Effect of dopamine D-1 and D-2 receptor selective drugs on dopamine release and metabolism in rat striatum in vivo

Summary The effect of the dopamine (DA) D-1 agonist SKF 38393, the D-2 agonist LY 171555 and the mixed D-1/D-2 agonist apomorphine on striatal DA release and metabolism was tested in vivo using an intracerebral dialysis method in halothane-anaesthetized rats. The specificity of responses to these agonists was tested using the selective DA antagonists SCH 23390 (D-1) and sulpiride (D-2).Both LY 171555, 0.01 mg/kg, and SKF 38393, 10 mg/kg, reduced levels of DA in striatal perfusates. Neither SCH 23390, 0.5 and 5 mg/kg, nor sulpiride, 10 mg/kg, affected levels of DA in striatal perfusates, but 250 mg/kg sulpiride caused a DA increase. The decrease of DA levels induced by LY 171555 (0.01 mg/kg) was prevented by pretreatment with sulpiride (10 mg/kg) but not SCH 23390 (0.5 mg/kg). In comparison, pretreatment with SCH 23390 (0.5 mg/kg) completely inhibited the reduction of DA induced by SKF 38393 (10 mg/kg) while sulpiride (10 mg/kg) was without effect. Apomorphine (0.05 mg/kg) also decreased DA in striatal perfusates and this action was partially inhibited by both SCH 23390 (0.5 mg/kg) and sulpiride (10 mg/kg).Levels of the DA metabolite DOPAC in striatal perfusates also significantly decreased following LY 171555 (0.01 mg/kg) and apomorphine (0.05 mg/kg) but not SKF 38393 (10 mg/kg). The antagonist SCH 23390, in a dose, 0.5 mg/kg, that alone did not increase levels of DOPAC, inhibited the reduction of DOPAC induced by both LY 171555 and apomorphine. Sulpiride, 10 mg/kg, caused a marked increase in striatal DOPAC and this was not affected by a subsequent injection of LY 171555, SKF 38393 or apomorphine.We conclude from these data that DA release in rat striatum is autoregulated by independent D-1 and D-2 receptor-linked mechanisms. In contrast, the level of DA metabolism is controlled by a D-2 receptor-coupled mechanism which can be influenced by the D-1 receptor. This study provides further evidence that DA release and DA synthesis/metabolism are able to change independent of each other.     

Responses to selective D-1 and D-2 agonists after repeated treatment with selective D-1 and D-2 antagonists

This study was aimed at achieving a better understanding of the functional role of D-1 and D-2 receptors in some dopamine-mediated behaviors. Hypermotility, grooming behavior and stereotyped behavior were induced, respectively, by LY 171555 (D-2 agonist), SKF 38393 (D-1 agonist) and apomorphine (mixed agonist). Acute pretreatment either with the D-1 selective antagonist SCH 23390 (0.02 mg/kg) or with the D-2 receptor blocker YM 09151-2 (0.02 mg/kg, IP) blocked all these behaviors, suggesting the existence of functional interactions between D-1 and D-2 receptors. Striatal membranes prepared from rats receiving repeated administrations with SCH 23390 (0.05 mg/kg, twice daily for 21 days) showed an increase in the number of D-1 but not of D-2 receptors. On the contrary the repeated treatments with YM 09151-2 increased only the Bmax values of D-2 receptors. While the D-1 supersensitive rats showed only enhancement of apomorphine-induced stereotyped behavior, the D-2 supersensitive rats exhibited an increase of both apomorphine-elicited stereotypy and LY 171555-elicited hypermotility. SKF 38393-induced grooming was unaffected by any pretreatments. Moreover when D-2 supersensitive rats were acutely pretreated with SCH 23390, the enhancement of apomorphine-induced stereotyped behavior was abolished. It is concluded that the behavioral expression of D-1 receptor supersensitivity requires the simultaneous activation of D-1 and D-2 receptors.     

SCH 23390 and its S-enantiomer stereoselectively prevent EEG and behavioral activation induced by dopamine agonists in the rabbit

The selective D-1 dopamine antagonist SCH 23390 (R-enantiomer) and its unselective S-enantiomer (SCH 23388) were compared for their ability to prevent EEG and behavioral activation induced by the dopamine receptor agonists SKF 38393, apomorphine and LY 171555 in the rabbit. SCH 23390, at very low doses (0.003 mg/kg IV), inhibited EEG responses elicited by SKF 38393 and apomorphine, while the S-enantiomer displayed similar effects at doses at least 300-fold higher (1-3 mg/kg IV). Both isomers were approximately equipotent in preventing behavioral excitation caused by the D-2 agonist LY 171555. The dose of SCH 23390 interacting with LY 171555 was at least 100-fold higher than that effective for D-1 mediated responses. Conversely, the doses of S-enantiomer which prevented the stimulating effects induced by the different dopamine agonists were similar. The data demonstrate the stereoselectivity of the R-isomer SCH 23390 for blockade of D-1 receptors in vivo and provide evidence for the sensitivity of the EEG models in studying D-1 mediated responses.     

Effects of locally applied D-1 and D-2 receptor agonists and antagonists studied with brain dialysis

The effect on dopamine (DA) release of D-1 and D-2 receptor agonists and antagonists applied locally in the caudate through a trans-striatal dialysis probe was studied in freely moving rats. D-2 agonists (LY 171555 and BHT 920) reduced DA release in a concentration-dependent manner. The same local application of haloperidol abolished the effect of 10 microM LY 171555 and BHT 920. A specific D-1 agonist, the catechol benzazepine SKF 38393, reduced DA release and this effect was not modified by systemic or local administration of the D-1 antagonist, SCH 23390, nor by the D-2 antagonist, haloperidol. In contrast, the non-catechol D-1 agonist, CY 208243, failed to modify DA release. Local application of the D-1 antagonist, SCH 23390, or of the D-2 antagonist, (-)-sulpiride, stimulated DA release in a concentration-dependent manner. The D-1 agonist, CY 20843, reversed the stimulatory effect of SCH 23390 but not that of (-)-sulpiride. It is concluded that D-1 and D-2 receptors located in the caudate control DA release separately in this area.     

Stimulation of dopamine D-2 but not D-1 receptors reduces immobility time of rats in the forced swimming test: implication for antidepressant activity

The involvement of dopamine D-1 and D-2 receptor mechanisms was investigated in the forced swimming test with rats. d,1-Sulpiride, a D-2 receptor antagonist, reported to reduce desipramine-induced anti-immobility, did not alter the brain levels of desipramine. In addition, the anti-immobility effect of desipramine was not antagonized by SCH 23390, a D-1 receptor antagonist. Amineptine (20 mg/kg i.p., 60 min before testing), a dopamine uptake blocker, and LY171555 (0.2 mg/kg i.p., 60 min before testing), a dopaminergic D-2 stimulant reduced immobility time in the forced swimming test, but benserazide + 1-DOPA (200 mg/kg p.o., 45 min before testing), which increases dopamine release, or SKF 38393A (20 mg/kg s.c., 60 min before testing), a D-1 agent, did not. The anti-immobility effect but not the stereotypy was increased following chronic (21 days) LY171555 (0.1 and 0.2 mg/kg i.p.) treatment. The effect of acute or repeated (7 days) LY171555 (0.2 mg/kg i.p.) treatment was antagonized by 1-sulpiride (50 mg/kg i.p., 90 min before testing), a D-2 receptor antagonist. Neither SKF 38393A (20 mg/kg s.c., 60 min before testing) nor SCH 23390 (0.05 mg/kg s.c., 30 min before testing) modified the acute anti-immobility effect of LY171555 (0.2 mg/kg i.p.) SCH 23390 (0.025 and 0.05 mg/kg) increased the immobility time at doses which decreased motor activity. The increase in immobility time brought about by SCH 23390 was not antagonized by SKF 38393A (20 mg/kg). The findings indicate that activation of dopamine D-2 receptors could reduce immobility time.     

Dopamine receptor-mediated spinal antinociception in the normal and haloperidol pretreated rat: effects of sulpiride and SCH 23390.

Nociceptive tail flick latencies (TFL) were recorded in response to noxious thermal stimuli applied to lightly anaesthetized rats. The effects of intrathecally administered dopamine receptor agonists alone and combined with dopamine receptor antagonists were examined upon the TFL. Experiments were repeated on animals made supersensitive to dopamine following withdrawal from 28 day administration of haloperidol. In untreated animals the D2-receptor agonist LY 171555 and apomorphine produced an increase in TFL. In contrast, the Di-receptor agonist SKF 38393 had no significant effect on TFL. TFL. Following haloperidol-induced dopamine-supersensitivity, SKF 38393 produced an increase in TFL. In contrast, LY171555 and apomorphine had minimal effects on TFL in this preparation. In animals not treated with haloperidol, the dopamine receptor antagonists SCH 23390 and (+/-)-sulpiride both blocked the increase in TFL produced by the D2-agonists. SCH23390 and (+/-)-sulpiride also blocked the increase in TFL produced by SKF 38393 in haloperidol-supersensitized animals. The antinociceptive action of intrathecally administered dopamine agonists appears to be mediated via D2-receptors. Whether the antinociception produced by SKF 38393 is exclusively contingent upon the activation of D1-receptors in the dopamine-supersensitive animal is as yet unresolved.     

Effects of adrenalectomy on responses mediated by dopamine D-1 and D-2 receptors

The effects of surgical adrenalectomy were investigated on behavioural responses produced by the selective D-1 agonist, SK&F 38393, alone, and in combination with the D-2 agonist, quinpirole (LY171555). Further, stereotyped responses to apomorphine and LY171555 were assessed following treatment with either the D-1 or the D-2 antagonists, SCH 23390 and raclopride, respectively. There was no difference between sham-adrenalectomized (sham) and adrenalectomized (ADX) groups in responses to SK&F 38393. Although concomitant stimulation of both receptor subtypes increased the incidence of stereotyped sniffing behaviour, there was no difference in the magnitude of this effect between the sham and ADX groups. Raclopride reduced LY171555-induced sniffing and hypothermia less in ADX rats than in sham controls, which was consistent with the hypothesis that adrenocortical hormones affect D-2 receptor responsiveness. SCH 23390 had a greater inhibitory effect on LY171555 responses, but a smaller effect on apomorphine responses in the ADX group compared with their sham controls. It is concluded that the amplified D-2-stimulated response observed in ADX rats may be more dependent on tonic D-1 receptor activation than the control D-2 response of shams.     

Motor activity following the administration of selective D-1 and D-2 dopaminergic drugs to normal common marmosets

In normal common marmosets administration of the D-1/D-2 agonist apomorphine or the selective D-2 agonist quinpirole caused a dose-dependent increase in motor activity and induced stereotyped behaviour. Both the selective D-2 antagonist raclopride and the selective D-1 antagonist SCH 23390 inhibited normal locomotor activity and induced catalepsy. Quinpirole- and apomorphine-induced motor activity were potently inhibited by pretreatment with raclopride. The effects of quinpirole, but not apomorphine, were weakly inhibited by SCH 23390. The selective D-1 partial agonist SKF 38393 decreased motor activity and did not induce grooming, oral movements or other behaviours. SKF 38393 inhibited motor activity induced by the administration of quinpirole but did not alter apomorphine-induced motor behaviour. Locomotor activity in normal common marmosets appears to be mediated mainly via D-2 systems. In contrast to rodents, administration of SKF 38393 does not induce behavioural activation and there does not appear to be a facilitating effect of D-1 systems on D-2 function in the normal common marmoset. However, the ability of both SKF 38393 and SCH 23390 to inhibit quinpirole locomotor activity suggests some interaction between D-1 and D-2 systems to occur in this species.     

Importance of D-2 mechanisms in the reversal of reserpine hypothermia in the mouse

The D-2 agonist LY 171555 (0.05, 0.1, 0.2 mg kg-1 s.c.) but not the D-1 agonist SK&F 38393 (5, 10, 20 mg kg-1 s.c.) reduced reserpine-induced hypothermia (RIH) in mice. This effect was antagonized by the D-2 antagonist (-)-sulpiride (50 mg kg-1 i.p.) but not by the D-1 antagonist SCH 23390 (0.1 mg kg-1 s.c.). SK&F 38393 (20 and 1 mg kg-1 s.c.) did not alter the effect of LY 171555 (0.1 and 0.2 mg kg-1) on RIH, but administration of both LY 171555 (0.2 mg kg-1 s.c.) and SK&F 38393 (1 mg kg-1 s.c.) antagonized the reserpine-induced sedation.     

Evaluation of selective actions of dopamine D-1 and D-2 receptor agonists and antagonists on opioid antinociception

The effect of the selective dopamine receptor agonists SKF 38393 (D-1) and quinpirole (D-2) on nociception was studied in the mouse tail immersion test. The D-1 receptor agonist induced mild hyperalgesia whereas the D-2 agonist produced antinociception. Pretreatment with either the selective D-1 receptor antagonist SCH 23390 or the D-2 receptor antagonist (-)-sulpiride converted the hyperalgesia produced by the D-1 agonist into an antinociceptive response whereas the effect of the D-2 receptor agonist was significantly antagonised. The antinociceptive response of selective opioid agonists was also studied in combination with selective dopamine receptor agonists and antagonists. Sufentanil (mu-opioid) antinociception was enhanced in animals pretreated with (-)-sulpiride but not SCH 23390. In animals co-administered sufentanil with SKF 38393 there was a reduced antinociceptive effect whilst quinpirole enhanced the action of sufentanil. Likewise, antinociception induced by the kappa-opioid agonist U50,488H was unaltered in animals pretreated with SCH 23390, increased by (-)-sulpiride, and reduced by SKF 38393. delta-Opioid antinociception induced by [D-Ala2,D-Leu5]enkephaline remained unmodified following pretreatment with either (-)-sulpiride or SCH 23390 but was potentiated in animals which received both the delta-agonist and the D-2 receptor agonist. It is concluded that D-2 receptor agonists not only have intrinsic antinociceptive activity, but can also potentiate opioid-induced antinociception. Similarly, dopamine D-2 receptor antagonists appear to potentiate opioid-induced antinociception in this nociceptive model.     

Pharmacological activity profiles of dopamine D-1 and D-2 reception agonists and antagonists on striatal neuronal activity and the response to dexamphetamine in freely moving rats

1. The effects of dopamine D-1 and D-2 receptor agonists and antagonists were investigated by recording extracellular striatal action potentials in freely moving rats. Dopamine receptor antagonist effects were also evaluated on dexamphetamine-induced excitation of striatal neurons. 2. Striatal neurons responded to SKF 38393, a D-1 agonist, with dose-dependent reductions in activity. At a 2.0 mg/kg dose neuronal activity decreased to 50% of control values. 3. The D-1 antagonist, SCH 23390, at a dose of 4.0 mg/kg decreased striatal neuronal activity by more than 50% and also effectively blocked the effects of 2.5 mg/kg dexamphetamine. 4. LY 171555, a D-2 agonist, at 1.0 or 2.5 mg/kg, did not significantly increase striatal neuronal activity. Although behavioral activation was noted, the neuronal response at the high dose was biphasic with inhibition predominant. 5. The D-2 antagonists haloperidol and sulpiride decreased striatal neuronal activity in a dose-dependent manner and also effectively antagonized the effects of dexamphetamine. The D-2 antagonist, RO 22-1319, at a dose of 2.0 mg/kg completely antagonized increases in striatal neuronal activity after dexamphetamine. 6. These findings suggest that dexamphetamine-induced increases in striatal neuronal activity are due to either stimulation of both D-1 and D-2 receptors, or alternatively, a third dopamine receptor subtype sensitive to both D-1 and D-2 antagonists but not agonists. Furthermore, the concept of specific D-1 and D-2 receptor agonists may require revision as neither SKF 38393 or LY 171555 increased striatal neuronal activity.     

Increased grooming behaviour is induced by apomorphine in mice treated with discriminant benzamide derivatives

Grooming behaviour in mice was dose dependently increased by SK&F 38393 (1.87-30 mg/kg), whereas it was dose dependently decreased by RU 24926 (2.5-10 mg/kg) or LY 171555 (0.4-1.6 mg/kg) alone or combined with SK&F 38393 or apomorphine (0.39-6 mg/kg). The inhibitory effect of 0.75 mg/kg apomorphine on grooming behaviour was not modified by SCH 23390, chlorpromazine, clozapine and thioridazine. In contrast, it was antagonized by eight other dopamine antagonists: a partial restoration to grooming scores lower or similar to those determined in control mice was obtained with flupentixol, haloperidol, metoclopramide, thioproperazine and tiapride, whereas a reversal to grooming scores higher than those determined in control mice was obtained with mice treated with (+/-)-sulpiride, amisulpride or RIV 2093. Furthermore, only SCH 23390, chlorpromazine and clozapine antagonized SK&F 38393 (1.87 mg/kg)-induced grooming behaviour, whereas the effects of flupentixol, thioridazine, metoclopramide, haloperidol and amisulpride in SK&F 38393-treated mice were parallel to those of control mice. Finally, SCH 23390 (20 micrograms/kg) antagonized the apomorphine-induced grooming in mice treated with amisulpride, (+/-)-sulpiride or tiapride. These data confirm the potential role of D-1 dopamine receptors in the expression of grooming behaviour and indicate that the dopamine receptors involved in the inhibition of grooming could be of the D-4 subtype. Our results also reveal that chlorpromazine and clozapine have D-1 antagonist properties and suggest that the modulation of apomorphine-induced grooming behaviour by dopamine antagonists in mice could be used as a test for their classification according to their activity at the different dopamine receptor subtypes.     

Synergistic effects between D-1 and D-2 dopamine antagonists on catalepsy in rats

The effect of selective D-1 and D-2 dopamine agonists on catalepsy induced by various dopamine antagonists was studied. A potent and selective D-2 antagonist, YM-09151 (YM-09151-2) at a dose of 1.2 mg/kg, SC and a selective D-1 antagonist, SCH 23390 at 1.0 mg/kg, SC induced catalepsy in rats. Mixed D-1/D-2 antagonists, haloperidol (HPD) and cis-flupentixol (FLU) also induced catalepsy at doses of 2.0 and 0.8 mg/kg, SC, respectively. A mixed D-1/D-2 agonist, apomorphine (1.0 mg/kg, SC), a selective D-2 agonist, bromocriptine (10 mg/kg, IP) and a muscarinic antagonist, scopolamine (1.0 mg/kg, SC), prevented or markedly reduced the incidence of catalepsy by the tested antagonists. In contrast, a selective D-1 agonist, SKF 38393 (4.0 mg/kg, SC) did not reduce the cataleptogenic effects of HPD, FLU and SCH 23390, but did reduce the effect of YM-09151. Moreover, co-administration of YM-09151 with SCH 23390 produced a marked increase in the incidence of catalepsy. The incidence seen after the combination of YM-09151 and SCH 23390 at low doses was significantly different from that seen after each drug alone at the doubled dose. Thus, D-1 and D-2 antagonists potentiated each other's effect in producing catalepsy. These results suggest an important role of both D-1 and D-2 receptors in the catalepsy and the existence of synergistic effects of D-1 and D-2 receptor blockade.     

Dopamine D-1 but not D-2 receptor stimulation of the dorsal striatum potentiates apomorphine-induced jaw movements in rats

The effects of bilateral injections of selective D-1 and D-2 agonists and antagonists into the dorsal striata on apomorphine-induced jaw movements were studied in ketamine-anaesthetized rats after C1 spinal transection. A phototransducer attached to the lower mandible automatically detected jaw movements. YM-09151-2 (0.2 and 0.5 micrograms) and cis(Z)-flupentixol (0.5 and 1 microgram) injected into the dorsal striatum increased the frequency of jaw movements after apomorphine (0.2 mg/kg i.v.). The effects were prevented by administration of SCH23390 (1 microgram) with YM-09151-2 (0.5 microgram) or cis(Z)-flupentixol (1 microgram). Injection of SCH23390 (1 microgram) alone into the dorsal striatum failed to alter the apomorphine (0.5 mg/kg i.v.)-induced jaw movements. Local application of the selective D-1 agonists, SKF38393 (5 micrograms) and SKF75670 (10 micrograms), into the dorsal striatum potentiated the apomorphine (0.2 mg/kg i.v.)-induced jaw movements, while a D-2 agonist, quinpirole (10 micrograms), injected into the same site attenuated these movements. These data are suggestive of an oppositional D-1: D-2 receptor interaction in the dorsal striatum.     

Dopaminergic mechanisms and motor function: characterization of D-1 and D-2 dopamine receptor interactions

The effect of selective D-1 and D-2 dopamine receptor agonists (SKF 38393 and LY 171555, respectively) on motor function was studied in rats with unilateral, quinolinic acid-induced striatal lesions. Dose-dependent turning ipsilateral to the side of the lesion was elicited by LY 171555, but not by SKF 38393. When the drugs were given together, however, SKF 38393 was able to increase the total number (but not the duration) of turning induced by LY 171555 in a dose-dependent fashion. Furthermore, either alpha-methyl-paratyrosine pretreatment, a DA-depleting agent, or SCH 23390, a D-1 antagonist, inhibited the LY 171555-induced rotation, which would be restored by SKF 38393. These observations suggest that both the D-1 and D-2 dopamine receptor systems participate in the regulation of rotational behaviors in striatally lesioned rats with normosensitive DA receptors.     

Behavioural effects of dopamine D-1 and D-2 receptor agonists in monkeys previously treated with haloperidol

The effects of dopamine D-1 and D-2 receptor agonists were evaluated in five Cebus apella monkeys. During a previous haloperidol treatment (2 years), three of the monkeys had developed oral tardive dyskinesia (tongue protrusion and/or chewing). The partial D-1 agonist, SKF 38393, induced/aggravated oral dyskinesia and slight sedation, but no non-oral repetitive movements. Conversely, the selective D-2 agonist, LY 171555, produced non-oral repetitive movements and increased reactivity (arousal), but no significant change in the oral movements. Apomorphine (a mixed D-1/D-2 agonist) induced non-oral repetitive movements, increased reactivity, and increased oral dyskinesia. Pretreatment with SKF 38393 inhibited the LY 171555-induced non-oral repetitive movements, while in four monkeys the SKF 38393-induced oral movements were inhibited by LY 171555. The results suggest that oral dyskinesia (tardive dyskinesia) is more related to D-1 receptor stimulation than to D-2 receptor supersensitivity.     

The D2 dopamine receptor agonist LY171555 induces catalepsy in the mouse

The dopamine agonist LY171555 (quinpirole), a specific D2 receptor agonist, induces catalepsy in mice at doses ranging from 0.3 to 10 mg/kg. The effects of an intermediate dose of this compound (1 mg/kg SC) were antagonized by 25 mg/kg of the selective D2 antagonist (-)-sulpiride (IP) injected 20 min before LY171555. SCH 23390, a selective D1 antagonist, administered (0.3 mg/kg IP) 20 min before LY171555 (1 mg/kg) enhanced the cataleptic effects of this compound. Finally, when the D1 dopamine receptor agonist SKF 38393 (20 mg/kg SC) was administered immediately beforehand, the cataleptic effects of 1 mg/kg of LY171555 were markedly reduced. These results suggest that there is a functional interaction between D1 and D2 dopamine receptors in the modulation of catalepsy.     

Unilateral inactivation of dopamine receptors after intrastriatal injection of N-ethoxy-carbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ): a novel rotational model to investigate dopamine receptor interactions

The interaction between D1 and D2 dopamine (DA) receptors was investigated in a novel rotational model. Rats were unilaterally injected into the striatum with the irreversible DA receptor blocker N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ). This treatment induced a marked decrease in the density of D1 (-48%) and D2 (-45%) DA receptors available for binding to 3H-SCH 23390 and 3H-spiperone, respectively. Under these experimental conditions, the effect of DA receptor agonists were predominant on the intact side and resulted in rotations ipsilateral to the injected side. The effects of different agonists and antagonists for D1 and D2 DA receptors were evaluated 24 hr after EEDQ administration. The D2 agonist LY 171555 induced ipsilateral rotations in a dose-dependent manner (0.1-10.0 mg/kg, IP) in rats treated intrastriatally with EEDQ. In contrast, the D1 agonist SKF 38393 (1-20 mg/kg, IP) was unable to elicit circling behavior per se. However, SKF 38393 increased the number of rotations caused by LY 171555. The circling behavior induced by LY 171555 was blocked by the D2 antagonists (-)sulpiride and raclopride and by the D1 antagonist SCH 23390. Moreover, the inhibition of circling behavior induced by SCH 23390 was reversed by SKF 38393 in a dose-dependent manner. LY 171555 (1 mg/kg, IP) was unable to induce rotations in EEDQ-treated rats following DA depletion by alpha-methyl-p-tyrosine, whilst the combined administration of LY 171555 (1 mg/kg, IP) and SKF 38393 (10 mg/kg, IP) elicited intense circling behavior in DA depleted rats.(ABSTRACT TRUNCATED AT 250 WORDS)     

Dopamine D2 receptor mediation of the discriminative stimulus properties of LY 171555 (quinpirole)

The mechanisms subserving the behavioral effects of the putatively selective dopamine D2 agonist LY 171555 (0.025 mg/kg) were analyzed in rats (N = 23) using a two-lever, water-reinforced drug discrimination task. Substitution (generalization) tests showed that the DA agonist apomorphine mimicked LY 171555 while the selective D1 agonist SKF 38393 did not. When given in combination with the training drug, haloperidol but not the D1 antagonist Sch 23390 dose dependently blocked the LY 171555 cue; given alone, Sch 23390 mimicked LY 171555 and haloperidol elicited responding on the saline-appropriate lever. These results suggest that stimulus properties of LY 171555 are mediated primarily by D2-containing neuronal systems but that the effects of stimulating either D1 or D2 receptor subtypes in vivo are complex and interdependent.     

Dopamine receptor subtypes that induce hyperactive urinary bladder response in anesthetized rats

In anesthetized rats, SKF 38393 (10 mg/kg, i.v.) did not facilitate urinary bladder motility, but bromocriptine (BR, 5 mg/kg, i.v.) alone and the combination of BR (1 mg/kg, i.v.) and SKF 38393 (1 mg/kg, i.v.) induced a hyperactive bladder response (HBR). Both HBR induced by BR alone or BR and SKF 38393 combined was suppressed by SCH 23390, sulpiride or haloperidol. These results indicate that HBR is mediated by the activation of D-2 receptors, and the effects of D-2 agonists on bladder motility are potentiated by the simultaneous stimulation of D-1 receptors.