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PubMed1990

Induction of c-fos mRNA expression in rat striatum by neuroleptic drugs.

The effect of selective dopamine D2 receptor-acting drugs on striatal c-fos mRNA expression in the rat has been investigated by Northern hybridization and autoradiography to determine a possible role for c-fos in the initiation of adaptive changes in D2 receptor number by neuroleptic drugs. The neuroleptic drug haloperidol, a D2 receptor antagonist, was found to produce a rapid and transient induction of c-fos mRNA expression as compared with the expression in animals treated with saline. This induction by haloperidol was found to be dose dependent and D2 receptor mediated, inasmuch as a D2 agonist completely reversed the induction and the inactive isomer of the neuroleptic butaclamol, which does not produce an increase in D2 receptors, had no effect on c-fos mRNA expression. From these data, it can be concluded that c-fos expression in striatum is under dopamine D2 receptor-mediated inhibitory control. It is suggested that c-fos may play a role in the initiation of the increase in D2 receptor number produced by chronic neuroleptic drug treatment.

Animals↗
PubMed1988

No evidence of vascular dopamine receptors in the rat portal vein.

Dopamine (5.3 X 10(-6) to 5.3 X 10(-5) M) decreased the force of spontaneous myogenic contractions of the rat portal vein in a concentration-dependent manner in the presence of the alpha-adrenoreceptor antagonist BE-2254. The DA1-selective agonist fenoldopam and the DA2-preferential agonist (-)-EOE were both inactive. Dopamine-induced relaxation was not inhibited by (+)-butaclamol (10(-8) M), but was reduced by a potent beta 2-selective adrenoreceptor antagonist ICI 118,551 (2 X 10(-8) M). Our results demonstrate that the rat portal vein is devoid of postsynaptic DA1 and DA2 dopamine receptors.

Adrenergic beta-Antagonists↗
PubMed1989

The action of dopamine and vascular dopamine (DA1) receptor agonists on human isolated subcutaneous and omental small arteries.

1. Human small arteries were obtained from surgical specimens and studied in vitro by use of a myograph technique. Following induction of tone with a potassium depolarizing solution, dopamine in the presence of beta-adrenoceptor and catecholamine uptake blockade relaxed isolated omental and subcutaneous arteries. Preincubation of tissues with phentolamine increased the maximum relaxation in response to dopamine. 2. The selective vascular dopamine receptor agonists, fenoldopam and SKF 38393 also relaxed isolated subcutaneous and omental arteries in a concentration-dependent manner. The order of potency for agonists was dopamine greater than fenoldopam greater than SKF 38393. 3. Dopamine-induced relaxation was competitively antagonized by SCH 23390, (R)- and (S)-sulpiride, and fenoldopam induced relaxation by SCH 23390 and (+)- but not (-)-butaclamol. 4. These results indicate the presence of vascular dopamine receptors (DA1 subtype) on human isolated resistance arteries from omental and subcutaneous sites.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1986

[125I]Spiperone is not a useful ligand for studying the CHAPS solubilized dopamine D-2 receptor from rat striatum.

The interaction of [125I]spiperone and [3H]spiperone with CHAPS solubilized preparations of rat striatal tissue has been compared. Only about 15% of [125I]spiperone binding was displaced by sulpiride compared with about 67% of [3H]spiperone binding. In the presence of (+)-butaclamol the displacement of [125I]spiperone was twice that found with sulpiride suggesting an interaction with sites other than D-2 receptors. The specific binding of [125I]spiperone was not saturable within the maximum concentration range that could be employed and its affinity for soluble preparations was far lower than that of [3H]spiperone. Despite its very high specific activity [125I]spiperone offers no advantage over [3H]spiperone in the identification of dopamine receptors in soluble tissue preparations.

Animals↗
PubMed1986

Prenatal neuroleptic exposure alters postnatal striatal cholinergic activity in the rat.

Previous studies in our laboratory have shown that prenatal exposure to a neuroleptic during a critical period of gestation in the rat results in a marked deficit in the number of striatal dopamine-binding sites and in a diminution of dopamine agonist-induced stereotyped behavior. In the present studies, we examined the effect of prenatal neuroleptic exposure on biochemical parameters of cholinergic activity to determine whether the balance between striatal dopaminergic and cholinergic activity might be altered. The number of muscarinic cholinergic-binding sites and the specific activity of choline acetyltransferase were found to be significantly increased by prenatal treatment with the neuroleptics haloperidol or (+)-butaclamol. From the present studies and previous observations made in our laboratory, it is concluded that the ability of a neuroleptic to affect the number of muscarinic cholinergic receptors in postnatal life may be a result of the phenotypically undifferentiated state of the developing dopamine-binding site. Our findings of increased striatal cholinergic activity accompanied by a marked decrease in dopaminergic activity may have implications for an increased vulnerability to extrapyramidal motor disturbances during postnatal development.

Animals↗
PubMed1981

Central catecholamine depletion: effects on physiological growth hormone and prolactin secretion.

The effects of depletion of central nervous system (CNS) catecholamines (CA) upon growth hormone (GH) and prolactin (Prl) secretion were examined in unanaesthetized male rats. Animals were chronically implanted with cannulae for blood sampling and for intracerebroventricular (i.c.v.) injections. GH and Prl secretory profiles were obtained by radioimmunoassay of blood samples drawn every 15 min for a 6-hour period. Hormone profiles were obtained before, 1 day (day 1) and 7 days (day 7) after i.c.v. injection of 6-hydroxydopamine (6-OHDA, total dose 600 microgram). GH secretion on day 1 was almost completely abolished (mean GH concentrations 25.2 +/- 10.1 vs. baseline 177.2 +/- 34.1 ng/ml), but secretory patterns tended to return towards normal by day 7. Prl secretion was markedly increased at day 1 (18.8 +/- 5.1 vs. 6.7 +/- 1.9 ng/ml), but levels had fallen by day 7. Treatment of animals at day 8 with the norepinephrine antagonist phentolamine (7.5 mg/kg i.v.) suppressed GH secretion, but stimulated Prl secretion. The administration of the dopamine antagonist butaclamol (1 mg/kg i.v.) on day 9 had no effect on Gh secretion, but stimulated Prl release. Histofluorescence examination of tissue sections confirmed extensive disruption of CA structures throughout the CNS. These findings indicate that central CA neurons are facilitatory to GH secretory rhythms, but inhibitory to Prl secretion. Furthermore, it is apparent that the effects of i.c.v. 6-OHDA treatment are transient, recovery being due to re-establishment of functional CA mechanisms.

Animals↗
PubMed1982

Coat color in intact and neurointermediate lobe-grafted agouti mice: effect of dopamine agonists and antagonists.

The natural variation in the coat color of agouti C3H Avy mice was observed and reflectometrically recorded during the first 6 months of life. Three well-defined color stages were detected: (a) yellow coat from birth to the 6th week; (b) dark-gray coat from the 8th week to the 6th month, and (c) from the 6th month onward a yellow coat prevailed. To clarify the role played by the pituitary pars intermedia on these coat color variations, pimozide or d-butaclamol were chronically administered to newborn and 6-month-old mice. These drugs produced an intense darkening in the color of the growing hairs in newborn mice and in the color of the newly grown hair of adult preplucked mice. Pituitary pars intermedia grafted in adult yellow mice also produced an intense coat darkening of newly grown hair. Dopaminergic agonists, administered either subcutaneously or close to the grafts, prevented this darkening effect. It is suggested that pars intermedia peptides might be responsible for the hair color cycle in this mouse strain and that peptide secretion is controlled by a tonic inhibitory dopaminergic mechanism which operates from the first days of life.

Age Factors↗
PubMed1989

Action of fenoldopam, a selective dopamine (DA1) receptor agonist, on isolated human arteries.

The effects of a DA1 dopamine receptor selective agonist, fenoldopam, were examined on human blood vessels. Fenoldopam relaxed precontracted human arteries in vitro from brachial, cerebral, cervical, colic, coronary, lumbar, pulmonary, renal and splenic sites. Fenoldopam failed to relax uterine or external iliac arteries or saphenous vein segments. These effects of fenoldopam were not endothelium dependent, but were antagonised by the selective DA1 receptor antagonists, SCH 23390, (+)-butaclamol, and (R)- more than (S)-sulpiride. The effect of fenoldopam may involve cyclic adenosine monophosphate. These studies indicate the presence of DA1 receptors on a variety of large isolated human arteries.

1-Methyl-3-isobutylxanthine↗
PubMed1995

Effects of dopamine on adenylyl cyclase activity and amylase secretion in rat parotid tissue.

Several previous studies have shown that dopamine causes amylase secretion from rat parotid tissue. However, the mechanism of this dopamine action is still unclear. The present study was designed to characterize dopamine action in rat parotid gland tissue by examining the effects of dopamine on cyclic AMP accumulation, adenylyl cyclase activity, and amylase release. Dopamine significantly enhanced accumulation of cyclic AMP in parotid slices and stimulated adenylyl cyclase activity in parotid membrane preparations. It also significantly stimulated amylase release from parotid slices. The stimulatory effects of dopamine on cyclic AMP accumulation, adenylyl cyclase activity, and amylase release were effectively blocked with propranolol, a beta-adrenergic antagonist, but not by either SCH 23390, a preferential D1 antagonist, or butaclamol, a preferential D2 antagonist. No substantial specific binding sites for D1 receptors were detectable by [3H]SCH 23390 binding in parotid membranes. These results suggest that the stimulatory effect of dopamine on amylase secretion in rat parotid tissue is not mediated through specific D1 dopamine receptors but rather through beta-adrenergic receptors.

Adenylyl Cyclases↗
PubMed2006

Prototypical antipsychotic drugs protect hippocampal neuronal cultures against cell death induced by growth medium deprivation.

BACKGROUND: Several clinical studies suggested that antipsychotic-based medications could ameliorate cognitive functions impaired in certain schizophrenic patients. Accordingly, we investigated the effects of various dopaminergic receptor antagonists--including atypical antipsychotics that are prescribed for the treatment of schizophrenia--in a model of toxicity using cultured hippocampal neurons, the hippocampus being a region of particular relevance to cognition. RESULTS: Hippocampal cell death induced by deprivation of growth medium constituents was strongly blocked by drugs including antipsychotics (10(-10)-10(-6) M) that display nM affinities for D2 and/or D4 receptors (clozapine, haloperidol, (+/-)-sulpiride, domperidone, clozapine, risperidone, chlorpromazine, (+)-butaclamol and L-741,742). These effects were shared by some caspases inhibitors and were not accompanied by inhibition of reactive oxygen species. In contrast, (-)-raclopride and remoxipride, two drugs that preferentially bind D2 over D4 receptors were ineffective, as well as the selective D3 receptor antagonist U 99194. Interestingly, (-)-raclopride (10(-6) M) was able to block the neuroprotective effect of the atypical antipsychotic clozapine (10(-6) M). CONCLUSION: Taken together, these data suggest that D2-like receptors, particularly the D4 subtype, mediate the neuroprotective effects of antipsychotic drugs possibly through a ROS-independent, caspase-dependent mechanism.

Animals↗
PubMed1986

Hypothalamic D2 receptors mediate the preferential release of somatostatin-28 in response to dopaminergic stimulation.

We have studied the effect of dopamine (DA) together with agonist and antagonist drugs of varying specificity on the release of immunoreactive forms of somatostatin (SS) from the perfused, adult rat hypothalamus in vitro. Levels of SS increased from 14.7 +/- 3.7 pg (mean +/- SE) under basal conditions to 137 +/- 23.0 pg after exposure to 10(-6) M DA. This dopaminergic effect was mimicked by the specific D2 agonists bromocriptine (10(-7) M) and LY 171555 (10(-6) M) but not by the D1 agonist SKF 38393A (10(-6) M). The stimulatory action of DA (10(-6) M) was blocked by the active (d) but not the inactive (l) isomer of butaclamol (10(-7) M). Similar blockade was achieved with the specific D2 antagonists metoclopramide (10(-8) M) and domperidone (10(-8) M), whereas the D1 antagonist SCH 23390 partially blocked the stimulation of DA but only when used at X100 greater concentration (10(-6) M). SCH 23390 (10(-8) M) did not affect the dopaminergic stimulation of SS release. HPLC characterization of the immunoreactive forms of SS yielded two peaks which corresponded to SS-28 and SS-14. The ratio of these forms varied significantly under different conditions. In the basal state the ratio of SS-28 to SS-14 was 1:4.4; in response to stimulation with DA, the ratio was 1:1.7 and in response to depolarization with 60 mM K+ the ratio was 1:3.1. In conclusion, the stimulatory action of DA on SS release is mediated via hypothalamic D2 receptors. Furthermore dopaminergic stimulation increases the molar ratio of SS-28 to SS-14 in the total immunoreactive SS which is released.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1985

Responses to prolactin secretagogues in oestrogen-treated rats suggest that the defect in prolactin regulation produced by oestrogen is at the level of the pituitary gland.

Prolactin responses to pharmacological agents were used to characterize the defect in prolactin regulation which occurs after administration of high doses of oestrogen to rats. Animals with chronically implanted venous cannulae were injected with 2 mg oestradiol benzoate in oil and 2-3 days later prolactin concentrations were measured after injections of saline, thyrotrophin-releasing hormone (TRH), fenfluramine, apomorphine and butaclamol. The responses were compared with those in oil-injected animals. Hyperprolactinaemia in oestrogen-treated animals was unresponsive to apomorphine, but was even more sensitive to dopamine receptor blockade than controls. These results suggest that the lactotrophs in oestrogen-treated animals are already maximally suppressed by endogenous dopamine, though ineffectively. Although there was an increased prolactin response to TRH in oestrogen-treated animals, there was an impaired response to fenfluramine, indicating suppressed serotonergic prolactin-releasing factor mechanisms. Maximal endogenous dopaminergic activity and suppressed prolactin-releasing factor mechanisms are appropriate hypothalamic responses to hyperprolactinaemia. The operation of these responses in the earliest stages of the development of pituitary hyperplasia indicates that oestrogen induces a disturbance of prolactin regulation in the lactotroph, independent of hypothalamic control.

Animals↗
PubMedDate not supplied

Fluorine-18 radiolabelling, biodistribution studies and preliminary PET evaluation of a new memantine derivative for imaging the NMDA receptor.

A synthetic method has been established for preparing [18F]1-amino-3-fluoromethyl-5-methyl-adamantane ([18F]AFA). Biodistribution of the radiotracer in mice showed high brain uptake. The peak uptake (3.7% I.D/g organ) for the brain occurred at 30 min after injection. Accumulation of radioactivity in mouse brain was consistent with the known distribution of the NMDA receptors. The binding of [18F]AFA to the phencyclidine (PCP) binding sites of the NMDA receptor complex and the sigma recognition sites in a Rhesus monkey was also examined using positron emission tomography (PET). The regional brain distribution of [18F]AFA was changed by memantine and by (+)-MK-801, indicating competition for the same binding sites. Treatment with haloperidol caused a marked reduction of radioactivity uptake in all the brain regions examined. (-)-Butaclamol, which has pharmacological specificity for sigma sites, did not have any significant effects.

Animals↗
PubMed1987

Cyclo (Leu-Gly) attenuates the striatal dopaminergic supersensitivity induced by chronic morphine.

Cyclo(Leu-Gly) (CLG), a diketopiperazine analog of Pro-Leu-Gly-NH2 (MIF), has direct effects on dopamine (DA) mediated behaviors as well as on D-2 DA receptors. Endogenous opioids, as well as morphine have also been implicated as neuromodulators of dopaminergic function. We studied these interactions in an animal model in which chronic morphine administration induces a dopaminergic supersensitivity that can be detected during the 48 hour (h) period following withdrawal of morphine. At 24 h following morphine withdrawal, there was a 3.5-fold increase in stereotypic behavior in rats following a challenge dose of apomorphine (APO) (0.5 mg/kg). By 48 h this effect had disappeared. Co-administration of CLG (8 mg/kg s.c.) with morphine attenuated the development of the behavioral supersensitivity to APO. D-2 DA receptor binding analysis indicated that parallel molecular changes occurred. There was a morphine-induced increase in the affinity (+167 percent) in antagonist (i.e. 3H-spiroperidol displaced by butaclamol) binding at 24 h after withdrawal. Co-administration of CLG with morphine attenuated these DA receptor changes at 24 hours which is consistent with the peptide's effect on stereotyped behavior. However, antagonist binding parameters did not parallel changes in behavior at 48 h. Agonist binding was then studied by examining DA displaceable 3H-spiroperidol (75 pM) binding to the D-2 DA receptor. Two receptor subpopulations D-2-HI and D-2-LO were revealed. Morphine caused an increase in the affinity for agonist binding to the D-2-HI site (83-fold increase). Affinity changes at the D-2-HI site correlated positively and strongly with the behavioral changes in all groups at both 24 and 48 h. We conclude that changes in agonist binding to D-2 DA receptors rather than antagonist binding is more consistent with the behaviors induced by morphine and CLG.

Animals↗
PubMed1989

Substitution and antagonism in rats trained to discriminate (+)-N-allylnormetazocine from saline.

(+)-N-Allylnormetazocine (NANM) binds to at least two sites in the mammalian central nervous system, a high-affinity, haloperidol-sensitive site and a lower-affinity site identified as the phencyclidine (PCP) receptor. The relevance of these sites to the discriminative stimulus properties of (+)-NANM was evaluated in rats trained to discriminate (+)-NANM from saline. Drugs with a high affinity for the haloperidol-sensitive site, including haloperidol, (+)-ketocyclazocine, 1,3-di-ortho-tolyl-guanidine and (-)-butaclamol failed to substitute for the (+)-NANM stimulus. In addition, when they were tested in combination with (+)-NANM, only haloperidol evidenced any antagonistic effects. The antagonistic effects of haloperidol were incomplete and only occurred at doses that substantially disrupted responding. Evidence obtained earlier that (+)-3-(3-hydroxyphenyl)-N-(1-propyl) piperidine could antagonize (+)-NANM was not replicated. On the other hand, PCP-like drugs from diverse chemical classes, including PCP, ketamine, MK-801, (-)-2-methyl-3,3-diphenyl-3-propanolamine, etoxadrol and dextrorphan, all substituted fully for the (+)-NANM stimulus with a potency predicted by their relative potency for PCP-like discriminative stimulus effects and relative affinity for the PCP receptor. Taken together, these results fail to provide evidence for an important role for the high-affinity haloperidol-sensitive binding site for (+)-NANM in its discriminative stimulus properties. Instead, activity at the PCP receptor is predictive of (+)-NANM-like effects.

Animals↗
PubMed1985

Photoaffinity labeling of the D2-dopamine receptor using a novel high affinity radioiodinated probe.

The ligand binding subunit of the D2 subtype of the dopamine receptor has been identified by photoaffinity labeling. In order to develop a specific covalent receptor probe, an analogue of the potent D2 selective antagonist spiperone, N-(p-aminophenethyl)spiperone (NAPS) has been synthesized. The aminophenethyl substituent of NAPS can be radioiodinated to theoretical specific radioactivity (2,175 Ci/mmol) and then the arylamine group converted to an arylazide to yield a photosensitive probe [( 125I]N3-NAPS). In rat striatal membranes, the nonradiolabeled azide probe (N3-NAPS) binds to the receptor with high affinity (KD congruent to 1.6 +/- 0.05 nM) and upon photoactivation irreversibly decreases the number of available receptors in these membranes as measured by [3H]spiperone binding. More importantly, however, incubation of rat striatal membranes with [125I]N3-NAPS leads to the photodependent covalent incorporation of the probe into a peptide of Mr = 94,000 as assessed by autoradiography of gels after sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Labeling of this Mr = 94,000 peptide can be blocked specifically and stereoselectively by dopaminergic antagonists such as (+)- and (-)-butaclamol but not by non-dopaminergic antagonists. Moreover, dopaminergic agonists also attenuate the covalent labeling of this peptide with an order of potency which is typically D2-dopaminergic. Therefore, the specificity of [125I]N3-NAPS labeling of the Mr = 94,000 peptide suggests that this peptide represents the ligand binding subunit of the D2-dopamine receptor.

Affinity Labels↗
PubMed1978

Dopamine receptors in the central nervous system.

Dopamine receptors in the central nervous system can be studied by measuring the specific binding of [3H]dopamine, [3H]haloperidol, d-[3H]LSD, [3H]dihydroergocryptine or [3H]apomorphine. The receptors are stereoselectively blocked by +)-butaclamol, a neuroleptic. All neuroleptics inhibit the specific binding of [3H]haloperidol in relation to their clinical potencies. The radioligand that desorbs most slowly from the receptor is [3H]apomorphine, thus making it a reliable ligand for dopamine receptors. Dopamine agonists that compete for [3H]apomorphine binding do so at concentrations that correlate with their potency in stimulating striatal adenylate cyclase. Structure-activity analysis, using [3H]apomorphine, confirms that the active dopamine-mimetic conformation is the beta rotamer of dopamine. Prolonged exposure in vitro of caudate homogenate to high concentrations of dopamine leads to increased binding of [3H]apomorphine or [3H]haloperidol, suggesting receptor "sensitization." Chronic haloperidol treatment of rats leads to an increased number of dopamine/neuroleptic receptors in the striatum, but a decrease in the pituitary.

Adenylyl Cyclases↗