- Email: [email protected]
Substance P (NK1) receptors in the cingulate cortex in unipolar and bipolar mood disorder and schizophrenia
BRIEF REPORT Substance P (NK1) Receptors in the Cingulate Cortex in Unipolar and Bipolar Mood Disorder and Schizophrenia Philip W.J. Burnet and Paul J. Harrison Background: The substance P receptor (neurokinin-1 receptor) has been implicated in stress responses and anxiety traits in the rodent, and neurokinin-1 receptor antagonism may have antidepressant and anxiolytic effects. This suggests that the function and/or expression of neurokinin-1 receptor might be affected in subjects with mood disorders. Methods: We measured neurokinin-1 receptor densities in the anterior cingulate cortex in subjects with unipolar (major) depression (n ⫽ 13), bipolar disorder (n ⫽ 13), schizophrenia (n ⫽ 14), and controls (n ⫽ 14) using quantitative autoradiography with [125I]BH–substance P. The anterior cingulate cortex was chosen for initial analysis since recent positron emission tomography, magnetic resonance imaging, and neuropathological data suggest its involvement in mood disorders. Results: Neurokinin-1 receptor densities were higher in superficial than in deep laminae. Neurokinin-1 receptor densities increased with age and declined with prolonged autopsy interval. No differences were seen between the four groups. However, the ratio of superficial to deep laminar binding was lower in the subjects with unipolar depression compared with all other groups (p ⬍ .01). Neurokinin-1 receptor binding and the laminar ratio were unaffected by sex, medication history, pH, suicide, comorbid substance abuse, or a family psychiatric history. Conclusions: No overall change in neurokinin-1 receptor densities occurs in the cingulate cortex in subjects with mood disorders or schizophrenia. However, the changed laminar ratio in unipolar depression may reflect alterations in specific neural circuits expressing neurokinin-1 receptor. Biol Psychiatry 2000;47:80 – 83 © 1999 Society of Biological Psychiatry
Introduction
Key Words: Affective disorder, autoradiography, bipolar disorder, depression, neurokinin-1
Frozen sections (14 m) of anterior cingulate gyrus were kindly provided by the Stanley Foundation Brain Bank. Although 15 subjects in each group were provided, some were inadvertently omitted from the study. Demographic details are summarized in Table 1. Diagnoses were made according to DSM-IV criteria. No brains exhibited any significant neuropathological abnormalities. All brains were coded by the Stanley Foundation, and experiments were performed blind to all clinical details. Neurokinin-1 receptor binding site densities were measured using [125I]BH–substance P (Amersham, Little Chalfont, Buckinghamshire, UK) as described in Beaujouan et al 1986. Briefly,
From the University Department of Psychiatry, Warneford Hospital, Headington, Oxford, United Kingdom. Address reprint requests to Philip W.J. Burnet, University Department of Psychiatry, Neurosciences Building, Warneford Hospital, Headington, Oxford, OX3 7JX, UK. Received July 8, 1999; revised September 10, 1999; accepted September 20, 1999.
© 1999 Society of Biological Psychiatry
T
he neuropeptide substance P, acting via neurokinin-1 receptors (NK1Rs), has a key role in nociception, and NK1R antagonists are generally considered to be potential analgesics. However, NK1R blockade in rats can also have anxiolytic effects (File 1997), whereas substance P and related agonists have anxiogenic profiles (Aguiar and Brandao 1996). The production of NK1R anatagonists led to the development of MK-869, which in an animal model and a randomized control trial displayed anxiolytic and antidepressant activity (Kramer et al 1998). Although the efficacy of MK-869 has not been corroborated (Enserink 1999), the data as a whole suggest that NK1Rs may play a role in the pharmacotherapy, and perhaps the pathophysiology, of mood disorders. To our knowledge, no previous studies have investigated the status of NK1Rs in these disorders, though recently NK1R densities were shown to be increased in schizophrenia (Rioux et al 1998). We have therefore carried out an autoradiographic study to determine NK1R binding site densities in subjects with mood disorder (both unipolar and bipolar) or schizophrenia compared with normal subjects. The anterior cingulate gyrus was chosen for this initial analysis, given that this region and other parts of the ventromedial prefrontal cortex have been strongly implicated in the functional and structural neuropathology of mood disorders (Drevets et al 1998; Ongur et al 1998; Rajkowska et al 1999).
Methods and Materials
0006-3223/00/$20.00 PII S0006-3223(99)00264-4
Neurokinin-1 Receptors and Depression
BIOL PSYCHIATRY 2000;47:80 – 83
81
Table 1. Demographic Details of Cases and Controls
a
Number Age (years) Sex (M, F) Brain pH Autopsy interval (hours) Age at onset (years) Duration of illness (years) Suicides Medication history Antidepressants ever used Lithium ever used Valproate ever used Antipsychotics—total exposured Unmedicated ⬎6 months before death Moderate or severe substance abuse Definite family psychiatric history
Controls
Unipolar depressionb
Bipolar disorderc
Schizophrenia
14 47 ⫾ 11 (29 – 68) 9, 5 6.29 ⫾ 0.24 (5.8 – 6.6) 24 ⫾ 10 (8 – 42) — — 0
14 45 ⫾ 8 (30 –56) 8, 5 6.17 ⫾ 0.23 (5.8 – 6.5) 28 ⫾ 11 (7– 47) 33 ⫾ 14 (11–54) 13 ⫾ 11 (1– 42) 7
13 42 ⫾ 11 (25–57) 8, 5 6.15 ⫾ 0.23 (5.8 – 6.5) 31 ⫾ 15 (13– 62) 22 ⫾ 9 (7–39) 21 ⫾ 7 (6 –32) 7
13 44 ⫾ 13 (25– 62) 8, 6 6.16 ⫾ 0.24 (5.8 – 6.6) 35 ⫾ 14 (14 – 61) 23 ⫾ 8 (13– 62) 21 ⫾ 11 (5– 45) 3
0 0 0 0
9 1 0 0
— 2 0
4 5 8
6 4 5 18,646 ⫾ 25,102 (0 – 60,000) 3 10 6
5 1 0 45,286 ⫾ 57,971 (0 –200,000) 2 7 2
Values are mean ⫾ SD with range in parentheses. a See “Methods and Materials.” b Major depression (n ⫽ 13) or depressive disorder not otherwise specified (n ⫽ 1). No cases had psychotic features. c With (n ⫽ 9) or without (n ⫽ 4) psychotic features. One case was bipolar II disorder. d Converted to chlorpromazine equivalents (g).
sections in duplicate were thawed, dried, and preincubated at room temperature in Tris buffer (50 mmol/L Tris-HCl, pH ⫽ 7.4 with 0.02% bovine serum albumin) for 15 min. Sections were then incubated in Tris buffer containing MnCl2 (3 mmol/L), bacitracin (40 g/ml), chymostatin (2 g/ml), leupeptin (4 g/ml) and [125I]BH–substance P (50 pmol) for 45 min at room temperature, followed by washes (3 ⫻ 25 sec) in ice-cold Tris buffer. Tissue sections were dried at room temperature and apposed to tritium-sensitive film (Amersham) for 4 days at 4°C. The optimal concentration of [125I]BH–substance P used was predetermined in pilot experiments on sections of cingulate cortex from other control subjects. The nonspecific binding of [125I]BH–substance P to the cingulate cortex was defined as the total binding of the ligand in the presence of nonradioactive substance P (2 mol/L). Autoradiograms were analyzed using computer-based densitometry (Burnet et al 1996). Readings were averaged from several representative strips of the cortical grey matter, either through the full depth of the cortical ribbon or over superficial and deep laminar compartments separately. The optical densities of signals, which were the means of several measurements over cortical grey matter, were converted to fmol/mg protein using [125I] calibrations made as described in Beaujouan et al 1986. Correlations were performed using the Pearson coefficient. Group differences were determined using one-way analysis of variance (ANOVA) and post hoc Bonferroni test.
the cingulate cortex is illustrated in Figure 1. A higher density of NK1Rs was observed in the superficial layers compared with the deeper layers. Inspection of Nisslstained sections indicates that this division corresponds to laminae I–III and Va–VI, respectively (Vogt et al 1995; data not shown). The overall density of NK1Rs correlated positively with age (R ⫽ ⫹.289, p ⫽ .038) and negatively
Results Specific binding of [125I]BH–substance P was observed in all cortical sections. Nonspecific binding was ⬍20%. The laminar distribution of substance P binding to NK1Rs in
Figure 1. The distribution of neurokinin-1 receptor binding sites in the cingulate cortex of a control subject showing characteristic enhancement of signal in superficial (s) laminae relative to deep (d) laminae.
82
BIOL PSYCHIATRY 2000;47:80 – 83
P.W.J. Burnet and P.J. Harrison
with autopsy interval (R ⫽ ⫺.388, p ⫽ .004) but was unaffected by sex, side of brain sampled, death by suicide, or brain pH (data not shown). Neurokinin-1 receptor densities in the cingulate cortex in controls, subjects with mood disorder, and subjects with schizophrenia are summarized in Figure 2. No significant differences between any of the four groups were observed when NK1R densities in the superficial (Figure 2A) or deep (Figure 2B) laminar compartments or overall cortical signal (not shown) were compared using ANOVA with age and autopsy interval as covariates. However, when the ratios of NK1R densities in superficial:deep laminae were analyzed (Figure 2C) there was an effect of group (F ⫽ 7.81, df ⫽ 3.48, p ⬍ .001) with a significant decrease in unipolar depression compared to controls, bipolar disorder subjects, and schizophrenic subjects (p ⬍ .01). Inspection of Figures 2A and 2B suggests that the lowered ratio reflects the trend towards decreased NK1R densities in the superficial laminae, rather than an increase in the deeper laminae. The ratio in unipolar depression subjects did not correlate with age at onset or duration of illness, nor did it differ between those with or without a history of suicide, family psychiatric history, or comorbid substance abuse. Nor was there any discernible relationship with lifetime or recent medication exposures.
Discussion This study demonstrates that NK1R binding site densities in the anterior cingulate cortex remain unchanged in mood disorders and schizophrenia (Figures 2A and 2B). This result suggests that in this brain region there is no gross abnormality of NK1R expression. However, the ratio of receptor densities in the superficial laminae compared with the deep laminae was found to be decreased in subjects with unipolar depression. This may suggest a more subtle alteration in the status of NK1R, which may be noteworthy given the potential antidepressant effects of NK1R antagonism (Kramer et al 1998). Altered receptor densities in particular laminar compartments have precedents. For example, in schizophrenia increased densities of 5-HT1A receptor binding sites in the prefrontal cortex are limited to the superficial laminae (Burnet et al 1996, 1997; Simpson et al 1996). Since neuron populations in different laminae participate in different neural circuits, one interpretation is that the altered NK1R ratio seen here reflects, and perhaps contributes to, a preferential dysfunction of superficial circuits of the cingulate gyrus in depression. Another advantage of calculating the ratio of binding is that it reduces the influence of intersubject variability in NK1R expression due to perimortem and other demographic factors, effectively increasing the power of the study. Nevertheless, the
Figure 2. The density of neurokinin-1 (NK1) receptor binding sites in the superficial (A) and deep (B) laminae of the cingulate cortex in unipolar depression, bipolar disorder, schizophrenia, and control subjects. The ratios of NK1 receptor densities in superficial:deep laminae are depicted in C. *p ⬍ 0.01 compared with all other groups. Data points in parentheses indicate outliers (values ⬎ 2 SDs from the group mean), which were omitted from the statistical analyses and from calculation of the line showing the mean ratio value for each group. The result remains significant if the outliers are included.
lack of alteration in overall NK1R densities in mood disorders (Figures 2A and 2B) must be emphasized, and a larger study is needed to confirm the finding of a changed laminar ratio of NK1R binding before further speculation as to its meaning is warranted. We found no difference in NK1R densities, or in the balance between superficial and deep laminae, in the bipolar disorder subjects (Figure 2). This suggests that any involvement of NK1R in the cingulate cortex may be related to processes specific to unipolar depression rather than to elements common to all mood disorders. Similarly,
Neurokinin-1 Receptors and Depression
the lack of change in schizophrenia suggests that the involvement of the cingulate gyrus in that disorder (Benes 1998) affects cells and circuits different from those affected in unipolar depression. In summary, we have demonstrated that NK1R densities in the cingulate cortex are unaltered in mood disorders and schizophrenia, though a laminar-specific alteration in unipolar depression was identified. The results do not appear to be confounded by medication or other perimortem variables. Given the interest in NK1R antagonists as potential antidepressants, further study of central NK1R expression in mood disorders is needed— e.g., in other areas such as the amygdala. Other factors such as the status of substance P– expressing neurons, the human cingulate cell types bearing NK1R, the regulation of NK1R, and the postsynaptic mechanisms to which the receptors are coupled also warrant investigation. Inclusion of these aspects of NK1R pharmacology in future studies will contribute to the evidence and understanding of the roles of this receptor in depression, and possibly its importance as a therapeutic target. Postmortem brains were donated by the Stanley Foundation Brain Bank courtesy of Drs. Michael Knable, E. Fuller Torrey, Maree J. Webster, and Robert Yolken. Our work is generously supported by the Stanley Foundation and the Wellcome Trust.
References Aguiar MS, Brandao ML (1996): Effects of microinjections of the neuropeptide substance P in the dorsal periaqueductal grey on the behaviour of rats in the plus maze test. Physiol Behav 60:1183–1186. Beaujouan JC, Torrens Y, Saffroy M, Glowinski J (1986): Quantitative autoradiographic analysis of the distribution of binding sites for [125I]Bolton Hunter derivatives of eledoisin and substance P in the rat brain. Neuroscience 18:857– 875. Benes FM (1998): Model generation and testing to probe neural
BIOL PSYCHIATRY 2000;47:80 – 83
83
circuitry in the cingulate cortex of postmortem schizophrenic brain. Schizophr Bull 24:219 –230. Burnet PWJ, Eastwood SL, Harrison PJ (1996): 5-HT1A and 5-HT2A receptor mRNAs and binding site densities are differentially altered in schizophrenia. Neuropsychopharmacology 15:442– 455. Burnet PWJ, Eastwood SL, Harrison PJ (1997): [3H]WAY100635 for 5-HT1A receptor autoradiography in human brain: A comparison with [3H]8-OH-DPAT and demonstration of increased binding in the frontal cortex in schizophrenia. Neurochem Int 30:565–574. Drevets WC, Ongur D, Price JL (1998): Neuroimaging abnormalities in the subgenual prefrontal cortex: Implications for the pathophysiology of familial mood disorders. Mol Psychiatry 3:220 –226. Enserink M (1999): Can the placebo be the cure? Science 284:238 –240. File SE (1997): Anxiolytic action of a neurokinin 1 receptor anatagonist in the social interaction test. Pharmacol Biochem Behav 58:747–752. Kramer MS, Cutler N, Feighner J, Shrivastava R, Carman J, Sramek JJ, et al (1998): Distinct mechanism for antidepressant activity by blockade of central substance P receptors. Science 281:1640 –1645. Ongur D, Drevets WC, Price JL (1998): Glial reduction in the subgenual prefrontal cortex in mood disorders. Proc Natl Acad Sci U S A 95:13290 –13295. Rajkowska G, Miguel-Hidalgo JJ, Wei J, Dilley G, Pittman SD, Meltzer HY, et al (1999): Morphometric evidence for neuronal and glial prefrontal cell pathology in major depression. Biol Psychiatry 45:1085–1098. Rioux L, Nissanov J, Joyce JN (1998): Increased number of [125I] BH-substance P in schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 22:1295–1299. Simpson MDC, Lubman DI, Slater P, Deakin J (1996): Autoradiography with [3H]8-OH-DPAT reveals localised increases in ventral prefrontal cortex in schizophrenia. Biol Psychiatry 39:919 –928. Vogt BA, Nimchinsky EA, Vogt LJ, Hof PR (1995): Human cingulate cortex: Surface features, flat maps and cytoarchitecture. J Comp Neurol 359:490 –506.
Introduction
Key Words: Affective disorder, autoradiography, bipolar disorder, depression, neurokinin-1
Frozen sections (14 m) of anterior cingulate gyrus were kindly provided by the Stanley Foundation Brain Bank. Although 15 subjects in each group were provided, some were inadvertently omitted from the study. Demographic details are summarized in Table 1. Diagnoses were made according to DSM-IV criteria. No brains exhibited any significant neuropathological abnormalities. All brains were coded by the Stanley Foundation, and experiments were performed blind to all clinical details. Neurokinin-1 receptor binding site densities were measured using [125I]BH–substance P (Amersham, Little Chalfont, Buckinghamshire, UK) as described in Beaujouan et al 1986. Briefly,
From the University Department of Psychiatry, Warneford Hospital, Headington, Oxford, United Kingdom. Address reprint requests to Philip W.J. Burnet, University Department of Psychiatry, Neurosciences Building, Warneford Hospital, Headington, Oxford, OX3 7JX, UK. Received July 8, 1999; revised September 10, 1999; accepted September 20, 1999.
© 1999 Society of Biological Psychiatry
T
he neuropeptide substance P, acting via neurokinin-1 receptors (NK1Rs), has a key role in nociception, and NK1R antagonists are generally considered to be potential analgesics. However, NK1R blockade in rats can also have anxiolytic effects (File 1997), whereas substance P and related agonists have anxiogenic profiles (Aguiar and Brandao 1996). The production of NK1R anatagonists led to the development of MK-869, which in an animal model and a randomized control trial displayed anxiolytic and antidepressant activity (Kramer et al 1998). Although the efficacy of MK-869 has not been corroborated (Enserink 1999), the data as a whole suggest that NK1Rs may play a role in the pharmacotherapy, and perhaps the pathophysiology, of mood disorders. To our knowledge, no previous studies have investigated the status of NK1Rs in these disorders, though recently NK1R densities were shown to be increased in schizophrenia (Rioux et al 1998). We have therefore carried out an autoradiographic study to determine NK1R binding site densities in subjects with mood disorder (both unipolar and bipolar) or schizophrenia compared with normal subjects. The anterior cingulate gyrus was chosen for this initial analysis, given that this region and other parts of the ventromedial prefrontal cortex have been strongly implicated in the functional and structural neuropathology of mood disorders (Drevets et al 1998; Ongur et al 1998; Rajkowska et al 1999).
Methods and Materials
0006-3223/00/$20.00 PII S0006-3223(99)00264-4
Neurokinin-1 Receptors and Depression
BIOL PSYCHIATRY 2000;47:80 – 83
81
Table 1. Demographic Details of Cases and Controls
a
Number Age (years) Sex (M, F) Brain pH Autopsy interval (hours) Age at onset (years) Duration of illness (years) Suicides Medication history Antidepressants ever used Lithium ever used Valproate ever used Antipsychotics—total exposured Unmedicated ⬎6 months before death Moderate or severe substance abuse Definite family psychiatric history
Controls
Unipolar depressionb
Bipolar disorderc
Schizophrenia
14 47 ⫾ 11 (29 – 68) 9, 5 6.29 ⫾ 0.24 (5.8 – 6.6) 24 ⫾ 10 (8 – 42) — — 0
14 45 ⫾ 8 (30 –56) 8, 5 6.17 ⫾ 0.23 (5.8 – 6.5) 28 ⫾ 11 (7– 47) 33 ⫾ 14 (11–54) 13 ⫾ 11 (1– 42) 7
13 42 ⫾ 11 (25–57) 8, 5 6.15 ⫾ 0.23 (5.8 – 6.5) 31 ⫾ 15 (13– 62) 22 ⫾ 9 (7–39) 21 ⫾ 7 (6 –32) 7
13 44 ⫾ 13 (25– 62) 8, 6 6.16 ⫾ 0.24 (5.8 – 6.6) 35 ⫾ 14 (14 – 61) 23 ⫾ 8 (13– 62) 21 ⫾ 11 (5– 45) 3
0 0 0 0
9 1 0 0
— 2 0
4 5 8
6 4 5 18,646 ⫾ 25,102 (0 – 60,000) 3 10 6
5 1 0 45,286 ⫾ 57,971 (0 –200,000) 2 7 2
Values are mean ⫾ SD with range in parentheses. a See “Methods and Materials.” b Major depression (n ⫽ 13) or depressive disorder not otherwise specified (n ⫽ 1). No cases had psychotic features. c With (n ⫽ 9) or without (n ⫽ 4) psychotic features. One case was bipolar II disorder. d Converted to chlorpromazine equivalents (g).
sections in duplicate were thawed, dried, and preincubated at room temperature in Tris buffer (50 mmol/L Tris-HCl, pH ⫽ 7.4 with 0.02% bovine serum albumin) for 15 min. Sections were then incubated in Tris buffer containing MnCl2 (3 mmol/L), bacitracin (40 g/ml), chymostatin (2 g/ml), leupeptin (4 g/ml) and [125I]BH–substance P (50 pmol) for 45 min at room temperature, followed by washes (3 ⫻ 25 sec) in ice-cold Tris buffer. Tissue sections were dried at room temperature and apposed to tritium-sensitive film (Amersham) for 4 days at 4°C. The optimal concentration of [125I]BH–substance P used was predetermined in pilot experiments on sections of cingulate cortex from other control subjects. The nonspecific binding of [125I]BH–substance P to the cingulate cortex was defined as the total binding of the ligand in the presence of nonradioactive substance P (2 mol/L). Autoradiograms were analyzed using computer-based densitometry (Burnet et al 1996). Readings were averaged from several representative strips of the cortical grey matter, either through the full depth of the cortical ribbon or over superficial and deep laminar compartments separately. The optical densities of signals, which were the means of several measurements over cortical grey matter, were converted to fmol/mg protein using [125I] calibrations made as described in Beaujouan et al 1986. Correlations were performed using the Pearson coefficient. Group differences were determined using one-way analysis of variance (ANOVA) and post hoc Bonferroni test.
the cingulate cortex is illustrated in Figure 1. A higher density of NK1Rs was observed in the superficial layers compared with the deeper layers. Inspection of Nisslstained sections indicates that this division corresponds to laminae I–III and Va–VI, respectively (Vogt et al 1995; data not shown). The overall density of NK1Rs correlated positively with age (R ⫽ ⫹.289, p ⫽ .038) and negatively
Results Specific binding of [125I]BH–substance P was observed in all cortical sections. Nonspecific binding was ⬍20%. The laminar distribution of substance P binding to NK1Rs in
Figure 1. The distribution of neurokinin-1 receptor binding sites in the cingulate cortex of a control subject showing characteristic enhancement of signal in superficial (s) laminae relative to deep (d) laminae.
82
BIOL PSYCHIATRY 2000;47:80 – 83
P.W.J. Burnet and P.J. Harrison
with autopsy interval (R ⫽ ⫺.388, p ⫽ .004) but was unaffected by sex, side of brain sampled, death by suicide, or brain pH (data not shown). Neurokinin-1 receptor densities in the cingulate cortex in controls, subjects with mood disorder, and subjects with schizophrenia are summarized in Figure 2. No significant differences between any of the four groups were observed when NK1R densities in the superficial (Figure 2A) or deep (Figure 2B) laminar compartments or overall cortical signal (not shown) were compared using ANOVA with age and autopsy interval as covariates. However, when the ratios of NK1R densities in superficial:deep laminae were analyzed (Figure 2C) there was an effect of group (F ⫽ 7.81, df ⫽ 3.48, p ⬍ .001) with a significant decrease in unipolar depression compared to controls, bipolar disorder subjects, and schizophrenic subjects (p ⬍ .01). Inspection of Figures 2A and 2B suggests that the lowered ratio reflects the trend towards decreased NK1R densities in the superficial laminae, rather than an increase in the deeper laminae. The ratio in unipolar depression subjects did not correlate with age at onset or duration of illness, nor did it differ between those with or without a history of suicide, family psychiatric history, or comorbid substance abuse. Nor was there any discernible relationship with lifetime or recent medication exposures.
Discussion This study demonstrates that NK1R binding site densities in the anterior cingulate cortex remain unchanged in mood disorders and schizophrenia (Figures 2A and 2B). This result suggests that in this brain region there is no gross abnormality of NK1R expression. However, the ratio of receptor densities in the superficial laminae compared with the deep laminae was found to be decreased in subjects with unipolar depression. This may suggest a more subtle alteration in the status of NK1R, which may be noteworthy given the potential antidepressant effects of NK1R antagonism (Kramer et al 1998). Altered receptor densities in particular laminar compartments have precedents. For example, in schizophrenia increased densities of 5-HT1A receptor binding sites in the prefrontal cortex are limited to the superficial laminae (Burnet et al 1996, 1997; Simpson et al 1996). Since neuron populations in different laminae participate in different neural circuits, one interpretation is that the altered NK1R ratio seen here reflects, and perhaps contributes to, a preferential dysfunction of superficial circuits of the cingulate gyrus in depression. Another advantage of calculating the ratio of binding is that it reduces the influence of intersubject variability in NK1R expression due to perimortem and other demographic factors, effectively increasing the power of the study. Nevertheless, the
Figure 2. The density of neurokinin-1 (NK1) receptor binding sites in the superficial (A) and deep (B) laminae of the cingulate cortex in unipolar depression, bipolar disorder, schizophrenia, and control subjects. The ratios of NK1 receptor densities in superficial:deep laminae are depicted in C. *p ⬍ 0.01 compared with all other groups. Data points in parentheses indicate outliers (values ⬎ 2 SDs from the group mean), which were omitted from the statistical analyses and from calculation of the line showing the mean ratio value for each group. The result remains significant if the outliers are included.
lack of alteration in overall NK1R densities in mood disorders (Figures 2A and 2B) must be emphasized, and a larger study is needed to confirm the finding of a changed laminar ratio of NK1R binding before further speculation as to its meaning is warranted. We found no difference in NK1R densities, or in the balance between superficial and deep laminae, in the bipolar disorder subjects (Figure 2). This suggests that any involvement of NK1R in the cingulate cortex may be related to processes specific to unipolar depression rather than to elements common to all mood disorders. Similarly,
Neurokinin-1 Receptors and Depression
the lack of change in schizophrenia suggests that the involvement of the cingulate gyrus in that disorder (Benes 1998) affects cells and circuits different from those affected in unipolar depression. In summary, we have demonstrated that NK1R densities in the cingulate cortex are unaltered in mood disorders and schizophrenia, though a laminar-specific alteration in unipolar depression was identified. The results do not appear to be confounded by medication or other perimortem variables. Given the interest in NK1R antagonists as potential antidepressants, further study of central NK1R expression in mood disorders is needed— e.g., in other areas such as the amygdala. Other factors such as the status of substance P– expressing neurons, the human cingulate cell types bearing NK1R, the regulation of NK1R, and the postsynaptic mechanisms to which the receptors are coupled also warrant investigation. Inclusion of these aspects of NK1R pharmacology in future studies will contribute to the evidence and understanding of the roles of this receptor in depression, and possibly its importance as a therapeutic target. Postmortem brains were donated by the Stanley Foundation Brain Bank courtesy of Drs. Michael Knable, E. Fuller Torrey, Maree J. Webster, and Robert Yolken. Our work is generously supported by the Stanley Foundation and the Wellcome Trust.
References Aguiar MS, Brandao ML (1996): Effects of microinjections of the neuropeptide substance P in the dorsal periaqueductal grey on the behaviour of rats in the plus maze test. Physiol Behav 60:1183–1186. Beaujouan JC, Torrens Y, Saffroy M, Glowinski J (1986): Quantitative autoradiographic analysis of the distribution of binding sites for [125I]Bolton Hunter derivatives of eledoisin and substance P in the rat brain. Neuroscience 18:857– 875. Benes FM (1998): Model generation and testing to probe neural
BIOL PSYCHIATRY 2000;47:80 – 83
83
circuitry in the cingulate cortex of postmortem schizophrenic brain. Schizophr Bull 24:219 –230. Burnet PWJ, Eastwood SL, Harrison PJ (1996): 5-HT1A and 5-HT2A receptor mRNAs and binding site densities are differentially altered in schizophrenia. Neuropsychopharmacology 15:442– 455. Burnet PWJ, Eastwood SL, Harrison PJ (1997): [3H]WAY100635 for 5-HT1A receptor autoradiography in human brain: A comparison with [3H]8-OH-DPAT and demonstration of increased binding in the frontal cortex in schizophrenia. Neurochem Int 30:565–574. Drevets WC, Ongur D, Price JL (1998): Neuroimaging abnormalities in the subgenual prefrontal cortex: Implications for the pathophysiology of familial mood disorders. Mol Psychiatry 3:220 –226. Enserink M (1999): Can the placebo be the cure? Science 284:238 –240. File SE (1997): Anxiolytic action of a neurokinin 1 receptor anatagonist in the social interaction test. Pharmacol Biochem Behav 58:747–752. Kramer MS, Cutler N, Feighner J, Shrivastava R, Carman J, Sramek JJ, et al (1998): Distinct mechanism for antidepressant activity by blockade of central substance P receptors. Science 281:1640 –1645. Ongur D, Drevets WC, Price JL (1998): Glial reduction in the subgenual prefrontal cortex in mood disorders. Proc Natl Acad Sci U S A 95:13290 –13295. Rajkowska G, Miguel-Hidalgo JJ, Wei J, Dilley G, Pittman SD, Meltzer HY, et al (1999): Morphometric evidence for neuronal and glial prefrontal cell pathology in major depression. Biol Psychiatry 45:1085–1098. Rioux L, Nissanov J, Joyce JN (1998): Increased number of [125I] BH-substance P in schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 22:1295–1299. Simpson MDC, Lubman DI, Slater P, Deakin J (1996): Autoradiography with [3H]8-OH-DPAT reveals localised increases in ventral prefrontal cortex in schizophrenia. Biol Psychiatry 39:919 –928. Vogt BA, Nimchinsky EA, Vogt LJ, Hof PR (1995): Human cingulate cortex: Surface features, flat maps and cytoarchitecture. J Comp Neurol 359:490 –506.