration of SP in the CSF is in the femtomolar range, and its measurement requires a high degree of sensitivity. In a recent study, SP levels in the CSF were
Agents
Dopamine antagonists: Haloperidol Dopamine agonists: Methamphetamine Central antieholinergic: Trihexyphenidyl Anticonvulsants: Carbamazepine Lithium *Variable effects with clozapine (5,50).
Effect
References
Decrease* Increase No effect Increase Increase
(5,26) (5,68) (46) (46) (29)
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mediated by not only the t u r n o v e r o f m o n o a m i n e s but also the changes in the t u r n o v e r o f the coexisting SP (6). CONCLUSIONS T h e role of SP in the p a t h o p h y s i o l o g y o f neuropsychiatric disorders is far f r o m clear. T h e r e is n o evidence that decreased p r o d u c t i o n a n d / o r increased d e g r a d a t i o n o f SP mediate physiological or biochemical changes in m o o d disorders. However, some preliminary studies indicate t h a t SP m a y mediate the effects o f a n t i d e p r e s s a n t drugs a n d ECT. The overactivity o f the b r a i n SP system in s c h i z o p h r e n i a is
a n intriguing hypothesis. The possibility t h a t SP a n d N K A are o f etiological i m p o r t a n c e in a s u b g r o u p o f schizophrenia c a n n o t be ruled out a n d deserves further investigation. Finally, the significance o f decreased SP content o f the b r a i n in patients with diseases o f the central nervous system is not completely u n d e r s t o o d . F u t u r e research o n a large n u m b e r o f u n m e d i c a t e d patients may shed some light on possible i n v o l v e m e n t o f SP in the p a t h o p h y s i o l o g y o f neuropsychiatric disorders. C o n t r o l l e d p o s t m o r t e m studies in c o n j u n c t i o n with investigations focusing o n SP a n d its interaction with o t h e r n e u r o t r a n s m i t t e r s are w a r r a n t e d .
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DISORDERS
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369 49. Nyberg, F.; LeGreves, P.; Terenius, L. Identification of substance P precursor forms in human brain tissue. Proc. Natl. Acad. Sci USA. 82:3921-3924; 1985. 50. Nylander, I.; Terenius, L. Chronic haloperidol and clozapine differentially affect dynorphin peptides and substance P in basal ganglia of the rat. Brain Res. 380:34-41; 1986. 51. Pearson, J.; Brandeis, L.; Cuello, A. C. Depletion of substance P-containing axons in substantia gelatinosa of patients with diminished pain sensitivity. Nature 295:61-63; 1982. 52. Pernow, B. Substance P. Pharmacological Rev 35:85-141; 1983. 53. Quirion, R.; Dam, T. V. Multiple neurokinin receptors: Recent developments. Regul. Peptides 22:18-25; 1988. 54. Rimon, R.; LeGreves, P.; Nyberg, F.; Heikkila, L.; Saimela, L.; Terenius, L. Elevation of substance P-like peptides in the CSF of psychiatric patients. Biol. Psychiatry 19:509-516; 1984. 55. Rosier, N.; Reuner, C.; Geiger, J.; Rissler, K.; Cramer, H. Cerebrospinal fluid levels of immunoreactive substance P and somatostatin in patients with multiple sclerosis and inflammatory CNS disease. Peptides 11:181-183; 1990. 56. Rossor, M. N. Peptides and dementia. In: Nemeroff, C. D., ed. Neuropeptides in psychiatric and neurological disorders. Baltimore, MD: The Johns Hopkins University Press, 1988: 116-136. 57. Rothman, R. B.; Herkenham, M.; Pert, C. B.; Liang, T.; Cascieri, M. A. Visualization of rat brain receptors for the neuropeptide, substance P. Brain Res. 309:47-54; 1984. 58. Schlesinger, K.; Lipsitz, D. U.; Peck, P. L.; Pelleymounter, M. A. Stewart, J. M.; Chase, T. N. Substance P reversal of electroconvulsive shock and cycloheximide-induced retrograde amnesia. Behav. Neural. Biol. 39:30-39; 1983. 59. Simmons, L. K.; Schuetze, S. M.; Role, L. W. Substance P modulates single-channel properties of neuronal nicotinic acetylcholine receptors. Neuron 2:393-403; 1990. 60. Sivam, S. P. Dt dopamine receptor-mediated substance P depletion in the striatonigral neurons of rats subjects to neonatal dopaminergic denervation: Implications for self-injurious behaviors. Brain Res. 500:119-130; 1989. 61. Sivam, S. P.; Krause, J. E. Compensatory activation of substance P biosynthesis by L-dihyroxyphenylalanine in striatonigral neurons of neonatal dopaminergic denervated rats. J. Pharmacol. Exp. Ther. 254:433-439; 1990. 62. Skrabanek, P.; Balfe, A.; Webb, M.; Maguire, J.; Powell, D. Electroconvulsive therapy (ECT) increases plasma growth hormone, prolactin, luteinizing hormone and follicule-stimulating hormone but not thyrotropin or substance P. Psychoneuroendocrinology 6:261-267; 1981. 63. Takeuchi, K.; Uematsu, M.; Ofuji, M.; Morikiyo, M.; Kaiya, H. Substance P involved in mental disorders. Prog. Neuro-psychopharmacol. Biol. Psychiatry 12:157-164; 1989. 64. Tam, P. K. H.; Dockray, G. J.; Lister, J. Substance P concentrations in human cerebrospinal fluid. Neurosci. Lett. 54:327-332; 1985. 65. Tamsen, A.; Sakurada, T.; Wahlstrom, A.; Terenius, L.; Hartvig, P. Postoperative demand for analgesics in relation to individual levels of endorphins and substance P in cerebrospinai fluid. Pain 13:171-183; 1982. 66. Toresson, G.; Brodin, E.; Wahlstrom, A.; Bertilsson, L. Detection of N-terminally extended substance P but not of substance P in human cerebrospinal fluid: Quantitation with HPLC-radioimmunoassay. J. Neurochem. 50:1701-1707; 1988. 67. Uhl, G. R. Neuropeptides system in Parkinson's disease and tardive dyskinesia. In: Nemeroff, C. D., ed. Neuropeptides in psychiatric and neurological disorders. Baltimore, MD: The Johns Hopkins University Press; 1988:156-177. 68. Ujike, H.; Ogawa, N.; Otsuki, S. Effects of acute and long-term treatment with methamphetamine on substance P concentration and receptor numbers in the rat brain. Brain Res. 453:136-142; 1988. 69. Yankner, B. A.; Duffy, L. K.; Kirschner, D. A. Neurotrophic and neurotoxic effects of amyloid beta protein: Reversal by tachykinin neuropeptides. Science 250:279-282; 1990.
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Substance P and Neuropsychiatric Disorders: An Overview PARVIZ MALEK-AHMADI
Department o f Psychiatry, School o f Medicine, Texas Tech University Health Sciences Center, Lubbock, T X 79430 Received 27 D e c e m b e r 1990 MALEK-AHMADI, P. Substance P and neuropsychiatric disorders: An overview. NEUROSCI BIOBEHAV REV 16(3) 365-369, 1992.- Substance P (SP) is a naturally-occurring tachykinin peptide isolated from brain tissues and gastrointestinal tract. In the brain, substantia nigra and basal ganglia contain relatively high amounts of substance P. There is evidence suggesting that substance P functions as a neurotransmitter. It has been implicated in the pathophysiology of several neuropsychiatric disorders. Substance P may also serve as a useful tool in studying the effects of antidepressant drugs and electroconvulsive therapy. However, the contribution of substance P to the understanding of neuropsychiatric disorders is far from clear. Future studies should focus on the interactions and coexistence of substance P with other neurotransmitters and neuropeptides. Tachykinins
Substance P
Central nervous system
Neurotransmitter
Neuropsychiatricdisorders
studies have shown the presence of several SP pathways in the brain. SP-containing neurons from striato-nigral, pallidonigral, septo-hippocampal, amygdalo-hypothalamic, habenulo-interpenduncularand tegmento-frontal pathways interacting with other neurotransmitters [for review (52)].
IN the past decade a number of neuropeptides have been implicated in the pathophysiology of some neuropsychiatric disorders. One of these peptides, substance P, is now considered a neurotransmitter and has received particular attention. It is the purpose of this article to review the possible role of substance P in neuropsychiatric disorders. It is not an exhaustive review, only an attempt to highlight some areas of psychiatric research pertinent to substance P.
SP Receptors A large number of studies have focused on identification and characterization of SP receptors in the brain. Autoradiographic studies have demonstrated the presence of SP receptors in the various regions of the central nervous system. SP receptors are not evenly distributed in the brain. For example, the substantia nigra contains the highest level of SP immunoreactivity, with almost no detectable SP receptors. On the other hand, high levels of SP receptors have been found in other areas of the brain, with very low concentrations of SP immunoreactivity. It has been suggested the SP/SP receptors' "mismatch" may indicate the presence of multiple receptors (57). Indeed, recent studies have provided evidence for the presence of at least three distinct postsynaptic neurokinin receptors (NK-I, 2, and 3), all of which are coupled to phosphatidylinositol cycle [for review (53)]. In the rat brain, high desities of NK-1 have been demonstrated in the striatum, while the substantia nigra apparently lacks NK-I receptors. The issue of transmitter/receptor "mismatch" has recently been reviewed. With respect to SP, technical limitations, the presence of occupied, low affinity receptors, and nonsynaptic transmission may explain the "mismatch" [for review (27)]. The possibility of nonsynaptic transmission suggests that the role of SP in physiological and pathological conditions is not always confined to the synapse. Low receptor density in synaptic area
SUBSTANCE P Substance P (SP) is a naturally-occurring and pharmacologically-active undecanopeptide (13). It is a member of a family of peptides, known as the tachykinins [for review (41)]. SP and neurokinin A (NKA), another tachykinin, are derived from three precursors termed alpha, beta, and gamma-preprotachykinins (49). Alpha-preprotachykinin generates only SP, the other two precursors give rise to both SP and NKA (38). It has been demonstrated that SP and NKA are colocalized in striato-nigral neurons (40). There is evidence suggesting that SP is an excitatory neurotransmitter. SP is synthesized by neurons and transported to synaptic vesicles. It is released by a calcium-dependent mechanism and has a depolarizing action [for review (52)1. The presence of a highly specific membrane-bound-SP-degrading enzyme in the human brain has been demonstrated (39). SP-positive cells have been identified in the brain, spinal cord, and gastrointestinal tract. In human subjects, the substantia nigra (pars compacta and pars reticulata), basal ganglia, (caudate nucleus, putamen and globus pallidus), hypothalamus, temporal cortex, and dorsal horns of the spinal cord contain SP-positive neurons (21,22,28,42). Immunohistochemical 365
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Animal studies indicate that the intestine is the main source of SP in plasma (25). In vitro studies indicate that human plasma SP is inactivated by a metalloendopeptidase (8). However, a recent study has demonstrated the endogenous plasma SP is bound to proteins and is more stable (16). It is not known to what extent (if any) brain SP reaches the circulation. However, in vitro studies also indicate that circulating SP penetrates the blood-brain barrier (4). The levels of SP in human cerebrospinal fluid (CSF) are much lower than those of plasma. In infants, children, and adults, CSF SP levels are inversely related to age (19,64). The levels are not affected by sex, body weight, or body height (2). Here again, the contribution of brain SP to its levels in the CSF is not known.
system, leading to clinical depression (12). There are only a few studies on the possible role of SP in the pathophysiology of mood disorders. In a postmortem study, there was not a significant difference between suicide victims and control subjects, with respect to SP content of the caudate nucleus (36). However, a review of the available data suggests that SP is a potential research tool in studying the effects of antidepressant agents and electroconvulsive therapy (ECT). Some studies have indicated increased cortical neuronal sensitivity to SP in rats following chronic (but not acute) administration of antidepressant agents (33,34). Opposite findings are seen after repeated electroconvulsive shock (ECS) (34). The contrasting results may be explained by the increased SP content of the brain (induced by ECS) causing reduced receptor sensitivity. The effects of ECS and ECT on SP have also been investigated in just a few studies. It has been reported that repeated ECS and antidepressant drugs increase the SP levels in rat cerebral cortex (10, l 1). A pilot study did not show any elevation of plasma SP immunoreactivity in depressed patients during the 30 minute period after bilateral ECT. It was suggested that changes in the brain SP induced by ECT might not have been detected in the periphery (62). In one study, it was found that patients with depressive and schizophrenic disorders had higher levels of SP immunoreactivity in their CSF when compared to normal volunteers (54). However, these finding were not confirmed in a later study involving bipolar patients (lithium treated and unmedicated) and control subjects (9). It should be pointed out that ECT increases the permeability of the blood-brain barrier. There is also evidence suggesting that blood-brain barrier permeability is altered in patients with mood disorders (47). Therefore, the possibility that SP changes in plasma may reflect changes in brain SP levels in ECT-treated patients cannot be dismissed and warrants further investigations. However, in a recent study ECT had no significant effect on the concentration of SP in the cerebrospinal fluids of four patients with schizophrenic disorders (15).
SP and Schizophrenic Disorders
SP and Neurologic Disorders
does not necessarily indicate that SPergic system lacks a functional significance. SP and Neuropsychiatric Disorders As stated earlier, there is growing evidence that SP is a neurotransmitter and plays a role in the pathophysiology of some neuropsychiatric disorders. SP receptors also interact with a number of other neurotransmitters. For example, it has been demonstrated that SP and NKA stimulate the release of serotonin in the rat cerebral cortex (32). There is also evidence suggesting that SP enhances desensitization of acetylcholine receptors via a second messenger (59). Perhaps the strongest evidence supporting the role of SP in the pathophysiology of neuropsychiatric disorders is based on the experimental data indicating that biosynthesis of tachykinins is controlled by dopamine receptors. It has been demonstrated that chronic administration of dopamine antagonists decreases the levels of SP in the basal ganglia (5). On the other hand, indirect dopamine agonists increase the SP levels of these structures (5). SP in Biological Fluids
The stimulating effect of SP on the dopaminergic system and the high density of the SP-containing neurons in some of the limbic structures have led to the hypothesis that "hyperfunction" of SP is of etiological importance in schizophrenia (63). A number of postmortem studies have focused on the SP changes in the brain tissues of schizophrenic patients [for review (63)]. Some studies have reported no difference in SP immunoreactivity in the brain tissues of schizophrenic patients when compared with control subjects. However, increased SP immunoreactivity has been reported in other studies. Since schizophrenia is considered a heterogeneous disorder, the possibility that SP is of etiological importance in a subgroup of schizophrenia cannot be totally ruled out. It has been demonstrated that SP and NKA differentially "modulate" dopaminergic neurons of the mesocortical and mesolimbic pathways (23). It has been postulated that SP is involved in the positive symptoms (e.g., delusions and hallucinations) of schizophrenia, while NKA is associated with the negative symptoms (e.g., apathy and flat affect). Stress, clinically associated with worsening of positive symptoms, induces the release of SP in the ventral tegmental area (23). SP and Mood Disorders It has been suggested that the "deficiency" of substance P in the brain results in underactivity of the monoaminergic
SP content of basal ganglia is altered by a number of centrally-acting pharmacological agents. A recent study has shown that L-dihydroxphenylalanine enhances SP synthesis in the neonatal dopaminergic denervated rats (60). Haloperidol and other antipsychotic agents, which induce parkinsonian symptoms, reduce SP content of the substantia nigra in laboratory animals (5). These observations have led to the hypothesis that reduced brain SP levels mediate the pathophysiology of the disorders of extrapyramidal system. Indeed, several controlled postmortem studies have consistently demonstrated decreased SP immunoreactivity in substantia nigra and globus pallidus in patients with Parkinson's and Huntington's diseases [for review (7,67)]. However, the studies on CSF SP immunoreactivity have produced inconsistent results. In one study, CSF SP immunoreactivity was significantly lower in patients with neuropathy and multiple system atrophy (48). In the same study, patients with parkinsonism, Huntington's disease, supranuclear palsy, amyotrophic lateral sclerosis, and dyskinesias did not differ in their CSF SP immunoreactivity from normal adults (48). On the other hand, another controlled study demonstrated a decreased CSF SP immunoreactivity in patients with parkinsonism (20). Increased CSF SP immunoreactivity has also been reported in patients with polyneuropathy and spinal cord disease (18). It seems that CSF SP changes reflect intraspinal pathology
NEUROPSYCHIATRIC DISORDERS rather than intracranial degenerative diseases (vide infra). In a more recent study, CSF SP immunoreactivity was measured in patients with "senile" parkinsonism and control "senile" subjects. The two groups did not differ in their CSF SP immunoreactivity (19). However, SP immunoreactivity has been reported to be low in the CSF and limbic structures of patients with Alzheimer's disease (14,17). In other studies no changes were reported [for review (56)]. The role of SP in memory functions has been extensively reviewed. Injections o f SP into the hypothalarnus and septum facilitate learning, whereas injections into the amygdala and substantia nigra impair memory tasks [for review (31)]. There is also evidence suggesting that subcutaneous administration of SP in mice counteracts the amnestic effects of ECS (58). These findings may have important clinical implications in that they suggest a possible role for SP in dementing disorders. In a recent study, the neurotoxic effects of amyloid beta protein of senile plaques on rat hippocampal ceils were "mimicked" by tachykinin antagonists. The study suggests that SP inhibits the effects of amyloid beta protein (69). Furthermore, it has been suggested that SP plays a protective role by counteracting the effects o f beta amyloid in the brain (37). The significance of the changes in the brain SP content in degenerative neurological disorders is not known. However, in the case of Parkinson's disease, the SP content of the brain may have some pathophysiological significance. Recent studies suggest that ECT has an ameliorating effect on the symptoms of Parkinson's disease (3). Animal studies indicate that repeated ECS increases SP content of the brain (11). These findings suggest that SP changes in the brain may mediate the therapeutic effects of ECT in Parkinson's disease. In neonatal animals, dopaminergic denervation is associated with decreased SP content of striatonigral neurons (60,61). The question of whether the SP changes are preceded or followed by degenerative processes certainly deserves further investigation.
SP and Chronic Pain Syndrome There is an abundance of animal data suggesting that SP is involved in transmission of pain [for review (44)]. However, the literature contains only a few studies on the possible role of SP in acute pain and chronic pain syndrome. In patients suffering from familial dysautonomia, sensitivity to pain is reduced. In a controlled study, a reduction of SP immunoreactivity in the spinal cord of five patients with familial dysautonomia was reported (51). On the other hand low CSF SP levels have been reported in patients with chronic pain syndromes as compared to healthy subjects (2). In a clinical study, the changes in CSF SP correlated with the CSF level of pethidine in patient-controlled analgesia (65). Increased CSF SP immunoreactivity has been reported in pain patients following treatment with dorsal column, intracerebral, and transcutaneous nerve stimulations (1,45).
36"l measured levels in a group of depressed patients. The study failed to detect SP, but "an N-terminally extended form of SP" was measured (43,66). Even with the aid of a highly sensitive and specific assay, CSF SP levels are not necessarily indicative of pathological changes in the brain. The lack of a rostrocaudal concentration gradient for SP in CSF suggests that the spinal cord and dorsal root ganglia are probably the main source of SP in the human CSF (48). In a recent study, CSF SP was measured in patients with multiple sclerosis and inflammatory diseases of the central nervous system. There was no significant difference between the patients and controls in their CSF SP immunoreactivity (55). Another complicating factor is the effect of ECT and various pharmacological agents, particularly psychoactive drugs, on the SP levels (35). In one postmortem study, antipsychotic drugs had no effect on brain SP levels (36). However, animal studies indicate that brain SP levels are affected by a number of centrally-acting drugs (Table 1). There is also evidence suggesting that CSF SP levels are altered by opioid drugs. Reduced CSF SP levels by systemic administration of morphine in arachnoiditis has been reported (30). Low CSF SP immunoreactivity has been reported in patients treated with levodopa (19). Clinical research on SP is further complicated by its close relationship with other peptides and the classical neurotransmitters. The link between SP and nonpeptide neurotransmitters also emphasizes the importance of studies in which SP and other neurotransmitters are simultaneously investigated. Immunohistochemical studies have demonstrated that in some areas of the brain SP coexists with several classical and peptide neurotransmitters. The implications of coexistence of SP with other neurotransmitters in the brain are not completely understood. It has been suggested that one of the functions of the neuropeptides is to potentiate the effect of their coexisting classical neurotransmitters (52). There is also the possibility of coexisting peptides functioning both as transmitter and modulator. The modulating effect may have important clinical implications in that it may extend to the effects of exogenous compounds. Receptor studies have addressed the modulating effects of SP on the action of antidepressant drugs on serotonin synapses. It has been demonstrated that chronic imipramine treatment increases the affinity of serotonin binding sites and this effect is counteracted when SP is added to the binding assay (24). It has been suggested that one of the action antidepressant drugs is to regulate the effect of SP on serotonin receptors (24). Antidepressant drugs lower the firing rate of serotonin and serotonin/SP-containing neurons as a result of which the release of serotonin is decreased but the release of SP is increased (6). It has been suggested that the effects of serotonin-uptake inhibitor antidepressant drugs are
TABLE 1 EFFECTS OF PSYCHOTROPIC AGENTS ON BRAIN (BASAL GANGLIA) SUBSTANCE P CONTENT
DISCUSSION
While the literature is replete with animal research publications on SP, there is a paucity of clinical psychiatric research on possible involvement of this peptide in neuropsychiatric disorders. This may have been due to complex issues associated with this type of clinical research. One particular problem is related to the measurement of SP in biological fluids and brain tissues. The concentration of SP in the CSF is in the femtomolar range, and its measurement requires a high degree of sensitivity. In a recent study, SP levels in the CSF were
Agents
Dopamine antagonists: Haloperidol Dopamine agonists: Methamphetamine Central antieholinergic: Trihexyphenidyl Anticonvulsants: Carbamazepine Lithium *Variable effects with clozapine (5,50).
Effect
References
Decrease* Increase No effect Increase Increase
(5,26) (5,68) (46) (46) (29)
368
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mediated by not only the t u r n o v e r o f m o n o a m i n e s but also the changes in the t u r n o v e r o f the coexisting SP (6). CONCLUSIONS T h e role of SP in the p a t h o p h y s i o l o g y o f neuropsychiatric disorders is far f r o m clear. T h e r e is n o evidence that decreased p r o d u c t i o n a n d / o r increased d e g r a d a t i o n o f SP mediate physiological or biochemical changes in m o o d disorders. However, some preliminary studies indicate t h a t SP m a y mediate the effects o f a n t i d e p r e s s a n t drugs a n d ECT. The overactivity o f the b r a i n SP system in s c h i z o p h r e n i a is
a n intriguing hypothesis. The possibility t h a t SP a n d N K A are o f etiological i m p o r t a n c e in a s u b g r o u p o f schizophrenia c a n n o t be ruled out a n d deserves further investigation. Finally, the significance o f decreased SP content o f the b r a i n in patients with diseases o f the central nervous system is not completely u n d e r s t o o d . F u t u r e research o n a large n u m b e r o f u n m e d i c a t e d patients may shed some light on possible i n v o l v e m e n t o f SP in the p a t h o p h y s i o l o g y o f neuropsychiatric disorders. C o n t r o l l e d p o s t m o r t e m studies in c o n j u n c t i o n with investigations focusing o n SP a n d its interaction with o t h e r n e u r o t r a n s m i t t e r s are w a r r a n t e d .
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