The effect of baclofen on alpha-flupenthixol-induced catalepsy in the rat.
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1 alpha-Flupenthixol (alpha-FPT; 0.2 mg/kg i.p.) when administered to rats produced catalepsy. 2 Baclofen (10 mg/kg i.p.) given 30 min after alpha-FPT had a biphasic effect on the catalepsy. Initially there was a potentiation of the effect, followed by a significant attenuation of the degree of catalepsy. 3 Possible mechanisms of action are discussed. (+info)
The actions of antipsychotic drugs on dopamine receptors in the rat substantia nigra.
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The activity of neurones in the zona compacta of the rat substantia nigra was recorded extracellularly in vitro. Dopamine produced a dose-dependent depression of firing, threshold doses being in the 3 microM range. The inhibitory effects of dopamine were antagonized by (-)-sulpiride (pA2 7.5), haloperidol (pA2 8.4) and cis-flupenthixol (pA2 6.9). The actions of gamma-aminobutyric acid (GABA) were not affected by these compounds. The gradients of Schild plots of data for (-)-sulpiride were less than unity while those for haloperidol and cis-flupenthixol were greater than unity, which suggests that the antagonism was not competitive. This is discussed with regard to the use of a bioassay system in the analysis of the effects of antagonists. Haloperidol and (-)-sulpiride were found to have similar potencies, as dopamine receptor antagonists, to those predicted from biochemical and clinical efficacy studies, but cis-flupenthixol was less potent than expected. (+info)
Calcium alters the sensitivity of intact horizontal cells to dopamine antagonists.
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Horizontal cells of the carp retina possess dopamine receptors linked to adenylate cyclase. Isolated, intact horizontal cells respond to micromolar concentrations of dopamine, whereas nanomolar concentrations of haloperidol, (+)-butaclamol, and flupenthixol block the dopamine response. Preincubation in Ringer's solution containing increased levels of Ca2+ (5-110 mM) decreases the sensitivity of the cells to these antagonists by 1,000-10,000 times. Dopamine sensitivity of the cells is not affected by Ca2+ levels in the preincubation medium. Preincubation of the cells in Ringer's solution containing 500 microM L-glutamate, an agent that increases intracellular Ca2+ levels in intact horizontal cells, also decreases the sensitivity of the cells to haloperidol. These data suggest that antagonist sensitivity of intact horizontal cells may be regulated by intracellular Ca2+. (+info)
Effect of dopamine system activation on substantia nigra pars reticulata output neurons: variable single-unit responses in normal rats and inhibition in 6-hydroxydopamine-lesioned rats.
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Previous single-unit recording studies have revealed that randomly selected pars reticulata neurons respond in a highly variable and complex fashion to intravenous administration of the dopamine agonist, apomorphine. The current studies were undertaken (1) to assess whether the variable pattern of responses of reticulata neurons to intravenous apomorphine correlates with their sites of projection and (2) to determine how reticulata responses to apomorphine might be altered by the presence of striatal dopaminergic supersensitivity. Extracellular, single-unit recording studies were conducted in anesthetized, paralyzed rats. Pars reticulata neurons were identified by antidromic activation from either the ventromedial nucleus of the thalamus or superior colliculus. Neurons of both subpopulations exhibited similar, highly variable changes in firing rate during the 10-min period immediately following intravenous injection of 320 micrograms/kg of apomorphine, a dose of the drug considered sufficient to stimulate striatal postsynaptic dopamine receptors. These responses, which were not qualitatively different from those previously observed among reticulata cells not distinguished on the basis of projection site, could be reversed by subsequent administration of dopamine antagonist drugs. In contrast to the variable responses in normal animals, the same dose of apomorphine caused a rapid and usually total inhibition of pars reticulata cell firing in rats which received 6-hydroxydopamine lesions of the nigrostriatal dopamine pathway 6 to 8 weeks prior to recording experiments. These inhibitions of firing could also be reversed by administration of dopamine antagonists.(ABSTRACT TRUNCATED AT 250 WORDS) (+info)
The uptake and release of [3-H]-2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthlane (ADTN) by striatal nerve terminals.
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A study has been made of the uptake and release of [G-3H]-2-amino 6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (ADTN) by crude striatal synaptosomes of the rat. 2 Uptake was rapid, temperature-dependent and could be suppressed by a variety of metabolic inhibitors. 3 The Michaelis-Menten kinetincs indicated the presence of two distinct transport systems in the striatum which were of much higher capacity than those found in the cerebellum, which lacks dopaminergic innervation. 4 Uptake of [3-H]ADTN was strongly inhibited by dopamine and the two potent dopamine-uptake inhibitors, benztropine and nomifensine, but only weakly by imipramine and amphetamine (the latter in non-reserpine-treated animals). 5 Accumulated [3-H]ADTN could be released from striatal slices by elevated K+. A similar release was evoked upon the addition of the ionophore, A23187. 6 The most potent releaser of [3-H]ADTN was (+)-amphetamine. This effect occurred at concentrations inactive against ADTN uptake. The neuroleptic cis-flupenthixol produced an inhibition of the spontaneous release. 7 It is concluded that [3-H]ADTN is accumulated preferentially into areas of the rat brain rich in dopamine. The pharmacological specificity of the uptake suggests that it is a good substrate for the dopamine carrier. Following uptake, [3-H]-ADTN may be released by K+ and a calcium ioniphore, which raises the possibility that ADTN might act as a false transmitter. (+info)
Effects of dopamine antagonists on receptive fields of brisk cells and directionally selective cells in the rabbit retina.
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The effects of dopamine antagonists on the extracellularly recorded activity of ON- and OFF-center brisk ganglion cells and ON-OFF directionally selective ganglion cells in the rabbit retina were investigated. Haloperidol, fluphenazine, and cis-flupenthixol, infused in the arterial system supplying the eye, produced similar effects. In general, these drugs reduced the antagonistic surround responses of brisk ganglion cells, reduced the sustained excitation of the center response of ON-center brisk-sustained cells, reduced the leading edge response of ON-OFF directionally selective cells to moving light stimuli along with any sustained excitation to stationary light stimuli, and affected the spontaneous activity of the cells. These drug effects appear to be due to a blockade of D-1 (adenylate cyclase-linked) receptors and not to D-2 receptors. Neither S-sulpiride nor metoclopramide, two specific D-2 antagonists, had much effect. The findings are the first to describe the functional effects of dopamine antagonists on single cells in the mammalian retina and on ganglion cell activity in the vertebrate retina. (+info)
A role for 5-hydroxytryptamine in the GABA-mimetic potentiation of alpha-flupenthixol-induced catalepsy in the rat.
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1 alpha-Flupenthixol (alpha-FPT)-induced catalepsy in the rat was potentiated by diaminobutyric acid (DABA), an inhibitor of the neuronal high affinity uptake of gamma-aminobutyric acid (GABA). 2 The depletion of 5-hydroxytryptamine (5-HT) with p-chlorophenylalanine (PCPA) abolished the DABA potentiation of alpha-FPT-induced catalepsy; this response was restored with 5-hydroxytryptophan. 3 Potentiation of alpha-FPT-induced catalepsy by clonazepam was significantly reduced by methysergide. Conversely, the potentiation of catalepsy by clomipramine was significantly reduced by picrotoxin. 4 These results are interpreted as evidence supporting a role for 5-HT in modifying the GABA-ergic inhibition of dopaminergic pathways, possibly by regulating the release of GABA. (+info)
Inhibitory action of dopamine on cat carotid chemoreceptors.
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1. The influence of some drugs which affect the dopaminergic system was studied on chemosensory responses to dopamine (DA), acetylcholine (ACh), sodium cyanide NaCN) and hypoxia during experiments on pentobarbitone anaesthetized cats in which chemoreceptor activity was recorded from the peripheral end of a sectioned sinus nerve. 2. Spontaneous chemosensory activity was inhibited in a dose-dependent manner by DA (0.5-5 microgram, I.A.). Higher doses (10-50 microgram) caused a delayed increase in discharge and were associated with inconsistent inhibitory responses. 3. The DA antagonist alpha-flupenthixol (0.2 mg/kg, I.A.) blocked the inhibitory response to DA without affecting either the spontaneous discharge frequency or the response to ACh. The effect of NaCN was potentiated, and during hypoxia chemoreceptor activity increased more rapidly, although the maximum frequency attained was not appreciably different from control values. Similar results were obtained with haloperidol (0.5 and 1.0 mg/kg, I.V.). 4. Higher doses of alpha-flupenthixol (0.5-1.0 mg/kg, I.A.) increased spontaneous chemoreceptor activity, but this was regarded as a non-specific effect of the drug since at these doses the inhibitory effect of 5-hydroxytryptamine (5-HT) was also abolished. 5. The animals were exposed to alternate periods of hypoxia and hyperoxia following administration of the tyrosine hydroxylase inhibitor alpha-methyl p-tyrosine (AMPT, 0.2-10 mg/kg, I.A.). The inhibitory response previously evoked by amphetamine was abolished, and electron microscopic studies showed a great reduction in the number of dense-cored granules, both of which suggested that DA levels in the carotid body had been substantially reduced. Responses to NaCN and hypoxia were slightly potentiated following AMPT, but neither spontaneous activity nor the response to ACh was affected. 6. Apomorphine (0.05-0.2 mg/kg, I.A.) inhibited the chemoreceptor discharge for up to 45 min, an effect which was antagonized by alpha-flupenthixol (0.2 mg/kg, I.A.), implying it resulted from DA receptor stimulation. Although responses to NaCN, hypoxia and higher doses of ACh were reduced following administration of apomorphine, the reduction was not very marked. 7. These results are not compatible with the theory of Osborne & Butler (1975), that in normoxia DA is tonically released in the carotid body and suppresses spontaneous chemosensory activity. 8. It is concluded that DA modulates chemosensory activity by influencing the rate of increase in discharge, without affecting maximum discharge frequency. The mechanism whereby DA is released in response to increased chemosensory activity remains to be established. (+info)