Chronic treatment with dopamine receptor antagonists: behavioral and pharmacologic effects on D1 and D2 dopamine receptors.
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Rats were treated for 21 d with the selective D1 dopamine receptor antagonist SCH23390, the selective D2 dopamine receptor antagonist spiperone, the nonselective dopamine receptor antagonist cis-flupentixol, or a combination of SCH23390 and spiperone. In addition, a group of rats received L-prolyl-L-leucyl-glycinamide (PLG) for 5 d after the 21 d chronic spiperone treatment. Chronic treatment with SCH23390 resulted in a significant increase in D1 dopamine receptor density with no change in the D2 dopamine receptor density. Conversely, spiperone treatment resulted in a significant increase in D2 dopamine receptors and no change in D1 dopamine receptor density. PLG treatment had no effect. SCH23390 plus spiperone treatment resulted in a significant increase in both D1 and D2 dopamine receptor densities. However, although in vitro cis-flupentixol has an equal affinity for D1 and D2 dopamine receptors, only the D2 dopamine receptor density increased after chronic treatment with cis-flupentixol. In vivo treatment with the protein-modifying reagent N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), which irreversibly inactivates D1 and D2 dopamine receptors, was used to investigate the paradoxical, selective D2 dopamine receptor up-regulation induced by cis-flupentixol treatment. In vivo treatment with cis-flupentixol before EEDQ administration prevented the D1 and D2 dopamine receptor reductions induced by EEDQ. However, cis-flupentixol protected, in a dose-dependent manner, a greater percentage of D2 dopamine receptors than of D1 dopamine receptors from EEDQ-induced modification. These data indicate that, in vivo, cis-flupentixol preferentially interacts with D2 dopamine receptors and could explain why only D2 dopamine receptors were up-regulated following chronic treatment with cis-flupentixol. Rats were tested for their cataleptic response to the administered drug over the course of the chronic drug treatment. Catalepsy scores of rats receiving spiperone decreased over the course of treatment, with a significant reduction in catalepsy occurring by treatment day 5. The profound catalepsy observed in rats receiving SCH23390 did not change over the 21 d of treatment. Rats receiving cis-flupentixol demonstrated tolerance to its cataleptogenic effects, with a significant reduction in catalepsy observed by treatment day 7. During the 3 week treatment, the time between drug injection and a full cataleptic response to cis-flupentixol increased from 20 to 60 min, suggesting a tolerance to the D2, but not D1, dopamine receptor antagonism by cis-flupentixol.(ABSTRACT TRUNCATED AT 400 WORDS) (+info)
Picomolar affinity of 125I-SCH 23982 for D1 receptors in brain demonstrated with digital subtraction autoradiography.
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Iodinated SCH 23390, 125I-SCH 23982 (DuPont-NEN), was examined using quantitative autoradiography for its potency, selectivity, and anatomical and neuronal localization of binding to the dopamine D1 receptor in rat brain sections. 125I-SCH 23982 bound to D1 sites in the basal ganglia with very high affinity (Kd values of 55-125 pM), specificity (70-85% of binding was displaced by 5 microM cis-flupenthixol), and in a saturable manner (Bmax values of 65-176 fmol/mg protein). Specific 125I-SCH 23982 binding was displaced by the selective D1 antagonists SCH 23390 (IC50 = 90 pM) and cis-flupenthixol (IC50 = 200 pM) and the D1 agonist SKF 38393 (IC50 = 110 nM) but not by D2-selective ligands (I-sulpiride, LY 171555) or the S2 antagonist cinanserin. Compared with 3H-SCH 23390, the 5- to 10-fold greater affinity for the D1 site and 50-fold greater specific radioactivity of 125I-SCH 23982 makes it an excellent radioligand for labeling the D1 receptor. The concentrations of D1 sites were greatest in the medial substantia nigra and exceeded by over 50% the concentration of D1 sites in the lateral substantia nigra, caudoputamen, nucleus accumbens, olfactory tubercle, and entopeduncular nucleus. Lower concentrations of D1 sites were present in the internal capsule, dorsomedial frontal cortex, claustrum, and layer 6 of the neocortex. D1 sites were absent in the ventral tegmental area. Intrastriatal injections of the axon-sparing neurotoxin, quinolinic acid, depleted by 87% and by 46-58% the concentrations of displaceable D1 sites in the ipsilateral caudoputamen and medial and central pars reticulata of the substantia nigra, respectively. No D1 sites were lost in the lateral substantia nigra. Destruction of up to 94% of the mesostriatal dopaminergic projection with 6-hydroxydopamine did not reduce D1 binding nor, with one exception, increase striatal or nigral D1 receptor concentrations. 125I-SCH 23982 selectively labels D1 binding sites on striatonigral neurons with picomolar affinity, and these neurons contain the majority of D1 sites in rat brain. (+info)
Dopamine influences the light peak in the perfused mammalian eye.
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Dopamine, cis-flupenthixol, and dibutyryl cAMP affected the standing potential and light-evoked responses of the perfused cat eye in vitro. At micromolar concentrations, dopamine, a retinal neurotransmitter, increased the standing potential of the eye. At slightly higher concentrations, dopamine abolished the "light peak," a slow voltage response to light generated by the retinal pigment epithelium. The light peak was depressed by cis-flupenthixol, a dopamine antagonist, at micromolar concentrations. Dibutyryl cAMP produced effects similar to those produced by dopamine. A possible interpretation is that the generation of the light peak involves a catecholamine-stimulated adenylate cyclase in retinal pigment epithelium that is influenced by dopamine released from retinal neurons. (+info)
Two therapeutic experiments on stubborn pain in spinal cord lesions: coupling melitracen-flupenthixol and the transcutaneous nerve stimulation [proceedings].
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A drug combination was used against sub-lesional pain with some good results. Transcutaneous stimulation was used in three cases of pain in the roots without result. (+info)
Depletion of dopamine in the caudate nucleus but not in nucleus accumbens impairs reaction-time performance in rats.
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Impairment of the dopaminergic system in the brain induced by dopamine-receptor antagonists or by specific neurotoxin terminal lesions results in motor disturbances in rats. In order to specify further the role of the different dopamine pathways in the brain on motor function, the performance of rats trained in an operant reaction-time task was examined after systemic administration of a dopamine-receptor antagonist, alpha-flupenthixol, and after specific destruction of dopamine neurons by 6-hydroxydopamine perfusion into the nucleus accumbens or caudate nucleus. Rats were trained to press a lever and release it as quickly as possible after a light-cue conditioned stimulus (CS). Reaction time was measured from the CS to the release of the lever for each trial. alpha-Flupenthixol (0.2 and 0.4 mg/kg) injected intraperitoneally impaired the reaction-time performance of the rats. While disruption of dopamine activity in the nucleus accumbens did not affect the performance of the rats, lesions of the dopamine terminals of the nigrostriatal pathway in the corpus striatum (59% decrease in posterior striatal dopamine) significantly impaired reaction-time performance. These results show that moderate decreases in dopamine function restricted to the corpus striatum can disrupt sensitive motor performance, and support the hypothesis that dopamine in the corpus striatum has a role in the initiation of complex goal-directed responses. (+info)
Chronic muscle contraction headache: the importance of depression and anxiety.
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Seventy consecutive patients presenting with a clinical diagnosis of chronic muscle contraction headache over a two-year period were evaluated for depression and anxiety scores, along with other possible aetiological factors in this form of headache. Fifty-five of these patients (33 from a hospital neurology clinic and 22 from a local general practice) completed a double-blind study to evaluate flupenthixol 0.5 mg twice daily, diazepam 5 mg twice daily and placebo as prophylactic agents. Patients evaluated in the hospital neurology clinic had more frequent headaches of longer duration, higher analgesic consumption and higher depression, but no higher anxiety scores than those in general practice. Flupenthixol and diazepam were both significantly superior to placebo in reducing headaches and analgesic consumption. The trend was for flupenthixol to be superior to diazepam without reaching statistical significance. Flupenthixol was significantly better than diazepam and placebo in the reduction of Hamilton depression scores. This effect was independent of the effect on headache and analgesic reduction. (+info)
In vitro secondary activation (memory effect) of avian vitellogenin II gene in isolated liver nuclei.
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The vitellogenin II gene is specifically reactivated in vitro (secondary stimulation, memory effect) in purified liver nuclei that had ceased to express the gene in vivo a month after the roosters had received a single injection of estradiol (primary stimulation). The in vitro reactivation depends on the addition to the nuclei of nuclear and cytoplasmic extracts from estradiol-stimulated livers, polyamines (0.1-1.0 mM), and calmodulin (0.1 mM). Under identical incubation conditions the vitellogenin gene could not be reactivated in oviduct, embryonic, and immature chicken liver nuclei. Two other genes, those for ovalbumin and lysozyme, which are regulated by estradiol in the oviduct, could not be activated in the liver nuclei. The correct initiation of vitellogenin gene transcription in the liver nuclei was tested by primer extension studies. Addition of the antiestrogen tamoxifen (0.1 microM) to the system decreased vitellogenin mRNA synthesis by about 45% without affecting total RNA synthesis. Addition of quercetin (0.1 mM) and trans-flupenthixol (0.2 mM), inhibitors of nuclear protein kinase II and calmodulin-dependent kinase, respectively, inhibited the synthesis of vitellogenin mRNA by about 55% without affecting total RNA synthesis. The inhibitory effects of the antiestrogen and the kinase inhibitors were not additive, suggesting that both classes of inhibitor act on the same target or related targets. Depleting the estradiol receptors from the cell and nuclear extracts by means of estradiol-receptor antibodies covalently bound to Matrex beads reduced the stimulation of the vitellogenin gene by 40%. We conclude that in addition to the estradiol receptor and phosphorylation of nuclear protein(s) there are additional factors responsible for the in vitro secondary activation of the avian vitellogenin II gene. (+info)
Comparison of the actions of octopamine and catecholamines on single neurones of the rat cerebral cortex.
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1. The technique of microelectrophoresis was used to compare the actions of octopamine, noradrenaline and dopamine on single cortical neurones of the rat. 2. Octopamine both excited and depressed neurones of the cortex. Frequently cells depressed by noradrenaline were excited by octopamine; occasionally the converse was true. The time courses of action of the two amines also differed. Dopamine-elicited excitations were observed, but also were not correlated with octopamine-elicited effects. 3. When octopamine and noradrenaline both caused depressant effects, octopamine frequently was of less apparent potency than noradrenaline. When these amines were excitatory, octopamine appeared at least as and sometimes more potent than noradrenaline. 4. Octopamine was only weakly effective on cortical neurones identified by antidromic stimulation of the pyramidal tract, or synaptically excited by stimulation of the ventrobasal thalamus. 5. alpha-Flupenthixol and propranolol were without effect on octopamine-elicited changes in firing rate at doses which were effective in blocking the actions of dopamine and noradrenaline respectively. Metoclopramide did not block the actions of any of the three agonists, but had strong effects of its own. 6. The results suggest that receptors sensitive to octopamine, and which appear to be pharmacologically distinct from those previously categorized as noradrenaline and dopamine receptors, may exist on central neurones of the rat. (+info)