The effects of selective dopamine D1 or D2 receptor antagonists on the establishment of agonist-induced place conditioning in rats

The ability of the dopamine D1 antagonist, SCH 23390 (0.01, 0.1, 1.0, 2.0 mg/kg) or the D2 antagonist, metoclopramide (1.0, 10.0, 20.0 mg/kg), to block the establishment of place conditioning with either the nonselective dopamine agonist, amphetamine (2.0 mg/kg), the D1 agonist, SKF 38393 (10.0 mg/kg), or the D2 agonist, quinpirole (1.0 mg/kg), was evaluated in rats. The experimental protocol consisted of three phases. During the preexposure phase, rats explored two distinctive compartments joined by a small tunnel. During the 8-day conditioning phase, rats were pretreated with either saline, SCH 23390 or metoclopramide; 1 hr later the animals were treated with an agonist and confined to one compartment for 30 min. On alternate days, rats received saline and were placed in the opposite compartment. Test days occurred over the remaining 3 days during which drug-free animals were allowed access to both compartments. A significant increase or decrease in the amount of time spent in the drug-paired environment was indicative of a place preference or aversion, respectively. SCH 23390 and metoclopramide were effective in blocking amphetamine-induced place preference and SKF 38393-induced place aversion. At lower doses, the D1 and D2 antagonist blocked the place preference induced by quinpirole, however, higher doses were not effective. In general, these data suggest that both receptor subtypes participate in the establishment of place conditioning with amphetamine, SKF 38393 or quinpirole.     

Effects of selective D1 and D2 dopamine antagonists on cocaine self-administration in the rat

The effect of the selective D1 antagonist, SCH 23390, and the selective D2 antagonist, spiperone, was investigated in rats trained to self-administer intravenous cocaine on a fixed-ratio (FR) 5 schedule of reinforcement. Both SCH 23390 and spiperone pretreatment increased responding up to doses of 10.0 µg/kg, and decreased responding at higher doses. Since rate of responding maintained by a drug can be influenced by factors other than its reinforcing efficacy, behavior maintained by cocaine was also investigated under a progressive-ratio schedule. The breaking point obtained under this schedule is used as a measure of the efficacy of the reinforcer and this value is not exclusively determined by response rate. With the progressive-ratio schedule, both SCH 23390 and spiperone produced dose-dependent decreases in the highest ratio completed in rats self-administering cocaine. The results obtained using the FR 5 and progressive-ratio schedules suggest that both D1 and D2 receptors are involved in mediating the reinforcing effects of cocaine.     

The effects of developmental cadmium exposure on morphine sensitization and challenge with selective D(1) and D(2) antagonists

The purpose of this investigation was to determine the effects of developmental (perinatal) cadmium exposure on the development and expression of behavioral sensitization to morphine. Adult female rats were maintained ad libitum on diets containing 0, 25, or 50 ppm added cadmium (administered as cadmium chloride) for 30 days prior to breeding with nonexposed males. This exposure regimen continued throughout the gestational period and for 15 days postnatally during lactation, at which time regular rat chow was provided. On postnatal day (PND) 21, male pups from the respective litters were weaned and placed on an unadulterated food supply (no added cadmium) and tap water for the remainder of the study. Beginning on PND 70, animals from each exposure condition (0, 25, 50 ppm exposure conditions) received, for 21 consecutive days, either vehicle (distilled water) or 10 mg/kg morphine sulfate injections (ip) prior to being monitored for locomotor activity during 80-min test sessions. Following this 21-day period of morphine sensitization training, dose-effect profiles were determined for each exposure condition with successive daily challenges of 0, 10, and 20 mg/kg morphine. Subsequently, different doses of the D(1) antagonist SCH 23390 (0.01, 0.056, and 0.10 mg/kg) and the D(2) antagonist eticlopride (0.01 and 0.056 mg/kg) were presented prior to administration of the training dose of morphine (10 mg/kg). The results of the investigation revealed that developmental cadmium exposure attenuated the development/expression of morphine sensitization. Furthermore, it was found that the suppressive effects of the D(2) antagonist eticlopride were decreased by early cadmium exposure.     

Lack of specific effects of selective D(1) and D(2) dopamine antagonists vs. risperidone on morphine-induced hyperactivity

In the present study, three different dopamine antagonists were challenged in order to counteract hyperactivity induced by 50 mg/kg of morphine. A wide range of doses of morphine (50, 25, 12.5, 6.25, or 3.12 mg/kg) were evaluated on spontaneous locomotor activity. A significant increase was observed only with the two higher doses tested (25 and 50 mg/kg). No decrease was found with any of the doses used at any period of time. After analyzing doses of SCH 23390 (0.5, 0.1, and 0.05 mg/kg), raclopride (0.5, 0.25, and 0.125 mg/kg) and risperidone (0.1, 0.05, and 0.025 mg/kg) administered alone, only the 0.5 mg/kg dose of SCH 23390 decreased locomotor activity. The three compounds counteracted morphine-induced hyperactivity, but with SCH 23390 it was only achieved with the dose of 0.5 mg/kg, which also decreased spontaneous locomotor activity and induced catalepsy. On the other hand, raclopride and risperidone neutralized morphine-induced hyperactivity at doses that did not affect locomotor activity, although the former induced catalepsy when administered with morphine. It is concluded that although the blockade of D(1) and D(2) DA receptors decreases morphine-induced hyperactivity, this action is not specific, contrary to the action of risperidone, which counteracts this hyperactivity without any other motor effects.     

Effects of selective D1 and D2 dopamine antagonists on the development of behavioral sensitization to apomorphine

The objective of the present study was to determine whether the development of behavioral sensitization to apomorphine could be blocked by either D₁ or D₂ selective dopamine antagonists. In three experiments, male rats received 10–21 daily injections of a selective D₁ (SCH 23390; 0 or 0.5 mg/kg IP) or D₂ (sulpiride; 0, 30, or 100 mg/kg IP) antagonist followed by an apomorphine (0 or 1.0 mg/kg SC) injection. In two experiments, the rats were tested for locomotor activity in photocell arenas after the daily injections. In all experiments, the rats were tested for sensitization to apomorphine following the training phase. The results indicated that apomorphine produced a progressively greater increase in locomotor activity with each injection, and this apomorphine-induced increase in activity was completely blocked by both sulpiride and SCH 23390 treatments. However, although both sulpiride and SCH 23390 blocked apomorphine-induced activity, only SCH 23390 injections prevented the development of sensitization to apomorphine. That is, rats pretreated with sulpiride and apomorphine displayed significant sensitization when subsequently tested with a challenge dose of apomorphine alone. These findings suggest that the development of behavioral sensitization to apomorphine is related specifically to the stimulation of dopamine D₁ receptors.Portions of this paper were presented at the 1990 Society for Neuroscience meetings, St. Louis, MO, USA     

Effects of dopamine D1- or D2-like receptor antagonists on the hypermotive and discriminative stimulus effects of (+)-MDMA

Rationale Both dopamine (DA) and serotonin (5-HT) release are evoked by (+)-MDMA; however, little is known of the contribution of DA D₁- and D₂-like receptors (D₁R and D₂R, respectively) in the behavioral effects of (+)-MDMA.Objectives To test the hypothesis that a D₁R or D₂R antagonist would attenuate the hypermotive or discriminative stimulus effects of (+)-MDMA.Methods Male Sprague-Dawley rats (n=164) were pretreated with the D₁R antagonist SCH 23390 (3.125–50 g/kg, SC) or the D₂R antagonist eticlopride (12.5–50 g/kg, SC) prior to treatment with (+)-MDMA (3 mg/kg, SC) and locomotor activity was recorded using photobeam monitors. Twelve additional rats trained to discriminate (+)-MDMA (1 mg/kg, IP) from saline in a two-lever water-reinforced FR20 task were administered SCH 23390 (6.25 g/kg, IP) or eticlopride (12.5 g/kg, IP) prior to (+)-MDMA (0.375–1.0 mg/kg, IP). Rats were then placed in the drug discrimination chambers and the percent (+)-MDMA appropriate responding and response rate were measured.Results Both SCH 23390 and eticlopride blocked (+)-MDMA-evoked hyperactivity in a dose-related manner; the highest doses of the antagonists also effectively suppressed basal locomotor activity. In rats trained to discriminate (+)-MDMA from saline, SCH 23390 (6.25 g/kg), but not eticlopride (12.5 g/kg), blocked the stimulus effects of (+)-MDMA without altering response rate.Conclusion These data indicate that DA released indirectly by (+)-MDMA administration results in stimulation of D₁R and D₂R to enhance locomotor activity. Furthermore, the D₁R appears to play a more prominent role than the D₂R in the discriminative stimulus properties of (+)-MDMA.     

Selective effects of low-dose dopamine D1 and D2 receptor antagonists on rat information processing

It is well established that the dopaminergic system influences simple reaction time (RT) performance. However, the role of this system in more complex information processing remains to be clarified. The present study was aimed at addressing this issue. To this end, we used an inferential method that relies on choice RT procedures and allows one to identify information processing stages in both humans and rats. Long-Evans rats responded to lateral visual cues (left or right). Two task factors, signal intensity and foreperiod duration, were manipulated. Low doses of two pharmacological agents, SCH 23390 (a D1 receptor antagonist; 0.015 and 0.025 micromol/kg) and eticlopride (a D2 receptor antagonist; 0.01 and 0.02 micromol/kg), were administrated systemically. Both drugs increased choice RT: eticlopride interacted with signal intensity on RT, showing that D2 receptors mediate at least the sensory stage of stimulus preprocessing. In addition, eticlopride interacted with signal intensity on omission rate, thereby suggesting an involvement of D2 receptors in attentional processes; and SCH 23390 interacted with foreperiod duration on RT, indicating that D1 receptors specifically mediate the response adjustment stage. The effect of this drug on RT rests entirely in its interaction with foreperiod duration, allowing us to conclude that this D1 antagonist affects the response adjustment stage while sparing all other processing stages.     

Antagonism of cocaine self-administration by selective dopamine D(1) and D(2) antagonists

Effects of the dopamine D(1) antagonist SCH 39166 were compared with those of the D(2) antagonist eticlopride in squirrel monkeys responding under a second-order fixed-interval schedule of i.v. self-administration of cocaine. Dose-response curves were determined for a range of doses of self-administered cocaine (0.01-1.7 mg/kg/injection) alone and after pretreatment with SCH 39166 (0.01-0.1 mg/kg) or eticlopride (0.001-0.006 mg/kg). Cocaine maintained self-administration behavior in a dose-related manner; as the dose of cocaine was increased, rates of responding first increased and then either decreased or leveled off. Optimum doses (0.03-0.3 mg/kg) maintained high rates of responding (0.7-1.7 responses per second) among the different monkeys, and patterns of responding that were characteristic for second-order schedules. Pretreatment with either SCH 39166 or eticlopride altered self-administration behavior in all monkeys. In most cases, dose-response curves for cocaine were shifted to the right, indicative of surmountable antagonism, and a 3 to 6-fold increase in dose of cocaine was necessary to restore optimal performances. In some instances, dose-response curves were shifted either downward or downward and to the right, indicating that the antagonistic effects of SCH 39166 and eticlopride were not always fully surmountable. These results show that self-administration of cocaine can be comparably modified by drugs that selectively block dopamine D(1) or D(2) receptors.     

Comparison of the effects of NMDA and AMPA antagonists on the locomotor activity induced by selective D1 and D2 dopamine agonists in reserpine-treated mice

This study examined the interaction between various glutamate antagonists and selective D₁ (SKF 38393) and D₂ (RU 24213) dopamine agonists in the production of locomotion in the reserpine-treated mouse. Firstly, in normal mice, the NMDA channel blocker MK 801 (0.1–1.6 mg/kg) caused a biphasic stimulation/depression of locomotor activity, whereas the competitive NMDA antagonists CGP 40116 (0.25–8 mg/kg) and CPP (0.2–20 mg/kg), and the NMDA glycine site antagonist HA 966 (0.4–10 mg/kg) inhibited locomotion monophasically. These compounds caused varying degrees of muscle weakness and impairment of posture and gait, whilst the AMPA receptor blocker NBQX (0.2–25 mg/kg) had no significant effect on unconditioned mouse motor behaviour. None of the antagonists reversed reserpine-induced akinesia by themselves, but they all potentiated the locomotor movements induced by 30 mg/kg SKF 38393. Movements remained fluent with low doses of CPP, HA 966 and NBQX, but became ataxic with MK 801 and CGP 40116, with sedation prevailing at high doses of all the antagonists, as in normal mice. CPP and NBQX also combined synergistically with SKF 38393 to promote tonic convulsions. By contrast, RU 24213-induced locomotion was dose-dependently depressed by MK 801, CGP 40116 and HA 966, but was unaffected by CPP or NBQX. These differential effects of NMDA and AMPA antagonists on D₁ and D₂ motor responding in the monoamine-depleted mouse are discussed in terms of possible mechanisms and sites of action within the brain, and the implications for their putative use as adjuvants tol-dopa in antiparkinson therapy.     

Behavioral effects of selective and nonselective dopamine agonists on young rats after irreversible antagonism of D1 and/or D2 receptors

In general, preweanling and adult rats respond similarly when challenged with competitive dopamine (DA) agonists or antagonists. In contrast, results using a noncompetitive antagonist suggest that the D₁ and D₂ receptor systems of preweanling and adult rats differ in some critical way. To further assess this phenomenon, the behavioral effects of irreversible receptor blockade were assessed across 8 days in NPA (a nonselective DA agonist), quinpirole (a D₂ agonist), or SKF 38393 (a D₁ agonist) treated 17-day-old rat pups. The irreversible antagonist N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) did not block the locomotor activity and rearing of NPA- or quinpirole-treated rat pups, nor did EEDQ reduce SKF 38393-induced grooming. Moreover, pretreatment with EEDQ appeared to potentiate the normal increases in locomotor activity and rearing produced by NPA, but only when D₂ receptors were not protected by a previous injection of sulpiride (a D₂ antagonist). Taken together, these results are consistent with the presence of large reserves of D₁ and D₂ receptors in the preweanling rat pup.     

Two directions of dopamine D1/D2 receptor interaction in studies of behavioural regulation: a finding generic to four new, selective dopamine D1 receptor antagonists.

A range of new, chemically distinct D1 dopamine receptor antagonists, SCH 39166, NO 756, A-69024 and BW 737C, were studied for their effects on behavioural responses to the selective D2 agonist RU 24213. Each D1 antagonist not only blocked typical sniffing and locomotor responses to RU 24213 but also released atypical myoclonic jerking behaviour, while the selective D2 antagonist YM 09151 blocked these typical responses but did not release jerking. The rank order of effectiveness of these D1 antagonists to release such D2 agonist-induced jerking was similar to that of their selectivities as D1 antagonists; also, the action of BW 737C showed complete enantioselectivity, the inactivity of its R-antipode BW 736C paralleling enantioselective blockade of D1 but not D2 receptors. It appears that while tonic activity through D1 receptors is necessary for the expression of typical D2-stimulated behaviour, via well-known cooperative/synergistic D1:D2 interactions, D1 tone also normally inhibits, via oppositional D1:D2 interactions, the expression of atypical D2-stimulated behaviours such as jerking. Oppositional D1:D2 interactions are evident using all of the classes of selective D1 antagonist currently known, and appear to constitute another general mode of dopaminergic regulation.     

Behavioural effects of selective dopamine D-1 and D-2 agonists and antagonists in guinea-pigs

This study describes specific behaviours in guinea-pigs after dopamine D-1 and D-2 receptor activation which differed to those described in other rodent species. Intraperitoneal (IP) administration of the dopamine D-2 receptor agonist quinpirole (1.5, 3 and 6 mg/kg) to guinea-pigs dose-dependently initiated locomotor activity and other behaviours including rearing, head-down sniffing, chewing, circling, licking and head/body shaking. Locomotor activity induced by quinpirole (3 mg/kg) was reduced by the D-2 receptor antagonists sulpiride, (100 mg/kg IP) and raclopride (10 mg/kg IP). The dopamine D-1 receptor agonist SKF 38393 (8, 16 and 32 mg/kg IP) produced little or no behavioural effect, nor did the D-1 receptor antagonist SCH 23390 (0.2 and 0.4 mg/kg IP). A 16 mg/kg dose of SKF 38393, given in combination with 3 mg/kg quinpirole, produced responses similar to quinpirole alone, whereas 32 mg/kg SKF 38393 combined with quinpirole induced vacuous oral chewing, with attenuation of locomotor activity and circling, but not other behaviours produced by this dose of quinpirole. In contrast to previous studies in rats, the responses to quinpirole (3 mg/kg) were not significantly affected by SCH 23390 (0.2 and 0.4 mg/kg). It is concluded that the guinea-pig may be a useful and interesting species for study of the behavioural effects of D-1 and D-2 agonists and antagonists, as its responses appear to differ from those of other rodent species, but are similar to some responses to D-1 agonists observed in primates.     

Chronic neuroleptic-induced mouth movements in the rat: suppression by CCK and selective dopamine D1 and D2 receptor antagonists

Fluphenazine decanoate (25 mg/kg IM every 3 weeks x 6) resulted in spontaneous vacuous chewing mouth movements and jaw tremor in male Sprague-Dawley rats. These movements could be suppressed by the selective D1 or D2 dopamine antagonists SCH 23390 (0.5 mg/kg) and raclopride (0.5 mg/kg), respectively, and by CCK-8S (50 g/kg). Fluphenazine-induced mouth movements were unaffected by the selective CCK antagonist MK-329, and by a dose of physostigmine (50 g/kg) sufficient to stimulate mouth movements in placebo treated rats. Scopolamine (0.1 mg/kg) suppressed spontaneous mouth movements in placebo-treated rats, but the effect on fluphenazine-induced mouth movements was not significant. A higher dose of scopolamine (0.5 mg/kg) did suppress the neuroleptic-induced mouth movements, but also induced hyperactivity, characterized by increased sniffing and grooming. These findings indicate that mouth movements resulting from the chronic administration of neuroleptics to the rat may serve as a useful pharmacological model of tardive dyskinesia in the human, and suggest that a relative increase of D1 activity as well as impaired CCK function may contribute to the pathogenesis of this disorder.     

Hypotensive and bradycardic effects elicited by spinal dopamine receptor stimulation: effects of D1 and D2 receptor agonists and antagonists.

In anesthetized rats, intrathecal (i.t.) administration, at the upper thoracic level of the spinal cord of fenoldopam (a selective dopamine D1-receptor agonist) or quinpirole (a selective D2-receptor agonist) decreased blood pressure (BP) and heart rate (HR) in a dose-dependent manner. Apomorphine, a nonselective DA receptor agonist, produced similar effects. Apomorphine-induced hypotension was competitively antagonized by either SCH 23390 or remoxipride, selective D1- and D2-receptor antagonists, respectively, but only remoxipride antagonized the bradycardia. Furthermore, SCH 23390 antagonized the hypotensive effect of fenoldopam but did not change that induced by quinpirole. Remoxipride antagonized the hypotensive effect of quinpirole but did not alter the hypotensive effect of fenoldopam. Quinpirole-induced bradycardia was antagonized only by remoxipride. Bradycardia elicited by fenoldopam did not appear to be generated by dopamine receptor stimulation, as suggested by the lack of blocking effects of SCH 23390 and remoxipride. Data obtained with fenoldopam were corroborated with use of SK&F 38393, another dopamine D1-receptor agonist. We conclude that hypotensive effects of i.t.-administered DA receptor agonists appear to result from activation of spinal D1- and D2-receptors whereas bradycardia is related only to activation of spinal D2-receptors.     

Comparison of the effects of dopamine D1 and D2 receptor antagonists on nerve growth factor mRNA expression

Regulation of the expression of the nerve growth factor (NGF) gene has been reported previously to be mediated by the interaction of c-fos with an activator protein-1 (AP-1) binding site present in the first intron on the NGF gene. Using an RNase protection assay and in situ hybridization, we examined the effects of dopamine D1 and D2 receptor antagonists on NGF mRNA. Haloperidol (0.1-8 mg/kg) and (-)-sulpiride (10-100 mg/kg), induced NGF mRNA in a dose-dependent fashion in the hippocampus, piriform cortex, striatum and nucleus accumbens. The haloperidol (1 mg/kg)- and (-)-sulpiride (20 mg/kg)-induced NGF mRNA expression attained a maximum level 120 min after injection and returned to control levels 24 h later. Prior administration of the protein synthesis inhibitor cycloheximide blocked the haloperidol- and (-)-sulpiride-mediated induction of NGF mRNA. In contrast, R-(-)-8-chloro-2,3,4,5-tetrahydro-3,1-methyl-5-phenyl-11-3-benzyoepin e-7-ol (SCH23390) did not induce NGF mRNA expression in either a dose-dependent or time-dependent manner. Our previous studies have shown that haloperidol and (-)-sulpiride induce the expression of c-fos and c-jun mRNAs and increase their AP-1 DNA binding activities. Thus, the data suggest that neuroleptics induce NGF gene expression by increasing AP-1 DNA binding activity.     

Imaging brain regional and cortical laminar effects of selective D3 agonists and antagonists

Rationale  

Dopamine D3 receptors (D3R) may be important therapeutic targets for both drug abuse and dyskinesias in Parkinson’s disease; however, little is known about their functional circuitry.     

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. Received: 28 May 1997/Final version: 2 April 1998     

Similar effects of D(1)/D(2) receptor blockade on feeding and locomotor behavior

Recent evidence suggests an important relationship between dopamine (DA) modulation of feeding and locomotor activity. To investigate this relationship, the free-feeding and locomotor behavior of rats under the influence of D(1)/D(2) antagonist cis-flupenthixol was examined. DA antagonists are known to produce within-session declines in reinforced behavior, with behavioral suppression occurring only after a number of normal responses have been emitted. In the present study, cis-flupenthixol (0.30 mg/kg ) produced a within-session decrement in both free-feeding behavior and in locomotor/exploratory activity of animals in an environment that had never been paired with food. In addition to producing similar patterns of disruption in feeding and locomotion, the drug also produced a similar magnitude of suppression in the two behaviors. The results show that disruption of DA activity suppresses locomotor/exploratory activity in a manner that closely mirrors neuroleptic suppression of feeding. Although neuroleptic-induced suppression of locomotion and feeding are traditionally presumed to reflect an attenuation of DA motor and reward functions, respectively, the present results suggest that DA plays a similar role in the modulation of these two behaviors.     

Rotation following intranigral injections of a selective D1 or a selective D2 dopamine receptor agonist in rats

Injections of various nonselective dopamine agonists into the substantia nigra, pars reticulata (SNpr), have been reported to produce contralateral rotation in rats. Since a number of recent dopamine receptor distribution studies have indicated a preponderance of D1 compared to D2 dopamine receptor subtypes within the SNpr, we examined the relative behavioral functions of these two subtypes within the nigra by studying rotation following unilateral, local injections of a D1 (SKF38393) and D2 (quinpirole) agonist, Significant, dose-dependent contralateral rotation was observed following injections of R,S-SKF38393. This effect was found to be stereoselective to the R- enantiomer, suggesting that the effect is receptor mediated. In contrast, quinpirole (LY171555) produced significant, dose-dependent ipsilateral rotation following nigral injection. These results suggest that the rotation seen following intranigral injections of nonselective dopamine agonists is due to the simulation of the D1 dopamine receptor, and that nigral D1 and D2 dopamine receptors may play opposite roles in the control of behavior.     

The anorectic effect of SK&F 38393, a selective dopamine D1 receptor agonist: a microstructural analysis of feeding and related behaviour

An observational study was undertaken to provide a microstructural analysis of the effects of the selective dopamine D₁ receptor agonist, SK&F 38393, on feeding and associated behaviours in the rat. Adult, male non-deprived rats were adapted to eating a meal of sweetened mash in a 30-min period. SK&F 38393 (3.0 and 10 mg/kg, SC) significantly reduced food consumption). It also reduced the frequency of feeding bouts and the local rate of eating, while there was an increase, at 10 mg/kg, in the mean duration of individual feeding episodes. The D₁ receptor agonist also reduced the total duration of locomotor activity, but did not affect the total duration of rearing, grooming, sniffing, oral behaviours (other than feeding), or resting. The frequency of bouts of locomotion, rearing, grooming, and sniffing were reduced by SK&F 38393. Consideration of the time-courses for the several responses suggested that SK&F 38393 did not materially affect the form and sequence of behavioural responses in the test, although some changes occurred.