Parametric and pharmacological analyses of the enhanced grooming response elicited by the D1 dopamine receptor agonist SKF 38393 in the rat

The present report investigated several parametric and pharmacological aspects of the enhanced self-grooming behavior of rats following systemic administration of the selective D₁ dopamine (DA) receptor agonist SKF 38393. The amount of time that rats spent grooming themselves was measured continuously for 30 min following drug administration to provide a quantitative measure of the drug-induced behavior. SKF 38393 increased the amount of grooming in a dose-dependent manner (0.5–16 mg/kg, SC). The onset of this effect required at least 5 min and it persisted for at least 60 min. The ability of SKF 38393 to enhance grooming was shared by R-SKF 38393, but not S-SKF 38393, consistent with the affinities of these enantiomers for the D₁ DA receptor. Unlike SKF 38393, the peripheral D₁ agonist fenoldopam (SKF 82526) failed to cause an increased grooming response, suggesting a central site of action for elicitation of this behavior. The SKF 38393-induced increase in grooming was competitively antagonized by the D₁ selective antagonist SCH 23390 (0.5 mg/kg, SC). Although the D₂ DA receptor-selective antagonist eticlopride reduced SKF 38393-elicited grooming, this antagonism appeared to be of a physiological rather than pharmacological nature. When eticlopride was coadministered with the non-selective (mixed) D₁/D₂ agonist apomorphine, an increase in grooming behavior similar to that produced by SKF 38393 was observed. Inactivation of D₁ and D₂ DA receptors produced by pretreatment with the irreversible antagonistN-ethoxycarbonyl-2-ethoxy-1, 2-dihydroquinoline (EEDQ), at a dose which reduces D₁ and D₂ receptor density by 50% (8.0 mg/kg, IP), reduced SKF 38393-induced grooming by approximately 50%. Prior protection of D₁ receptors by SCH 23390 completely prevented the effect of EEDQ whereas prior protection of D₂ receptors by eticlopride did not. These results demonstrate that enhanced grooming behavior elicited by dopamine agonists in rats, when measured as the amount of time spent grooming, provides a reliable, quantifiable index of selective D₁ DA receptor activation in the CNS. In addition, this behavior does not appear to require concurrent stimulation of D₂ DA receptors by endogenous DA.     

D1/D2 dopamine and N-methyl-d-aspartate (NMDA) receptor participation in experimental catalepsy in rats

Mixed D₁/D₂ dopamine (DA) antagonists, perphenazine (5 mg/kg) and haloperidol (2 mg/kg) induced catalepsy in rats. SCH 23390 (1 mg/kg), a D₁ DA antagonist, also produced catalepsy. Co-administration of perphenazine (0.5 mg/kg) and SCH 23390 (0.1 mg/kg), at low doses, produced a marked increase in cataleptic response. B-HT 920, a D₂ agonist, reversed the cataleptogenic effects of perphenazine, haloperidol and SCH 23390. SKF 38893 (5 mg/kg) reduced the cataleptogenic effect of SCH 23390 but failed to reverse haloperidol- or perphenazine-induced catalepsy. SKF 38393 (10 mg/kg), however, protected the animals against perphenazine- induced catalepsy. Combined administration of B-HT 920 (0.1 mg/kg) and SKF 38393 (5 mg/kg) enhanced the protective effect of B-HT 920 in SCH 23390-treated animals but not in animals treated with haloperidol or perphenazine. MK-801 (0.025–0.5 mg/kg), a non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist, reduced the cataleptogenic effects of perphenazine, haloperidol as well as SCH 23390. The anticataleptic action of MK-801 was enhanced by scopolamine (0.1 mg/kg) but not by bromocriptine (1 mg/kg) or clonidine (0.05 mg/kg) in perphenazine-treated rats. Unlike B-HT 920 (0.1 mg/kg), SKF 38393 (5 mg/kg) potentiated the anticataleptic effect of MK-801 (0.01 mg/kg) against SCH 23390-induced catalepsy. The above data suggests D₁/D₂ interdependence in catalepsy and a modulatory role of D₁ and D₂ DA receptor stimulation on the anticataleptic effect of MK-801.     

A comparison of the effects of the D1 receptor antagonists SCH 23390 and SCH 39166 on suppression of feeding behavior by the D1 agonist SKF38393

The hypophagic effect of the D₁ receptor agonist SKF 38393 is not dose-dependently antagonized by the D₁ antagonist SCH 23390. Moreover, the receptor specificity of this interaction remains in question, since SCH 23390 has significant activity at both 5-HT₂ and 5-HT_1C receptors, and SKF 38393 also interacts with 5-HT_1C receptors. To determine the relative significance of these actions, a comparison was made between the anorectic effects in rats of SCH 23390 (0.1–1.0 mg/kg) and the benzonaphthazepine SCH 39166 (0.1–3.0 mg/kg), a D₁ antagonist with negligible affinity for 5-HT sites. Both compounds inhibited food-intake dose-dependently, with SCH 23390 being approximately twice as potent as SCH 39166. Behaviorally inactive and active doses of both antagonists were tested in combination with the D₁ agonist SKF 38393 (10–56 mg/kg). Neither antagonist was able to produce more than a marginal attenuation of the agonist-induced hypophagia. This demonstrates that previous failures to reverse the behavioral actions of SKF 38393 by SCH 23390 were not due to specific actions of this particular antagonist. Finally, like SCH 23390, SCH 39166 (0.3 mg/kg) was able to attenuate fully the anorectic effects of the D₁ agonist SKF 82958 (1.0 and 3.0 mg/kg), demonstrating that neither compound is intrinsically unable to block D₁ receptor-mediated hypophagia. The results demonstrate the generality of the D₁ antagonist-mediated effect on feeding and call into question the use of SKF 38393 as a D₁ agonist in studies of feeding, and perhaps in other contexts as well.     

Yawning is elicited by D2 dopamine agonists but is blocked by the D1 antagonist,SCH 23390

The subtype of dopamine (DA) receptors mediating the yawning response to DA agonists was determined in rats. Yawning was elicited both by the mixed D₁–D₂ agonist apomorphine and by the specific D₂ agonist LY 171555, but not by the selective D₁ agonist SKF 38393. Both apomorphine- and LY 171555-induced yawning were antagonized not only by the selective D₂ antagonist sulpiride but, unexpectedly, also by the selective D₁ antagonist SCH 23390. The results suggest that DA receptors mediating the yawning response are of the D₂ type, and that these receptors are connected with D₁ receptors in such a way that the blockade of the latter results in the functional inactivation of the former.     

Enhanced oral activity responses to intrastriatal SKF 38393 andm-CPP are attenuated by intrastriatal mianserin in neonatal 6-OHDA-lesioned rats

Enhanced oral activity is induced in neonatal 6-hydroxydopamine- (6-OHDA-) lesioned rats by systemic administration of the dopamine (DA) D₁ receptor agonist SKF 38393 and serotonin (5-HT) 5-HT_2A,2C agonistm-chlorophenylpiperazine (m-CPP). The DA D₁ receptor antagonist SCH 23390 effectively attenuates the effect of SKF 38393 but notm-CPP. The 5-HT₂antagonist mianserin attenuates the effects of bothm-CPP and SKF 38393, suggesting that DA agonist effects are mediated by 5-HT neurochemical systems. To test whether DA and 5-HT agonist effects and interactions might occur within the neostriatum, rats were implanted with permanent injection cannulae, with tips in the ventral striatum. One group of rats was lesioned at 3 days after birth with 6-OHDA HBr (100 µg salt form, in each lateral ventricle; desipramine HCl pretreatment, 20 mg/kg IP, base form, 1 h), while controls received the vehicle in place of 6-OHDA. Cannulae were implanted when rats weighed 200–250 g. During a 1-h observation session SKF 38393 (5 nmol per side) produced 74.3±19.2 oral movements in intact rats and 310.7±97.0 oral movements in 6-OHDA-lesioned rats.m-CPP (10 nmol per side) produced 72.6±15.1 and 274.5±65.0 oral movements in these respective groups. These responses were several-fold greater than the 25.3±7.3 and 41.8±9.5 oral movements in the same groups after saline (0.5 µl per side) (P<0.05). Mianserin (6 nmol per side) alone had no effect on oral activity but attenuated responses to both SKF 38393 andm-CPP in intact and 6-OHDA-lesioned rats. These findings demonstrate that enhanced oral activity responses are produced by intrastriatal SKF 38393 andm-CPP in neonatal 6-OHDA-lesioned rats. Also, when the 5-HT₂ receptor antagonist mianserin was administered intrastriatally, induction of oral activity by the DA D₁ agonist SKF 38393 was attenuated. These findings indicate that ventral striatum represents at least one brain focus at which DA and 5-HT systems interact to modulate oral activity in rats.     

Differential anti-parkinsonian effects of benzazepine D1 dopamine agonists with varying efficacies in the MPTP-treated common marmoset

In common marmosets systemically treated with MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), the behavioural effects of benzazepine D₁ dopamine (DA) agonists with full/supramaximal (SKF 80723 and SKF 82958), partial (SKF 38393, SKF 75670 and SKF 83565) and no efficacies (SKF 83959) in stimulating adenylate cyclase (AC) activity were investigated. The benzazepine derivatives, with the exception of SKF 82958 (8 fold D₁ DA receptor selectivity), demonstrated high D₁ DA receptor affinity and selectivity (approximately 100 fold or more) in rat striatal homogenates. Administration of MPTP in marmosets induced locomotor hypoactivity, rigidity and motor disability. SKF 38393 (7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine) and SKF 75670 (3-CH₃ analogue) further reduced locomotor activity (by –70 to –80%) and increased motor disability (by +22 to +67%) in these animals. SKF 83565 (6-Cl, 3-CH₃, 3-Cl analogue) and SKF 82958 (6-Cl, 3-C₃H₅ analogue) had only a slight effect on locomotor activity but decreased motor disability at high doses (–46 to –60%). In contrast, SKF 83959 (6-Cl, 3-CH₃, 3-CH₃ analogue) and SKF 80723 (6-Br analogue) produced pronounced increases in locomotion (6–10 fold) and a reversal in motor disability (by –64 to –77%). Oral activity, consisting largely of abnormal, dyskinetic tongue protrusions and vacuous chews, was increased in animals treated with SKF 38393, SKF 83565, SKF 82958 and more especially with SKF 80723 and SKF 83959. Grooming was increased with SKF 82958 and more especially with SKF 80723 and SKF 83959. In contrast, quinpirole (D₂ DA agonist), reversed the MPTP-induced motor deficits in the marmoset, with no effect on grooming and oral activity. The present findings further demonstrate the antiparkinsonian actions of some D₁ DA agonists in MPTP-treated primates. However, in general the behavioural effects of benzazepines failed to correlate with either their D₁ DA receptor affinity/selectivity or their efficacy in stimulating adenylate cyclase (AC) activity. These observations further implicate a behavioural role for D₁ DA receptors uncoupled to AC and/or a role for extrastriatal D₁ DA receptors in mediating the behavioural response to D₁ DA agonists.     

Characterization of dopamine D<Subscript>1</Subscript> and D<Subscript>2</Subscript> receptor function in socially housed cynomolgus monkeys self-administering cocaine

Rationale Social rank has been shown to influence dopamine (DA) D₂ receptor function and vulnerability to cocaine self-administration in cynomolgus monkeys. The present studies were designed to extend these findings to maintenance of cocaine reinforcement and to DA D₁ receptors.Objective Examine the effects of a high-efficacy D₁ agonist on an unconditioned behavior (eyeblinking) and a low-efficacy D₁ agonist on cocaine self-administration, as well as the effects of cocaine exposure on D₂ receptor function across social ranks, as determined by positron emission tomography (PET).Methods Effects of the high-efficacy D₁ agonist SKF 81297 and cocaine (0.3–3.0 mg/kg) on spontaneous blinking were characterized in eight monkeys during 15-min observation periods. Next, the ability of the low-efficacy D₁ agonist SKF 38393 (0.1–17 mg/kg) to decrease cocaine self-administration (0.003–0.1 mg/kg per injection, IV) was assessed in 11 monkeys responding under a fixed-ratio 50 schedule. Finally, D₂ receptor levels in the caudate and putamen were assessed in nineteen monkeys using PET.Results SKF 81297, but not cocaine, significantly increased blinking in all monkeys, with slightly greater potency in dominant monkeys. SKF 38393 dose-dependently decreased cocaine-maintained response rates with similar behavioral potency and efficacy across social rank. After an extensive cocaine self-administration history, D₂ receptor levels did not differ across social ranks.Conclusions These results suggest that D₁ receptor function is not substantially influenced by social rank in monkeys from well-established social groups. While an earlier study showed that dominant monkeys had higher D₂ receptor levels and were less sensitive to the reinforcing effects of cocaine during initial exposure, the present findings indicate that long-term cocaine use changed D₂ receptor levels such that D₂ receptor function and cocaine reinforcement were not different between social ranks. These findings suggest that cocaine exposure attenuated the impact of social housing on DA receptor function.     

Differential antagonism of the effects of dopamine D1-receptor agonists on feeding behavior in the rat

A series of experiments was conducted to examine the effects of dopamine D₁ receptor agonists on food intake in rats. In the first experiment, the D₁ agonist SKF 38393 (3.0–30.0 mg/kg) dose-dependently suppressed feeding during a 40 min food-access period, both in food-deprived rats and in non-deprived rats fed a highly palatable diet. Non-deprived rats were more sensitive to these effects of SKF 38393. Using the limited-access, food-deprivation procedure, a comparison was made between the anorectic effects of three D₁ agonists with differing intrinsic efficacies and receptor selectivities. Rank order of potencies for reducing food intake was SKF 82958 > SKF 77434 > SKF 38393 (ED₅₀ values: 0.7, 3.6 and 15.7 mg/kg, respectively). Dose-related, surmountable antagonism by the D₁ antagonist SCH 23390 (0.01 and 0.03 mg/kg) was only obtained with SKF 82958 (0.1–10.0 mg/kg). In contrast to the other compounds, the effects of SKF 38393 were not appreciably altered by the D₁ antagonist. The effects of SKF 82958 were also antagonized by the D₂ receptor antagonist spiperone (0.05 and 0.1 mg/kg), although not in a dose-dependent manner. The present results support a role for D₁ receptors in central feeding mechanisms. They also suggest that the effects of SKF 38393 on feeding may not be mediated exclusively by the D₁ receptor and, further, that SKF 38393 may not serve well in behavioral studies as a prototypical D₁ agonist. The results also demonstrate the need for comparisons among several compounds in studies of D₁ mediated behavioral effects.     

Time course of bromocriptine induced excitation in the rat: behavioural and biochemical studies

The aim of the present study was to further investigate the behavioural and biochemical pharmacology of the directly acting dopamine (DA) receptor agonist bromocriptine (BRC).BRC produced an initial depression of locomotion followed after about an hour by a weak but significant locomotor stimulation. The stimulation was potentiated by concomitant administration of the D₁ agonist SKF38393.Ex vivo biochemical determinations indicated that reductions in dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) levels occurred in the striatum after BRC injection without a significant change in DA levels, indicating a reduced DA turnover. An increase in 5-hydroxytryptamine (5HT) and 5-hydroxyindoleacetic acid (5HIAA) levels occurred in the striatum leading to a significant increase in turnover (i.e. ratio of 5HIAA to 5HT). Noradrenaline concentrations increased in the striatum. In the cortex, sharp falls in HVA and DOPAC levels without a corresponding change in DA were observed. While there was no significant change in noradrenaline levels in this brain region, an increase in 5HIAA, but not in 5HT, levels occurred. These changes indicate an increase in 5HT turnover (ratio of 5HIAA to 5HT).In vivo dialysis indicated that extracellular levels of DA, DOPAC and HVA in the striata of freely moving rats were sharply reduced for at least 6 h after injection.In vitro binding studies showed that BRC exhibited high (K_i values in low nanomolar range) affinities for DA D_2A, D_2B, D₃, ₁ and ₂ adrenergic receptors together with unexpectedly high affinity (about 1 nM) for 5HT_1A receptors.The data indicate that the initial behavioural depression and later locomotor stimulation induced by BRC are accompanied by a sharp monophasic fall in striatal extracellular DA levels as indicated by dialysis studies. Since the behavioural stimulation was augmented by concomitant D₁ receptor stimulation, the data suggest that the reduced DA turnover is influencing the amount of DA available to stimulate postsynaptic D₁ receptors. However, the biochemical studies indicated that BRC has a high affinity for 5HT_1A receptors and affects the turnover of 5HT in the brain. Thus, the behavioural effects of BRC may depend not only on effects on the DA system but also on 5HT systems.[/p]     

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.     

Differential effects of fluphenazine-N-mustard,on calmodulin activity and on D1 and D2 dopaminergic responses

Fluphenazine-N-mustard (FNM) has been shown to irreversibly block dopaminergic receptor sites and inhibit certain dopaminergically-mediated behaviors. In this study we measured whether FNM has any differential effects on D₁ and D₂ dopaminergic events. Accordingly, we examined the relative effects of FNM on rotational behavior induced by SKF 38393 (D₁ agonist) and Ly 171555 (D₂ agonist) in mice with unilateral, 6-hydroxydopamine-induced lesions of the striatum and the effects of FNM on the binding of [³H]Sch 23390 (D₁ ligand) and [³H]spiroperidol (D₂ ligand) to mouse striatal membranes. FNM inhibited rotational behavior induced by Ly 171555 at doses 10-fold lower than those required to block rotations induced by SKF 38393 (ID₅₀ values: Ly 171555=1.8 mole/kg, IP; SKF 38393=16 mole/kg, IP). The inhibitory effect of high doses of FNM (20 mole/kg) on rotational behavior was overcome by increasing the dose of SKF 38393 and apomorphine, a nonselective dopaminergic agonist. By contrast, the inhibitory effect of FNM was not overcome by Ly 171555, even when given in doses more than 100 times its ED₅₀. Using striatal homogenates in vitro, FNM inhibited the specific binding of [³H]spiroperidol at concentrations about 10-fold lower than those required to inhibit the binding of [³H]Sch 23390 (IC₅₀ values: [³H]spiroperidol=90 nM; [³H]Sch 23390=840 nM). Considerably higher concentrations of FNM were needed to irreversibly inhibit calmodulin activity in striatal homogenates (IC₅₀=10 M). In vivo, FNM inhibited the binding of [³H]spiroperidol measured ex vivo (ID₅₀=4 mole/kg), but did not inhibit the binding of [³H]Sch 23390, even when given in doses as high as 100 mole/kg. These studies indicate that FNM was approximately 10 times more potent at inhibiting D₂-than D₁-mediated behavior and at displacing D₂ versus D₁ ligands and suggest that FNM may be useful for studying and differentiating D₂- and D₁-mediated events.     

Activation of dopamine D1 receptors does not affect D2 receptor-mediated inhibition of acetylcholine release in rabbit striatum

Summary The possible involvement of dopamine D₁ receptors in the regulation of acetylcholine release in the rabbit caudate nucleus was investigated. Caudate slices, preincubated with [³H]choline, were superfused continuously and subjected to electrical field stimulation with only a single pulse. In agreement with the view that the release of acetylcholine evoked by a single electrical pulse is not influenced by endogenous transmitters, atropine and domperidone failed to icnrease the evoked release of [³H]acetylcholine, whereas oxotremorine and quinpirole caused a concentration-dependent inhibition of transmitter release. Neither the dopamine D₁ receptor antagonist SCH 23390 nor the Dt agonist SKF 38393 in a concentration range of 0.01–1 mol/l changed the evoked [³H]acetylcholine release. The inhibitory effect of the dopamine D₂ receptor agonist quinpirole was virtually abolished in the presence of 0.1 mol/l domperidone and diminished in the presence of 1 mol/l SCH 23390. It remained unchanged in the presence of 1 mol/l SKF 38393. It is concluded that the inhibition of acetylcholine release by dopamine is mediated exclusively via presynaptic dopamine D₂ receptors and that the antagonistic effect of SCH 23390 on the inhibition of acetylcholine release by quinpirole is due to its interaction with dopamine D₂ rather than D₁ receptors located on cholinergic nerve terminals. Send offprint requests to C. Allgaier at the above address     

Relative roles of ventral striatal D1 and D2 dopamine receptors in responding with conditioned reinforcement

Several experiments investigated the involvement of D₁ and D₂ dopamine receptors in the ventral striatum in the control over behaviour by a conditioned reinforcer using an acquisition of new response procedure. Intra-accumbens infusion of either the D₁ receptor antagonist, SCH 23390, or the D₂ receptor antagonist, raclopride, completely blocked the potentiative effects of intra-accumbensd-amphetamine on responding with conditioned reinforcement and reduced responding to control levels. SCH 23390 was more potent than raclopride. At higher doses in the absence ofd-amphetamine, both antagonists also blocked the preference for responding on the lever producing the conditioned reinforcer. Intra-accumbens infusions of either the D₁ receptor agonist, SKF 38393, or the D_2/3 receptor agonist, LY 171555 (quinpirole), selectively potentiated responding on the lever producing the conditioned reinforcer. Various combined infusions of the D₁ and D₂ agonists in specific low doses had additive, but not synergistic, effects on responding with conditioned reinforcement. None of the drugs affected the drinking of water in deprived subjects when infused intra-accumbens. These results suggest that both D₁ and D₂ receptors in the nucleus accumbens are involved in mediating the effects of dopamine in potentiating the control over behaviour by conditioned reinforcers.     

Chronic treatment with the D1 receptor antagonist,SCH 23390, and the D2 receptor antagonist,raclopride, in cebus monkeys withdrawn from previous haloperidol treatment

The effects of chronic treatment with dopamine (DA) D₁ and D₂ receptor antagonists were evaluated in eightcebus apella monkeys with mild oral dyskinesia after previous haloperidol treatment. SCH 23390 (D₁ antagonist) was given daily to investigate the direct behavioural effect during long-term treatment and the subsequent supersensitivity to DA agonists. Raclopride (D₂ antagonist) was investigated for comparison. All drugs were given subcutaneously. SCH 23390 and raclopride induced dystonic syndromes, catalepsy, sedation and reduced locomotor activity. The monkeys developed marked tolerance to the dystonic effect of SCH 23390, while they showed increased sensibility to the dystonic effect of raclopride. Baseline oral dyskinesia (24 h after injection) remained unchanged during D₁ antagonist treatment, while it increased during D₂ antagonist treatment. SCH 23390 induced supersensitivity to the oral dyskinesia- and grooming-inducing effects of SKF 81297 (D₁ agonist) after 9 weeks, while the subsequent treatment with raclopride induced supersensitivity to the reactivity- and stereotypy-inducing effects of quinpirole (D₂ receptor agonist) after 3 weeks. Because of the possibility of a carry-over effect (SKF 81297-induced oral hyperkinesia and grooming), other changes in raclopride-induced behaviours cannot be ruled out. The development of tolerance to the dystonic effect of SCH 23390 and the unchanged baseline oral dyskinesia during SCH 23390 treatment indicate an advantageous profile of side effects of DA D₁ receptor blockade.     

3- and 4-O-sulfoconjugated and methylated dopamine: highly reduced binding affinity to dopamine D2 receptors in rat striatal membranes

Summary The binding properties of 3- and 4-O-sulfoconjugated dopamine (DA-3-0-S, DA-4-0-S) as well as 3-O-methylated dopamine (MT) to rat striatal dopamine D₂ receptors were investigated. ³H-spiperone was used as a radioligand in the binding studies. In saturation binding experiments (+)butaclamol, which has been reported to bind to dopaminergic D₂ and serotoninergic 5HT₂ receptors, was used in conjunction with ketanserin and sulpiride, which preferentially label 5HT₂ and D₂ receptors, respectively, in order to discriminate between ³H-spiperone binding to D₂ and to 5HT₂ receptors. Under our particular membrane preparation and assay conditions, ³H-spiperone binds to D₂ and 5HT₂ receptors with a maximal binding capacity (B _max) of 340 fmol/mg protein in proportions of about 75%:25% with similar dissociation constants K _D (35 pmol/l; 43 pmol/l). This result was verified by the biphasic competition curve of ketanserin, which revealed about 20% high (K _D = 24 nmol/l) and 80% low (K _D = 420 nmol/l) affinity binding sites corresponding to 5HT₂ and D₂ receptors, respectively. Therefore, all further competition experiments at a tracer concentration of 50 pmol/l were performed in the presence of 0.1 mol/l ketanserin to mask the 5HT₂ receptors. DA competition curves were best fitted assuming two binding sites, with high (K _H = 0.12 mol/l) and low (K_L = 18 mol/l) affinity, present in a ratio of 3:1. The high affinity binding sites were interconvertible by 100 mol/l guanyl-5-yl imidodiphosphate [Gpp(NH)p], resulting in a homogenous affinity state of DA receptors (K _D = 2.8 mol/l). Competition experiments with various compounds confirmed the binding of ³H-spiperone to D₂ receptors. DA-3-O-S, DA-4-O-S, and MT were more than 5,000-, more than 10,000-, and 530-fold less potent in competing for ³H-spiperone binding when compared with DA at the high affinity binding site which mediates biological effects. Therefore, it is concluded that these DA metabolites are biologically ineffective at central D₂ receptors. Send offprint requests to E. Werle at the above address     

Dopaminergic control of locomotion,mouthing, snout contact,and grooming: opposing roles of D1 and D2 receptors

The study compares the behavioral profiles induced in rats (N=118) by the D₂-dopaminergic receptor agonist quinpirole (0.03 and 0.5 mg/kg), and the D₁-agonist SKF38393 (1.25–40 mg/kg), and both agonists administered together. Locomotion and snout contact frequency were reduced by the low but increased by the high dose of quinpirole; SKF38393 also reduced these behaviors and attenuated the effect of the high quinpirole dose. Only the high dose of quinpirole increased the duration of snout contact bouts and the frequency of mouthing; SKF38393 had no effect but in combination with the high dose of quinpirole, it enhanced the performance of these behaviors greatly. The duration of mouthing bouts was not affected by either agonist but was greatly extended when SKF38393 was administered together with the high dose of quinpirole. Grooming was inhibited by both the low and the high dose of quinpirole, and stimulated by the injection of SKF38393 or its addition to the low dose of quinpirole. These findings suggest that snout contact is controlled by modulating the frequency of episodes whereas mouthing is controlled by modulating the duration of episodes. Moreover, although they do not disprove the prevailing notion of D₁–D₂ receptor synergism, the present data are consistent also with an oppositional model of D₁–D₂ receptor interaction in the regulation of locomotion, snout contact, mouthing, and grooming in intact animals.     

Self-administration of the D1 agonist SKF 82958 is mediated by D1, not D2, receptors

We have previously reported that two D₁ dopamine agonists, SKF 82958 and SKF 77434, are readily self-administered by rats. However, due to the limited selectivities of these agents, it was not possible to attribute their reinforcing effects exclusively to their D₁ actions. To assess the relative involvement of D₁ and D₂ receptors in SKF 82958 reinforcement, rats were pretreated 30 min before self-administration sessions with either the D₁-selective antagonist (+)SCH 23390 or the D₂-selective antagonist raclopride. The D₁ antagonist (+)SCH 23390 (5–20 µg/kg, SC) produced significant, dose-related (compensatory) increases in SKF 82958; in contrast, the D₂ antagonist raclopride (25–400 µg/kg, SC) did not significantly increase SKF 82958 self-administration, although raclopride did increase cocaine self-administration. Compensatory increases in self-administration rates are thought to reflect antagonist-induced reductions in drug reinforcement. Hence, we conclude that SKF 82958 self-administration depends on activation of a D₁-regulated reinforcement substrate.This work was supported by U.S.P.H.S. grants DA-05107, DA-05379, and DA-07747. All animal procedures were performed in accordance with the Guide for the Care and Use of Laboratory Animals (NIH pub. no. 86-23, revised 1985).     

Effects of haloperidol and SCH 23390 on acoustic startle in animals depleted of dopamine as neonates: implications for neuropsychiatric syndromes

Animals depleted of dopamine (DA) in the neonatal period and tested in adulthood exhibit some similarities to patients with schizophrenia, including increased sensitivity to DA agonists, altered sensitivity to DA receptor antagonists, and abnormalities of the acoustic startle response (ASR). In this study, we examined the contributions of D₁-like and D₂-like DA receptors to ASR measures in animals depleted of DA as neonates. Male rat pups received intracerebroventricular injections of 6-hydroxydopamine (DA depleted) or its vehicle (controls) at 3 days of age. Animals underwent startle testing ad adults (60–75 days of age) after administration of DA antagonists (haloperidol: 0.1 or 0.3 mg/kg, SCH 23390: 0.01 or 0.05 mg/kg) with and without DA agonist administration (apomorphine 0.5 mg/kg). ASR amplitude and prepulse inhibition (PPI: percentage decrease in startle amplitude due to a low intensity prepulse) were measured. DA depleted animals showed increased ASR amplitude and reduced PPI compared to controls. Administration of D₁-like or D₂-like DA antagonists significantly reduced overall ASR and increased PPI in both control and DA depleted animals, with DA depleted animals showing a relatively greater sensitivity to the D₁-like antagonist SCH 23390. Findings are discussed in terms of the role of residual DA in mediating ASR phenomena in depleted animals, differences between D₁/D₂ DA receptor mediation of ASR compared to other behaviors in DA depleted animals, and potential implications for neuropsychiatric syndromes such as schizophrenia.     

Biphasic locomotor effects of the dopamine D1 agonist SKF 38393 and their attenuation in non-habituated mice

The locomotor stimulatory effects of the dopamine D₁ receptor partial agonist SKF 38393 were examined in male C57B1/6J mice. Non-habituated mice showed marked dose-related (3–300 mg/kg, SC) locomotor stimulation. The time-course effect was biphasic at very high doses (100–300 mg/kg), with dose-related locomotor depression followed by dose-related long-term hyperlocomotion. For all doses, locomotor effects were detectable throughout the 4-h test period. To determine whether these effects were mediated by D₁ receptor stimulation, effects of SKF 38393 were assessed in combination with behaviorally inactive and active doses (0.1 and 0.2 mg/kg, respectively) of the selective D₁ receptor antagonist SCH 39166. Both doses of SCH 39166 attenuated the hyperlocomotion induced by 30 mg/kg of the agonist to a similar degree. However, neither dose was able to reverse either the depressant or the stimulatory effects of 300 mg/kg SKF 38393. These results demonstrate effects of the prototypical D₁ agonist previously unobserved, and raise questions concerning the nature of agonist/antagonist interactions at the D₁ receptor subtype.     

Differential attenuation of d-amphetamine-induced disruption of conditional discrimination performance by dopamine and serotonin antagonists

Rationale Recent experimental findings suggest that a core cognitive deficit of schizophrenia is the degraded ability to use task-setting cues to guide goal-directed behaviour, that this deficit is evident in acute as well as chronic schizophrenia, and that such deficits can me modelled in animals using conditional discrimination tasks.Objective To establish the reversal potential of D₁, D₂ and 5-HT receptor antagonists acutely, and D₁ and D₂ receptor antagonists chronically, on d-amphetamine-induced disruption of a conditional discrimination task that depends on the ability to use task-setting cues to direct goal directed performance.Method A conditional discrimination paradigm was employed in which rats learned to respond on an appropriate lever, conditional upon specific auditory stimuli.Results d-Amphetamine (1.5 mg/kg) disruption of conditional discrimination was attenuated by acute pre-treatment with the selective D₁ antagonist SCH 23390 and the atypical anti-psychotic clozapine (Cloz). Acute pre-treatment with the selective D₂ antagonist eticlopride (Eti) and the anti-psychotic haloperidol (Hal) failed to reverse d-amphetamine disruption, as did pre-treatment with the selective 5HT_1A antagonist WAY 100635 and the selective 5HT_2A/C antagonist ritanserin. However, Eti and Hal did reverse d-amphetamine-induced task disruption when administered chronically (as did SCH 23390, α-flupenthixol and Cloz).Conclusions These results suggest that D₁ receptors are involved in tasks that require the use of conditional relationships and that D₂ receptor antagonism can come to exert a similar influence after chronic treatment.