The regional distribution of somatostatin, substance P and neurotensin in human brain

doi:10.1016/0006-8993(81)91302-0

Brain Research

Volume 218, Issues 1–2, 10 August 1981, Pages 219-232

https://doi.org/10.1016/0006-8993(81)91302-0 Get rights and content

Abstract

The regional distribution of somatostatin-, substance P- and neurotensin-like immunoreactivity was determined in 41 areas of 10 human brains. Each peptide is distributed widely in the human central nervous system and for each the pattern of distribution is unique. No significant relationship was found between peptide levels and patient age, interval between death and autopsy, and tissue storage time prior to assay. The regional distribution of these peptides is similar to that seen in several animal species and the pattern of this distribution is consistent with the idea that peptides function as neurotransmitters within the central nervous system.

The problems of using human post-mortem material for peptide assay are discussed.

References (46)

H. Bernheimer et al.
Brain dopamine and the syndromes of Parkinson and Huntington — clinical morphological and neurochemical correlations
J. neurol. Sci.
(1973)
D.M. Bowen et al.
Brain-decarboxylase activities as indices of pathological changes in senile dementia
Lancet
(1974)
M.J. Brownstein et al.
Regional distribution of substance P in the brain of the rat
Brain Research
(1976)
R.E. Carraway
Neurotensin and related peptides
R. Carraway et al.
Radioimmunoassay for neurotensin, a hypothalamic peptide
J. biol. Chem.
(1976)
R. Carraway et al.
Characterization of radioimmunoassayable neurotensin in the rat
J. biol. Chem.
(1976)
A.C. Cuello et al.
Substance P: a naturally occurring transmitter in human spinal cord
Lancet
(1976)
P. Davies et al.
Selective loss of central cholinergic neurons in Alzheimer's disease
Lancet
(1976)
M.J. Duffy et al.
Stimulation of adenylate cyclase activity in different areas of human brain by substance P
Neuropharmacology
(1975)
P.C. Emson et al.
Regional distribution of methionine-enkephalin and sustance P-like immunoreactivity in normal human brain and in Huntington's disease
Brain Research
(1980)

I. Kanazawa et al.

Post-mortem changes and regional distribution of substance P in the rat and mouse nervous system

Brain Research

(1976)

I. Kanazawa et al.

Evidence for a decrease in substance P content of substantia nigra in Huntington's chorea

Brain Research

(1977)

K. Kataoka et al.

Regional distribution of immunoreactive neurotensin in monkey brain

Brain Res. Bull

(1979)

R.M. Kobayashi et al.

Regional distribution of neurotensin and somatostatin in rat brain

Brain Research

(1977)

E.A. Mroz et al.

Substance P.

E.K. Perry et al.

Neurotransmitter enzyme abnormalities in senile dementia

J. neurol. Sci.

(1977)

T.L. Perry et al.

γ-Aminobutyric-acid deficiency in brain of schizophrenic patients

Lancet

(1979)

G.R. Uhl et al.

Regional and subcellular distributions of brain neurotensin

Life Sci.

(1976)

W. Vale et al.

Biologic and immunologic activities and applications of somatstatin analogs

Metabolism

(1978)

J.L. Barker

Physiological roles of peptides in the nervous system

E.D. Bird et al.

Huntington's chorea — post-mortem measurement of glutamic acid decarboxylase, choline acetyltransferase and dopamine in basal ganglia

Brain

(1974)

E.D. Bird et al.

Brain immunoreactive gonadotropin — releasing hormone in Huntington's chorea and in non-choreic subjects

Nature (Lond.)

(1976)

E.D. Bird et al.

Increased dopamine concentration in limbic areas of brain from patients dying with schizophrenia

Brain

(1979)

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However, synaptophysin immunocytochemistry was decreased significantly in mouse neocortex and hippocampus when the brain was stored for 4 h at 22°C instead of 4°C to mimic postmortem conditions that occur in human situation (Hilbig et al., 2004). In contrast, several neuropeptides and receptors remain very stable over the period of several days (Cooper et al., 1981). Hypothalamic TRH levels remain stable from 2.5 and 21 h postmortem (Parker Jr. and Porter, 1982).
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In postmortem studies, the patient and control groups must be matched for as many as possible of the known confounding factors. This is necessary to make the groups as similar as possible, except for the topic being investigated. Confounding factors are present (i) before, (ii) during, and (iii) after death. They are, respectively: (i) genetic background, systemic diseases, duration and gravity of illness, medicines and addictive compounds used, age, sex, gender identity, sexual orientation, clock- and seasonal time of death, and lateralization; (ii) agonal state, stress of dying; and (iii) postmortem delay, freezing procedures, fixation, and storage time. Agonal state is generally estimated by measuring the pH of the brain. However, there are disorders in which pH is lower as a part of the disease process. Because of the large number of potentially confounding factors that differ according to, for instance, brain area and disease, a brain bank should have a large number of controls at its disposal for appropriate matching. If matching fails for some confounders, the influence of the confounders may be determined by statistical methods, such as analysis of variance or the regression models.
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NT is widely distributed in the mammalian central nervous system, where it acts as a neurotransmitter and neuromodulator [2,3]. High concentrations of NT were shown in the substantia nigra, nucleus accumbens (NAC), hypothalamus, periaqueductal gray matter and amygdala (AMY) [2,4–6]. Numerous NT-containing pathways have been identified to be originating from the ventral tegmental area (VTA), amygdala (AMY) and subiculum [7,8].
Tridecapeptide Neurotensin (NT) is widely distributed in the central nervous system where it acts as a neurotransmitter and neuromodulator. The central nucleus of amygdala (CeA), part of the limbic system, plays an important role in learning, memory, anxiety and reinforcing mechanisms. Our previous data showed that NT microinjected into the CeA has positive reinforcing properties. We supposed that these effects might be due to modulations of the mesolimbic dopamine system. The aim of our study was to examine in the CeA the possible effects of NT and dopamine interaction on reinforcement by conditioned place preference test.
Male Wistar rats were microinjected bilaterally with 100 ng NT or 2 μg D1 dopamine receptor antagonist alone, or D1 dopamine antagonist 15 min before 100 ng NT treatment or vehicle solution into the CeA. Other animals received 4 μg D2 dopamine receptor antagonist Sulpiride alone, or administration of D2 dopamine receptor antagonist 15 min before 100 ng NT treatment or vehicle solution into the CeA.
Rats that received 100 ng NT spent significantly more time in the treatment quadrant during the test session. Pre-treatment with the D1 dopamine antagonist, blocked the effects of NT. D2 dopamine receptor antagonist pretreatment could prevent the positive reinforcing effects of NT as well. Antagonists themselves did not influence the place preference.
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The quality of postmortem research depends strongly on a thorough clinical investigation and documentation of the patient's disorder and therapies. In addition, a systematic and professional neuropathologic investigation of both cases and controls is absolutely crucial. In the experience of the Netherlands Brain Bank (NBB), about 20% of clinical neurologic diagnoses, despite being made in first-rate clinics, have to be revised or require an extra diagnosis after a complete and thorough review by the NBB. The neuropathology examination may reveal for instance that the “controls” already have preclinical neurodegenerative alterations.
In postmortem studies the patient and control groups must be matched for as many of the known confounding factors as possible. This is necessary to make the groups as similar as possible, except for the topic being investigated. Confounding factors are present before, during, and after death. They are respectively: (1) genetic background, systemic diseases, duration and gravity of illness, medicines and addictive compounds used, age, sex, gender identity, sexual orientation, circadian and seasonal fluctuations, lateralization; (2) agonal state, stress of dying; and (3) postmortem delay, freezing procedures, fixation and storage time. Consequently, a brain bank should have a large number of controls at its disposal for appropriate matching. If matching fails for some confounders, then their influence may be determined by statistical methods such as analysis of variance or regression models.
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Neurotensin is an endogenous neuropeptide closely associated with the mesolimbic dopaminergic system and shown to possess antipsychotic-like effects. In particular, acute neurotensin receptor activation can inhibit conditioned avoidance response (CAR), attenuate phencyclidine (PCP)-induced prepulse inhibition (PPI) disruptions, and reverse PCP-induced hyperlocomotion. However, few studies have examined the long term effects of repeated neurotensin receptor activation and results are inconsistent. Since clinical administration of antipsychotic therapy often requires a prolonged treatment schedule, here we assessed the effects of repeated activation of neurotensin receptors using an NTS1 receptor selective agonist, PD149163, in 3 behavioral tests of antipsychotic activity. We also investigated whether reactivity to the atypical antipsychotic clozapine was altered following prior PD149163 treatment. Using both normal and prenatally immune activated rats generated through maternal immune activation with polyinosinic:polycytidylic acid, we tested PD149163 in CAR, PCP (1.5 mg/kg)-induced PPI disruption, and PCP (3.2 mg/kg)-induced hyperlocomotion. For each paradigm, rats were first repeatedly tested with vehicle or PD149163 (1.0, 4.0, 8.0 mg/kg, sc) along with vehicle or PCP for PPI and hyperlocomotion tests, then challenged with PD149163 after 2 drug-free days. All rats were then challenged with clozapine (5.0 mg/kg, sc). During the repeated test period, PD149163 exhibited antipsychotic-like effects in all three models. On the PD149163 challenge day, prior drug treatment only caused a tolerance effect in CAR. This tolerance in CAR was transferrable to clozapine, as it enhanced clozapine tolerance in the same group of animals. Although no tolerance effect was seen in the PD149163 challenge for the PCP-induced hyperlocomotion test, the clozapine challenge showed increased sensitivity in groups previously exposed to repeated PD149163 treatment. Our findings suggest that repeated exposure to NTS1 receptor agonists can induce a dose-dependent tolerance and cross-tolerance to clozapine to some of its behavioral effects but not others.
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The involvement of NTergic neurons in the regulation of neuroendocrine secretion has been supported by numerous observations. High NT endogenous levels have been detected in the hypothalamic region of both the rat and human as demonstrated by radioimmunoassay (Uhl and Snyder, 1976; Cooper et al., 1981; Manberg et al., 1982). NT-immunoreactive (IR) cell bodies have also been seen in many hypothalamic structures such as the paraventricular and infundibular nuclei, which send their fibers to the median eminence (Merchenthaler and Lennard, 1991).
The aim of the present investigation was to determine a detailed mapping of neurotensin (NT) in the human hypothalamus, the brain region involved in neuroendocrine control. For this, we investigated the presence and the distribution of neurotensin binding sites in the human hypothalamus, using an in vitro quantitative autoradiography technique and the selective radioligand monoiodo-Tyr3-neurotensin (2000 Ci/mM). This study was performed on nine adult human postmortem hypothalami. We first determined the biochemical kinetics of the binding and found that binding affinity constants were of high affinity and do not differ significantly between all cases investigated. Our analysis of the autoradiographic distribution shows that NT binding sites are widely distributed throughout the rostrocaudal extent of the hypothalamus. However, the distribution of NT binding sites is not homogenous and regional variations exist. In general, the highest densities are mainly present in the anterior hypothalamic level, particularly in the preoptic region and the anterior boarding limit (i.e. the diagonal band of Broca). Important NT binding site densities are also present at the mediobasal hypothalamic level, particularly in the paraventricular, parafornical and dorsomedial nuclei. At the posterior level, relatively moderate densities could be observed in the mammillary complex subdivisions, apart from the supramammillary nucleus and the posterior hypothalamic area. In conclusion, the present study demonstrates the occurrence of high concentrations of NT binding sites in various structures in many regions in the human adult hypothalamus, involved in the control of neuroendocrine and/or neurovegetative functions.

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Research reportThe regional distribution of somatostatin, substance P and neurotensin in human brain

Abstract

J. neurol. Sci.

Lancet

Brain Research

J. biol. Chem.

J. biol. Chem.

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Lancet

Neuropharmacology

Brain Research

Brain Research

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Brain Res. Bull

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J. neurol. Sci.

Lancet

Life Sci.

Metabolism

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Huntington's chorea — post-mortem measurement of glutamic acid decarboxylase, choline acetyltransferase and dopamine in basal ganglia

Brain

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Nature (Lond.)

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Brain

Research report
The regional distribution of somatostatin, substance P and neurotensin in human brain