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Biomedical subjects

A Enz

Publications and source records attributed to A Enz.

At least 37 records · Page 2Linked to original sources
PubMed1992

M1 muscarinic receptors mediate intracellular calcium release in NB-OK1 human neuroblastoma cells.

Muscarine acetylcholine receptors were characterized in NB-OK1 cells using radioligand (3H-NMS) binding experiments and second messenger (calcium and phosphatidylinositol (PI) turnover) studies. In radioligand binding experiments the displacement curves of pirenzepine (KI = 1.3 x 10(-8) M), AF-DX 116 (KI = 8.2 x 10(-7) M), methoctramine (KI = 8.4 x 10(-8) M) and parafluorohexahydrosiladifenidol (pF-HHSiD) (KI = 1.8 x 10(-8) M) were monophasic and indicated the presence of M1 muscarinic receptors. Schild analysis with the muscarinic antagonists pirenzepine, AF-DX 116, methoctramine and pF-HHSiD yielded pA2 values of 8.40 +/- 0.13, 6.48 +/- 0.09, 7.61 +/- 0.12 and 7.22 +/- 0.08 in the calcium experiments and pA2 values of 8.13 +/- 0.30 and 6.26 +/- 0.26, 7.65 +/- 0.16 and 7.46 +/- 0.11, respectively, in the PI turnover experiments. These results indicate that both the carbachol-induced increase in intracellular calcium and the increase in PI turnover are mediated by M1 muscarinic receptors. In calcium free buffer, stimulation with carbachol induced similar responses to those seen under control conditions. From functional and radioligand binding experiments we conclude that the muscarinic receptor expressed in NB-OK1 cells is the M1 subtype. In addition, the M1 receptor-induced calcium response is related to PI turnover and is independent on extracellular calcium.

Calcium↗
PubMed1990

Continuous presence of nerve growth factor is required for maintenance of cholinergic septal neurons in organotypic slice cultures.

In co-cultures of rat septum and hippocampus, cholinergic neurons, identified by immunocytochemical techniques using antibodies against choline acetyltransferase, were found to be exclusively located in septal tissue. The presence of nerve growth factor during the entire growth period of four weeks increased the activities of acetylcholinesterase and choline acetyltransferase about 10-fold and strongly increased the number of acetylcholinesterase-positive neurons. Application of nerve growth factor yielded different effects depending on the age of the cultures. During the first two weeks in vitro, nerve growth factor enhanced the number of acetylcholinesterase-positive neurons, an effect which was no longer observed following later applications of nerve growth factor. Nerve growth factor increased the activities of cholinergic enzymes during all phases of in vitro development, but the effects of one-week applications were always considerably smaller than those observed following continuous application of nerve growth factor. The results of different application schedules suggest that the continuous presence of nerve growth factor is needed for maximal increases in cholinergic enzyme activities and maintenance of cholinergic neurons in septohippocampal co-cultures.

Acetylcholinesterase↗
PubMed1990

Partial dopamine-agonistic and atypical neuroleptic properties of the amino-ergolines SDZ 208-911 and SDZ 208-912.

The aminoergolines SDZ 208-911 [N-[(8-alpha)-2,6-dimethylergoline-8-yl]-2,2- dimethylpropanamide] and SDZ 208-912 [N-[8-alpha)-2-chloro-6-methylergoline-8-yl]- 2,2-dimethylpropanamide] exhibit nonclassical, neuroleptic-like properties in rodents. Thus, they are equipotent to haloperidol as inhibitors of apomorphine-induced gnawing behavior and conditioned avoidance responding, but are essentially devoid of cataleptogenic activity. In addition, they show high affinity for central D-2 receptors in vitro and elevate striatal homovanillic acid levels. In contrast to haloperidol, however, SDZ 208-911 and 208-912 strongly inhibit prolactin secretion and induce contralateral circling behavior in 6-hydroxydopamine-lesioned animals. These profiles are consistent with the drugs exhibiting varying degrees of partial agonistic activity at dopamine D-2 receptors, with SDZ 208-911 being considerably more agonistic than SDZ 208-912. Support for this contention stems from the ability of SDZ 208-911 to reduce the elevation of striatal L-dopa formation induced by gamma-butyrolactone, and SDZ 208-912's partial reversal of apomorphine's inhibitory action on gamma-butyrolactone activity. SDZ 208-911's effects are reduced after the partial alkylation of D-2 receptors with N-ethoxy-carbonyl-2-ethoxy-1,2-dihydroquinoline, confirming its partial agonistic properties. SDZ 208-911 and SDZ 208-912 could be effective against both the positive and negative symptoms of schizophrenia, while exhibiting a reduced incidence of dystonic and parkinsonian side-effects. In addition, their clinical testing might throw more light on the central dopaminergic status of schizophrenic subjects.

4-Butyrolactone↗
PubMed1990

Dopamine agonist-induced elevation of striatal acetylcholine: relationship between receptor occupancy and response in normal and denervated rat striatum.

Unilateral denervation of the nigrostriatal dopamine (DA) pathway with 6-hydroxydopamine resulted in a supersensitive response for elevation of striatal acetylcholine concentrations by the full DA agonist (R)-(-)-N-n-propylnorapomorphine (NPA), reflected in a parallel 4-fold leftward shift in the dose-response curve (ED50, intact, 8.8 micrograms/kg; denervated, 2.2 micrograms/kg). The maximal response, however, was not changed. In the intact striatum, irreversible DA receptor inactivation with N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) (6 mg/kg) produced a depression in the maximal acetylcholine increase elicited by NPA (control, 52.4%; EEDQ, 25.0%), without altering the ED50 for the agonist. In contrast, in the denervated striatum, EEDQ treatment produced a much smaller reduction in the maximal response (to 39.6%), as well as a small rightward shift in the ED50 (from 2.2 to 3.5 micrograms/kg). Double-reciprocal analysis of equieffective doses of NPA necessary to elicit response yielded similar values for the pseudo-dissociation constant (pseudo-KA, in units of dose) in intact and denervated striatum (8.3 and 7.0 micrograms/kg, respectively). A plot of receptor occupancy versus response was linear for the intact striatum, indicating the absence of a receptor reserve. In contrast, a nonlinear relationship was obtained for the denervated side, and a small apparent receptor reserve for NPA of 25-30% was estimated to be present. The results suggest that 6-hydroxydopamine-induced supersensitivity reflects the generation of a postsynaptic D2 DA receptor reserve, which may account for the observation that weak partial agonist elicit measurable response in supersensitive animals (and at presynaptic DA receptors, which normally exhibit a receptor reserve for agonists) but not at normosensitive receptors devoid of spare receptors.

Acetylcholine↗
PubMed1989

Development of the septohippocampal projection in vitro.

Slices were prepared from septal and hippocampal tissue and co-cultured for periods up to one month. The presence of cholinergic neurons within the septal slices was demonstrated by histochemical staining techniques for acetylcholinesterase or by Golgi-like immunoperoxidase techniques with antibodies raised against the enzyme choline acetyltransferase. Cholinergic fibers originating in the septal explants started to grow radially in all directions. By day 7, the first fibers were seen to reach their target, but maximal hippocampal ingrowth occurred between day 8 and 14 in vitro. Only those fibers reaching the target were maintained, whereas cholinergic fibers growing in other directions degenerated. Electrophysiological studies showed that cholinergic fibers established functional cholinergic connections with hippocampal pyramidal cells. As a result of septal stimulation, two different potassium currents were inhibited in pyramidal cells: a calcium-independent current, IM, and a calcium-dependent current, IAHP, underlying spike afterhyperpolarization. Application of nerve growth factor (NGF) strongly increased the number of cholinergic fibers which invaded the hippocampal slices and raised the activities of the cholinergic enzymes choline acetyltransferase and acetylcholinesterase, effects which were completely blocked by anti-NGF antibodies. The response of septohippocampal co-cultures to NGF depended on the time of application. During the first two weeks in vitro, NGF elicited sustained increases in enzyme activities, whereas later administration of NGF produced effects which were only maintained for several days.

Acetylcholine↗
PubMed1989

Partial brain dopamine D2 receptor agonists in the treatment of schizophrenia.

Partial dopamine agonists showing high affinity but low efficacy at D2 receptors can act as dopaminergic "buffers," reducing dopaminergic activity when it is excessive, and promoting it when reduced. This makes them of interest as potential therapeutic agents for the treatment of both positive and negative symptoms in schizophrenia, where they should also result in fewer or less severe motor disturbances than classical neuroleptics. SDZ 208-911 and SDZ 208-912 are amino-ergolines exhibiting partial agonistic properties in the rat, where they inhibit apomorphine-induced stereotypies, are only weakly cataleptogenic, induce varying degrees of circling behavior after unilateral lesioning of the nigrostriatal pathway, and strongly suppress prolactin secretion. The least agonistically acting agent, SDZ 208-912, should be effective against positive symptoms, whereas SDZ 208-911 could be suitable for the treatment of negative symptoms. In addition to possible therapeutic effects, the clinical testing of this class of agent should help to elucidate the status of central dopaminergic function in schizophrenic psychosis.

Brain Chemistry↗
PubMed1989

Muscarinic agonists for senile dementia: past experience and future trends.

Clinical experience with muscarinic agonists in the symptomatic treatment of Alzheimer's disease includes studies of the effects of pilocarpine, arecoline, bethanechol, oxotremorine and RS 86. Although the results are somewhat conflicting, there is evidence that a subgroup of patients may respond with an improvement of cognitive and/or behavioural function. The existing agents tend to induce adverse effects due to the stimulation of peripheral muscarinic receptors. Furthermore they reduce (at least in vitro) acetylcholine release by an action on presynaptic receptors. Strategies to overcome these problems include the development of potent agonists with high blood-brain barrier penetration, the search for agents selective for muscarinic receptor subtypes (using cloned receptors as tools) and the identification of agents acting as presynaptic receptor antagonists, to increase acetylcholine release.

Alzheimer Disease↗
PubMed1988

Absence of receptor reserve at striatal dopamine receptors regulating cholinergic neuronal activity.

N-propylnorapomorphine (NPA) dose dependently increased rat striatal ACh levels (ED50 = 18 micrograms/kg). After irreversible dopamine (DA) receptor inactivation with N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), neither the ED50 nor the slope of the dose-response curve for NPA was altered, whereas the maximal response was reduced to 56% of control. Analysis of the results yielded a linear relationship between receptor occupancy and response (i.e. no receptor reserve). In contrast, DA autoreceptors display a large receptor reserve for NPA. The results support the hypothesis that a differential receptor reserve at pre- vs. postsynaptic DA receptors in rat striatum accounts for the autoreceptor selectivity of DA agonists.

Acetylcholine↗
PubMed1988

Pharmacodynamic profile of CQP 201-403, a novel 8 alpha-amino-ergoline.

The profile of action in animals of CQP 201-403, a novel 8 alpha-amino-ergoline, is in most aspects that of a very potent dopaminomimetic, both as a prolactin secretion inhibitor, and at the levels of the CNS and the cardiovascular system. Qualitatively CQP 201-403 differs slightly from bromocriptine and apomorphine in its effects on the CNS (no influence on serotonin metabolism in the rat cortex; induction of masculine mounting behavior in rats) and the cardiovascular system of the dog (reflex tachycardia in response to a blood-pressure fall). In man the new compound proved to be highly active in lowering prolactin serum levels and be more potent than bromocriptine (Parlodel).

Animals↗
PubMed1988

CY 208-243: a unique combination of atypical opioid antinociception and D1 dopaminomimetic properties.

Here we describe the potent antinociceptive action of the indolophenanthridine, CY 208-243, which has high affinities to the dopamine D1 binding and the opioid sites as well as to the 5-HT1A site. The antinociceptive action was comparable to that of morphine in most, but not all models of nociception, nevertheless, basic differences exist in its overall profile. Antagonism of CY 208-243's antinociceptive action was only possible with either high doses of naloxone or not at all and no cross-tolerance with morphine in CY 208-243 tolerant rats occurred. The biochemical basis for dependence liability may be absent and no opioid activity was observed in cultured hippocampal cells. Physical dependence did not occur after programmed administration in the rhesus monkey, nor did CY 208-243 cause respiratory depression in the rat (rather a stimulation). Lack of generalization in fentanyl-trained rats strongly suggests that CY 208-243 lacks opioid-like subjective cues. The coexistence of D1 dopaminergic and atypical opioid agonist properties represents a unique pharmacodynamic combination which is not shared with any other analgesic, and may provide safe and innovative pain therapy.

Analgesics↗
PubMed1987

Nerve growth factor promotes development of the rat septo-hippocampal cholinergic projection in vitro.

There is now widespread evidence indicating that nerve growth factor (NGF) is involved in the function of central cholinergic neurons. Its possible role in the establishment of cholinergic fiber connectivities was studied in co-cultures of rat septum and hippocampus. Application of 100 ng/ml NGF greatly increased the number of acetylcholinesterase (AChE)-positive fibers which invaded the hippocampal slices, an effect which was accompanied by a more than 6-fold elevation of the two major cholinergic enzymes, choline acetyltransferase and AChE. In contrast, application of anti-NGF antiserum, but not a non-immune serum, reduced the number of AChE-positive fibers which grew into and remained within the hippocampal slices. Since no diffuse outgrowth of AChE-positive fibers from the septum was observed following application of NGF, these results suggest that NGF plays a role in the stabilization and long-term maintenance of the cholinergic septo-hippocampal projection in vitro.

Acetylcholinesterase↗
PubMed1987

Biochemical, behavioural, and endocrine effects of CK 204-933, a novel 8 beta-ergolene.

CK 204-933 displaces [3H]dopamine and [3H]spiperone with high affinity from D-1 and D-2 recognition sites in membranes of calf caudate. Results from functional in vitro tests suggest that it is a partial agonist at D-1 receptors and an antagonist at D-2 receptors. These opposite effects at dopamine receptor subtypes are also expressed in vivo. For instance, in 6-hydroxydopamine lesioned rats, CK 204-933 induces contralateral rotations which are antagonised by SCH 23390 but not by sulpiride. On the other hand, CK 204-933 induces a long lasting increase of dopamine turnover in rat striatum and antagonises apomorphine-induced gnawing behaviour in rats. CK 204-933 increases prolactin serum levels in rats after subcutaneous administration, whereas after oral administration a moderate decrease of prolactin serum levels was seen. The latter effect is probably due to the formation of active metabolites. CK 204-933 exhibits also a high affinity to [3H]prazosin binding sites and antagonises serotonin-mediated stimulation of adenylate cyclase in rat hippocampus. On the other hand, CK 204-933 has no effect of only very weak effects on noradrenaline and serotonin release from rat cerebral cortex slices, which is consistent with its weak effects on noradrenaline- and serotonin-turnover in rat brain. Based on these properties it is suggested that CK 204-933 could be of therapeutic value in brain diseases associated with disturbances of monoaminergic neurotransmission.

Animals↗
PubMed1986

The pharmacological assessment of RS 86 (2-ethyl-8-methyl-2,8-diazaspiro-[4,5]-decan-1,3-dion hydrobromide). A potent, specific muscarinic acetylcholine receptor agonist.

The effects of the compound RS 86 (2-ethyl-8-methyl-2,8-diazaspiro-[4,5]-decan-1,3-dion hydrobromide) in a number of in vitro and in vivo test systems for muscarinic cholinergic activity were analyzed and compared to those of classical muscarinic receptor agonists. In radioligand binding assays RS 86 presented high nanomolar apparent affinity only for sites labeled by 3H-muscarinic receptor agonists while its apparent affinity for sites labeled by 3H-muscarinic receptor antagonists including [3H]QNB, [3H]NMS and [3H]pirenzepine was in the micromolar range. RS 86 had no or only low affinity (IC50 greater than 10 microM) for other neurotransmitter or drug receptor sites. The compound induced scopolamine-sensitive contractions of the isolated guinea-pig ileum showing a pD2 of 6 in this model. In the isolated rat superior cervical ganglion RS 86 was also an agonist with a pD2 of 6.7. When given to mice or rats by different routes RS 86 induced central and peripheral effects typical of a muscarinic receptor agonist, such as hypothermia, tremor, mydriasis, salivation, lacrimation, diarrhoea and modification of behavior as observed in an open field. In several of these tests RS 86 was about 10 times less potent than oxotremorine but more potent than arecoline, pilocarpine, aceclidine or the compound (cis) AF-30. The ED50 values for some central effects, including the induction of hypothermia and alert non-mobile behavior were lower than those for tremor and peripheral effects. Some of the effects lasted for up to 6 h, depending on the dose. Finally, RS 86 administration resulted in modifications of brain acetylcholine turnover and high affinity choline uptake typical of a central muscarinic receptor agonist. Taken together these results demonstrate clearly that RS 86 is a potent, centrally acting, selective muscarinic receptor agonist. RS 86 appears to be an adequate tool for the clinical examination of the cholinergic hypothesis of Alzheimer's disease.

Acetylcholine↗
PubMed1986

Supernumerary locus coeruleus neurons as a determinant of inherited epilepsy in the convulsive mutant mouse quaking.

In quaking mice (a genetic model of epilepsy with an increased number of noradrenergic neurons) bilateral electrolytic coagulation of locus coeruleus (LC) in adult mice inhibited the convulsions elicited by somatic stimulations while neonatal 6-hydroxydopamine (6-OHDA) treatment remained ineffective upon the convulsions. Biochemical effects of the two treatments differed only in the brainstem where electrolytic lesion decreased while 6-OHDA treatment increased noradrenaline (NA) and 3-methoxy 4-hydroxyphenylethyleneglycol (MHPG) levels. Our results suggest that supernumerary LC neurons mediate the convulsions of the mutants through an action presumably restricted to the brainstem.

Animals↗
PubMed1986

Pharmacological profile of the abeorphine 201-678, a potent orally active and long lasting dopamine agonist.

The central dopaminergic effects of an abeorphine derivative 201-678 were compared to those of apomorphine and bromocriptine in different model systems. After oral administration, this compound induced contralateral turning in rats with 6-hydroxydopamine induced nigral lesions and exhibited strong anti-akinetic properties in rats with 6-hydroxydopamine induced hypothalamic lesions. It decreased dopamine metabolism in striatum and cortex, but did not modify noradrenaline and serotonin metabolism in the rat brain. 201-678 counteracted the in vivo increase of tyrosine hydroxylase activity induced by gamma-butyrolactone. In vitro it stimulated DA-sensitive adenylate cyclase and inhibited acetylcholine release from rat striatal slices. This compound had high affinity for 3H-dopamine and 3H-clonidine binding sites. These results indicate that 201-678 is a potent, orally active dopamine agonist with a long duration of action. Furthermore it appears more selective than other dopaminergic drugs.

Acetylcholine↗
PubMed1985

Direct evidence for brain-specific release of dopamine from a redox delivery system.

Dopamine (1) was transformed into a lipoidal redox chemical delivery system which crosses the blood brain barrier and is converted to a quaternary ammonium precursor of 1, thus "locking in" this ionized moiety. Systemic administration of this chemical delivery system for 1 increased concentrations of the major acid metabolite of 1, dihydroxyphenylacetic acid, (6) in several brain regions, and despite sustained inhibition of prolactin secretion, concentrations of 1 were unchanged. Inhibition of monoamine oxidase did not encourage the formation of 1 from this delivery system. When de novo synthesis of 1 was inhibited, however, regional brain concentrations of both 1 and dihydroxyphenylacetic acid acid were increased by systemic administration of the delivery system. This study provides direct evidence for the brain-specific delivery of 1 by a redox chemical delivery system and indicates that the 1 formed is delivered to sites which normally store newly biosynthesized 1.

Animals↗
PubMed1985

Partial lesions of the nigrostriatal pathway in the rat. Acceleration of transmitter synthesis and release of surviving dopaminergic neurones by drugs.

In rats with partial, unilateral lesions of the dopaminergic nigrostriatal pathway, synthesis of dopamine (DA) per surviving neurone was assessed by measuring the ratio of DOPA accumulated after inhibition of aromatic amino acid decarboxylase to dopamine (DOPA/DA ratio). Release of DA per surviving neurone was assessed by measuring the ratios of the concentrations of 3,4-dihydroxyphenylalanine (DOPAC) and homovanillic acid (HVA) to DA. In striata ipsilateral to the lesion, the DOPA/DA ratio was elevated 4-fold, and the DOPA/DA and HVA/DA ratios were elevated 2-fold as compared to values in contralateral striata. Administration of gamma-butyrolacetone (750 mg/kg, 30 min), i.e. of a drug which accelerates synthesis of DA, further increased the DOPA/DA ratio in lesioned striata to levels 37 times higher than those measured on the control side of saline-injected controls. Morphine (20 mg/kg, 30 min) and haloperidol (2.5 mg/kg, 60 min), i.e. drugs known to accelerate the turnover and release of DA, further elevated the DOPAC/DA and HVA/DA ratios in lesioned striata to levels approx. 5 times higher than the ratios measured on contralateral sides of saline-treated controls. The data indicate that dopaminergic neurones surviving partial lesions of the nigrostriatal pathway synthesize and release DA at an elevated but submaximal rate. Synthesis and release of DA can be further enhanced to a large extent by drugs.

3,4-Dihydroxyphenylacetic Acid↗