Selective Dopamine Receptor Antagonist Research Articles

Selective dopamine receptor antagonists with an ‘atypical’ profile?

Selective dopamine receptor antagonists with an ‘atypical’ profile?

RGS mRNA expression in rat striatum: modulation by dopamine receptors and effects of repeated amphetamine administration.

Single injections of cocaine, amphetamine, or methamphetamine increased RGS2 mRNA levels in rat striatum by two- to fourfold. The D1 dopamine receptor-selective antagonist SCH-23390 had no effect by itself but strongly attenuated RGS2 mRNA induction by amphetamine. In contrast, the D2 receptor-selective antagonist raclopride induced RGS2 mRNA when administered alone and greatly enhanced stimulation by amphetamine. To examine the effects of repeated amphetamine on RGS2 expression, rats were treated with escalating doses of amphetamine (1.0-7.5 mg/kg) for 4 days, followed by 8 days of multiple daily injections (7.5 mg/kg/2 h x four injections). Twenty hours after the last injection the animals were challenged with amphetamine (7.5 mg/kg) or vehicle and killed 1 h later. In drug-naive animals, acute amphetamine induced the expression of RGS2, 3, and 5 and the immediate early genes c-fos and zif/268. RGS4 mRNA levels were not affected. Prior repeated treatment with amphetamine strongly suppressed induction of immediate early genes and RGS5 to a challenge dose of amphetamine. In sharp contrast, prior exposure to amphetamine did not reduce the induction of RGS2 and RGS3 mRNAs to a challenge dose of amphetamine, indicating that control of these genes is resistant to amphetamine-induced tolerance. These data establish a role for dopamine receptors in the regulation of RGS2 expression and suggest that RGS2 and 3 might mediate some aspects of amphetamine-induced tolerance.

Effects of selective dopamine D1- and D2-type receptor antagonists on the development of behavioral sensitization to 7-OH-DPAT.

The primary objective of this study was to determine whether the development of behavioral sensitization to the putative dopamine D3 receptor agonist 7-OH-DPAT could be prevented by either selective D1-type or D2-type dopamine receptor antagonists. In three experiments, male Wistar rats (250-350 g) were given seven to nine injections (at 48-h intervals) of 7-OH-DPAT (1.0 mg/kg, SC) or vehicle in combination with the D2-type dopamine antagonist eticlopride (0.3 mg/kg, SC), the D1-type dopamine antagonist SCH 23390 (0.1 or 0.2 mg/kg, SC), or vehicle. After the injections, the rats were tested for locomotor activity in photocell arenas for 2 h. In the first two experiments, after seven injections, all rats were tested for activity following vehicle injections to test for possible conditioning effects. In each experiment, after the last pre-exposure session, all rats were given a challenge injection of 7-OH-DPAT (1.0 mg/kg, SC) and tested for activity. Major findings were as follows: a) 7-OH-DPAT treatments produced a progressively greater increase in locomotor activity with repeated treatment; b) concurrent treatment with eticlopride or SCH 23390 (0.1 and 0.2 mg/kg) blocked the acute locomotor-activating effects of 7-OH-DPAT across days; c) eticlopride, but not SCH 23390, completely blocked the development of behavioral sensitization to 7-OH-DPAT. Although the low dose of SCH 23390 (0.1 mg/kg) produced a partial attenuation of sensitization, the higher dose (0.2 mg/kg) of SCH 23390 appeared to augment, rather than block, sensitization to 7-OH-DPAT; d) rats previously treated with SCH 23390 (0.2 mg/kg, but not 0.1 mg/kg) without 7-OH-DPAT displayed a hyperactive response to the 7-OH-DPAT challenge injection; and e) after vehicle injections, rats previously given 7-OH-DPAT, SCH 23390, or eticlopride either alone or in combination were more active than vehicle control rats. These findings suggest that the neurochemical mechanisms mediating the development of behavioral sensitization to 7-OH-DPAT may differ from those of other dopamine D2-type agonists such as quinpirole or bromocriptine. Moreover, these results demonstrate that hyperactivity responses following vehicle injections in drug-pretreated animals do not necessarily reflect conditioning mechanisms.

Interactions of Buprenorphine and Selective Dopamine Receptor Antagonists in the Rat Nucleus Accumbens

1. Extracellular recording of spontaneously active nucleus accumbens neurons was employed to characterize interactions of the mixed opioid buprenorphine and selective dopamine receptor antagonists. 2. Buprenorphine caused depression of single-unit activity at all doses tested but evoked facilitation only at low doses. 3. In experiments with the D 1 antagonist SCH 23390, buprenorphine-induced depression was consistently blocked, but facilitation was unaffected. 4. Conversely, the D 2 antagonist eticlopride blocked buprenorphine-induced facilitation, though it was ineffective against depression.

Dopamine receptor-mediated mechanisms involved in the expression of learned activity of primate striatal neurons.

To understand the mechanisms by which basal ganglia neurons express acquired activities during and after behavioral learning, selective dopamine (DA) receptor antagonists were applied while recording the activity of striatal neurons in monkeys performing behavioral tasks. In experiment 1, a monkey was trained to associate a click sound with a drop of reward water. DA receptor antagonists were administered by micropressure using a stainless steel injection cannula (300 microm ID) through which a Teflon-coated tungsten wire for recording neuronal activity had been threaded. Responses to sound by tonically active neurons (TANs), a class of neurons in the primate striatum, were recorded through a tungsten wire electrode during the application of either D1- or D2-class DA receptor antagonists (total volume <1 microl, at a rate of 1 microl/5-10 min). Application of the D2-class antagonist, (-)-sulpiride (20 micrograms/microl, 58 mM, pH 6.8), abolished the responses of four of five TANs examined. In another five TANs, neither the D2-class antagonist nor the D1-class antagonists, SCH23390 (10 micrograms/microl, 31 mM, pH 5.7) or cis-flupenthixol (30 micrograms/microl, 59 mM, pH 6.6) significantly suppressed responses. In experiment 2, four- or five-barreled glass microelectrodes were inserted into the striatum. The central barrel was used for extracellular recording of activity of TANs. Each DA receptor antagonist was iontophoretically applied through one of the surrounding barrels. SCH23390 (10 mM, pH 4.5) and (-)-sulpiride (10 mM, pH 4.5) were used. The effects of iontophoresis of both D1- and D2-class antagonists were examined in 40 TANs. Of 40 TANs from which recordings were made, responses were suppressed exclusively by the D2-class antagonist in 19 TANs, exclusively by the D1-class antagonist in 3 TANs, and by both D1- and D2-class antagonists in 7 TANs. When 0.9% NaCl, saline, was applied by pressure (<1 microl) or by iontophoresis (<30 nA) as a control, neither the background discharge rates nor the responses of TANs were significantly influenced. Background discharge rate of TANs was also not affected by D1- or D2-class antagonists applied by either micropressure injection or iontophoresis. It was concluded that the nigrostriatal DA system enables TANs to express learned activity primarily through D2-class and partly through D1-class receptor-mediated mechanisms in the striatum.

The effects of dopaminergic agents on reaction time in rhesus monkeys.

Many CNS pathologies, including Parkinson's, Alzheimer's and Huntington's diseases, as well as AIDS dementia complex, involve some degree of movement dysfunction. Reaction time (RT) performance has been shown to be a sensitive measure of motor function for these disorders. Useful models of RT performance exist in a variety of species, but few are performed in the same manner as with humans. To facilitate species comparisons, the present RT task was developed from a human RT task. Dopaminergic drugs were then used to characterize the sensitivity of the model to CNS changes and to investigate their effects on RT performance in intact rhesus monkeys. With cumulative dosing, the selective dopamine receptor antagonists (D1) SCH 39166 and (D2) raclopride produced dose-dependent slowing of RT performance. Results following bolus administration of these drugs were consistent with the cumulative dosing procedure, although of smaller magnitude and higher variability. Amphetamine had no significant effect on group RT performance with either dosing scheme, but RT performance in individual monkeys was either speeded or slowed by d-amphetamine. The present results suggest that blockade of either D1-like or D2-like dopamine receptors can slow RT performance in rhesus monkeys and that this paradigm may be useful to study movement dysfunction in non-human primates.

Heterogeneity of behavioural profile between three new putative selective D3 dopamine receptor antagonists using an ethologically based approach.

The effects on behaviour of the putative selective D3 dopamine receptor antagonists GR 103691, nafadotride and U 99194A were compared with those of the generic D2-like antagonist haloperidol, using an ethologically based approach. Neither GR 103691 (0.008-1.0 mg/kg) nor nafadotride (0.025-1.6 mg/kg) influenced any element of behaviour. Conversely, U99194A (1.67-45 mg/kg) effected a dose-dependent stimulation of episodes of non-stereotyped sniffing, locomotion, chewing and eating, with some stimulation of rearing, and reduced baseline levels of grooming; thereafter, as sniffing and locomotion declined, stimulation of episodes of grooming emerged. Haloperidol (0.0008-0.1 mg/kg) failed to promote any element of behaviour and reduced baseline levels of grooming; responsivity to U99194A was antagonised by pretreatment with haloperidol. The lack of effect of GR 103691 (> 100-fold D3/D2 selectivity) and nafadotride (10-fold D3/D2 preference), in contrast to the characteristic "ethogram" for U99194A (25-fold D3/D2 selectivity), indicated a fundamental difference in their mechanisms of action. This topography of responsivity to U99194A overlapped somewhat with the profiles of both D2-like and D1-like agonists, and its sensitivity to antagonism by haloperidol also indicated a dopaminergic basis thereto. However, differences among GR 103691, nafadotride and U99194A bore no relation to their relative selectivities for the D3 receptor, and the basis thereof remains unclear. Theorising as to the behavioural role of the D3 receptor may need to be tempered pending the identification of a range of chemically distinct D3 antagonists of higher selectivity.

Pharmacological evidence for the presence of a peripheral postjunctional D2-like dopamine receptor in rabbit splenic artery.

1. This study was designed to investigate the involvement of postjunctional D2-like receptors in a rabbit vasculature model used to evaluate the D1-like agonist activity. Dopamine, epinine and (-)-DP-5,6-ADTN, three mixed D1/D2-like agonists, fenoldopam and SKF 82958, two selective D1-like agonists and SKF 89124, a selective D2-like agonist, were administered cumulatively in precontracted and alpha/beta-blocked rabbit splenic artery rings in order to evaluate their D1-like-mediated vasorelaxant activity before and after pretreatment with the selective D2-like antagonist YM 09151-2 (1 nM). 2. Dopamine (pD2=6.35+/-0.09), epinine (pD2=6.73+/-0.13), (-)-DP-5,6-ADTN (pD2=7.56+/-0.09) and SKF 82958 (pD2=8.55+/-0.10) reversed completely the U46619-induced contracture whereas SKF 89124 was inactive up to 10 microM and fenoldopam acted like a partial agonist (pD2=8.31+/-0.09, alpha=0.62). The selective D2-like dopamine receptor antagonist YM 09151-2 (1 nM) significantly (P<0.05) potentiated the vasorelaxant activity of dopamine (pD2=7.01+/-0.07), epinine (pD2=7.14+/-0.08), (-)-DP-5,6-ADTN (pD2=8.19+/-0.09) and SKF 89124 (40% relaxation at 10 microM), whereas it did not alter the effects of fenoldopam (pD2=8.40+/-0.09, alpha=0.68) and SKF 82958 (pD2=8.58+/-0.08). 3. The D2-like antagonist YM 09151-2 induced the same degree of effect with all the substances tested in both endothelium-denuded and endothelium-intact preparations. 4. The selective D2-like dopamine receptor agonist SKF 89124 did not produce any intrinsic effect on the splenic artery, but was able to produce a rightward shift of the forskolin-induced relaxation. 5. The results of these experiments support the existence of a non-endothelial postjunctional D2-like dopamine receptor counteracting the D1-like-mediated vasodilatation in rabbit splenic artery, probably by the inhibition of adenylate cyclase.

Central 5-HT depletion enhances impulsive responding without affecting the accuracy of attentional performance: interactions with dopaminergic mechanisms.

A series of ten experiments examined the effects of profound central 5-HT depletion on attentional performance in the rat in the five-choice serial reaction time task, and also determined the effects of such depletion on responding affected by d-amphetamine and by selective dopamine receptor antagonists. Rats were trained to detect and locate brief visual stimuli randomly presented in one of five spatial locations. When performance had stabilised (> 80% correct, < 20% omissions), selective central 5-HT depletion was induced by intracerebroventricular administration of the neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) following pretreatment with both a noradrenergic and a dopaminergic re-uptake inhibitor. The lesioned animals performed the five-choice serial reaction time task with the same degree of accuracy as the sham-operated controls. However, 5-HT depletion reduced the percentage of omitted trials and increased the number of premature/anticipatory responses. This pattern of behaviour following 5-HT depletion could not be attributed to enhanced primary motivation as demonstrated by measures of food intake and latencies to collect food reinforcement. The lesion attenuated the increase of premature responding induced by high doses of systemically administered d-amphetamine. 5-HT depletion also attenuated the dose-dependent decrease in accuracy induced by (-)-sulpiride, a D2 receptor antagonist, although the effects of this drug on response latencies and premature responding were similar in both groups. However, the systemic administration of the D1 receptor antagonist, SCH 23390, blocked the impulsive responding produced by the lesion as indicated by a lack of lesion effects on the percentage of omitted trials and premature responding. The results suggest that central 5-HT depletion results in impulsive, fast responding, which nevertheless does not impair accuracy of visual discrimination performance. The increased impulsivity may be mediated by altered 5-HT-dopamine interactions, with the lesion removing an inhibitory influence over dopamine neurotransmission.

Existence of dopamine D 1 receptor on the sympathetic nerve endings in the guinea-pig vas deferens

The effects of selective dopamine receptor agonists and antagonists on sympathetic neuromuscular transmission were investigated in the guinea-pig vas deferens in order to test for the presence of presynaptic dopamine receptors. A single-pulse field stimulus induced a rapid monophasic contraction which was strongly inhibited by α,β-methylene ATP, a P 2X purinoceptor desensitizing agent. The contraction was also inhibited by 5-bromo- N-(4,5-dihydro-1 H-imidazol-2-yl)-6-quinoxalinamine (UK 14,304), a selective α 2-adrenoceptor agonist. This inhibition was antagonized by idazoxan, an α 2-adrenoceptor antagonist, but not by R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1 H-3-benzazepine hydrochloride (SCH-23390), a dopamine D 1 receptor antagonist. Furthermore, the contractions were inhibited in a dose-dependent manner by R(+)-1-phenyl-2,3,4,5-tetrahydro-(1 H)-3-benzazepine-7,8-diol hydrochloride (SKF-38393) and (±)-6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1 H-3-benzazepine hydrobromide (SKF-82958), dopamine D 1 receptor agonists, and the inhibition was antagonized by both SCH-23390 and idazoxan, but not by spiperone, a dopamine D 2 receptor antagonist. The results suggest that dopamine D 1 receptors are located on the sympathetic nerve endings of guinea-pig vas deferens.

Dopamine antagonist and "binge' cocaine effects on rat opioid and dopamine transporter mRNAs.

The modulation by selective dopamine receptor antagonists of the effects of "binge' cocaine (3 x 15 mg kg-1 day-1, i.p., for 3 days after 11 days of adaptation to saline injections) on preproenkephalin, preprodynorphin, kappa opioid receptor and dopamine transporter mRNAs was determined. Administration of cocaine was preceded by daily single injections of a D1 (SCH 23390; 2 mg kg-1) or the D2 (sulpiride; 50 mg kg-1) dopamine receptor antagonist. The D1, and not the D2, antagonist blocked cocaine-induced preprodynorphine and preproenkephalin increases in the caudate-putamen. Sulpiride alone, and sulpiride plus cocaine, increased preproenkephalin mRNA. Dopamine transporter mRNA levels showed a cocaine treatment-antagonist interaction. These data indicate that this administration paradigm elevates both preprodynorphin and preproenkephalin mRNAs by a D1-dependent mechanism not requiring D2 activation.

Quantitative autoradiographic analysis of D 1 and D 2 dopamine receptors in rat brain in early and late pregnancy

This study examined the levels of D 1 and D 2 dopamine receptors in the rat brain during pregnancy, a physiologically unique and important naturally occurring state. We are particularly interested in changes in the dopamine receptor complement of the brain during pregnancy because these receptors might support some components of the immediate postpartum onset of normal maternal behavior. Quantitative in vitro receptor autoradiography was applied particularly focusing on brain areas that control maternal behavior. The D 1 dopamine receptor selective antagonist [ 3H]SCH23390 and the D 2 dopamine receptor selective antagonist [ 3H]spiperone were used as the ligands. We examined the levels of binding to D 1 and D 2 dopamine receptors in brains in females on day 2 (early pregnancy) and day 21 (late, but prepartum pregnancy) of pregnancy. In addition, brains from females on diestrus-1 and from males provided reference points to the existing literature. Late in pregnancy females had significantly 18–27% lower levels of binding to D 1 dopamine receptors in the lateral striatum, the medial striatum, and the nucleus accumbens when compared to all other groups. Late in pregnancy, females had also significantly 11–25% lower levels of binding to D 2 dopamine receptors in the lateral striatum, the anterior striatum, the nucleus accumbens and the olfactory tubercle compared to all other experimental groups. We examined all of the brain regions already established to be important for maternal behavior, and found that dopamine receptor binding changed across pregnancy only in one such region, the nucleus accumbens. Thus pregnancy, perhaps the hormones of pregnancy, reduces the levels of D 1 and D 2 dopamine receptors in the striatum, and the nucleus accumbens, but not in other brain regions.

Effect of haloperidol and (−)-sulpiride on dopamine agonist-induced hypoactivity

High doses of dopamine D 2 receptor agonists produce hyperactivity in rodents whereas low doses suppress activity. In this study, low doses of a range of dopamine agonists were examined for their effects on locomotor activity in rats. All agonists caused a dose-related hypolocomotor effect with a rank order of potency of quinelorane > (−)-quinpirole > 7-OHDPAT > PBTO. (−)-Sulpiride (1.6–160 μmol/kg), a neuroleptic with atypical properties caused a dose-related reversal of the hypolocomotor effect produced by all four agonists whereas the typical neuroleptic haloperidol (0.005–0.16 μmol/kg) did not reverse hypolocomotion. Neither sulpiride (5–160 μmol/kg) nor haloperidol (0.005–0.16 μmol/kg) affected locomotor activity per se, although haloperidol (1.6–5 μmol/kg) did reduce locomotor activity. The different behavioural profiles shown by (−)-sulpiride and haloperidol in these tests may reflect some of the clinical characteristics of these neuroleptics. The question of whether these effects can be ascribed to differential actions at dopamine receptor subtypes will only be answered when more selective dopamine receptor antagonists are developed.

Dopamine receptor antagonists prevent expression, but not development, of morphine sensitization

The present experiments determined the effects of selective dopamine receptor antagonists on the initiation and expression of sensitization to the locomotor-stimulating effects of morphine in rats. Although both the dopamine D 1 receptor antagonist R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1 H-3-benzazepine hydrochloride (SCH 23390, 0.25 mg/kg) and the dopamine D 2 receptor antagonist eticlopride (0.1 mg/kg) suppressed the ability of morphine (10 mg/kg) to elicit sensitized locomotor activity during the course of a 12 day treatment schedule, subsequent tests with morphine alone revealed significant sensitization. Sensitization in the SCH 23390 + morphine group could not be attributed to dopamine D 1 receptor supersensitivity caused by repeated SCH 23390 administration because electrophysiological recordings indicated that nucleus accumbens neurons in SCH 23390-treated rats were not more sensitive to the inhibitory effects of either dopamine or a dopamine D 1 receptor-selective agonist. Thus, dopamine receptor stimulation may be involved in expression, but not development, of morphine sensitization.

Selective antagonism of dopamine D1 and D2 receptors does not block the development of behavioral sensitization to cocaine

The objective of this study was to determine whether the development of behavioral sensitization to cocaine could be prevented by either D1 or D2 selective dopamine receptor antagonists. Male Wistar rats were treated daily for 7 days with either cocaine (15 mg/kg, IP) or vehicle in combination with the D1 dopamine antagonist SCH 23390 (0.3 mg/kg, SC), the D2 dopamine antagonist sulpiride (100 mg/kg, IP), or vehicle. After the daily injections, the rats were tested for locomotor activity in photocell arenas. Twenty-four hours after the last pre-exposure test session, all rats were given a challenge injection of cocaine (15 mg/kg, IP) and tested for activity. Cocaine treatments produced a greater relative increase in locomotor activity with repeated exposure (i.e. sensitization). Moreover, this increase in cocaine-induced locomotor activity was attenuated by both SCH 23390 and sulpiride. In contrast, neither sulpiride nor SCH 23390 blocked the development of behavioral sensitization to cocaine. That is, rats pretreated with sulpiride or SCH 23390 and cocaine did not differ from rats pre-exposed only to cocaine when given a cocaine challenge injection. These results suggest that behavioral sensitization to cocaine may develop through either D1 or D2 dopamine receptor stimulation or possibly through stimulation of some non-dopaminergic receptor.

Understanding the Mechanism of Action of Atypical Antipsychotic Drugs

The thrust of development of new antipsychotic drugs has been to identify new compounds that have enhanced antipsychotic efficacy and have lesser side-effects than standard neuroleptic compounds. Drug development strategies no longer concentrate on D2 receptor antagonism but aim to produce novel compounds. The following have been pursued: (a) selective dopamine receptor antagonists; (b) serotonin receptor agonists and antagonists (5-HT1a,e'5-HT2,5-HT3) or mixed 5-HT2-D2 receptor antagonist; (c) selective dopamine agonists or partial agonists; and (d) sigma-site and excitatory amino-acid antagonists. Such compounds are at various stages of development. The only drug which has truly distinguished itself as 'atypical' is clozapine. Its mechanism of action is unknown and the search for it, in large part, has been the impetus for development of the compounds listed above.

Behavioral effects of dopaminergic agonists and antagonists alone and in combination in the squirrel monkey.

The effects on schedule-controlled operant behavior of the D2 receptor agonist, quinpirole, and the D1 agonist, SKF 38393, were assessed alone and in combination with selective dopamine-receptor antagonists. Squirrel monkeys (Saimiri sciureus) were trained to press a response key under fixed-interval and fixed-ratio schedules of food reinforcement. The fixed-interval schedule maintained relatively low rates of responding that increased up to food presentation. The fixed-ratio schedule maintained relatively constant high rates of responding. Quinpirole increased rates and disrupted the temporal pattern of responding under the fixed-interval schedule at doses (0.1-1.0 mg/kg) that decreased rates of responding under the fixed-ratio schedule. Under the fixed-interval schedule, the D2 antagonists, spiperone (0.003-0.006 mg/kg) and haloperidol (0.003-0.01 mg/kg), and the D1 antagonist, SCH 23390 (0.03 mg/kg), shifted the quinpirole dose-effect curve to the right. The maximal effects of quinpirole were decreased at the highest doses of the antagonists. However, only spiperone antagonized effects of quinpirole on the rates of responding under the fixed-ratio schedule. The D1 agonist, SKF 38393, dose-dependently (1.0-10.0 mg/kg) decreased rates of responding under both schedules. Those effects were not antagonised by any doses studied of either spiperone (0.003 mg/kg) or SCH 23390 (0.003-0.3 mg/kg). Rather, both antagonists enhanced the effects of SKF 38393.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacological characterization of the dopamine receptor coupled to cyclic AMP formation expressed by rat mesenteric artery vascular smooth muscle cells in culture

1. Mesenteric artery vascular smooth muscle cells derived from male Wistar rats and grown in culture were prelabelled with [3H]-adenine and exposed to a range of dopamine receptor agonists and antagonists. Resultant [3H]-cyclic AMP formation was determined and concentration-effect curves constructed, in the presence of propranolol (10-6) M) and the phosphodiesterase inhibitor IBMX (5 x 10(-4) M). 2. Ka apparent values for D1/DA1 dopamine receptor agonists SKF 38393, fenoldopam, 6,7-ADTN, and dopamine were 0.06, 0.59, 4.06 and 5.77 x 10(-6) M respectively. Although fenoldopam and SKF 38393 were more potent than dopamine, they were partial agonists with efficacies, relative to dopamine of approximately 48% and 24% respectively. 6,7-ADTN, in contrast, behaved as a full agonist. 3. Dopamine-stimulated cyclic AMP formation was inhibited in a concentration-dependent manner by the D1/DA1 dopamine receptor selective antagonists, SCH 23390 and cis-flupenthixol (Ki values 0.53 and 36.1 x 10(-1) M respectively). In contrast, the D2/DA2 dopamine receptor selective antagonists, domperidone and (-)-sulpiride, were less potent (Ki values 2.06 and 5.82 x 10(-6) M respectively). Furthermore, the stereoisomers of SCH 23390 and cis-flupenthixol, SCH 23388 and trans-flupenthixol, were at least two orders of magnitude less potent (Ki values 0.14 and 13.2 x 10(-6) M respectively) indicating the stereoselective nature of this receptor. 4. Our results indicate that rat mesenteric artery vascular smooth muscle cells in culture express a dopamine receptor coupled to cyclic AMP formation, which has the pharmacological profile, characteristic of the D1 dopamine receptor subfamily.

Disruption of conditioned reaction time performance by dopamine receptor antagonists in the rat

The effects of the neuroleptics haloperidol, cis-flupenthixol and chlorpromazine, and the selective dopamine (DA) receptor antagonists raclopride and SCH 23390, were assessed in a conditioned reaction time task. In this operant task, rats were required to hold down a lever for a randomly determined hold duration (0.5-2.0s) and to release the lever within 1s of a light cue to obtain food reinforcement. All drugs dose-dependently reduced the total number of lever presses and the number of rewarded responses, and all but chlorpromazine produced an abrupt cessation of responding before the end of the experimental session. However, there were variations in the ability of these drugs to impair lever release performance. Chlorpromazine and the selective D2 antagonist raclopride significantly elevated rewarded and total reaction times. The former drug also increased the number of delayed responses (i.e. those occurring with a latency of greater than 1s) and reduced the percentage of rewarded responses occurring following light onset (percentage success), whilst raclopride also increased delayed reaction times. Haloperidol failed significantly to influence rewarded and total reaction times, as well as the percentage success measure. However, the lowest dose of haloperidol increased the number of delayed responses, indicating a subtle impairment of lever release performance. cis-Flupenthixol and the selective D1 antagonist SCH 23390 failed significantly to influence any aspect of lever release performance. Only haloperidol and cis-flupenthixol increased the time rats took to move from the lever to the food hopper, whilst all drugs increased the time taken to return to the lever. Although feeding animals prior to the experimental session, or removing food pellets from the dispensers during the session, reduced overall response levels, the former did not influence any reaction time measure, whilst extinction only reduced percentage success. The present findings reveal that certain DA receptor antagonists impair conditioned lever release performance. However, this reaction time deficit is not obtained with all DA receptor antagonists, despite their consistent effects on other aspects of performance in the task.

Time sampling observation procedure for studying drug effects: Interaction between d-amphetamine and selective dopamine receptor antagonists in the rat

A rapid time sampling observation procedure combined with two forms of automatic activity assessment is described. The methods are illustrated by examination of the behavioral effects of d-amphetamine, administered to rats either alone or in combination with antagonists selective for D 1 or D 2 dopamine (DA) receptors. Low doses of d-amphetamine (0.5–4.0 mg/kg) increased photocell counts, rearing, ambulation, and various forms of sniffing. Similar effects were observed in the first 30 min following administration of 8.0 mg/kg d-amphetamine. However, animals exhibited licking, intense sniffing down, and repetitive head and limb movements in the following 30 min; minimal ambulation, rearing, and sniffing up were observed. The “traditional” total photocell count measure did not differentiate between these time-dependent changes in locomotion. On the other hand, latch counts—where subjects had to move between the beams to register a count—adequately demonstrated this change in locomotion. The selective D 1 receptor antagonist SCH23390 and selective D 2 antagonist raclopride dose dependently inhibited the behavioral changes produced by 1.5 mg/kg d-amphetamine. Higher doses of SCH23390, but not raclopride, produced a behavioral pattern indistinguishable from that observed in control sessions. Both DA antagonists equipotently blocked the intense sniffing down and repetitive head/body movements produced by 8.0 mg/kg d-amphetamine. A narrow intermediate range of doses of SCH23390 reduced the incidences of these behaviors and produced levels of locomotion and sniffing straight that were significantly higher than those observed in control session. This form of behavioral activation was not observed with raclopride. Therefore, this observation procedure revealed subtle differences between the inhibitory effects of SCH23390 and raclopride on d-amphetamine-induced behavioral changes.