Effects of dopamine D1 and D2 receptor agonists and antagonists on bombesin-induced behaviors

Central administration of bombesin elicits excessive grooming and locomotor activity in rats. This grooming activity is one characterised by vigorous scratching of the face, nape and body flanks. Pretreatment with the D1 receptor antagonist SCH 23390 inhibited the expression of bombesin-induced activity with grooming being more inhibited than locomotion. Blockade of D2 receptors with eticlopride significantly attenuated the behavioral responses to bombesin. When SCH 23390 and eticlopride were administered concurrently, it was apparent that D1 blockade had a greater effect on grooming and D2 blockade a larger effect on locomotion. Stimulation of D1 receptors by SKF 38393 elicited non-stereotyped locomotor activity and a form of grooming behavior characterised by vigorous washing of the face and ventral body surfaces. Co-administration of bombesin and SKF 38393 resulted in a form of grooming which resembled that elicited by SKF 38393 alone. The specific D2 agonist PPHT elicited a form of locomotion characterised by a downward oriented head posture and slow ambulatory activity around the cage perimeter. Co-administration of PPHT and bombesin resulted in a complete suppression of bombesin-induced behaviors and was largely indistinguishable from activity observed under PPHT alone conditions. These data implicate both D1 and D2 receptor based mechanisms in the modulation/mediation of the behavioral effects of bombesin. Part of the bombesin-induced behavioral effects may be explained by (indirect) activation of (a) dopamine system(s).     

Effects of kappa receptor agonists on D1 and D2 dopamine agonist and antagonist-induced behaviors

Striatal dynorphin-containing neurons receive dopaminergic inputs from the substantia nigra pars compacta and project primarily to the substantia nigra pars reticulata and entoped uncular nucleus. These neurons mainly express dopamine (DA) D₁ receptors and thus dynorphin system stimulation might be expected largely to influence D₁ receptor agonist or antagonist effects on motor function. It is well known the interaction existing between DA D₁ and D₂ drugs in the induction of behavioral effects. However, the effects of dynorphin on selective D₁ and D₂ DA agonist and antagonist-induced behaviors have not yet been investigated. Administration of the kappa agonists spiradoline (0.5, 1 and 5 mg/kg) or U50,488H (1, 10 and 25 mg/kg) decreased non-stereotyped grooming induced by the selective D₁ agonist SKF38393. This effect was inhibited by the non-selective opioid receptor antagonist naloxone (20 mg/kg) and by the selective kappa antagonist nor-binaltorphimine (nor-BNI, 20 mg/kg). Stereotypies induced by the selective D₂ agonist quinpirole were decreased by spiradoline (1 and 5 mg/kg) and by U50,488H (1, 10 and 25 mg/kg), while jerking movements of a type associated with increased D₂ receptor and decreased D₁ receptor stimulation emerged. Kappa agonist effects were inhibited by the prior administration of SKF38393 (10 mg/kg); these inhibitory effects were blocked by prior administration of the D₁ antagonist SCH23390 (5 mg/kg). Naloxone reversed the effects of both kappa agonists on quinpirole-induced stereotypies. Kappa agonists increased D₁ antagonist-induced catalepsy, but had no effect on D₂ antagonist-induced catalepsy. Naloxone and nor-BNI inhibited this effect. These results suggest that the motoric effects of D₁ receptor antagonists in part reflect stimulation of striatal dynorphin containing efferents.     

Effects of dopamine receptor agonists on passive avoidance learning in mice: interaction of dopamine D1 and D2 receptors.

The present study examined the effects of dopamine D1 and D2 receptor agonists on the acquisition stage of passive avoidance learning and on locomotor activity in mice. The D2 agonist, RU 24213 (1-10 mg/kg s.c.), and the non-selective agonist, apomorphine (0.3-3 mg/kg s.c.), but not the D1 agonist, SKF 38393 (1-10 mg/kg s.c.), impaired learning and activated locomotion. RU 24213 (1 mg/kg s.c.) was more effective in impairing learning than in activating locomotion. The concurrent administration of SKF 38393 (10 mg/kg i.p.) and RU 24213 (1 and 3 mg/kg s.c.) produced a synergistic effect in both behavioral situations. The D1 antagonist, SCH 23390 (0.025 mg/kg i.p.), slightly inhibited the effects of apomorphine and of the combination of SKF 38393 and RU 24213 on learning but not on locomotion. The D2 antagonist, (-)-sulpiride (40 mg/kg i.p.), completely blocked these effects in both situations. These results suggest that dopamine receptor agonists impair passive avoidance learning through the D2 receptor, and that D1 and D2 receptors act synergistically in this impairment, as they do in their effects on locomotion. The involvement of D1 and D2 receptors is qualitatively similar in each of these behaviors, although some small differences may exist.     

Effects of dopamine D1-like receptor agonists on food-maintained operant behavior in rats

The effects on learned operant behavior of agonist actions at dopamine D1-like receptors have not been fully characterized. We compared three D1-like receptor agonists (SKF 38393, SKF 77434 and SKF 82958), both alone and in combination with the D1-like receptor antagonist, SCH 23390. Binding affinities for the agonists at dopamine D1 receptors from rat striatum membranes were determined and compared with effects on behavior. Lever pressing was maintained by food reinforcement under a fixed-ratio 30-response schedule (each 30th response produced reinforcement), and the effects of the three agonists were assessed by cumulative dosing. Each drug produced dose-related reductions in response rates, with an order of potency (SKF 82958>SKF 77434>SKF 38393) that agreed with rank order of binding affinities. Antagonism of these behavioral effects by SCH 23390 was only significant for SKF 82958; surprisingly, SCH 23390 enhanced the effects of SKF 38393. For SKF 82958, the antagonism was receptor subtype-specific, as the D2-like receptor antagonist spiperone was ineffective. The nonselective serotonergic antagonist metergoline produced a significant rightward shift of the SKF 38393 dose-response function, indicating effective antagonism, although the degree of antagonism was not dose-related. These results support the view that the behavioral effects of D1-like receptor agonists differ in their susceptibility to antagonism by D1-like receptor antagonists, and that some effects of SKF 38393 may be mediated by serotonergic activity rather than by activity at D1-like receptors.     

Effects of selective dopamine D1 and D2 receptor agonists on the rate of GABA synthesis in mouse brain

The effects of dopamine D1 and D2 receptor agonists and antagonists on the rate of GABA synthesis in four regions of mouse brain (corpus striatum, cerebellum, cortex and hippocampus) were examined after irreversible inhibition of 4-aminobutyrate: 2-oxoglutarate aminotransferase (EC 2.6.1.19; GABA-T) by gabaculine. The dopamine D2 receptor agonists PPHT, LY 171555 and RU 24213 exerted a dose-related inhibitory effect on GABA synthesis in these four regions. The decreases in the rate of GABA formation were prevented by the dopamine D2 receptor antagonist S(-)-sulpiride. The dopamine D1 receptor agonists SKF 77434 and SKF 38393 augmented gabaculine-induced GABA accumulation in the corpus striatum only, and this effect was blocked by the dopamine D1 receptor antagonist SCH 23390. However, SKF 81297 and SKF 82958, two other dopamine D1 receptor agonists, did not affect or only marginally altered the rate of GABA synthesis. Stimulation of D2 receptors thus induces a decrease in the rate of GABA formation in the four brain areas examined, whereas stimulation of D1 receptors either increases GABA synthesis in the corpus striatum or does not alter it. This effect appears to be independent of the degree of receptor occupancy.     

Dopamine receptor agonists: selectivity and dopamine D1 receptor efficacy

Dopamine receptor selectivity was investigated for a number of dopamine receptor agonists. In vitro, the benzazepine derivatives, e.g., SKF 38393 and SKF 75670 as well as the isoquinoline derivatives, SKF 89626 and SKF 89615, were D1 receptor-selective. All other compounds like apomorphine, CY 208-243, 6,7-ADTN and 3-PPP were either D2-selective or did not discriminate between subtypes. In general, the same receptor profile seen in vitro was observed in vivo. The exceptions to this pattern were: compounds which did not cross the blood-brain barrier, like 6,7-ADTN and SKF 89626, and compounds which appeared nonselective in vitro but demonstrated D2 selectivity in vivo like apomorphine, CI 201-678 and CY 208-243. A number of compounds were characterized in detail with respect to a GTP-induced affinity shift in inhibition of [3H]SCH 23390 binding, and potency and efficacy in stimulating adenylate cyclase from rat striatum. Inhibition of specific [3H]SCH 23390 binding by these agonists in the absence of GTP occurred with Hill slopes below unity and could best be explained by a two-site model with a high (KH)- and low-affinity (KL) component. Inhibition of [3H]SCH 23390 binding in the presence of 15 microM GTP occurred with Hill slopes of unity. The KI values obtained in the presence of 15 microM GTP were similar to the KL values, the low-affinity component observed in the absence of GTP. The capability of the agonists to stimulate the adenylate cyclase was analyzed in relation to dopamine (efficacy = 100%). The efficacy of the benzazepine derivatives varied from 24 (SKF 75670) to 100% (SKF 83189), dependent on the substituents on the benzazepine core. The isoquinolines, SKF 89626 and SKF 89615 had full efficacy, whereas most other agonists tested appeared to have only partial efficacy. In summary, the present paper presents data on dopamine receptor selectivity and efficacy in stimulating adenylate cyclase for a number of dopaminergic agonists. These data may create a basis for selection of agonists in future characterizations of dopaminergic-mediated events.     

Behavioural profile of partial D2 dopamine receptor agonists

The effects of partial D2 dopamine (DA) receptor agonists on the behavioural activation produced by 1.5 and 8.0 mg/kgd-amphetamine were compared with the changes produced by the classical DA antagonist haloperidol. Alterations in behaviour were assessed in standard activity monitoring cages by direct observation of the rats using a rapid time sampling procedure. Haloperidol blockedd-amphetamine (1.5 mg/kg)-induced increases in photocell counts, ambulation, rearing and sniffing up, and after the highest dose of the DA antagonist the animals were mainly inactive. The partial D2 DA agonist SDZ 208–911 was equipotent to haloperidol in blocking the increase in photocell counts and rearing produced byd-amphetamine. However, even high doses of the drug did not reduce the incidence of sniffing or induce inactivity, but qualitative changes in the form of sniffing did occur. Although considerably less potent, preclamol exerted similar effects to SDZ 208–911. The profiles of SDZ 208–912 and terguride were intermediary to those of SDZ 208–911 and haloperidol. All compounds blocked the repetitive sniffing down produced by 8.0 mg/kgd-amphetamine. After a low dose of haloperidol, these stereotyped behaviours were replaced by a behavioural syndrome similar to that observed with low dosed-amphetamine, but inactivity was observed following a further small increase in antagonist dose. The blockade of stereotypy by SDZ 208–911, preclamol and terguride was accompanied only by the low dosed-amphetamine behavioural syndrome; no inhibition of sniffing or induction of inactivity occurred. SDZ 208–912 exhibited a profile with features very similar to that noted with haloperidol. These findings suggest that partial D2 agonists exert similar, but not identical, behavioural effects to classical DA antagonists when dopaminergic function in increased byd-amphetamine. The differences in behavioural profile are discussed in relation to variations in the intrinsic efficacy of the dopaminergic compounds and to differences in the response capability of D2 receptor populations underlying the different behaviours produced byd-amphetamine.     

Effects of dopamine D1 receptor agonists in rats trained to discriminate dihydrexidine

Rationale The full D₁ receptor agonist dihydrexidine (DHX) [(+/−)-trans-10,11-dihydroxy-5,6,6a,7,8,12b-hexahydrobenzo[a]phenanthridine hydrochloride] is under clinical development (DAR-100) for Parkinson’s disease and schizophrenia. Despite the clinical development of DHX, very little is known about its discriminative stimulus properties in rats. To more fully characterize the discriminative stimulus properties of DHX, we trained rats to discriminate DHX (3 mg/kg, i.p.) from vehicle. Methods: Substitution tests in rats discriminating DHX (3 mg/kg, i.p.) from vehicle were performed with structurally distinct D₁ receptor agonists with both partial and full intrinsic efficacy. In addition, the peripherally restricted D₁ agonist, fenoldopam, was evaluated.Results SKF 75670A, ABT-431, dinapsoline, SKF 81297, and SKF 82958 all fully substituted in a dose-dependent manner. The rank order of potency for substitution was SKF 82958<ABT-431<SKF 75670A≤dinapsoline<SKF 81297<DHX. Fenoldopam (10 and 30 mg/kg) did not substitute and was without effect on rates of responding.Conclusions DHX produces prominent dopamine D₁ receptor agonist effects in vivo and is likely to produce subjective effects in humans similar to other D₁ receptor agonists.     

Effects of acute dopamine depletion on responsiveness to D1 and D2 receptor agonists in infant and weanling rat pups

The behavioral responses to separate and combined administration of the D₁ agonist SKF-38393 and the D₂ agonist quinpirole following acute dopamine (DA) depletion via alpha-methyl-p-tyrosine (AMPT) or AMPT/reserpine were examined in infant (10-day-old) and weanling (21-day-old) rat pups. At both ages, AMPT pretreatment generally had little impact on D₁- or D₂-agonist-induced responding, whereas the greater DA depletion observed following AMPT/reserpine pretreatment was generally associated with suppression of both D₁ and D₂ agonist-typical responding. Thus, whereas in adult animals some degree of D₁ receptor activation by endogenous dopamine appears to be necessary for D₂ responding but not vice versa (e.g. White et al. 1988), in young animals there appears to be a reciprocal co-dependence of these two receptor subtypes, with extensive DA depletion suppressing responding to both agonists when administered separately. At 10 days of age, some D₁ and D₂ agonist-induced behaviors that were previously blocked by AMPT/reserpine were reinstated following combined administration of both agonists. In contrast, no clear evidence for reinstatement was seen following administration of the combined agonists to AMPT/reserpine-pretreated weanlings, perhaps due to the induction of potential competing behaviors. Whereas DA depletion blocked many D₁- and D₂-induced behaviors, such depletion conversely promoted the expression in agonist-treated animals of a number of behaviors that were not normally induced by the agonists in non-depleted animals. These behaviors typically involved an oral component and included grooming and mouthing following SKF-38393 in depleted 10-day-old pups, mouthing following administration of either agonist to depleted weanlings, and probing and intense self-mutilation (forepaw and tongue biting) following the combined agonists in depleted weanlings. This rapid induction of potentiated agonist responsiveness following acute DA depletion early in life may have significant implications with regard to animal models for the developmental disorder of Lesch-Nyhan syndrome.     

Reinforcing effects of D2 dopamine receptor agonists and partial agonists in rhesus monkeys.

Dopamine (DA) receptors play a role in the reinforcing effects of psychomotor stimulants and other drugs. Both D1 and D2 DA receptor agonists have been reported to function as positive reinforcers in maintaining self-administration in non-human subjects. The purpose of the present study was to evaluate, in monkeys, the reinforcing effects of DA D2 receptor agonists that vary in their efficacy as D2 agonists. Rhesus monkeys were prepared with venous catheters and lever pressing was maintained by i.v. cocaine (n=5, 0.03 mg/kg/inj) in daily baseline sessions (2 h/day, fixed ratio 25). Various doses of cocaine or D2 agonists were then made available for at least four to seven sessions, and until responding was stable. At least one dose of the higher-efficacy D2 agonists, R(-)-propylnorapomorphine (NPA) (n=4, 0.001-0.01 mg/kg/inj), R(-)-apomorphine (APO) (n=4, 0.003-0.1 mg/kg/inj) and R(+)-3-(3-hydroxyphenyl)-N-propylpiperidine HCl [R(+)-3-PPP] (n=4, 0.03-0.3 mg/kg/inj), functioned as a positive reinforcer in all the monkeys tested. In contrast, no dose of the lower-efficacy D2 agonists, R(+)-terguride (n=4, 0.001-0.3 mg/kg/inj) and S(-)-3-(3-hydroxyphenyl)-N-propylpiperidine HCl [S(-)-3-PPP] (n=4, 0.001-0.3 mg/kg/inj), maintained self-administration. In in vitro binding studies with monkey brain tissue NPA and terguride had high affinities for the D2 receptor, while APO had intermediate affinity, and the 3-PPPs had low affinity. Among the compounds that were reinforcers potency as a reinforcer was directly related to D2 affinity in three of the four monkeys, consistent with D2 receptor involvement in the reinforcing effect of these compounds. The data suggest that the efficacy at D2 receptors is directly related to the reinforcing effect.     

Effects of dopamine D1 and D2 receptor antagonists on oral activity in rats

Two experiments were performed to investigate the actions of the selective D1 blocker SCH 23390 and the selective D2 blocker sulpiride, on oral movements in rats; these were quantified by a human observer scoring vacuous chewing movements (VCMs), jaw tremor and head movements, as well as a computer analysis system which measured the amplitude and slope of each movement. In the first experiment it was found that both SCH 23390 and sulpiride decreased VCMs and head movements in a dose-dependent manner, with SCH 23390 more effectively decreasing head movements and sulpiride more effectively decreasing VCMs. In a second experiment, the effectiveness of these two drugs in blocking the actions of selective D1 (SKF 38393) and D2 (LY 171555) agonists was studied. The SKF 38393-induced increase in computer-scored movement was attenuated by both sulpiride and SCH 23390, whereas the LY 171555-induced decrease in VCMs was attenuated by sulpiride, while SCH 23390 exacerbated it. These findings, together with our earlier results, suggest a simple relationship of D1 receptors to oral movement, with increased activation resulting in increased oral movement and decreased activation resulting in decreased oral movement. The relationship of D2 receptors to oral movement shows a more complex pattern, with both stimulation and blockade decreasing oral movement. One possibility may be the existence of more than one subpopulation of D2 receptors mediating these effects.     

Effects of dopamine D1 receptor full agonists in rats trained to discriminate SKF 38393

Although the dopaminergic pharmacology of the D1 receptor full agonists, dinapsoline, dihydrexidine and the prodrug ABT-431 have been studied, no information is available on the ability of these agonists to substitute for the D1 agonist SKF 38393 in rats trained to discriminate this compound from vehicle. The present study was designed to characterize the potential D1 discriminative stimulus effects of these compounds. The selective dopamine D1-receptor agonists dihydrexidine [(+/-)-trans-10,11-dihydroxy-5,6,6a,7,8,12b-hexahydrobenzo[a] phenanthridine hydrochloride], ABT-431 [(-)-trans-9,10-diacetyloxy-2-propyl-4,5,5a,6,7,11b-hexahydro-3-thia-5-azacyclopent-1-ena[c]phenanthrene hydrochloride], the diacetyl prodrug derivative of A-86929, and dinapsoline [9-dihydroxy-2,3,7,11b-tetrahydro-1H-naph[1,2,3-de]isoquinoline] were studied in rats trained to discriminate racemic SKF 38393 [(+/-)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol], a selective D1 receptor partial agonist from vehicle. All of the agonists substituted fully for the discriminative stimulus effects of SKF 38393. The rank order of potency for substitution was ABT-431 > dinapsoline > dihydrexidine > SKF 38393. The D1 receptor antagonist, SCH 23390, blocked the discriminative stimulus effects of SKF 38393. The D3/D2-receptor agonist PD 128,907 [S(+)-(4aR,10bR)-3,4,4a,10b-tetrahydro-4-propyl-2H,5H-[1]-benzopyrano[4,3-b]-1,4-oxazin-9-ol] did not substitute up to doses that produced profound rate-suppressant effects. Thus, consistent with their D1 receptor pharmacology, the full D1-receptor agonists substituted completely for the discriminative stimulus of SKF 38393.     

Relative dopamine D1 and D2 receptor affinity and efficacy determine whether dopamine agonists induce hyperactivity or oral stereotypy in rats

The effects of a range of dopamine (DA) agonists on stereotyped behaviour in rats were analysed and compared both with the affinity of the compounds for D1 and D2 receptor binding sites in vitro and their ability to stimulate the adenylate cyclase activity in rat striatal homogenates. Full and partial agonists at the D1 receptor coupled to adenylate cyclase do not induce sterotypies when given alone, whereas full D2 agonists (e.g. quinpirole) induce hyperactivity but not oral sterotypies. Partial D2 agonists (e.g. (-)-3-PPP) only induce sedation. Mixed D1/D2 agonists (e.g. apomorphine) induce both hyperactivity and oral stereotypies. Maximum stereotypies were induced by combination of SK & F 38393 and a series of D2 agonists, including full agonists and the partial D2 agonist B-HT 920, whereas partial agonists with low intrinsic activity (e.g. (-)-3-PPP, EMD 23448) did not induce stereotypies when given together with SK & F 38393. However, these partial agonists reduced the maximum effect of apomorphine, whereas the full agonists (e.g. quinpirole, (-)-NPA) and B-HT 920 had no apomorphine antagonistic activity. The mixed D1/D2 agonists apomorphine and N,N-dipropyl-5,6-ADTN were only weakly influenced by SK & F 38393, or not at all. D1 agonists with central effects, including SK & F 38393, SK & F 81297 (with relatively high efficacies), and the partial agonist SK & F 75670 with low efficacy, changed the hyperactivity induced by quinpirole into maximum oral stereotypy, whereas the peripheral D1 agonist fenoldopam had no such effect. Inhibition of DA and NA synthesis with alpha-methyl-p-tyrosine depleted striatal DA levels by 72 per cent and antagonized the hyperactivity induced by the D2 agonists quinpirole and (-)-NPA, but not that of apomorphine. Combination of SK & F 38393 and quinpirole induced maximum stereotypy in DA-depleted animals. These results suggest that D1 receptor tonus is a necessary prerequisite for the expression of a DA agonist's effect. The hyperactivity induced by full D2 agonists appears to be mediated by D1 tonus provided by endogenous DA activity, but stronger D1 stimulation is necessary to induce oral stereotypy. A high degree of D1 receptor activation increases the ability of partial D2 agonists to induce hyperactivity or oral stereotypies since treatment with both SK & F 38393 and B-HT 920 had marked effects while B-HT 920 was ineffective.(ABSTRACT TRUNCATED AT 400 WORDS)     

Synergistic behavioural effects of dopamine D1 and D2 receptor agonists are determined by circadian rhythms.

The effects of continuous subcutaneous infusions of rats for 336 h with vehicle, SKF 38393 (a dopamine D1 receptor agonist), (+)-4-propyl-9-hydroxynaphthoxazine (PHNO, a dopamine D2 receptor agonist) or both D1 and D2 receptor agonists, on locomotor activity were investigated. Rats were maintained under constant lighting conditions, either continuous dark (dark:dark) or continuous light (light:light), before and during drug treatments in order to determine the influence of free-running circadian rhythms on drug responses. The D2 receptor agonist initially increased locomotion in rats kept under dark:dark during both subjective night (period of maximum locomotion) and day (period of minimum locomotion), but had no effect in rats maintained in light:light throughout the 336 h of treatment. The motor stimulant effects of the D2 receptor agonist on rats kept in dark:dark increase during the course of treatment during subjective night (sensitization), but decreased during the rats' subjective day (tolerance). The D1 receptor agonist, SKF 38393, had no effect on its own regardless of the lighting conditions and the duration of treatment. However, the D1 receptor agonist interacted synergistically with the D2 receptor agonist in rats maintained under light:light, depending on the duration of treatment. Synergistic effects were also observed on initiation of treatment in rats under dark:dark but only during subjective day. Tolerance to the synergistic effects of the receptor agonists occurred as a function of treatment duration, but only during subjective day. The D1 receptor agonist blocked the effects of the D2 receptor agonist during the rats' subjective night after 100 h of treatment, but not after 25 or 325 h.(ABSTRACT TRUNCATED AT 250 WORDS)     

Differential activation of adenylate cyclase and receptor internalization by novel dopamine D1 receptor agonists

Structurally dissimilar dopamine D(1) receptor agonists were compared with dopamine in their ability to activate adenylate cyclase and to internalize hemagglutinin-tagged human D(1) receptors in a stably transfected human embryonic kidney cell line. Thirteen dopamine D(1) receptor agonists were selected rationally from three different structural classes: rigid fused ring compounds [dihydrexidine, dinapsoline, dinoxyline, apomorphine, and (5aR,11bS)-4,5,5a,6,7,11b-hexahydro-2-propyl-3-thia-5-azacyclopent-1-ena[c]-phenanthrene-9,10-diol (A86929)]; isochromans [(1R,3S)-3-(1'adamantyl)-1-aminomethyl-3,4-dihydo-5,6-dihydroxy-1H-2-benzopyran (A77636) and (1R,3S)-3-phenyl-1-aminomethyl-3,4-dihydo-5,6-dihydroxy-1H-2-benzopyran (A68930)]; and benzazepines [7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SKF38393), (+/-)-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SKF77434), 6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SKF82958), 3-methyl-6-chloro-7,8-hydroxy-1-[3-methylphenyl]-2,3,4,5-tetrahydro-]H-3-benzazepine (SKF83959), R(+)-6-chloro-7,8,-dihydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SKF82957), and R(+)-6-chloro-7,8,-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SKF81297)]. The working hypothesis was that some agonists have differential effects on adenylate cyclase versus receptor internalization that could be correlated to the structural class of the agonist. First, the affinity for the hemagglutinin-hD(1) receptor and the intrinsic activity and potency of adenylate cyclase activation were determined for each compound. The internalization time course and internalization efficacy were then determined for each agonist. It was surprising that internalization efficacy was found to be independent of either agonist structural class or affinity. Only agonists that had both high adenylate cyclase functional potency and high intrinsic activity caused internalization. In addition, four agonists from two structural classes were identified that were capable of fully activating adenylate cyclase without eliciting an internalization response. This study provides the first extensive characterization of D(1) receptor internalization in response to structurally diverse agonists and, at least for the D(1) receptor, shows that functional selectivity is not predictable by simple structural examination. These data are consistent with the hypothesis that functional selectivity reflects subtle ligand-induced conformational changes as opposed to simple agonist trafficking among discrete receptor active states.     

Lesions of the mesotelencephalic dopamine system enhance the effects of selective dopamine D1 and D2 receptor agonists on striatal acetylcholine release.

In vivo microdialysis was used to determine the effects of 6-hydroxydopamine (6-OHDA) lesions of the mesotelencephalic dopamine system on dopamine receptor agonist induced changes in extracellular acetylcholine (ACh) concentrations in the striatum. Such lesions increased the inhibitory effect of a low dose of the D2 receptor agonist quinpirole (0.05 mg/kg s.c.) on striatal ACh release. In addition, 6-OHDA lesions enhanced the facilitatory effect of the selective D1 receptor agonist CY 208-243 on striatal ACh release, enabling a subthreshold (0.2 mg/kg s.c.) dose to increase striatal dialysate concentrations of ACh by over 60%. These results indicate that denervation supersensitivity potentiates both the facilitatory effects of D1 receptor agonists and the inhibitory effects of D2 receptor agonists on striatal cholinergic activity. It was also found that the 6-OHDA lesions reduced basal interstitial ACh concentrations by 75% in the ipsilateral striatum. The later results are consistent with the hypothesis that the prepotent action of dopamine in the forebrain is to enhance striatal ACh release via a D1 receptor mechanism.     

Effects of dopamine receptor agonists and antagonists at peripheral neuronal and vascular dopamine receptors in the anaesthetised dog

The interactions between several putative dopamine receptor agonists and antagonists have been examined at neuronal and vascular dopamine receptors in the femoral and mesenteric vascular beds, respectively, of anaesthetised dogs. N,N-di-n- propyldopamine (DPDA) and apomorphine caused vasodilatation in both vascular beds. Cis alpha-flupenthixol, fluphenazine, and sulpiride were much more potent at antagonising DPDA at neuronal than at vascular dopamine receptors. Fluphenazine and sulpiride were as potent against apomorphine as against DPDA at neuronal receptors, but cis alpha-flupenthixol was much less effective. Fluphenazine antagonised the vasodilator effect of apomorphine in the mesenteric vascular bed, but cis alpha-flupenthixol and sulpiride did not, even when used in doses much larger than were effective against DPDA. Further experiments, in dogs pretreated with phenoxybenzamine and propranolol, revealed that cis alpha-flupenthixol, fluphenazine, and sulpiride also antagonised the mesenteric vasodilator effects of dopamine, 2-amino-5,6-dihydroxy-1,2,3,4-tetrahydronaphthalene, 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene, and 2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine, suggesting a common site of action of these drugs and DPDA. Only fluphenazine antagonised responses to apomorphine. The results support the view that neuronal and vascular dopamine receptors in the dog are different. They also show that apomorphine stimulates different receptors from DPDA in the mesenteric vascular bed and, perhaps, in the femoral vascular bed as well.