Selective changes of receptor binding in brain regions of aged rats

Binding to several receptors was compared in brain regions of 3 and 21-23 month-old rats. In crude membrane preparations of aged rats the number of dopamine antagonist receptors in striatum was much reduced (-53%). beta-Noradrenergic receptors (cortex) and benzodiazepine receptors (hippocampus and cerebellum) were less but significantly reduced and serotonergic receptors, alpha 1 noradrenergic receptors (both in cortex) and dopamine agonist receptors (striatum) were unchanged. For each receptor binding the KD values were the same in young and old animals. GABA receptor binding (hippocampus and cerebellum) evaluated at only one 3H-GABA concentration (8 nM) was similar in both groups when expressed per protein content but significantly reduced in aged rats when expressed per tissue wet weight because of the partial purification of the synaptic membranes used for 3H-GABA binding. In our experimental conditions age-related changes of specific binding sites in the central nervous system were selective for some receptors studied and did not seem to be due to general non-specific modification of brain tissue composition.     

Regional Distribution of Neuropeptide Y and Its Receptor in the Porcine Central Nervous System

The regional distribution of neuropeptide Y (NPY) immunoreactivity and receptor binding was studied in the porcine CNS. The highest amounts of immunoreactive NPY were found in the hypothalamus, septum pellucidum, gyrus cinguli, cortex frontalis, parietalis, and piriformis, corpus amygdaloideum, and bulbus olfactorius (200-1,000 pmol/g wet weight). In the cortex temporalis and occipitalis, striatum, hippocampus, tractus olfactorius, corpus mamillare, thalamus, and globus pallidus, the NPY content was 50-200 pmol/g wet weight, whereas the striatum, colliculi, substantia nigra, cerebellum, pons, medulla oblongata, and medulla spinalis contained less than 50 pmol/g wet weight. The receptor binding of NPY was highest in the hippocampus, corpus fornicis, corpus amygdaloideum, nucleus accumbens, and neurohypophysis, with a range of 1.0-5.87 pmol/mg of protein. Intermediate binding (0.5-1.0 pmol/mg of protein) was found in the septum pellucidum, columna fornicis, corpus mamillare, cortex piriformis, gyrus cinguli, striatum, substantia grisea centralis, substantia nigra, and cerebellum. In the corpus callosum, basal ganglia, corpus pineale, colliculi, corpus geniculatum mediale, nucleus ruber, pons, medulla oblongata, and medulla spinalis, receptor binding of NPY was detectable but less than 0.5 pmol/mg of protein. No binding was observed in the bulbus and tractus olfactorius and adenohypophysis. In conclusion, immunoreactive NPY and its receptors are widespread in the porcine CNS, with predominant location in the limbic system, olfactory system, hypothalamoneurohypophysial tract, corpus striatum, and cerebral cortex.     

Regional Specificity in Alterations of Rat Brain Copper and Catecholamines Following Perinatal Copper Deficiency

Abstract: Perinatal copper deficiency was studied in 1-month-old female and male Sprague-Dawley rat offspring to investigate regional changes in brain copper and catecholamine levels. Offspring of dams given the low copper treatment beginning at day 7 of gestation exhibited signs characteristic of deficiency such as impaired growth and 10-fold lower liver copper levels compared with copper-adequate controls. Regional analysis of brain copper by graphite furnace atomic absorption spectroscopy revealed uniform and severe reduction of copper to levels 20 ± 3% of controls in all regions, except the hypothalamus, where reductions to 56 and 28% of those in copper-adequate females and males, respectively, were measured. HPLC analysis revealed significant reductions in norepinephrine levels in cerebrum, midbrain, corpus striatum, cerebellum, and medulla-pons of copper-deficient offspring ranging between 39 and 67% of control values. There were no significant differences in norepinephrine concentration in the hypothalamus. There was a significant, one-third reduction of dopamine in the corpus striatum of copper-deficient male rats. Consistent with altered in vivo dopamine β-monooxygenase activity, there were five-, three-, and twofold elevations of dopamine in cerebellum, medulla-pons, and hypothalamus of copper-deficient rats. Spectrophotometric measurement of in vitro dopamine β-monooxygenase activity of brain and adrenal homogenates was higher in copper-deficient rats, confirming prior work. An explanation for the in vitro data is unclear. Changes in copper and catecholamine levels were influenced by diet and were regionally selective, especially in the hypothalamus.     

α-Linolenic Acid Dietary Deficiency Alters Age-Related Changes of Dopaminergic and Serotoninergic Neurotransmission in the Rat Frontal Cortex

Abstract: The effects of α-linolenic acid diet deficiency on rat dopaminergic and serotoninergic neurotransmission systems were investigated in the frontal cortex, striatum, and cerebellum of male rats 2, 6, 12, and 24 months of age. The diet deficiency induced a severe decrease in the 22:6n-3 fatty acid levels in all regions and a compensatory increase in n-6 fatty acid levels. A recovery in the levels of 22:6n-3 was observed in deficient rats between 2 and 12 months of age; however, this recovery was lower in frontal cortex than in striatum and cerebellum. In the striatum and the cerebellum, dopaminergic and serotoninergic receptor densities and endogenous dopamine and serotonin levels were affected by aging regardless of the diet. In contrast, a 40–75% lower level of endogenous dopamine in the frontal cortex occurred in deficient rats according to age. The deficiency also induced an 18–46% increase in serotonin 5-HT₂ receptor density in the frontal cortex during aging, without variation in endogenous serotonin level, and a 10% reduction in density of dopaminergic D₂ receptors. Monoamine oxidase-A and -B activities showed specific age-related variations but regardless of the diet. Our results suggest that a chronically α-linolenic-deficient diet specifically affects the monoaminergic systems in the frontal cortex.     

Enhanced muscarinic M1 receptor gene expression in the corpus striatum of streptozotocin-induced diabetic rats

Acetylcholine (ACh), the first neurotransmitter to be identified, regulate the activities of central and peripheral functions through interactions with muscarinic receptors. Changes in muscarinic acetylcholine receptor (mAChR) have been implicated in the pathophysiology of many major diseases of the central nervous system (CNS). Previous reports from our laboratory on streptozotocin (STZ) induced diabetic rats showed down regulation of muscarinic M1 receptors in the brainstem, hypothalamus, cerebral cortex and pancreatic islets. In this study, we have investigated the changes of acetylcholine esterase (AChE) enzyme activity, total muscarinic and muscarinic M1 receptor binding and gene expression in the corpus striatum of STZ – diabetic rats and the insulin treated diabetic rats. The striatum, a neuronal nucleus intimately involved in motor behaviour, is one of the brain regions with the highest acetylcholine content. ACh has complex and clinically important actions in the striatum that are mediated predominantly by muscarinic receptors. We observed that insulin treatment brought back the decreased maximal velocity (V_max) of acetylcholine esterase in the corpus striatum during diabetes to near control state. In diabetic rats there was a decrease in maximal number (B_max) and affinity (K_d) of total muscarinic receptors whereas muscarinic M1 receptors were increased with decrease in affinity in diabetic rats. We observed that, in all cases, the binding parameters were reversed to near control by the treatment of diabetic rats with insulin. Real-time PCR experiment confirmed the increase in muscarinic M1 receptor gene expression and a similar reversal with insulin treatment. These results suggest the diabetes-induced changes of the cholinergic activity in the corpus striatum and the regulatory role of insulin on binding parameters and gene expression of total and muscarinic M1 receptors.     

Age related changes in weight and the concentrations of zinc and copper in the brain of the adult rat

Two groups of adult male rats aged 15 weeks and 49 weeks, 15 rats in each group, were analysed for the concentrations of the trace elements zinc (Zn) and copper (Cu) in serum, liver, kidney, and five parts of the brain (cortex, corpus striatum, hippocampus, midbrain + medulla, and cerebellum). All organs increased in weight from 15 weeks to 49 weeks. In all parts of the brain, except for corpus striatum, there was a significant increase of the weights. The dry weight (% of wet) increased in all parts of the brain. In serum, the Zn and Cu concentrations increased from 15 weeks to 49 weeks. In the liver, both concentrations decreased and in the kidney the concentrations increased with increasing age. The Zn concentrations increased in cortex and corpus striatum and decreased in cerebellum and hippocampus. The Cu levels increased in all parts of the brain with the largest changes in corpus striatum. For rats aged 49 weeks, a significant correlation was found between the Cu concentrations of corpus striatum or midbrain + medulla and the fluid consumption. The findings of the present study reveal a dynamic age-related pattern of changes in the concentrations of Zn and Cu in different organs of the adult rat. This stresses the need of age-matching as an important control in experiment studies.     

The striatum and cerebral cortex express different muscarinic receptor mRNAs

The existence of four distinct muscarinic acetylcholine receptor genes (m1 – m4) has recently been demonstrated. cDNAs for three of these receptors have been cloned from brain (m1, m3, m4) and one from heart (m2). To gain some understanding of the physiological role of the brain muscarinic receptors, we mapped the distribution of their mRNAs in rat brain by in situ hybridization. These mRNAs are barely detectable in the hindbrain and cerebellum. Within forebrain, each mRNA has a strikingly different pattern of distribution. The highest levels of m1 mRNA are in the cerebral cortex and hippocampus followed by the striatum. m3 mRNA is also prominent in the cerebral cortex, but has very low levels in the striatum. Conversely, the levels of m4 mRNA are highest in the striatum. Since the cognitive effects of muscarinic drugs have been localized to the cerebral cortex and hippocampus, and their psychomotor effects to the striatum, these data suggest that the muscarinic receptors which subserve these responses may be different gene products. Finally, we show that these muscarinic receptors can be distinguished pharmacologically, suggesting that it may be possible to develop drugs for the selective treatment of the psychomotor vs cognitive difficulties of Parkinson's and Alzheimer's disease, respectively.     

Neurotransmitter receptor alterations in Parkinson's disease.

Neurotransmitter receptor binding for GABA, serotonin, cholinergic muscarinic and dopamine receptors and choline acetyltransferase (ChAc) activity were measured in the frontal cortex, caudate nucleus, putamen and globus pallidus from postmortem brains of 10 Parkinsonian patients and 10 controls. No changes in any of these systems were observed in the frontal cortex. In the caudaye nucleus, only the apparent dopamine receptor binding was altered with a significant 30% decrease in the Parkinsonian brain. Both cholinergic muscarinic and serotonin receptor binding were significantly altered in the putamen, the former increasing and the latter decreasing with respect to controls. In addition, ChAc activity was decreased in the putamen. In the globus pallidus, only ChAc activity was significantly changed, decreasing about 60%, with no change in neurotransmitter receptor binding. The results suggest that a progressive loss of dopaminergic receptors in the caudate nucleus may contribute to the decreased response of Parkinsonian patients to L-dopa and dopamine agonist therapy.     

Cholinergic hyperinnervation in the cerebral cortex of microencephalic rats does not result in muscarinic receptor down-regulation or in alteration of receptor-stimulated phosphoinositide metabolism

Administration of methylazoxymethanol (MAM; 25 mg/kg) to pregnant rats at gestational day 15 (GD 15) induces a marked reduction of telencephalic areas of the offspring brain. Previous neurochemical studies demonstrated a marked cholinergic hyperinnervation in the cerebral cortex of microencephalic rats. In this study we have evaluated whether this cholinergic hyperinnervation could result in altered functionality of muscarinic receptors. Acetylcholinesterase activity (AChE) was increased by 69% in the cerebral cortex of MAM treated rats confirming a relative hyperinnervation, whereas in the hippocampus and striatum no significant changes were observed. Despite the marked hyperinnervation, in the cerebral cortex of microencephalic rats neither muscarinic receptor-stimulated phosphoinositide metabolism nor muscarinic, receptor density were altered. No differences in receptor density were also observed in the hippocampus and striatum. Chronic diisopropylfluorophosphate (DFP) administration induced a marked decrease of AChE activity and down-regulation of muscarinic receptors whereas atropine administration resulted in receptor up-regulation in cerebral cortex, striatum and hippocampus of both control and MAM rats. The results confirm a relative cholinergic hyperinnervation in the cerebral cortex of microencephalic rats and demonstrate that the regulation of muscarinic receptor-stimulated phosphoinositide metabolism and muscarinic receptor plasticity is not modified in a condition of increased cholinergic presynaptic terminals.     

Lack of desensitization of muscarinic receptor-mediated second messenger signals in rat brain upon acute and chronic inhibition of acetylcholinesterase.

We studied the effects of acute and chronic in vivo inhibition of acetylcholinesterase on both the density and function of brain muscarinic cholinergic receptors. Adult male rats were treated either once or multiple times over a period of 10 days with the irreversible acetylcholinesterase inhibitor diisopropylfluorophosphate (DFP). The concentration and affinity of muscarinic receptors in various brain regions were determined using radioligand binding techniques. Acute DFP treatment resulted in a significant reduction in receptor number only in the brain stem, while chronic treatment caused receptor down-regulation in the brain stem, cerebral cortex, and striatum. There was no change in ligand affinity in any of the brain regions. In sharp contrast, muscarinic receptor function was fully preserved, in terms of coupling of the receptors to increased phosphoinositide hydrolysis in the cerebral cortex, hippocampus, and striatum, or inhibition of cyclic AMP formation in the cerebral cortex or striatum. Therefore, there is a marked lack or correlation between DFP-induced muscarinic receptor down-regulation and receptor desensitization.     

A simple and rapid radio-receptor assay for the estimation of acetylcholine

The high potency with which acetylcholine (ACh) inhibits the binding of the specific muscarinic agonist, [³H]$\text{cis}$ methyldioxolane ([³H]CD), has provided the basis for the development of a radio-receptor assay for estimation of ACh. A synaptosomal preparation of the rat cerebral cortex was used as a source of muscarinic receptors. When binding assays were run at 0°C, the IC₅₀ value of ACh was approximately 5 × 10^?9 M, which corresponds to 2.5 – 10 pmoles of ACh, depending upon the assay volume. The ACh content of the rat cerebral cortex and corpus striatum was measured following fast microwave irradiation. By measuring the displacement of [³H]CD binding caused by aliquots of the supernatant from tissue homogenates and comparing the displacement values with an ACh standard curve, the ACh content of the cerebral cortex and corpus striatum was calculated to be 19 and 55 nmoles/g wet tissue weight, respectively.     

Lack of desensitization of muscarinic receptor–mediated second messenger signals in rat brain upon acute and chronic inhibition of acetylcholinesterase

We studied the effects of acute and chronic in vivo inhibition of acetylcholinesterase on both the density and function of brain muscarinic cholinergic receptors. Adult male rats were treated either once or multiple times over a period of 10 days with the irreversible acetylcholinesterase inhibitor diisopropylfluorophosphate (DFP). The concentration and affinity of muscarinic receptors in various brain regions were determined using radioligand binding techniques. Acute DFP treatment resulted in a significant reduction in receptor number only in the brain stem, while chronic treatment caused receptor downregulation in the brain stem, cerebral cortex, and striatum. There was no change in ligand affinity in any of the brain regions. In sharp contrast, muscarinic receptor function was fully preserved, in terms of coupling of the receptors to increased phosphoinositide hydrolysis in the cerebral cortex, hippocampus, and striatum, or inhibition of cyclic AMP formation in the cerebral cortex or striatum. Therefore, there is a marked lack or correlation between DFP-induced muscarinic receptor down-regulation and receptor desensitization.     

Regional Alterations in Rat Brain Neurotransmitter Systems Following Chronic Lithium Treatment

Abstract: Chronic, but not acute, consumption of lithium leads to a significant decrease in serotonin and GABA receptor binding in selected regions of the rat brain, with no changes noted in P-adrenergic or cholinergic muscarinic receptor binding. In addition, the concentration of β-methoxytyramine, a dopamine metabolite, in the corpus striatum was increased in the animals treated chronically with lithium, suggesting a possible enhancement in dopamine release, or inhibition of uptake, in this brain area. In contrast, chronic consumption of rubidium had no effect on any of the parameters studied. The results suggest that lithium administration causes selective changes in brain neurotransmitter receptor systems and that the net result of these changes may be a decrease in GABAergic and serotoninergic activity. The fact that these alterktions are noted only after chronic administration suggests that they may be related to the therapeutic action of lithium in the prophylactic treatment of recurrent manic- depressive psychosis.     

Reduced D2-mediated signaling activity and trans-synaptic upregulation of D1 and D2 dopamine receptors in mice overexpressing the dopamine transporter

The dopamine transporter (DAT) regulates the temporal and spatial actions of dopamine by reuptaking this neurotransmitter into the presynaptic neurons. We recently generated transgenic mice overexpressing DAT (DAT-tg) that have a 3-fold increase in DAT protein levels which results in a 40% reduction of the extracellular DA concentration in the striatum. The aim of this study was to examine the effect of this reduction in dopaminergic tone on postsynaptic responses mediated by dopamine receptors. We report here that DAT-tg mice have increased levels of striatal D1 (30%) and D2 (approximately 60%) dopamine receptors with D1 receptor signaling components not significantly altered, as evidenced by unaffected basal or stimulated levels of phospho-GluR1 (Ser845) and phospho-ERK2. However, the novel D2 mediated Akt signaling is markedly altered in DAT-tg animals. In particular, there is a 300% increase in the basal levels of phospho-Akt in the striatum of DAT-tg, reflecting the reduced extracellular dopamine tone in these animals. This increase in basal pAkt levels can be pharmacologically recapitulated by partial dopamine depletion in WT mice treated with the selective tyrosine hydroxylase inhibitor alpha-methyl-para-tyrosine (alpha-MPT). Behaviorally, DAT-tg animals demonstrate an augmented synergistic interaction between up-regulated D1 and D2 receptors, which results in increased climbing behavior in transgenic mice after stimulation with either apomorphine or a co-administration of selective D1 and D2 receptor agonists. In sum, our study reveals that hypodopaminegia caused by up-regulation of DAT results in significant alterations at postsynaptic receptor function with most notable dysregulation at the level of D2 receptor signaling.     

Dietary lithium during development: Changes in amino acid levels,ionic content,and [3H]spiperone binding in the brain of rats

We found that chronic lithium diet affects the sensitivity of neuroleptic receptors and the content of amino acids in the brain, and that the changes in adult animals differ from those in young rats. Pregnant rats were kept on lithium diet (pellets with 0.21% Li2CO3 and 0.21% NaCl) during the gestation period and the offspring were kept on lithium for six weeks after delivery. Control rats were kept on normal diet under identical conditions. In corpus striatum and cerebral cortex of lithium-treated young rats a reduction in apparent dissociation constant and no change in (3H)spiperone total binding sites were found, suggesting a sensitization of the neuroleptic receptor; this result was unlike that obtained with adult lithium-treated rats, where the total number of binding sites was decreased. The lithium content of brain was very high (2.32 meq/kg of wet weight), whereas in the serum only 0.75 meq/l was recorded. K+ and Na+ levels increased by 20% and 9% respectively in the brain and remained at normal levels in the serum. Analysis of free amino acids in the cerebral cortex, midbrain, and cerebellum showed increases in GABA and glycine levels in all three regions, a significant increase in taurine in midbrain, and an increase in lysine in cerebral cortex and cerebellum. The results indicate that the effect of chronic dietary lithium given during pregnancy on the neuroleptic receptor in young rats is different from that in adult animals. It produces an increase in the number of the neuroleptic receptor sites instead of the decline in the number of binding sites found in adult rats. It remains to be established whether this effect is related more to the age of the animal tested or to the stage of development of the CNS at which the lithium was administered.     

Distribution and Localization of Estrogen-Sensitive Dopamine Receptors in the Rat Brain

Administration of estrogen to adult male rats increases the density of striatal dopamine receptors. The densities of the dopamine receptors in the nucleus accumbens and cortex are not altered, while the density of those in the hippocampus is decreased. In the pituitary the density, on a whole pituitary basis, is not changed. The increased density of striatal dopamine receptors normally observed after estrogen treatment is prevented by prior injection into the striatum of kainic acid, which destroys the intrinsic neurons in the striatum. In addition, the benzodiazepine receptors in the striatum, cortex, hippocampus, and cerebellum are not altered by estrogen treatment, showing the specificity of the estrogen treatment and suggesting that the effects of estrogen are not mediated through benzodiazepine receptors.     

INTRASTRIATAL ADMINISTRATION OF AN OLIGODEOXYNUCLEOTIDE ANTISENSE TO THE D2 DOPAMINE RECEPTOR mRNA INHIBITS D2 DOPAMINE RECEPTOR-MEDIATED BEHAVIOR AND D2 DOPAMINE RECEPTORS IN NORMAL MICE AND IN MICE LESIONED WITH 6-HYDROXYDOPAMINE

Previous studies have shown that the intracerebroventricular injection of antisense oligodeoxynucleotides targeted to the mRNAs encoding the different subtypes of dopamine receptors inhibited behaviors mediated by these receptors. The present studies were designed to determine whether such antisense oligodeoxynucleotides could produce similar effects when injected into a discrete brain area. A D₂ dopamine receptor antisense oligodeoxynucleotide (D₂ antisense) was repeatedly injected into one corpus striatum of either normal mice or mice with unilateral lesions of the striatum induced by 6-hydroxydopamine. In the latter, intrastriatal injection of D₂ antisense blocked the contralateral rotational behavior induced by the parenteral administration of the D₂ dopamine receptor agonist quinpirole. The inhibitory effect of D₂ antisense was dose- and time-related and was reversed upon cessation of D₂ antisense treatment. This inhibitory effect was also selective in that D₂ antisense treatment inhibited the rotational behavior induced by quinpirole but not that induced by the D₁ dopamine receptor agonist SKF 38393 or by the muscarinic cholinergic agonist oxotremorine. Following repeated intrastriatal injections of D₂ antisense into normal mice, parenteral administration of quinpirole caused rotational behavior ipsilateral to the side in which the D₂ antisense was injected. No such rotational behavior was seen when similarly treated mice were challenged with SKF 38393 or oxotremorine. The quinpirole-induced rotational behavior in mice given intrastriatal injections of D₂ antisense disappeared upon cessation of D₂ antisense treatment. Repeated intrastriatal administration of D₂ antisense also caused a significant reduction in the levels of D₂, but not D₁, dopamine receptors in striatum, as determined by receptor autoradiography. The levels of D₂ dopamine receptors returned to normal upon cessation of D₂ antisense treatment. Intrastriatal administration of an oligodeoxynucleotide with randomly placed nucleotides failed to alter the rotational response to quinpirole in either 6-hydroxydopamine-lesioned or normal mice and failed to alter the levels of D₂ dopamine receptors in striatum. These results show that selective inhibition of behavioral responses mediated by D₂ dopamine receptors can be achieved by the direct injection of a D₂ antisense oligodeoxynucleotide into a discrete brain area. Copyright © 1996 Elsevier Science Ltd     

Electroconvulsive Shock and Reserpine: Effects on β-Adrenergic Receptors in Rat Brain

Abstract Electroconvulsive shock (ECS) administered once daily for up to 14 days decreases β-adrenergic receptor binding in the cortex and hippocampus in a time-dependent manner. The decrease in binding in the cortex lasts at least 1 week after the last shock. In the striatum, hypothalamus, or cerebellum, 14 days of ECS did not produce significant changes in β-adrenergic receptor binding. The brain regional pattern of β-adrenergic receptor changes suggests that repeated ECS affects β-adrenergic receptors in brain regions that receive a noradrenergic innervation activated by ECS. The effects of ECS on neurotransmitter receptor binding appear to be highly selective. Of five receptors in the cortex and three receptors in the hippocampus measured, only β-adrenergic receptor binding is decreased. Chronic footshock stress does not alter β-adrenergic receptor binding sites in the cortex, indicating that the effects of ECS are not due to stress alone. The effects of ECS on reserpine-induced alterations in β-adrenergic receptor binding sites were also examined. Ten days of ECS following chronic reserpine injections reverses the increased binding of β-adrenergic receptors     

Dopamine D1-stimulated adenylyl cyclase activity in cerebral cortex of autopsied human brain.

Although the cerebral cortical dopamine D(1) receptor is considered to play a role in normal and abnormal brain function, little information is available on its characteristics in human brain. We compared dopamine-stimulated adenylyl cyclase (AC) activity in homogenates of cerebral cortex (frontal, temporal, parietal, occipital and cingulate cortex) of autopsied brain of neurologically normal subjects to that in striatum. Cerebral cortical AC activity was modestly and dose-dependently stimulated by dopamine (maximal 20-30%) with low microM EC50s and such stimulation was inhibited by the selective dopamine D1 receptor antagonist SCH23390. The magnitude of the maximal stimulation by dopamine was similar in autopsied and biopsied cerebral cortex. The extent of maximal stimulation was similar to that in dopamine-rich striatum (caudate, putamen and nucleus accumbens), despite much lower density of dopamine D1 receptors in cerebral cortex vs. striatum. The EC50 for dopamine stimulation in cerebral cortex (approximately 1 microM) was lower than that for caudate and putamen (approximately 3 microM). No detectable dopamine stimulation was observed in cerebellar cortex, thalamus or hippocampus. Dopamine stimulation in both cerebral cortex and striatum was independent of calcium activation. We conclude that dopamine stimulated AC can be measured in cerebral cortex of human brain allowing for the possibility that this process can be examined in human brain disorders in which dopaminergic abnormalities are suspected.     

Distinct alpha-noradrenergic receptors differentiated by binding and physiological relationships.

Adult mice received two 70 μg doses of 6-hydroxydopamine intracisternally 72 hours apart, and the muscarinic binding properties of discrete brain regions were then investigated at various time intervals. Three days after the second injection, ³H-norepinephrine uptake was drastically reduced in all brain regions studied, and a distinct decrease in muscarinic receptor density was observed in the striatum (?18%), medulla-pons (?17%) and cerebellum (?15%) of lesioned animals as compared with controls. No changes were detected in muscarinic receptor density in the cortex or the hippocampus of treated animals, nor were any changes seen in the affinity of the labelled ligand for its receptor or in the displacement properties of the muscarinic binding by agonists in any of the regions studied. These effects still persisted after 60 days, with a further reduction in striatal muscarinic density to 74% of control values. Data are interpreted with respect to the proposed model for cholinergic modulation of central catecholamine release and cholinergic-catecholaminergic interactions in the striatum.