Changes in acetylcholinesterase activity and muscarinic receptor bindings in mu-opioid receptor knockout mice

Anatomical evidence indicates that cholinergic and opioidergic systems are co-localized and acting on the same neurons. However, the regulatory mechanisms between cholinergic and opioidergic system have not been well characterized. In the present study, we investigated whether there are compensatory changes of acetylcholinesterase activity and cholinergic receptors in mice lacking mu-opioid receptor gene. The acetylcholinesterase activity was determined by histochemistry assay. The cholinergic receptor binding was carried out by quantitative autoradiography using [3H]-quinuclidinyl benzilate (nonselective muscarinic receptors), N-[3H]-methylscopolamine (nonselective muscarinic receptors), [3H]-pirenzepine (M1 subtype muscarinic receptors) and [3H]-AF-DX384 (M2 subtype muscarinic receptors) in brain slices of wild-type and mu-opioid receptor knockout mice. The acetylcholinesterase activity of mu-opioid receptor knockout mice was higher than that of the wild-type in the striatal caudate putamen and nucleus accumbens, but not in the cortex and hippocampus areas. In addition, the bindings in N-[3H]-methylscopolamine and [3H]-AF-DX384 of mu-opioid receptor knockout mice were significantly lower when compared with that of the wild-type controls in the striatal caudate putamen and nucleus accumbens. However, there were no significant differences in bindings of [3H]-quinuclidinyl benzilate and [3H]-pirenzepine between mu-opioid receptor knockout and wild-type mice in the cortex, striatum and hippocampus. These data indicate that there are up-regulation of acetylcholinesterase activity and compensatory down-regulation of M2 muscarinic receptors in the striatal caudate putamen and nucleus accumbens of mu-opioid receptor knockout mice.     

Changes in γ-aminobutyric acid, μ-opioid and neurotensin receptors in the accumbens-pallidal projection after discrete quinolinic acid lesions in the nucleus accumbens

Discrete quinolinic acid lesions in the nucleus accumbens altered [³H]muscimol binding to γ-aminobutyric acid receptors, [¹²⁵I]neurotensin binding to neurotensin receptors, [¹²⁵I]Tyr-d-Ala-Gly-NMePhe-Gly-OH binding to μ-opioid receptors, and [³H]quinuclidinyl benzilate binding to muscarinic receptors. Within lesions of the lateral accumbens core, [³H]muscimol binding increased and [¹²⁵I]Tyr-d-Ala-Gly-NMePhe-Gly-OH, [¹²⁵I]eurotensin and [³H]quinuclidinyl benzilate binding decreased. Lesions of the medial nucleus accumbens resulted in decreased [¹²⁵I]Tyr-d-Ala-Gly-NMePhe-Gly-OH and [³H]quinuclidinyl benzilate binding while no alterations were observed for [³H]muscimol or [¹²⁵I]neurotensin binding. These data support anatomical distinctions between medial and lateral nucleus accumbens. Destruction of intrinsic neurons in the dorsomedial nucleus accumbens core increased [³H]muscimol binding in the dorsal rim of the ventral pallidum and the rostral globus pallidus without altering [¹²⁵I]Tyr-d-Ala-Gly-NMePhe-Gly-OH binding. Destruction of neurons in the lateral nucleus accumbens core or medial shell did not alter [³H]muscimol binding in the ventral pallidum. The lack of upregulation in γ-aminobutyric acid receptors suggests that the γ-aminobutyric acid-containing projection from the dorsomedial core to the dorsal rim of the ventral pallidum differs from the projection from the lateral accumbens core and medial shell to the more ventral regions of the pallidum. Fluoro-gold retrogade tracer histochemistry confirmed the specific projection from the dorsomedial core to the dorsal ventral pallidum; and from the shell of the nucleus accumbens to more ventral regions of the ventral pallidum.     

An autoradiographic analysis of cholinergic receptors in mouse brain

Autoradiographic techniques were used to localize cholinergic receptors in the central nervous system of female DBA mice. Nicotinic receptors were identified using [3H]-L-nicotine and alpha-[125I]-bungarotoxin (BTX); [3H]-quinuclidinyl benzilate (QNB) was used to examine muscarinic receptor binding. There was little overlap between the regional distribution of binding sites for these ligands. Nicotine binding was highest in thalamic nuclei, the superior colliculus and the interpeduncular nucleus. For BTX binding, high density receptor populations were identified in the hippocampus, caudate putamen, colliculi (superior and inferior) and various nuclei in the hypothalamus and hindbrain. Muscarinic receptors were distributed more uniformly than nicotinic receptors; the colliculi, hippocampus and cerebral cortex had the highest level of QNB binding. Species differences between rats and mice in terms of cholinergic receptor binding are discussed.     

Age-Related Changes in the N-Methyl- -aspartate Receptor Binding Sites within the Human Basal Ganglia

The present study examined the regional differences in dopamine transporter binding sites and NMDA receptor complex binding based on autoradiographic images obtained in postmortem sections of human normal brain tissues. In middle-aged control tissues, high and comparable levels of [³H]CFT binding were observed in the caudate nucleus, putamen, and accumbens nucleus without significant alteration along the rostrocaudal axis and ventral and dorsal parts of these nuclei. In aging normal brain tissues, dopamine binding sites for [³H]CFT were significantly reduced in the caudate nucleus, putamen, and accumbens nucleus. -[³H]Glutamate, [³H]MK-801, and [³H]glycine binding to the NMDA receptor complex was lower in aging brain tissues than in middle-aged controls. Significant correlation did occur between age and [³H]CFT binding and between age and -[³H]glutamate, [³H]MK-801, and [³H]glycine binding sites. These results demonstrate that the basal ganglia have age-associated reductions in dopamine transporter uptake and NMDA receptors. These data support hypoactive activity of the NMDA receptor complex system with advancing age. The dopamine transporter uptake and NMDA receptors appear to be vulnerable to the aging process in the basal ganglia.     

Cholinergic receptor binding and autoradiography in brains of non-neurological and senile dementia of Alzheimer-type patients

Muscarinic and nicotinic cholinergic receptor distribution was studied by dry-mount autoradiography in brains obtained postmortem from patients with senile dementia of Alzheimer-type (SDAT) and non-neurological controls. Sections were incubated with either [N-methyl-³H]scopolamine, ([³H]NMS) or [¹²⁵I]α-bungarotoxin, ([¹²⁵I]α-BTX). No significant difference in the affinity and number of muscarinic and nicotinic receptors was found in hippocampus, frontal, temporal and cingulate cortex between SDAT patients and non-neurological controls. However, some SDAT cases showed diffuse instead of laminar [³H]NMS labeling in cortical regions. The labeling pattern was not affected by the presence of neuritic plaques and neurofibrillary tangles.     

Autoradiographic localization and quantification of dopamine D2 receptors in normal human brain with [H]N-n-propylnorapomorphine

The precise distribution of dopamine receptors has been studied autoradiographically in the normal human brain using [³H]N-n-propylnorapomorphine ([³H]NPA) as a ligand. Preliminary experiments aimed at optimizing the binding assay conditions revealed that preincubation washing of caudate nucleus sections was a prerequisite to obtain a good ratio of specific to non-specific binding. The binding of [³H]NPA to caudate-putamen sections was saturable, stereospecific, reversible, of high affinity (K_d = 0.27–0.35 nM) and occurred at a single population of sites. Competition experiments with various drugs indicated that in the caudate-putamen the specific [³H]NPA binding sites possess the pharmacological features of the dopamine D₂ receptor. The highest levels of [³H]NPA binding sites were found in the caudate nucleus, putamen, globus pallidus and nucleus accumbens. There were also intermediate to low concentrations of the ³H-ligand in the hippocampus, the insular and cingular cortices and in the occipito-temporal gyrus, while almost undetectable levels of binding were found in the anteior frontal cortex. Thorough examination of the subregional distribution of [³H]NPA binding sites in the caudate-putamen-pallidum complex revealed heterogenous patterns of radioactivity. In these brain regions, the distribution of autoradiographic grains was punctate and islands of high and low densities were observed. Moreover, in the caudate nucleus, there was a subtle high lateral to low medial gradient in the topography of the [³H]NPA binding sites and a more pronounced gradient along the rostrocaudal axis; the highest levels of binding being located at the midbody of the nucleus. No gradients of [³H]NPA binding were observed in the putamen. The present data indicate that [³H]NPA is a suitable ligand for accurate autoradiographic labeling of dopamine D₂ receptors in human postmortem brain tissue and that dopamine receptors are heterogeneously distributed and topographically organized in patches and gradients in the basal ganglia regions.     

Altropane,a SPECT or PET imaging probe for dopamine neurons: III. Human dopamine transporter in postmortem normal and Parkinson's diseased brain

Increasing evidence suggests that the dopamine transporter is situated almost exclusively on dopamine neurons. Accordingly, it is an valuable marker for Parkinson's disease and other pathological states of dopamine neurons. We previously demonstrated that the potent dopamine transport inhibitor [¹²⁵I]altropane (IACFT:E-N-iodoallyl-2β-carbomethoxy-3β-(4-fluorophenyl)tropane) is a high affinity selective probe for the dopamine transporter in monkey brain and an effective SPECT imaging agent in nonhuman primate brain. We now report the binding properties of [¹²⁵I]altropane in postmortem tissue of normal human brain and compare the findings to Parkinson's diseased brain. In homogenates of human brain putamen, [¹²⁵I]altropane bound with high affinity (K_D: 4.96 ± 0.38 nM, n = 4) and site density (B_MAX: 212 ± 41.1 pmol/g original wet tissue weight) well within the density range reported previously for the dopamine transporter in this brain region. Drugs inhibited [¹²⁵I]altropane binding with a rank order of potency that corresponded closely to their rank order for blocking dopamine transport (r 0.98, P < 0.001). In postmortem Parkinson's diseased brain, bound [¹²⁵I]altropane (1 nM) was markedly reduced (89%, 99% in putamen, depending on measures of nonspecific binding) compared with normal aged-matched controls (normal putamen: 49.2 ± 8.1 pmol/g; Parkinson's diseased putamen: 0.48 ± 0.33 pmol/g; n = 4). In vitro autoradiography, conducted in tissue sections at a single plane of the basal ganglia, revealed high levels of [¹²⁵I]altropane binding the caudate nucleus and putamen, but lower levels (73% of the caudate-putamen) in the nucleus accumbens (n = 7). In Parkinson's diseased brains (n = 4), [¹²⁵I]altropane binding was 13% of the levels detected in normal putamen, 17% of normal values in the caudate nucleus, and 25% of normal levels in nucleus accumbens. The association of [¹²⁵I]altropane to the dopamine transporter in human postmortem tissue, the marked reduction of [¹²⁵I]altropane binding in Parkinson's diseased brains, its rapid entry into brain and highly localized distribution in dopamine-rich brain regions, support its use as a probe for monitoring the dopamine transporter in vitro and in vivo by SPECT imaging. Synapse 29:116–127, 1998. © 1998 Wiley-Liss, Inc.     

Neurotransmitter receptor alterations in Huntington's disease: autoradiographic and homogenate studies with special reference to benzodiazepine receptor complexes

In vitro receptor autoradiography was used to construct semiquantitative maps of subtypes of muscarinic cholinergic (labeled with [3H]N-methylscopolamine), benzodiazepine ([3H]flunitrazepam), gamma-aminobutyric acid ([3H]muscimol), dopamine, and serotonin ([3H]spiperone) receptors in frontal cortex, parietal cortex, caudate, putamen, and globus pallidus in tissue sections from 5 patients with clinically well-evaluated Huntington's disease and 5 controls matched with respect to age, sex, and postmortem delay. Homogenates were prepared from the remaining cortical and striatal tissue and used to characterize pharmacologically these same receptors, as well as histamine, adenosine, and nitrendipine receptors. Neuronal loss and gliosis were assessed in the contralateral formalin-fixed caudate and putamen. All binding sites measured (except serotonin) were reduced relative to control values in striatum primarily because of changes in the number of receptors rather than in affinity. Autoradiographic studies generally revealed that these changes were greater in the caudate than the putamen, paralleling the more severe neuropathological changes present in the caudate. In addition, autoradiographic studies demonstrated an increase in gamma-aminobutyric acid-related receptors in the globus pallidus. In the cortex, receptor alterations were limited to an increase in the number of benzodiazepine receptors in the frontal cortex which was most prominent in superficial cortical layers.     

Development of β1 and β2 adrenergic receptors in baboon brain: An autoradiographic study using [125I]iodocyanopindolol

[¹²⁵I]iodocyanopindolol (ICYP) autoradiography was used to investigate the temporal development and distribution of β₁ and beta;₂ receptors in brains of baboons at ages embryonic day 100 (E100), full-term gestation (E180), and 3 years. In all brain regions examined, with the exception of the hippocampus, binding to β₁ receptors exceeded that to β₂ receptors. The highest densities of ββ₁ receptors were found in the caudate nucleus, putamen, globus pallidus, substantia nigra, and cerebral cortex; intermediate receptor densities were observed in most nuclei of thalamus, and the lowest concentrations were in the hippocampus. At E100, β₁ receptors were identified in the striatum, globus pallidus, and thalamus. During maturation, the number of β₁ receptors declined in cortical areas but increased in the head of the caudate and putamen. Significant differences in the developmental distribution of β₁ receptors during development were also detected: at E100 and E180 β₁ receptors appeared as patches in the caudate and putamen, but by 3 years of age they were more homogeneously distributed in both regions; changes also occurred in the distribution of binding within cortical layers. Autoradiograms of [¹²⁵I]ICYP and [³H]mazindol binding show overlapping patches of labeling in the E180 striatum, suggesting a possible developmental association between β receptors and dopamine high-affinity uptake carrier sites. This study demonstrates that noradrenergic receptors in the primate forebrain undergo significant developmental reorganization with regional variations.     

Direct autoradiographic determination of M1 and M2 muscarinic acetylcholine receptor distribution in the rat brain: Relation to cholinergic nuclei and projections

The autoradiographic distributions of receptors with high affinity for [3H]oxotremorine-M (the M2 receptor) and [3H]pirenzepine (the M1 receptor) were studied in the rat brain. M1 receptors were seen in highest density only in telencephalic structures: cerebral cortex (layers I-II), hippocampus, dentate gyrus, medial and basolateral amygdala, nucleus accumbens and caudate/putamen. M2 receptors were detected throughout the brain, with highest levels observed in cerebral cortical layers III and V, forebrain cholinergic nuclei, caudate/putamen, various thalamic areas, inferior and superior colliculus, interpeduncular and pontine nuclei, brainstem cholinergic nuclei and cervical spinal cord regions. M2 receptors were found to be good markers for cholinergic cell groups and the majority of cholinergic projection areas, whereas M1 receptors were only found in a large sub-group of telencephalic cholinergic projection areas, and the pattern of distribution of receptors in these areas differed from that of M2 receptors. Scatchard analysis of [3H]oxotremorine-M binding to inferior collicular slices revealed one site with a dissociation constant (Kd) of 1.9 nM and a receptor density (Bmax) of 1.4 pmol/mg protein. Our data support the hypothesis that M1 and M2 receptors are physically distinct sub-types of the muscarinic acetylcholine receptor.     

D1 and D2-type dopamine receptors in patients with Parkinson's disease and progressive supranuclear palsy

The densities of D1- and D2-type dopamine receptors were measured with [3H]SCH23390 and [3H]spiperone, in the caudate nucleus and putamen of a large series of patients with Parkinson's disease or progressive supranuclear palsy, in relation to markers of dopaminergic and cholinergic innervation of the striatum ([3H]dihydrotetrabenazine binding and choline acetyltransferase activity). Correlations were sought between these parameters and clinical characteristics of the patients (abnormal involuntary movements, dementia, confusional syndrome or treatment). In Parkinson's disease, the densities of both types of receptors were unchanged, whereas in PSP, the density of D2, but not D1-type dopamine receptors, was decreased in the caudate nucleus and the putamen. No correlations between the biochemical and clinical data were found.     

Altropane,a SPECT or PET imaging probe for dopamine neurons: II. distribution to dopamine-rich regions of primate brain

The dopamine transporter in brain, localized almost exclusively on dopamine neurons, is an effective window on dopamine neurons. SPECT or PET imaging of the transporter in brain requires selective imaging agents that display appropriate pharmacokinetic properties. We previously reported that [¹²⁵I]altropane ([¹²⁵I]IACFT,2β-carbomethoxy-3β-(4-fluorophenyl)-n- (1-iodoprop-1-en-3-yl)nortropane) bound with high affinity (Kd: 5.33 nM) to a single site on the dopamine transporter and was selective for dopamine over the serotonin transporter in homogenates of monkey striatum. To determine whether the selective binding of [¹²⁵I]altropane is reflected in its brain distribution, the in vitro and ex vivo distribution of [¹²⁵I]altropane in squirrel monkey (Saimiri sciureus) brain was determined by quantitative autoradiography of coronal brain sections. In vitro, [¹²⁵I]altropane (2 nM) distribution was discrete and was detectable primarily in the dopamine-rich putamen, caudate nucleus, and nucleus accumbens. The resulting putamen:cerebellum ratio exceeded 120:1 (n = 3). The selective in vitro binding of [¹²⁵I]altropane to the dopamine transporter, at concentrations approaching its Kd value (Kd: 5.33 nM, a single high affinity site), highlight its suitability for investigating the density of the dopamine transporter in various brain regions in vitro. Ex vivo autoradiography was conducted in monkeys to determine whether the brain distribution of [¹²⁵I]altropane in vitro was predictive of its brain distribution pattern after intravenous administration. Thirty minutes after intravenous injection, highest levels of [¹²⁵I]altropane (0.3 nmol/kg) were detected in the caudate-putamen and nucleus accumbens and lowest levels in the cerebellum and cortex. The putamen or caudate:cerebellum ratio was 7. SPECT imaging of the brain within 30 min of i.v. injection confirmed the rapid and selective accumulation of [¹²³I]altropane to the striatum. The selective binding of altropane to the dopamine-rich striatum within 30 min of i.v. administration indicates that it is uniquely suited for SPECT or PET imaging of the dopamine transporter and associated dopamine neurons. Synapse 29:105–115, 1998. © 1998 Wiley-Liss, Inc.     

Oestradiol Modulation of Serotonin Reuptake Transporter and Serotonin Metabolism in the Brain of Monkeys

Serotonin (5-hydroxytryptamine; 5-HT) is an important brain neurotransmitter that is implicated in mental and neurodegenerative diseases and is modulated by ovarian hormones. Nevertheless, the effect of oestrogens on 5-HT neurotransmission in the primate caudate nucleus, putamen and nucleus accumbens, which are major components of the basal ganglia, and the anterior cerebral cortex, mainly the frontal and cingulate gyrus, is not well documented. The present study evaluated 5-HT reuptake transporter (SERT) and 5-HT metabolism in these brain regions in response to 1-month treatment with 17β-oestradiol in short-term (1 month) ovariectomised (OVX) monkeys (Macaca fascicularis). SERT-specific binding was measured by autoradiography using the radioligand [³H]citalopram. Biogenic amine concentrations were quantified by high-performance liquid chromatography. 17β-Oestradiol increased SERT in the superior frontal cortex and in the anterior cingulate cortex, in the nucleus accumbens, and in subregions of the caudate nucleus of OVX monkeys. 17β-Oestradiol left [³H]citalopram-specific binding unchanged in the putamen, as well as the dorsal and medial raphe nucleus. 17β-Oestradiol treatment decreased striatal concentrations of the precursor of 5-HT, 5-hydroxytryptophan, and increased 5-HT, dopamine and 3-methoxytyramine concentrations in the nucleus accumbens, caudate nucleus and putamen, whereas the concentrations of the metabolites 5-hydroxyindoleacetic acid, 3,4-dihydroxyphenylacetic acid and homovanillic acid remained unchanged. No effect of 17β-oestradiol treatment was observed for biogenic amine concentrations in the cortical regions. A significant positive correlation was observed between [³H]citalopram-specific binding and 5-HT concentrations in the caudate nucleus, putamen and nucleus accumbens, suggesting their link. These results have translational value for women with low oestrogen, such as those in surgical menopause or perimenopause.     

Lack of genotype effect on D1, D2 receptors and dopamine transporter binding in triple MOP‐, DOP‐, and KOP‐opioid receptor knockout mice of three different genetic backgrounds

We investigated D1, D2 receptors and dopamine transporter (DAT) binding levels in mice lacking all three opioid receptors and wild‐type (WT) mice on three different genetic backgrounds. Quantitative autoradiography was used to determine the level of radioligand binding to the D1 and D2 receptors and DAT labeled with [³H]SCH23390, [³H]raclopride, and [³H]mazindol, respectively in triple‐opioid receptor knockout (KO) and WT maintained on C57BL/6 (B6) and 129/SvEvTac (129) as well as C57BL/6 × 129/SvPas (B6 × 129) strains. No significant genotype effect was observed in D1, D2 receptors and DAT binding in any regions analyzed in any of the strains studied, suggesting that a lack of all three opioid receptors does not influence D1, D2 receptors and DAT expression, irrespective of their genetic strain background. However, strain differences were observed in D1 binding between the three strains of mice studied. Lower levels of D1 binding were observed in the substantia nigra of B6 × 129 WT mice compared with the 129 WT mice and in the olfactory tubercle of B6 × 129 WT compared with B6 WT and 129 WT mice. Lower levels of D1 binding were observed in the caudate putamen of B6 × 129 KO mice compared with 129 KO mice. In contrast, no significant strain differences were observed in D2 and DAT binding between the three strains of mice in any regions analyzed. Overall, these results indicate a lack of modulation of the dopaminergic system by the deletion of all three opioid receptors regardless of different background strains. Synapse 64:520–527, 2010. © 2010 Wiley‐Liss, Inc.     

Opioid receptor ligand binding in the human striatum: II. Heterogeneous distribution of kappa opioid receptor labeled with [3H]Bremazocine

Selective kappa opioid receptor autoradiography with [³H]bremazocine (BRM) was used to examine regional and subregional kappa receptor distribution patterns at five rostrocaudal levels through the human striatum. [³H]BRM binding densities were measured in the individual striatal nuclei and in subregions therein. The distribution of [³H]BRM binding sites was found to have a strongly heterogeneous character. At the regional level a rostral-to-caudal decrease in [³H]BRM binding densities was observed. Also, a dorsal-to-ventral differentiation was seen, with higher values in the ventral striatum, especially in the nucleus accumbens, and lower values in the dorsal parts of the caudate nucleus and putamen. These findings suggest an association of kappaa receptor function with limbic-related processes in the ventral striatum. Along the ventral edge of the nucleus accumbens and putamen, specific domains with extremely high [³H]BRM binding values were identified. © 1996 Wiley-Liss, Inc.     

Developmental profiles of various cholinergic markers in the rat main olfactory bulb using quantitative autoradiography

The existence of possible relationships among the developmental profile of various cholinergic markers in the main olfactory bulb (OB) was assessed by using in vitro quantitative autoradiography. Muscarinic receptors were visualized with [³H]pirenzepine (muscarinic M1-like sites) and [³H]AF-DX 384 (muscarinic M2-like sites); nicotinic receptors by using [³H]cytisine (nicotinic 42-like subtype) and [¹²⁵I]α-bungarotoxin (nicotinic 7-like subtype); cholinergic nerve terminals by using [³H]vesamicol (vesicular acetylcholine transport sites) and [³H]hemicholinium-3 (high-affinity choline uptake sites). These various cholinergic markers exhibited their lowest levels at birth and reached adult values by the end of the 4–5 postnatal weeks. However, the density of presynaptic cholinergic markers and nicotinic receptors at postnatal day 2 represented a large proportion of the levels observed in adulthood, and displays a transient overexpression around postnatal day 20. In contrast, the postnatal development of cholinergic muscarinic M1-like and M2-like receptors is apparently regulated independently of the presynaptic cholinergic markers and nicotinic receptors. Two neurochemically and anatomically separate olfactory glomeruli subsets were observed in the posterior OB of the developing rat. These atypical glomeruli expressed large amounts of [³H]vesamicol- and [³H]hemicholinium binding sites without significant amounts of muscarinic M1, M2, or nicotinic α4β2 receptor binding sites. A significant density of [¹²⁵I]α-bungarotoxin binding sites could be detected only at early postnatal ages. A few olfactory glomeruli specifically restricted to the dorsal posterior OB expressed a high density of [³H]cytisine binding sites but lacked significant binding of the two presynaptic cholinergic markers used here, suggesting their noncholinergic but cholinoceptive nature. © 1996 Wiley-Liss, Inc.     

Reduced density of striatal somatostatin receptors in Huntington's chorea

A marked increase of the endogenous somatostatin has been reported in the striatum in Huntington's chorea by radioimmunoassay and immunohistochemistry. Using quantitative receptor autoradiography we examined the density and distribution of somatostatin receptors in the striatum of 6 patients dying from Huntington's chorea degree 3, in 12 control healthy patients dying without neurological diseases and 7 schizophrenic patients, using the stable somatostatin octapeptide analogue [¹²⁵I]204-090 as a radioligand. Marked reductions of the density of somatostatin binding sites were observed in the caudate and putamen of all patients with Huntington's chorea. However, these receptors were well preserved in the nucleus accumbens and in the ventral aspects of the anterior putamen. No alteration of somatostatin receptors was observed in other brain areas. These results suggest that somatostatin receptors in the human striatum are markedly down-regulated or localized on a population of neurons which is at risk in Huntington's chorea and questions the postulated role for the elevated somatostatin levels in choreiform movements.     

Chronic cocaine alters brain mu opioid receptors

The possibility that dopamine may modulate the expression of opioid receptors was investigated by determining the effects of chronic cocaine administration on the density of μ opioid receptors. Quantitative in vitro autoradiography with the highly selective μ opioid ligand [³H]DAMGO was used to measure and localize changes in μ opioid receptors in the brains of rats administered cocaine or saline three times daily for 14 days. Significant increases in [³H]DAMGO binding were measured in areas of the cingulate cortex, nucleus accumbens, caudate putamen, and basolateral amygdaloid nucleus of the cocaine-treated animals. These results demonstrate that μ opioid receptors undergo upregulation in response to chronic cocaine exposure and suggest that dopamine activity can regulate the expression of μ opioid receptors.     

Autoradiographic localization of extrastriatal D2-dopamine receptors in the human brain using [125I]epidepride

Epidepride is a benzamide with high affinity for central D₂- and D₃-dopamine receptors. The anatomical distribution of [¹²⁵I]epidepride binding was examined by autoradiography, using postmortem human whole-hemisphere cryosections. The density of [¹²⁵I]epidepride binding sites was high in caudate nucleus and putamen. [¹²⁵I]epidepride also labeled receptors in extrastriatal region such as in the pallidum, some thalamic nuclei, the neocortex, and the substantia nigra. The neocortical binding was heterogeneously distributed. In most cortical regions, binding sites were located in superficial layers (I-II). However, in basal levels of the occipital cortex, [¹²⁵I]epidepride binding was located in a deeper layer, probably corresponding to layer V. Competition studies indicated that most of the [¹²⁵I]epidepride binding represented predominantly D₂-dopamine receptors, in striatal as well as in extrastriatal regions. The presence of extrastriatal D₂-dopamine receptor populations is of particular interest for research on schizophrenia and antipsychotic drug action. © 1996 Wiley-Liss, Inc.     

Characterization of [I]HEAT binding to α1-receptors in human brain: assessment in aging and Alzheimer's disease

The binding of [¹²⁵I]2-(β-4-hydroxyphenylethylamino-ethyltetralone ([¹²⁵I]HEAT), an α₁-adrenergic receptor antagonist, to human brain membranes was characterized and the binding assessed in tissue from subjects with Alzheimer's disease (AD) and aging controls. Under Na⁺-K⁺ phosphate buffer conditions, [¹²⁵I]HEAT bound to a single class of binding sites in prefrontal cortex (Brodmann area 10) with a K_d of about 120 pM. High binding capacities of [¹²⁵I]HEAT were evident in the hippocampus and neocortex but were low in subcortical areas and cerebral microvessels comparable to the regional distribution of [³H]prazosin binding reported previously. Displacement of [¹²⁵I]HEAT by various adrenergic drugs was consistent with its binding to α₁-adrenergic receptors. The specific binding was not affected by postmortem delay between death and freezing of tissue at autopsy. There was no correlation of [¹²⁵I]HEAT binding with age of subjects. In AD subjects, the binding was significantly decreased in prefrontal cortex by about 25% but not changed in hippocampus, putamen or cerebellum compared to age-matched controls. The reduced binding of [¹²⁵I]HEAT in prefrontal cortex may reflect a region-specific change in α₁-adrenergic receptors associated with neuronal loss in AD.