Effects Of Dopamine Antagonists Research Articles

An hypothesis regarding the antipsychotic effect of neuroleptic drugs

The antipsychotic effect of neuroleptic drugs appears gradually over the course of several weeks of chronic drug administration. Neuroleptic drugs are thought to act by blocking dopamine receptors; however, the dopamine-blocking effect of neuroleptics appears rapidly. One effect of dopamine antagonists which develops slowly is dopaminergic supersensitivity. It is suggested that this dopaminergic supersensitivity is related to the development of tolerance to some of the acute sedative properties of neuroleptics, but not to the antipsychotic effect. A population of glutamate receptors which are postsynaptic to the cortico-striatal afferents is located on the same neurons as striatal dopamine receptors. These glutamate synapses are located on the heads of dendritic spines of striato-nigral projection neurons, while the dopaminergic synapses are predominantly located on the necks of these same dendritic spines. Similar relationships could exist for mesolimbic and mesocortical dopamine systems. In peripheral systems, postjunctional denervation supersensitivity is known to be nonspecific; in other words, denervation of a single innervation of an excitable cell can alter the response to a range of stimuli. The antipsychotic effect of neuroleptics is therefore suggested to be due to nonspecific postjunctional subsensitivity at glutamate synapses, which develops concomitant with supersensitivity at dopaminergic synapses.

Time-dependent and schedule-dependent effects of dopamine receptor blockade

Rats were trained on one of two multiple random-interval schedules of reinforcement, which contained both ascending and descending reinforcement density sequences. The design of the schedules made it possible to determine whether performance changes in a particular component depended on the reinforcement density in that component, or on its temporal position within the schedule. Performance impairments following administration of the dopamine D1 antagonist SCH-23390 were both time- and schedule-dependent: SCH-23390 caused a relatively greater suppression of poorly reinforced responding that increased over time. The results, which are compatible with data on the effects of dopamine antagonists in other behavioural paradigms, illustrate the methodological problems of using Herrnstein's matching equation to interpret time-dependent behavioural changes.

Effects of dopamine antagonists injected through vortex veins on intraocular pressure.

In order to avoid the factors of the corneal barrier and tearing washout on absorption of eye drops, dopamine and antagonists were injected into rabbit eyeballs through vortex veins. Many dopamine antagonists, such as haloperidol, moperone, metoclopramide, trifluperidol, lenperone, and fluoropipamide, lowered the intraocular pressure (IOP), whereas a few of them, such as chlofluperol and trifluoperazine, raised the IOP. Furthermore, it was found that dopamine agonists also could either increase or decrease the IOP. The ocular hypertensive effect of dopamine was blocked by haloperidol as expected. However, when the hypotension-inducing dopamine agonist, bromocriptine, and antagonist, haloperidol, were combined, the IOP remained unchanged. It was concluded that dopamine agonists and antagonists act at different sites and changes in IOP resulted from a combined summary of these complex effects. As a result, dopamine agonists and antagonists, while they may both lower the IOP when given alone, can antagonize each other through different sites and produce no net change in IOP.

The effect of dopamine antagonists and/or VIP on TRH- or VIP-induced prolactin release in estrogen- and progesterone-treated ovariectomized rats.

These experiments were conducted to test the hypothesis that the effectiveness of VIP in releasing prolactin is, like TRH, enhanced when preceded by a short period of dopamine receptor antagonism. Chronically catheterized, ovariectomized rats pretreated with estradiol benzoate and progesterone to mimic early pregnancy were used throughout these studies. In the first experiment, animals were injected either with the dopamine (DA) antagonist domperidone (DOM, 0.01 mg/rat, iv) or with vehicle (acetic acid in saline). Five minutes later, all animals were treated with the DA agonist 2-Br-alpha-ergocryptine maleate (CB-154, 0.5 mg/rat, iv) followed 60 min later by the administration of thyrotropin-releasing hormone (TRH, 1.0 micrograms/rat iv) or vasoactive intestinal peptide (VIP, 25 micrograms/rat, iv). The injection of TRH following DOM treatment increased mean plasma PRL levels 100 ng/ml above levels found in vehicle-injected rats. VIP administration, however, increased PRL levels in the blood in DOM-treated rats only 6 ng/ml above the levels in vehicle-injected animals. The same treatment protocol was used in the second experiment except that the DA antagonist, sulpiride (0.01 mg/rat, iv) was administered instead of DOM, and CB-154 was not given. In this experiment both TRH and VIP released PRL. The response to TRH, but not to VIP, was significantly greater following sulpiride than in animals treated with sulpiride vehicle. In the third experiment animals were treated with DOM, VIP, DOM plus VIP, or vehicle. Five minutes later all rats received CB-154 injections, followed 60 min later by TRH administration. The final experiment was a replicate of the third except that sulpiride was substituted for domperidone and no CB-154 was given. The resulting data revealed that (1) dopamine antagonism enhanced the effectiveness of TRH but not VIP and (2) that VIP augmented the effectiveness of DA blockade on PRL release and was additive with domperidone (but not sulpiride) on increasing the responsiveness to TRH. However, VIP administration without concurrent administration of domperidone or sulpiride did not increase the effectiveness of TRH compared to vehicle-injected animals. From these data we concluded that VIP is a PRL-releasing hormone the effect of which is not affected by interruption in dopamine tone as is observed for TRH. Second, VIP can potentiate the stimulatory actions of at least one DA receptor antagonist and TRH on PRL release. This later finding suggests that VIP may play a modulatory role in the neuroendocrine regulation of PRL secretion in the female rat.

Effect of dopamine antagonists on the urine flow of rats infused with hypotonic saline.

1. The probable involvement of dopamine in the regulation of water excretion was investigated by administering dopamine antagonists intravenously to barbiturate--anaesthetized rats undergoing a water diuresis induced by the infusion of 0.83% glucose with 0.3% NaCl at the rate of 9 ml h-1. 2. Administration of 100 micrograms of the D1-/D2-dopamine antagonist, haloperidol, reduced the enhanced urine flow of rats infused with the hypotonic solution by 69% (from 75.4 +/- 13.0 to 23.6 +/- 6.0 microliter min-1, P less than 0.01). Similarly, the D1-receptor antagonist, SCH 23390, reduced urine flow by 58% (from 77.5 +/- 9.2 to 32.7 +/- 7.2 microliters min-1, P less than 0.01) and the D2-receptor antagonist, sulpiride, by 47% (from 66.2 +/- 8.6 to 35.1 +/- 6.8 microliter min-1, P less than 0.05). 3. The injection of SCH 23390 increased the urine osmolality from 189.6 +/- 27.5 to 479.8 +/- 45.8 mosm kg-1 (P less than 0.05). There was no significant change in sodium and potassium excretion in any of the experiments. Blood pressure (BP) decreased after haloperidol and SCH 23390 injection from control values of 121.7 +/- 1.7 and 116.5 +/- 7.4 to 113.3 +/- 3.3 and 106.0 +/- 8.8 mmHg respectively (P less than 0.05). 4. To study whether the influence of dopamine antagonists on urine flow during water diuresis depends on antidiuretic hormone (ADH), we administered 0.6 micrograms d(CH2)5-D-Phe-Ile-AVP (an ADH antagonist) shortly after the injection of 100 micrograms SCH 23390. The preferential V2 ADH-antagonist abolished the antidiuretic effect of SCH 23390 but did not affect its blood pressure reducing effect (from 118.6 +/- 5.6 to 103.2 +/- 4.6 mmHg, P <0.01). 5. These results suggest that dopamine antagonists blunted the hypotonic saline-induced diuresis by favouring ADH release through an interference with an inhibitory dopaminergic pathway.

Effects of acute thioridazine, metoclopramide and SCH 23390 on the basal activity of A9 and A10 dopamine cells

Extracellular single-unit recording techniques were employed to examine the effects of various dopamine (DA) antagonists on the basal activity of spontaneously active DA cells. Metoclopramide and thioridazine were both effective in reversing apomorphine-induced suppression of A9 and A10 DA cells. SCH 23390 produced only a partial reversal of this suppression. When the antagonists were given without any pretreatment, thioridazine preferentially increased the firing rate of A10 DA cells, and was relatively ineffective in altering A9 activity. Metoclopramide, on the other hand, increased the activity of most A9 DA cells, but was less effective in doing so with A10 cells. SCH 23390 did not significantly affect the basal activity of either cell subpopulation. These data support the hypothesis that the so-called ‘atypical” antipsychotic drugs act preferentially on the A10 DA system. Taken together with previous results, they also suggest that the acute effects of DA antagonists on DA cell subpopulations coincide with their chronic effects.

Effects of dopamine antagonists and apomorphine on regional energy metabolism in rat CNS.

Alterations in 2-[14C]deoxyglucose uptake were studied in 154 brain regions from animals acutely challenged with a dopamine (DA) agonist or antagonist. Doses of apomorphine inducing locomotion and stereotypic behavior produced increased uptake in the subthalamic nucleus, the substantia nigra reticulata, and the ventroanterior and ventrolateral nuclei of the thalamus while decreased uptake was observed in the lateral habenula and several midline thalamic nuclei. The six centrally active DA antagonists studied produced uniform increases in uptake in the lateral habenula and the anterior regions of both the n. accumbens and striatum whereas decreased uptake was observed in the mesencephalic reticular formation and the reticular nucleus of the thalamus. Low doses of apomorphine that produced behavioral hypoactivity resulted in a pattern of metabolic alterations that resembled those associated with DA antagonists more closely than metabolic alterations seen with DA agonists. These results suggest that unique alterations in neuronal activity in several brain regions, including the traditional dopaminergic projection areas, are associated with the expression of specific DA-mediated behaviors.

Differential effects of the dopamine antagonist remoxipride on apomorphine induced behaviour in the rat.

The effects of the novel substituted benzamide remoxipride on apomorphine induced behaviour in rats was investigated by means of an automatic holeboard apparatus. The ability of remoxipride to antagonise locomotion and gnawing induced by a high dose of apomorphine (5 mg/kg) and inhibition of exploration induced by a low dose of apomorphine (0.05 mg/kg) was tested. It was found that remoxipride in moderate doses potentiate locomotion and inhibit gnawing induced by the high dose of apomorphine while higher doses of remoxipride inhibits both apomorphine induced gnawing and locomotion. The inhibition of exploration following the low dose of apomorphine was not antagonised by remoxipride pretreatment. The results demonstrated that remoxipride has an interesting and unique profile of dopamine antagonistic effects in rat behavioural models.

Effects of dopamine antagonists on fluid intake and salt preference in male and female rats

The effects of three dopamine antagonists (pimozide, clozapine, sulpiride) on fluid consumption by water-deprived rats trained to choose between a saline solution and water in a 15 min drinking test were examined. Rats of each sex were allocated to three groups and given access to 0.125% NaCl, 0.6% NaCl, and 1.7% NaCl, respectively, as the alternative to water. Dose-dependent reductions in fluid consumption were produced by pimozide (0.1- 3.0 mg kg(-1)) and clozapine (0.3-10.0 mg kg(-1)), but not by sulpiride (1.0-30 mg kg(-1)). There were instances of a hyperdipsic effect of sulpiride. The dopamine antagonists produced significant changes in saline preference, but in no case was a decrease in preference detected. Instead, there was evidence for induction of preference, or enhancement of preference, in both sexes. So far as determinants of preference for the salt are concerned, it appears that in the rat, dopamine may have a predominantly inhibitory action.

Modulation of the endogenous acetylcholine release from rat striatal slices

The dopaminergic modulation of the acetylcholine release from rat striatal slices has been investigated using a chemiluminescent method. Dopamine, more efficiently than apomorphine, decreased the potassium-evoked release of acetylcholine. The effect of dopamine antagonists, haloperidol and sulpiride, has been studied, and haloperidol was a better antagonist than sulpiride to the dopamine effect. Haloperidol elicited an acetylcholine release from striatal slices at 0.1 nM, probably by removing endogenous dopamine from dopaminergic receptors.

The effect of dopamine antagonists in spontaneous and tardive dyskinesia.

Dopamine antagonists are effective in suppressing hyperkinetic symptoms in patients with tardive dyskinesia, spontaneous oral dyskinesia, Huntington's chorea, and Gilles de la Tourette's syndrome. These neuroleptics have no curative effect upon the conditions and may even aggravate symptoms in the long term. In many cases a single neuroleptic drug may lose its effect. A more lasting effect may be obtained by combining drugs with pre- and postsynaptic antidopamine effects.

Effects of dopamine antagonists on receptive fields of brisk cells and directionally selective cells in the rabbit retina

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.

Unilateral striatal dopamine denervation: reduced motor inhibitory effects of dopamine antagonists revealed in models of asymmetric and circling behaviour.

Circling and asymmetric behaviours to apomorphine (dopamine agonist/antagonist) challenge were studied in rats with unilateral striatal electrolesions or 6-hydroxydopamine (6-OHDA) lesions, each induced by combined lesions at 3 striatal locations, to allow an assessment of drug action on 'normal' receptors in the intact striatum or 'supersensitive' receptors in the lesioned striatum respectively. The minimally effective dose of 6-OHDA (given in the presence of DMI and tranylcypromine) to cause functional change was 3 X 8 micrograms, with 3 X 32 micrograms providing maximal change. Electrolesions were shown histologically to be confined to striatal tissue, and dopamine depletions caused by 6-OHDA were selective for the striatum. Temporal differences were recorded for onset of asymmetry and circling behaviour, both between behaviours and between lesions. Thus, asymmetry developed during the 2nd-4th days after 6-OHDA lesion but circling developed more abruptly on postoperative days 10-12. In contrast, both asymmetry and circling behaviours were apparent from the first day following electrolesion. The dose-dependent effects of apomorphine were apparent at much lower doses in 6-OHDA lesioned than electrolesioned rats. This potency difference was also demonstrated for two further dopamine agonists, 2-di-n-propylamino-5,6-dihydroxytetralin and SK & F 38393. In contrast, the agonist-induced asymmetric and circling behaviours of electrolesioned rats were some 9-44 times more sensitive than those of 6-OHDA lesioned rats to antagonism by the neuroleptic agents haloperidol, alpha-flupenthixol and oxiperomide, although tiapride antagonism was very similar in both the electrolesioned and 6-OHDA-lesioned rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of the effects of LSD and lisuride on A10 dopamine neurons in the rat

Extracellular single-unit recording techniques were used to compare the effects of d-lysergic acid diethylamide (LSD) and its non-hallucinogenic congener lisuride hydrogen maleate (LHM) on the activity of dopamine (DA) neurons in the A10 region of the rat ventral tegmental area. Lisuride hydrogen maleate potently suppressed the firing rates of A10 DA cells (ID 50 = 0.021 mg/kg). The DA antagonist haloperidol prevented, but did not reverse, the effect of lisuride. In addition, the DA agonist apomorphine was unable to suppress further the firing rates of A10 DA cells that had been partially suppressed by small doses of lisuride. These results suggest that lisuride acted as a non-competitive or irreversible DA agonist. In contrast to lisuride, LSD exerted mixed effects on A10 DA cells, partially depressing the firing rates of 54% of the cells tested, increasing the firing rates of 23% of the cells and exerting no effect on the other 23%. The response of a particular A10 DA cell to administration of LSD was dependent upon its baseline firing rate. Haloperidol readily reversed the LSD-induced partial suppression of the firing of A10 DA cells. Also, LSD effectively reversed apomorphine-induced suppression and increased the doses of apomorphine required to suppress firing of A10 DA neurons. These results suggest that, in addition to its weak DA agonist effects, LSD also exerted partial DA antagonist effects. Pharmacological and physiological manipulations of serotonergic neuronal systems failed to implicate a role for serotonin in the effects of LSD and lisuride on A10 DA neurons. These qualitative and quantitative differences between the effects of LSD and lisuride on A10 DA neurons suggest that the potent DA agonist actions of lisuride may contribute to its lack of hallucinogenic potential.

Pre- and postsynaptic effects of dopamine antagonists on dopaminergic synaptic transmission in Helix pomatia

1. 1. The rate of transmitter mobilization in identified dopaminergic synapses was decreased by the dopamine antagonists pimozide, chlorpromazine, haloperidol, cis-flupenthixol, curare, clozapine and high concentrations of ergometrine. 2. 2. The depolarizing postsynaptic potential was inhibited by pimozide, chlorpromazine, haloperidol, cis-flupenthixol, curare, clozapine, (+)-butaclamol and high concentrations of ergometrine. 3. 3. The hyperpolarizing synaptic potential was inhibited by naloxone, methysergide, (+)-butaclamol, haloperidol, 6-hydroxydopamine and low concentrations of ergometrine, while pimozide, cis-flupenthixol, trans-flupenthixol, curare, clozapine, promethazine, chlorpromazine and (−)-butaclamol had no clear effect. 4. 4. The presynaptic receptors involved in modulation of the mobilization rate showed similarities with the dopamine receptors mediating depolarizations. 5. 5. The dopamine antagonists changed dynamics of synaptic transmission.

Effects of dopamine antagonists on snail locomotion

Dopamine antagonists which affect the ergometrine-sensitive type of dopamine receptors produce characteristic motor disorders in a land snail,Helix pomatia L.

Dopamine antagonistic effects of a series of analogues of oxiperomide and spiroxatrine measured behaviourally in the rodent.

The activity spectra of oxiperomide, spiroxatrine and analogues were determined in two experimental models of abnormal peri-oral movements (induced by intrastriatal dopamine and subcutaneously administered 2-(NN-dipropyl)amino-5,6-dihydroxy-1,2,3,4-tetrahydronaphthalene (NN-diPr-5,6-diOHATN) in the guinea-pig), and in a stereotypy test (induced by subcutaneous apomorphine in the guinea-pig); the ability of the test compounds to induce catalepsy or catatonia in the rat was also determined. The parent compounds oxiperomide and spiroxatrine possessed optimal activity in all tests, although responses to the series of compounds allowed clear differentiation between an ability to antagonize the peri-oral movements (dopamine- or NN-di Pr-5,6-diOHATN induced) and an ability to antagonize apomorphine stereotypy. However, all compounds that antagonized the abnormal peri-oral movements also caused catalepsy/catatonia. The results are considered in terms of the selection of suitable agent(s) for the treatment of peri-oral dyskinesias.

Differential effects of dopamine antagonists on prolactin secretion from cultured rat pituitary cells

Various dopamine antagonists, including two novel non-neuroleptic drugs domperidone and halopemide, stimulated apomorphine-suppressed prolactin secretion from cultured rat pituitary cells. The potency of these drugs closely paralleled their rank-order in displacing in vitro H 3-haloperidol binding in rat striatum reported by others (10). Concentration-effect curves were parallel except those of pimozide and clopimozide which were biphasic : prolactin secretion was stimulated at low concentrations but depressed at concentrations above 25nM. When added alone, pimozide and clopimozide, but none of the other drugs tested, also depressed prolactin secretion. The present findings indicate that prolactin secretion from cultured pituitary cells may provide an in vitro test system suitable to differentiate antagonists of dopamine receptors and possibly to distinguish pure from partial antagonists.