Showing papers in "Journal of Neural Transmission in 1985"
TL;DR: Results are interpreted as indicating l-deprenyl's ability to prevent or retard the degeneration of striatal dopaminergic neurons, the first anti-Parkinson drug having such a property.
Abstract: In an open, uncontrolled study the longterm (9 years) effect of treatment with Madopar alone (n = 377) or in combination with l-deprenyl (selegiline, selective monoamine oxidase type B inhibitor) (n = 564) have been compared in Parkinsonian patients. In patients who lost their response to conventional Madopar therapy the addition of l-deprenyl resulted in a significant recouping of levodopa effect. The survival analysis revealed a significant increase of life expectancy in Madopar--l-deprenyl group regardless of the fact whether or not the significant demographic differences between the two groups were taken into account. Although the mechanism underlying this action of l-deprenyl is not known, the results are interpreted as indicating l-deprenyl's ability to prevent or retard the degeneration of striatal dopaminergic neurons. l-Deprenyl is the first anti-Parkinson drug having such a property. This hypothesis is not far fetched since l-deprenyl selectively prevents the degeneration of striatal dopaminergic neurons induced in animals by the illicit drug 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Since latter compound is known to cause Parkinsonism in man and primates or Parkinson-like neurochemical and pathological changes in other animals the implications of the present study involving monoamine oxidase activity and l-deprenyl are apparent.
404 citations
TL;DR: The potent, centrally acting 5-HT receptor agonist 8-OH-DPAT was shown to induce a clearcut hypothermic response in naive and PCPA-pretreated conscious rats, maintained at 22 °C, suggesting that body temperature measurements in the rat might provide a simplein vivo physiological means of studying central serotoninergic mechanisms, including 5- HT receptor sensitivity modification.
Abstract: The potent, centrally acting 5-HT receptor agonist 8-OH-DPAT was shown to induce a clearcut hypothermic response in naive and PCPA-pretreated conscious rats, maintained at 22 degrees C. PCPA pretreatment decreased the threshold dose of 8-OH-DPAT required to cause hypothermia, indicating that a sensitisation of 5-HT-receptor dependent mechanisms was involved. The results are discussed with reference to recent 5-HT receptor subclassification. It is suggested that body temperature measurements in the rat might provide a simple in vivo physiological means of studying central serotoninergic mechanisms, including 5-HT receptor sensitivity modification.
242 citations
TL;DR: Evidence is presented indicating that the 3-PPP enantiomers display selectivity for DA receptors, suggesting a new generation of DA agonists which exhibit variable intrinsic activity at different DA receptors.
Abstract: The behavioural, biochemical, neuroendocrinological and electrophysiological actions of the enantiomers of the dopamine (DA) analogue 3-(3-hydroxyphenyl)-N-n-propylpiperidine, 3-PPP, are extensively reviewed. (+)-3-PPP acts in a fashion similar to classical direct-acting DA agonists, stimulating both DA autoreceptors and postsynaptic DA receptors, although in some situations the drug appears to exhibit partial agonist activity. (-)-3-PPP exerts a variety of actions in different pharmacological models. Either agonistic, antagonistic or both agonistic and antagonistic activity are observed depending on the anatomical location of the relevant DA receptors and the experimental conditions. The actions of transdihydrolisuride (TDHL) and the trans-fused 7-OH-1,2,3,4,4a,5,6,10b-octahydrobenzo(f)quinoline (HW 165) are also discussed. These agents possess a similar spectrum of action to (-)-3-PPP suggesting a new generation of DA agonists which exhibit variable intrinsic activity at different DA receptors. Finally, evidence is presented indicating that the 3-PPP enantiomers display selectivity for DA receptors.
207 citations
TL;DR: Measurement of the frontal cortex and the medulla oblongata pH at autopsy revealed that those brains from individuals who died after long terminal phase had lower pHs than those who died quickly.
Abstract: Measurement of the frontal cortex and the medulla oblongata pH at autopsy revealed that those brains from individuals who died after long terminal phase had lower pHs than those who died quickly. These low pHs (pH 6.0-6.5) corresponded to lactic acid concentrations (20-25 mM) which are known to be neurotoxic. The cerebrospinal fluid pH and blood pH correlated with the cortical pH. The significance of these observations to the study of the biochemistry and histology on post-mortem human brain tissue and their possible clinical relevance are discussed.
177 citations
TL;DR: The occurrence of 5-S-cysteinyldopamine in dopaminergic brain regions supports the hypothesis that dopamine in part undergoes autoxidation, leading to formation of highly reactive quinones.
Abstract: 5-S-Cysteinyldopamine was synthesized and used as reference compound in HPLC analyses of extracts from various regions of human brain. The compound could be detected in brain regions rich in dopamine (caudate nucleus, putamen, globus pallidus and substantia nigra) but not in other regions (cerebellum, occipital cortex). The occurrence of 5-S-cysteinyldopamine in dopaminergic brain regions supports the hypothesis that dopamine in part undergoes autoxidation, leading to formation of highly reactive quinones. The newly discovered metabolite may prove useful in future studies of dopamine autoxidation and the possibly resultant cytotoxicity in aging and degenerative brain disorders.
147 citations
TL;DR: It is suggested that the intrinsic activity of these agents in different pharmacological models is dependent on the responsiveness of the relevant DA-receptors which, in turn, is related to the degree of previous agonist occupancy of these sites.
Abstract: In a companion article, we extensively reviewed the pharmacological actions of the enantiomers of the dopamine analogue 3-(3-hydroxyphenyl)-N-n-propylpiperidine, 3-PPP. The profiles of action exhibited by trans-dihydrolisuride (TDHL) and the trans-fused 7-OH-1, 2, 3, 4, 4a, 5, 6, 10b-octahydrobenzo(f)quinoline (HW 165) were also described. These latter agents, along with (−)-3-PPP, exert a variety of effects at different DA receptors depending on the anatomical location of these receptor sites and the experimental conditions. In the first part of the present article, it is suggested that the intrinsic activity of these agents in different pharmacological models is dependent on the responsiveness of the relevant DA-receptors which, in turn, is related to the degree of previous agonist occupancy of these sites. In situations where these agents exhibit partial agonist activity, their pharmacological effect is also dependent on the relative concentrations of drug and endogenous DA competing for common receptor sites. A number of theoretical implications will be discussed relevant to the suggestion that DA receptors exist in various adaptational states which can influence drug action. In the second part of this review, we will consider the behavioural profile exhibited by (−)-3-PPP in relation to that observed with classical DA antagonists. In addition, the potential clinical application of (−)-3-PPP and similar-acting agents will be discussed.
131 citations
TL;DR: Results are indicative of sex differences in the brain 5-HT neuronal systems in relation to differences between males and females in sexual behaviour, aggression and affective disorders.
Abstract: Male and female rats were compared with respect to brain serotonin (5-HT) levels, synthetic capacity, receptor sensitivity, and CNS functions. Levels of whole brain 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) were higher in females. The accumulation of 5-HT after treatment with the monoamine oxidase inhibitor pargyline alone and in combination with the 5-HT precursor L-tryptophan was greater in females than in males. 5-HT increased and 5-HIAA decreased to the same extent in both sexes after administration of the 5-HT agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). The temperature fall after all drug treatments was greater in females, but the “5-HT behavioural syndrome” was more pronounced in females merely after pargyline plus tryptophan; the behavioural response after 8-OH-DPAT did not differ between the sexes. These results are indicative of sex differences in the brain 5-HT neuronal systems. They are discussed in relation to differences between males and females in sexual behaviour, aggression and affective disorders.
120 citations
TL;DR: The elevated density of D2 receptors in non-treated patients may indicate dopaminergic supersensitivity in this disease and the elevated density was reversed with dopamine agonist therapy, but the density was not lower than control tissues.
Abstract: Striatal dopamine receptors were studied using [3H]-spiperone in postmortem tissues of thirty-six patients with Parkinson's Disease. Each tissue was analyzed by the receptor saturation method. In non-treated patients, the D2 dopamine receptor density was elevated in the caudate nucleus and putamen compared to controls. In L-DOPA-treated patients, the receptor density was the same as controls. The dissociation constant for [3H]-spiperone was similar in all groups. The elevated density of D2 receptors in non-treated patients may indicate dopaminergic supersensitivity in this disease. The elevated density was reversed with dopamine agonist therapy, but the density was not lower than control tissues.
85 citations
TL;DR: These studies provide further evidence for the selectivity of fluoxetine as an inhibitor of 5-HT reuptake, resulting in a selective down-regulation of5-HT1 receptors in the cerebral cortex of rat brain.
Abstract: Fluoxetine administration to rats at a dose of 10 mg/kg i.p. daily up to 12 or 24 days failed to change the concentration-dependent binding of [3H]WB4101, [3H]clonidine and [3H]dihydroalprenolol to alpha 1-, alpha 2- and beta-adrenergic receptors, respectively; [3H]quinuclidinyl benzilate to muscarinic receptors; [3H]pyrilamine to histamine H1 receptors and [3H]naloxone to opiate receptors. Persistent and significant decreases in receptor number (Bmax value) without changes in the dissociation constant (KD value) of [3H]5-HT binding in cortical membranes were observed upon chronic treatment with fluoxetine administered either by intraperitoneal injection or incorporation in the diet. A detectable reduction of 5-HT1 receptor number occurred after once-daily injections of fluoxetine at 10 mg/kg i.p. within 49 hours. After pretreatment for 3 days with p-chlorophenylalanine, an inhibitor of 5-HT synthesis, followed by repeated administration of fluoxetine, 5-HT1 receptor numbers were higher than those of normal rats, suggesting a dependence on synaptic concentration of 5-HT for fluoxetine to affect a receptor down-regulation. These studies provide further evidence for the selectivity of fluoxetine as an inhibitor of 5-HT reuptake, resulting in a selective down-regulation of 5-HT1 receptors in the cerebral cortex of rat brain.
83 citations
TL;DR: It is concluded that FFS and lithium long-term medication exert an agonistic influence onto central serotonergic neurotransmission in manic-depressive patients and healthy subjects.
Abstract: In order to investigate the influence of lithium long-term medication on serotonergic neurotransmission, fenfluramine stimulation (FFS) was used for the assessment of hormonal effects under serotonergic control. The cortisol plasma concentration following FFS was examined between 8 a.m. and 1 p.m. in 11 manic-depressive subjects under lithium prophylaxis and in 8 untreated euthymic patients. In addition, 11 healthy subjects with FFS, and 12 other subjects without FFS were investigated. The basal cortisol concentrations show considerable variation. Those of the lithium patients were in general found lower than those of the control groups. In both, the controls and the manic-depressive patients without lithium medication, no gross deviation from the expected physiological decline of morning cortisol values was found. A subtle effect of FFS in healthy subjects could be observed. In the lithium patients, however, a significant inversion of the cortisol secretion pattern with a steep increase between 10 and 12 a.m. could be demonstrated. It is concluded that FFS and lithium long-term medication exert an agonistic influence onto central serotonergic neurotransmission. Pharmacological challenge with fenfluramine may prove to be a useful tool for the investigation of serotonergic mechanisms in biological psychiatry.
76 citations
TL;DR: The cardiovascular effects of 8-OH-DPAT were not prevented by pretreatment with methergoline, methiothepin, pirenperone or cianserine or by 5-HT depletion by means of p-chlorophenylalanine, which suggests that the putative 5- HT receptor is not of a presynaptic type and does not have the pharmacological characteristics of a general5-HT1 receptor.
Abstract: 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) is a new serotonin (5-HT) receptor agonist that binds selectively to the 5-HT1A binding site. In the present paper we investigated the cardiovascular effects of 8-OH-DPAT in the normotensive Sprague-Dawley rat and in the spontaneously hypertensive rat. The acute i.v. administration of 8-OH-DPAT (5–150Μg/kg) was in both rat strains associated with a biphasic blood pressure response and a bradycardia. The initial pressor response was due to a direct vascular effect of 8-OH-DPAT involving activation ofα-adrenoceptors since it was present in pithed rats and in reserpine pretreated rats and since it was attenuated by prazosin. The longer lasting hypotension was not due to a direct vascular relaxation or a presynaptic inhibition of transmitter release since the hypotension was not evident in pithed rats and since 8-OHDPAT did not influence the pressor responses to electrical stimulation in pithed rats. Rather, the combination of hypotension and bradycardia would suggest a central site of action although the intracerebroventricular (lat. ventricles) route of administration was not more efficient (to induce hypotension) than i.v. administration. At least the bradycardia was mediated by changes in vagal as well as sympathetic discharge since it was prevented by pretreatment with atropine and propranolol in combination but not by pretreatment with either agent alone. The cardiovascular effects of 8-OH-DPAT were not prevented by pretreatment with methergoline, methiothepin, pirenperone or cianserine or by 5-HT depletion by means of p-chlorophenylalanine, which suggests that the putative 5-HT receptor that is responsible for the hypotension and bradycardia to 8-OH-DPAT is not of a presynaptic type and does not have the pharmacological characteristics of a general 5-HT1 receptor.
TL;DR: The data suggest that rolipram enhances noradrenergic transmission by direct stimulation of tyrosine hydroxylase and by an increase of neuronal activity, and does not appear to alter dopamine release and metabolism to a large extent.
Abstract: The phosphodiesterase inhibitor and putative antidepressant rolipram (0.3-30 mg/kg i.p.) stimulated the accumulation of dopa following inhibition of the aromatic amino acid decarboxylase with 3-hydroxybenzylhydrazine HCl dose-dependently in all brain regions investigated, suggesting that both dopamine and noradrenaline synthesis was enhanced. The stimulatory effect of rolipram on dopa accumulation in dopamine rich regions persisted even after pretreatment with gamma-butyrolactone which by itself increased dopa accumulation three fold. Following inhibition of catecholamine synthesis with alpha-amethyl-p-tyrosine rolipram accelerated the disappearance of noradrenaline and slowed the disappearance of dopamine. At low doses rolipram tended to reduce the pargyline-induced accumulation of 3-methoxytyramine. Rolipram attenuated the accumulation of 5-hydroxytryptophan in the neocortex and the diencephalon of 3-hydroxybenzylhydrazine HCl pretreated rats. The data suggest that rolipram enhances noradrenergic transmission by direct stimulation of tyrosine hydroxylase and by an increase of neuronal activity. Despite a stimulatory effect on tyrosine hydroxylase rolipram does not appear to alter dopamine release and metabolism to a large extent. In view of the occurrence of head-twitches the rolipram-induced reduction of 5-hydroxytryptamine metabolism may be due to feedback inhibition.
TL;DR: The difference between the plasma TRP/LNAA ratios after carbohydrate and protein breakfasts suggests that the brain may distinguish, by synthesizing more or less 5-HT, the composition of breakfast meals.
Abstract: The effect of a carbohydrate, a 20% protein, or a carbohydrate +0.3% tryptophan TRP breakfast on plasma large neutral amino acid ratios was studied in 6 healthy men. The carbohydrate-rich meal produced shifts in plasma amino acid concentrations such that plasma TRP/LNAA ratios increased from 0.13 to 0.15 (p less than 0.04) and the protein meal decreased the ratio from 0.14 to 0.11 (p less than 0.04) after 1 hour. Addition of 0.3% TRP to the carbohydrate-rich meal increased plasma TRP/LNAA ratios more than 2-fold. The TRP containing meal was thus the only one likely to influence brain 5-HT synthesis, although the difference between the plasma TRP/LNAA ratios after carbohydrate and protein breakfasts suggests that the brain may distinguish, by synthesizing more or less 5-HT, the composition of breakfast meals.
TL;DR: The analgesia induced by intrahypothalamic administration of aspirin was antagonized by pretreatment of monkeys with either a serotoninergic receptor blocker (cyproheptadine) or two catecholaminergic receptor blockers (haloperidol and yohimbine) to suggest the existence of a monoaminergic pain-inhibitory mechanism in the preoptic anterior hypothalamic area activated by aspirin.
Abstract: Microinjection of sodium acetylsalicylate (aspirin, 0.2–0.6 mg) into the preoptic anterior hypothalamic area, but not the dorsal raphe region or the periaqueductal central gray matter, produced a dose-related analgesia in conscious monkeys. The analgesia induced by intrahypothalamic administration of aspirin was antagonized by pretreatment of monkeys with either a serotoninergic receptor blocker (cyproheptadine) or two catecholaminergic receptor blockers (haloperidol and yohimbine). These suggest the existence of a monoaminergic pain-inhibitory mechanism in the preoptic anterior hypothalamic area activated by aspirin.
TL;DR: It is hypothesized that there are several different GABA-benzodiazepine receptor subtypes all of which have four distinct benzodiazepines binding sites which can exist in at least three different but freely interconvertible conformations.
Abstract: Several lines of evidence from reversible binding studies seem to indicate there are at least two "central" benzodiazepine receptor subtypes, the BZ1 and BZ2 receptors. Irreversible binding studies, using 3H-flunitrazepam as a photoaffinity label for benzodiazepine receptors, not only are in perfect agreement with the data from reversible binding studies but extend these studies by identifying P51, a protein with apparent molecular weight 51,000, as a protein associated with the BZ1 receptor and by suggesting that the BZ2 receptor might actually consist of several different benzodiazepine receptors associated with different and distinct proteins irreversibly labeled by 3H-flunitrazepam. Other reversible binding studies have accumulated indicating the existence of several different conformations of benzodiazepine receptors. Irreversible binding studies support this conclusion and in addition suggest the existence of four different benzodiazepine binding sites within the GABA-benzodiazepine receptor complex. It is therefore hypothesized that there are several different GABA-benzodiazepine receptor subtypes all of which have four distinct benzodiazepine binding sites which can exist in at least three different but freely interconvertible conformations. This hypothesis can account for all experimental observations obtained so far and might partially explain the distinct clinical effects of structurally similar benzodiazepines.
TL;DR: It may be concluded that functional postsynaptic but not presynaptic DA receptors exist in the brain of developing rats, i.e. during adolescent age, from experiments on 3-PPP and its enantiomers.
Abstract: The behavioural and biochemical effects of racemic 3-PPP (3-[3-hydroxyphenyl]-N-n-propyl-piperidine) and its enantiomers was studied in developing rats, aged 1–28 days. All three compounds exhibit dopamine (DA) autoreceptor-stimulating properties. Moreover, the (+)-enantiomer displays agonist and the (−)-enantiomer antagonist actions, respectively, on the postsynaptic DA receptor. This means that the racemate has a DA autoreceptor stimulatory action with slight or no effects on the postsynaptic receptor.
TL;DR: The data obtained show that inhibition of MAO-A but not B enzyme is responsible for pineal melatonin increase caused by MAO inhibitors, and it is suggested that the stimulation of melatonin synthesis caused byMAO inhibitors may contribute to their antidepressive effect.
Abstract: Clorgyline, a selective MAO-A inhibitor, increased (5 times) rat pineal melatonin and N-acetyl-serotonin (NAS) content, and decreased 5-HIAA level by 80% Deprenyl, a selective MAO-B inhibitor, did not change melatonin or other pineal indoles content The data obtained show that inhibition of MAO-A but not B enzyme is responsible for pineal melatonin increase caused by MAO inhibitors
TL;DR: The data suggest that the GABA-A receptor may be coupled to the presynaptic noradrenergic neuron and modulate the release of norepinephrine, while the GABA-B receptor is coupled toThe postsynaptic norADrenergic neurons and likely functions through the cyclic AMP generating system.
Abstract: The GABA-A receptor agonist THIP, or the mixed GABA-A/GABA-B receptor agonist progabide dose dependency increased the release of norepinephrine (as measured by the production of MHPG) in the cerebral cortex and hippocampus. This effect was partially reversed by treatment with the GABA-A receptor antagonist bicuculline. In contrast, the GABA-B receptor agonist baclofen decreased the release of norepinephrine in the cerebral cortex and hippocampus. Pretreatment with the presynaptic noradrenergic neurotoxin DSP4 increased the Bmax for beta-adrenergic receptor binding in the cerebral cortex and hippocampus. This effect was partially prevented by chronic (14 day) treatment with either the beta-adrenergic agonist clenbuterol or the GABA-B receptor agonist baclofen. In contrast, chronic (14 day) administration with either the GABA-A receptor agonist THIP or the antidepressant imipramine failed to alter the increase in betaadrenergic receptor binding produced by DSP4 pretreatment. These data suggest that the GABA-A receptor may be coupled to the presynaptic noradrenergic neuron and modulate the release of norepinephrine, while the GABA-B receptor is coupled to the postsynaptic noradrenergic neuron and likely functions through the cyclic AMP generating system.
TL;DR: This result is compatible with the hypothesis, that in certain degenerative processes such as aging, Alzheimer's disease, Huntington's disease and axotomy there is a stimulated growth of extraneuronal cells, which are relatively rich in MAO-B activity.
Abstract: Hemitransection of the left side of rat brain results in a selective increase (40%) in the activity of MAO-B in the left side striatum, as compared to the right, unoperated side. This increase is shown to be the result of an increase in the activity of extraneuronal MAO-B using a “low substrate concentration method” with dopamine as substrate. This result is compatible with the hypothesis, that in certain degenerative processes such as aging, Alzheimer's disease, Huntington's disease and axotomy there is a stimulated growth of extraneuronal cells, which are relatively rich in MAO-B activity.
TL;DR: Chronic lithium treatment was found to increase the synthesis of brain 5-hydroxytryptamine, an effect which may be mediatedvia increased brain levels of tryptophan, and the synthesis and release of dopamine were decreased.
Abstract: The aim of the present study was to investigate how chronic lithium treatment affects brain monoamine metabolism and amphetamine-induced locomotor stimulation in rats. Chronic lithium treatment was found to increase the synthesis of brain 5-hydroxytryptamine, an effect which may be mediatedvia increased brain levels of tryptophan. The synthesis and release of dopamine were, on the other hand, found to be decreased. Finally, chronic lithium treatment was found to suppress amphetamine-induced locomotor stimulation, probably due to counteraction by lithium on amphetamine-induced release of catecholamines.
TL;DR: The modulation of neuroleptic-induced increased D2 receptor binding reinforces the hypothesis that buspirone has a modulatory effect at an unknown site within the extrapyramidal system.
Abstract: Buspirone is a novel anti-anxiety drug which has neither a benzodiazepine structure nor any other benzodiazepine-like properties. Since buspirone is known to block dopamine autoreceptors and increase dopamine metabolism, it was compared to classical antipsychotic drugs for subchronic and chronic effects on dopaminergic function. When continuously infused into rats at 1.0 mg/kg/day s.c. for 2 weeks there was a small diminution of striatal dopamine metabolism response to acute injection of buspirone, but haloperidol produced a normal increase in DOPAC concentrations. In contrast, infusion of 0.3 mg/kg/day of haloperidol caused a marked subsensitivity to both acute buspirone and haloperidol challenge. The data from 3 months of treatment with buspirone or trifluoperazine (3.0 or 1.0 mg/kg/day, respectively) added to the rats' drinking water yielded similar results. Also, there was no alteration of dopamine autoreceptor sensitivity or postsynaptic D2 receptor sensitivity in 3 month buspirone treated rats. Three months of trifluoperazine produced a 45% increase in striatal binding of 3H-spiperone, which was reversed by simultaneous administration of buspirone during the final 2 weeks of trifluoperazine treatment. These data indicate that buspirone in moderate doses, such as used for treating anxiety, should be free of extrapyramidal side-effects. The modulation of neuroleptic-induced increased D2 receptor binding reinforces the hypothesis that buspirone has a modulatory effect at an unknown site within the extrapyramidal system.
TL;DR: The overall distribution of substance P-like immunoreactive (SPI) fibers in the rat urinary bladder was examined by means of frozen sections and whole mount preparations and the highest density was identified in the neck and the trigonum area.
Abstract: The overall distribution of substance P-like immunoreactive (SPI) fibers in the rat urinary bladder was examined by means of frozen sections and whole mount preparations. Two types of SPI fibers entered the urinary bladder from the neck; one forming thick fiber bundles and the other around the blood vessels. These SPI fiber bundles branched into several thinner segments which often project many collaterals to the smooth muscle and submucosal layers. In the smooth muscle layer, single SPI fibers were seen running parallel to both longitudinal and circular muscle bundles. They appeared to be evenly distributed in the smooth muscle layer. SPI fiber bundles located in the circular muscle layer dissociated SPI fibers which entered the submucosal layer, where they directed to the epithelium and formed a meshwork just beneath it. SPI fibers often left the meshwork to enter the epithelium where abundant arborization of fine SPI fibers was seen. The density of SPI fibers in the submucosal layer and epithelium was not even. The highest density was identified in the neck and the trigonum area.
TL;DR: Treatment of mice with DSP4 resulted in a decrease in the Bmax for the low affinity GABA-B receptor site in the cerebral cortex and hippocampus, which suggests that the GABA- B receptor may be associated with both the noradrenergic nerve terminal and the post-synaptic neuron receiving noradRenergic input.
Abstract: Treatment of mice with DSP4 (a neurotoxin that abolishes the presynaptic noradrenergic neuron;Dooley et al., 1983) resulted in: (A) a decrease in the Bmax for the low affinity GABA-B receptor site in the cerebral cortex and hippocampus, whereas the Bmax for the high affinity GABA-B receptor site was unaffected; (B) a greater potentiation of norepinephrine stimulated adenylate cyclase by baclofen in cerebral cortex slices; and (C) a decrease in the Bmax for both the high and low affinity GABA-A receptor sites in the cerebral cortex and hippocampus. These data, coupled with previous work from our laboratory, suggest that the GABA-B receptor may be associated with both the noradrenergic nerve terminal and the post-synaptic neuron receiving noradrenergic input, whereas the GABA-A receptor may be associated with the noradrenergic nerve terminal. These data further suggest a functional coupling between the noradrenergic and GABA-ergic systems.
TL;DR: The findings may indicate that, at least in some regions of the brain, synaptic turnover is increased during depression.
Abstract: The neuronal adhesion molecule, D2-protein, and the marker for mature synapses, D3-protein, were studied by crossed immunoelectrophoresis in postmortem samples of human brain hippocampus and frontal cortex. The samples were obtained from 6 patients with endogenous depression, 6 patients with Parkinson's disease, and 9 controls without known neurological or psychiatric disorders. Both D2-protein and D3-protein were significantly increased in hippocampus of depressed patients compared to controls (32% and 30%, respectively) and compared to Parkinson's disease patients (31% and 24%, respectively). However, no significant change was observed in frontal cortex. Combined with the previously observed increase in the level of D2-like protein in blood plasma from depressed patients the findings may indicate that, at least in some regions of the brain, synaptic turnover is increased during depression.
TL;DR: The data support the interpretation that quinpirole, by activating D2 receptors, results in a decreases in dopamine metabolites, a decrease in hypothalamic epinephrine concentration, and an increased conversion of norepinephrine to MHPG sulfate in rat brain probably through enhanced nore Pinephrine release.
Abstract: Quinpirole, (4 aR-trans)-4, 4 a, 5, 6, 7, 8, 8a, 9-octahydro-5-propyl-1 H-pyrazolo[3, 4-g] quinoline, is a dopamine agonist selective for the D2 subtype of dopamine receptors. In rats, quinpirole at doses of 0.3 mg/kg i.p. and higher decreased hypothalamic epinephrine concentrations. The doses required for this effect are only slightly higher than the minimum doses that decreased the concentration of dopamine metabolites in cerebral hemispheres. At higher doses of quinpirole (2–3 mg/kg i.p.), dopamine concentration was increased and norepinephrine concentration was decreased in hypothalamus, and MHPG sulfate (the norepinephrine metabolite) concentration was increased in brain stem and in hypothalamus. All of these neurochemical effects of quinpirole were blocked by pretreatment with spiperone, a dopamine antagonist. The effects were not produced by SKF 38393, a selective D1 agonist, or by the dextrorotatory enantiomer of quinpirole, which lacks D2 agonist activity. The data support the interpretation that quinpirole, by activating D2 receptors, results in a decrease in dopamine metabolites, a decrease in hypothalamic epinephrine concentration, and an increased conversion of norepinephrine to MHPG sulfate in rat brain probably through enhanced norepinephrine release.
TL;DR: The present results suggest that alaproclate may potentiate muscarinic responses by a mechanism involving serotonergic receptor mechanisms rather than by a direct interaction with the musCarinic cholinergic receptors.
Abstract: Alaproclate (10–60 mg/kg) injected i.p. into male mice potentiated and prolonged the oxotremorine and physostigmine-induced tremor in a dosedependent manner. Atropine completely blocked the tremor caused by oxotremorine or physostigmine both in the presence and absence of alaproclate. Pretreatment with the 5-HT receptor antagonist metitepine completely blocked the enhancement of oxotremorine-induced tremor caused by alaproclate. Biochemical studies indicated that the above effects cannot be explained by assuming that alaproclate a) acts as a cholinergic agonist, b) inhibits the acetylcholine esterase, c) interferes with choline uptake or acetylcholine synthesis, or d) directly potentiates the release of acetylcholine. In ligand binding studies alaproclate was found to be a weak competitive inhibitor of muscarinic antagonist binding to membranes from the rat cerebral cortex, rat striatum, human cerebral cortex and human striatum. (Ki∼28–40μM in all four tissues. The present results suggest that alaproclate may potentiate muscarinic responses by a mechanism involving serotonergic receptor mechanisms rather than by a direct interaction with the muscarinic cholinergic receptors.
TL;DR: Results, observed in four different brain structures, strengthen those first obtained withβ-vinyllactic acid, another inhibitor of GAD, and neither diazepam nor valproate prevented the decrease in GABA concentrations produced by isoniazid alone.
Abstract: Amino acid concentrations were measured in the cortex, cerebellum and hippocampus of the mouse brain before and during seizures induced by isoniazid (250 mg/kg i.p.), an inhibitor of L-glutamate-1-decarboxylase (EC 4.1.1.15: GAD). Valproate sodium and diazepam dose-dependently delay the onset of convulsive fits caused by isoniazid. However, neither diazepam nor valproate prevented the decrease in GABA concentrations produced by isoniazid alone. Also, these antiepileptic drugs did not modify the rate of GABA depletion elicited by isoniazid. These results, observed in four different brain structures, strengthen those first obtained withβ-vinyllactic acid, another inhibitor of GAD.
TL;DR: The data show that BRC by itself is incapable of causing excitation in rats and mice unless another DA-receptor agonist such as apomorphine or DA is present, and that when BRC and DA were applied together to the nucleus accumbens, BRC enhanced the stimulant effect of DA.
Abstract: Bromocriptine (BRC) produced neither locomotor stimulation nor stereotyped behavior in mice and rats pretreated with reserpine plus alphamethyl-p-tyrosine (AMPT). However, the blockade of locomotor stimulation in mice by AMPT could be reversed by their prior treatment with a low, behaviorally inactive dose of L-DOPA. BRC potentiated the stereotypy (rats) and locomotor stimulation (mice) produced by apomorphine in animals pretreated with reserpine plus AMPT. Moreover, BRC potentiated the stimulant effect of d-amphetamine in reserpinised mice, while nomifensine, but not fluoxetine or desipramine, potentiated the stimulant effect of BRC in mice. After direct application to the nucleus accumbens or caudate nucleus of rats, BRC was inactive. However, when BRC and DA were applied together to the nucleus accumbens, BRC enhanced the stimulant effect of DA. These data show that BRC by itself does not cause behavioral stimulation in rodents. Despite having affinity for the DA D 2-receptor, BRC is incapable of causing excitation in rats and mice unless another DA-receptor agonist such as apomorphine or DA is present. The data are discussed in relation to the published literature and the hypothesis presented that BRC affects the signal transmitted by DA-receptor agonists such as apomorphine at or beyond the postsynaptic DA-receptor.
TL;DR: The results suggest that the activity of tryptophan hydroxylase in serotonergic neurons is reduced in the brains of parkinsonian patients and of patients with degenerative nervous diseases.
Abstract: The activity of tryptophan hydroxylase was measured in nine regions of human brains from controls and patients with Parkinson's disease, striato-nigral degeneration, Shy-Drager syndrome and progressive supranuclear palsy by high performance liquid chromatography with fluorescence detection. The regional distribution of the enzyme activity in control brains was similar to that of serotonergic neurons; relatively high activity was found in the raphe nucleus, locus coeruleus and substantia nigra. The activity in the thalamus in Parkinson's disease and that in the locus coeruleus, raphe nucleus and substantia nigra in striato-nigral degeneration were significantly lower than that of controls (p<0.05). In most other brain regions in parkinsonian patients the activity was relatively lower than that of controls except the caudate nucleus and nucleus accumbens where the activity was relatively higher than that of controls. Marked decrease in the enzyme activity in various brain regions was observed in striato-nigral degeneration, Shy-Drager syndrome, and progressive supranuclear palsy. These results suggest that the activity of tryptophan hydroxylase in serotonergic neurons is reduced in the brains of parkinsonian patients and of patients with degenerative nervous diseases.
TL;DR: The view that CSF 5-HIAA may serve as a good index of brain serotonin turnover is confirmed by measuring the levels of this metabolite in ventricular CSF and in the striatal extracellular fluid after administration of inhibitors of serotonin synthesis or degradation.
Abstract: The relationship between the concentrations of 5-hydroxyindoleacetic acid (5-HIAA) in the CSF and in the striatum has been evaluated in the rat by measuring the levels of this metabolite in ventricular CSF (by liquid chromatography coupled with electrochemical detection) and in the striatal extracellular fluid (byin vivo voltammetry) after administration of inhibitors of serotonin synthesis or degradation. Pargyline, NSD 1015 andα-propyldopacetamide all caused an exponential decline of 5-HIAA in both CSF and striatum. For a given drug, the rate constants for 5-HIAA disappearance were identical in the CSF and in the striatal extracellular fluid. These results confirm the view that CSF 5-HIAA may serve as a good index of brain serotonin turnover.