DA Agonists Research Articles

Effect of MK 801 on priming of D 1-dependent contralateral turning and its relationship to c- fos expression in the rat caudate-putamen

In rats with a unilateral 6-hydroxydopamine lesion of the ascending dopamine neurons, we investigated the relationship between the expression of Fos-like immunoreactivity in the caudate-putamen and contralateral turning behavior in response to dopamine agonists during the induction and expression of sensitization (priming) to D 1-dependent turning behavior. Priming was induced by apomorphine (0.1 mg/kg s.c.) or by SKF 38393 (10 mg/kg s.c.) 14 days after 6-hydroxydopamine lesions and was expressed by challenge with SKF 38393 (3 mg/kg s.c.). In the induction phase of priming, administration of MK 801 (0.1 mg/kg s.c.) potentiated contralateral turning but differentially influenced stimulation of Fos expression in the caudate-putamen by apomorphine and by SKF 38393. Thus, MK 801 reduced in the expression phase of priming the stimulation of Fos expression by apomorphine in the dorsolateral caudate-putamen, but did not affect that by SKF 38393. MK 801, while preventing priming of SKF 38393-induced turning by apomorphine, failed to affect priming by SKF 38393. MK 801, given with apomorphine in the induction phase, reduced the stimulation of Fos expression in the dorsolateral caudate-putamen by SKF 38393. No such inhibitory effect of MK 801 on SKF 38393-stimulated Fos expression was observed in rats primed with SKF 38393. These results are consistent with the possibility that MK 801 disrupts sensitization of D 1 transduction by reducing the activation of c- fos by the DA agonist during the induction phase of priming.

Improved Models for Pharmacological Null Experiments: Calculation of Drug Efficacy at Recombinant D1A Dopamine Receptors Stably Expressed in Clonal Cell Lines

Modern drug discovery demands accurate knowledge of the drug properties of affinity and efficacy at specific receptor proteins. Furthermore, drugs with well defined properties make better tools with which to explore and understand receptor regulation. The use of clonal cell lines stably expressing a given recombinant receptor may provide a highly useful model in which drug effects may be studied on one receptor subtype at a time. The present report was designed to evaluate the utility of a general method in which a clonal cell line stably expressing a recombinant D1A dopamine receptor was used as a model system for studying drug actions by null models. The null model for receptor occlusion (to calculate agonist K a) and the null model for relative efficacy (to calculate test agonist affinity and ε r) were evaluated in these studies. To initiate these studies, rat C6 glioma cells that do not normally express DA receptors have been modified by stable transfection with the primate D1A DA receptor [ Machida et al., 1992( Molec. Pharmacol. 41: 652–659)] to a density of ≈ 200 fmol/mg protein. The recombinant receptors show robust stimulation of cAMP in the stably transfected C6 cells. Calculation of agonist K a from dose-response data requires that a portion of the cell's receptors be occluded in the absence of changes in post-receptor events leading to the response. Receptor reserve is typically reduced by alkylation, thereby lowering maximal response. Unfortunately, most of the currently available alkylating agents are not selective either for a particular receptor or for receptors vs other proteins within a signaling pathway. Short-term agonist treatment offers a possible complement to the use of non-selective or poorly characterized alkylating drugs for reducing maximum response in appropriate cell systems. The null method of receptor occlusion was used to determine the K a for dopamine when maximum response was decreased by alkylation vs short-term agonist treatment. Direct non-linear curve fitting was used to analyze the data. In addition to DA, two other compounds were used to reduce receptor reserve to validate the method: fenoldopam (relatively high efficacy) and SKF38393 (low efficacy). Analyses indicated that the affinity of DA was similar whether calculated by alkylation (1.1 ± 0.58 μM), 75 min DA treatment (0.57 ± 0.16 μM) or 45 min treatment with DA (0.86 ± 0.11 μM). Short-term agonist treatment experiments using multiple concentrations of DA, fenoldopam, or SKF38393 to decrease receptor reserve provided additional support for the validity of the K a determinations using this procedure. Other experiments were conducted according to the null model for relative efficacy in which the affinity for DA is calculated by comparing the DA response before and after receptor occlusion, and the affinity and relative intrinsic efficacy of the test agonist are determined as a function of its actions relative to DA. We used the following four test drugs: + Br-APB, a novel agent with potential dopamine agonist properties, and three high-affinity DA agonists, fenoldopam, R-(−)-apomorphine (APO), and SKF38393. Intrinsic efficacy values relative to that of DA (1.0) were as follows: fenoldopam, 0.46 ± 0.11; APO, 0.19 ± 0.13; SKF38393, 0.07 ± 0.01; and +Br-APB, 0.26 ± 0.40. The agonist affinities ( K a) were: fenoldopam, 0.018 ± 0.008 μM; APO, 0.80 ± 0.18 μM; SKF38393, 0.16 ± 0.04 μM; Br-APB, 0.43 ± 0.29 μM; and DA, 0.58 ± 0.17 μM. EC 50/ K a ratios were consistent with relative intrinsic efficacies and K a values were similar to K L values reported for membrane binding studies. Finally, Monte Carlo simulations were conducted to determine the precision of the parameter estimates. These simulations of 1000 experiments each, using the empirical variance of ≈ 3% of the maximum response, indicated a precision for the DA K a of ≈ 16%, for the independently determined fenoldopam K a of ≈ 24%, and of the fenoldopam ε r of ≈ 16% of the parameter values. To our knowledge, this represents the first report of agonist affinity plus relative intrinsic efficacy measurement at any recombinant receptor. The present results also provide the first report of the precision of these important drug parameter measurements using Monte Carlo methods. Together, these results suggest that clonal cell lines which stably express a recombinant receptor of interest may offer a unique system with which to determine essential drug properties. The method is able to accommodate agonists with very high potency and intrinsic activity, extremely low relative intrinsic efficacy, and can determine whether or not a drug is behaving as expected for a classical partial agonist. Copyright © 1996 Elsevier Science Ltd

Absence of DA1/DA2 dopamine receptor interactions in proximal tubules of spontaneously hypertensive rats.

The impact of defective DA1 dopamine receptors in proximal tubules (PT) of the spontaneously hypertensive rat (SHR) on DA1/DA2 receptor interactions was assessed with the DA1-selective photoaffinity ligand, (+/-)-7-[125I]iodo-8-hydroxy-3-methyl-1-(4-azidophenyl)- 2,3,4,5-tetrahydro-1H-3-benzazepine ([125I]MAB). In PT membranes from both normotensive (Wistar-Kyoto, WKY) and spontaneously hypertensive rats (SHR), [125I]MAB was specifically incorporated into a polypeptide with an M(r) of 74,000 Da, corresponding to the DA1 receptor. The labeling of this band by [125I]MAB in both SHR and WKY was not prevented by SKF-82526, a potent DA1-selective agonist. However, in the presence of the DA2 antagonist, (-)-sulpiride, but not DA2 agonist, LY-171555, SKF-82526 abolished photoincorporation of [125I]MAB into the 74,000-Da band in WKY. In SHR, (-)-sulpiride failed to enhance the ability of SKF-82526 to compete with [125I]MAB for binding to the 74,000-Da subunit. In competition binding studies with SKF-82526, (-)-sulpiride induced the formation of agonist high-affinity binding sites in WKY but not in SHR. These data suggest that in membranes of SHR, but not WKY, DA1/DA2 dopamine receptor interactions are lacking.

Age-related changes in hippocampal drug facilitation of memory processing in SAMP 8 Mice

SAMP8/TaJf(P8) mouse strain has an inherited age-related impairment of learning and memory, while age-matched subjects of the closely related SAMR1/TaJf(R1) show no impairment. After training on footshock avoidance, P8 and R1 received a drug injection into the hippocampus. Retention was tested 1 week later. The results indicate that bicuculline (GABA antagonist), SKF38393 (DA agonist), and ST587 (NE agonist) facilitated retention with little change in the dose-response curves for P8 mice 4, 8, and 12 months of age. L-glutamate, acting at the NMDA receptor, showed a modest decline in ability to improve retention with increasing age. Arecoline, a muscarinic agonist, had the strongest trend for an age-related decline in potency. The same drug treatments yielded dose-dependent facilitation of retention but no age-related changes in R1 mice. Reduced cholinergic activity in the hippocampus may be, in part, responsible for age-related decline in memory retention in P8 mice.

Restoration of brain protein synthesis in mature and aged rats by a DA agonist, piribedil.

Brain ageing affects numerous cerebral metabolic pathways such as cerebral glucose consumption or protein synthesis rate. The pharmacological effect of a mixed D1-D2 dopaminergic agonist, piribedil, on this last metabolism is reported. Cerebral Protein Synthesis Rate (CPSR) was measured by the [35S]L-methionine autoradiographic procedure in 38 main brain regions of 11 and 26-month-old Wistar rats after a 2-month treatment per os at 9 and 30 mg/kg/day with piribedil. Mean decrease of CPSR was -21% during the 15-month ageing we followed, with important local variations. Mean CPSR increased with the two treatments, +25% in mature and +35% in aged rats. Treatments restored CPSR of aged rats to the exact mature subjects levels in quite all the brain regions. No dose-effect or asymetrical modification was statistically revealed for the two treatments. Metabolic increases involved particularly central brain gray structures, especially some DA-targeted brain nuclei concerned with behaviour and learning. This effect argued for a general metabotrophic effect of D1-D2 dopamine stimulation of the brain. The original pattern of local ageing of brain protein synthesis in rat was also incidentally reported. This was the first direct report of a wide and effective metabolic activation of CPSR in the brain during ageing by a curative dopaminergic agonist treatment.

Effect of adding the D-1 agonist CY 208–243 to chronic bromocriptine treatment of MPTP-monkeys: Regional changes of brain dopamine receptors

1. 1. Eleven monkeys were administered N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP): eight were treated with bromocriptine for one week and then CY 208–243 (four monkeys) or saline (four monkeys) was added to the bromocriptine treatment. 2. 2. Addition of CY 208–243 increased the therapeutic response observed with the ergot alone without inducing dyskinesia. 3. 3. Following MPTP, [ 3H]-SCH 23390 specific binding to D-1 receptors as well as [ 3H]-spiperone and [ 3H]-N-n-propylnorapomorphine specific binding to D-2 receptors increased in posterior striatum compared to control animals, whereas [ 3H]-SKF 38393 binding to D-1 receptors tended to decrease. 4. 4. Dopamine receptor density was unchanged in anterior striatum of untreated MPTP-monkeys. 5. 5. In the posterior striatum, both dopaminergic treatments decreased towards control values [ 3H]-SCH 23390, [ 3H]-spiperone and [ 3H]-N-n-propylnorapomorphine binding whereas they did not significantly change [ 3H]-SKF 38393 specific binding. [ 3H]-SKF 38393 specific binding increased in anterior striatum of bromocriptine-treated MPTP-monkeys, compared to untreated MPTP-animals, and this increase was abolished in animals treated with bromocriptine + CY 208–243. 6. 6. The present study shows that in MPTP-monkeys, treated or not with DA agonists, the D1 and D2 receptor changes are concentrated in the posterior striatum and that denervation appears to cause a shift from the high to the low affinity agonist state of D1 receptors but not for the D2 subtype.

Auditory ERPs in schizophrenia: Diagnostic and symptom correlates

ceived one dose of MK801 (0.05, 0.1 or 0.5 mg/kg) and saline in a counterbalanced design (l week between tests). Thirty minutes after injection, animals were exposed to 5 minutes background noise (70 dB) followed by 5 types of startle stimuli (total of 111 trials): startle pulse alone (PA, 116 dB, 30 msec duration), and PA preceded by inhibitory prepulses (75, 80, or 85 dB, 30 msec duration), or by a facilitatory prepulse (73 dB, 10 msec duration). Baseline startle, percent inhibition/facilitation, and within session habituation were calculated. Complete disruption of PPI for all inhibitory trials occurred at the two higher doses of MK-801. Baseline amplitude and PPF were enhanced by low-dnse MK-801 but reduced by higher doses, and habituation of ASR was impaired by the higher doses. These findings further support the involvement of PCP or NMDA receptors in the modulation of sensory gating and suggest that unique sensory gating abnormalities result from NMDA antagonists and DA agonists. Similar patterns, if present in subgroups of schizophrenia patients, would provide indirect evidence for DA hyperactivity vs. hypoglutamatergia. Such differentiation could further our understanding of the pathophysiology and treatment resl:xmse of schizophrenic patients. (Supported by MH00859.)

Sensitization to DA agonists induced by chronic imipramine and electroconvulsive shock

Dept. Neuroscience, University of Cagliari; 1Inst. Biochemistry, School of Pharmacy, University of Sassari; Italy.

Behavioural assessment in rats of the antipsychotic potential of the potent dopamine D 2 receptor antagonist, (-)eticlopride

The effects of the selective D 2 DA receptor antagonist, (-)eticlopride, a drug belonging to the benzamide class, were investigated on the D 2 DA agonist SND 919- and CQP 201–403-induced stereotyped behaviour and on CQP 201–403-induced shaking, in rats, and on isolation-induced aggression, in mice. (-)Eticlopride was also tested over a wide dose range (52–1200 μg kg −1, s.c.) for sedative and cataleptic activity, in rats. For comparison, some experiments were performed with (-)sulpiride (10 and 40 mg kg −1, s.c.) The data obtained show that (-)eticlopride differs from (-)sulpiride and potentially modifies animal behaviour, whether spontaneous or induced; moreover, they suggest a potential clinical use for this neuroleptic in the management of psychotic states.

Mechanisms of dopamine effects on Na-K-ATPase activity in Madin-Darby canine kidney (MDCK) epithelial cells.

Dopamine decreases tubular sodium reabsorption, attributed in part to Na-K-ATPase inhibition in the proximal convoluted tubule (PCT). Because the final regulation of sodium excretion occurs in the collecting duct, where specific dopamine DA1 binding sites have been demonstrated, we examined the effects of dopamine, as well as of DA1 and DA2 receptor agonists on Na-K-ATPase activity and on the number of units in Madin-Darby canine kidney (MDCK) cells, which retain differentiated properties of the renal cortical collecting tubule epithelium. Dopamine (10(-5) M) inhibited pump activity (by 50%) and reduced the number of units. This effect was reproduced by the DA1 agonist SKF 38393, which inhibited pump activity in a dose- and time-dependent manner (maximum, 10(-5) M). The DA2 agonist quinpirole hydrochloride was without effect, either alone or in combination with SKF 38393. Inhibition of pump activity by dopamine was totally abolished by H7 (100 microM), an inhibitor of protein kinase (PK), but partially by 2',5'-dideoxy-adenosine (DDA) and H4, respective inhibitors of cAMP production and PKA, which suggests that the dopamine effect on Na-K-ATPase activity may be linked to activation of both PKC and PKA. In these cells, amiloride addition during preincubation did not alter the effect of dopamine on Na-K-ATPase activity; in contrast, furosemide increased further the inhibitory effect of dopamine on the enzyme activity. Monensin addition (10(-3) M) reversed the inhibitory effect of dopamine after a 30-min preincubation.(ABSTRACT TRUNCATED AT 250 WORDS)

7‐OH‐DPAT, a dopamine D3‐selective receptor agonist, produces contralateral rotation in 6‐hydroxydopamine‐lesioned rats

AbstractThe purpose of the present study was to characterize the rotational behavior in unilateral 6‐OHDA‐lesioned rats produced by the high affinity and selective dopamine D3 receptor ligand 7‐OH‐DPAT. Qualitatively similar to the direct‐acting DA agonist apomorphine, 7‐OH‐DPAT causes rats to rotate in a direction contralateral to the side of the nigrostriatal DA pathway lesion. This effect is dose‐dependent and the minimum effective dose is 0.03 mg (0.12 m̈mol)/kg. 7‐OH‐DPAT‐induced rotation is blocked in a dose‐dependent manner by oral pretreatment with the “D2‐like” receptor antagonists haloperidol, eticlopride, or clozapine, but not by the “D1‐like” antagonist SCH 23390. The rank order potency for inhibition of 7‐OH‐DPAT rotation for haloperidol [ID50 = 0.067 mg (0.18 m̈mol)/kg], eticlopride [ID50 = 0.41 mg (1.2 m̈mol)/kg], clozapine [ID50 = 13 mg (40 m̈mol)/kg], and SCH 23390 [ID50 > 90 mg (313 m̈mol)/kg] closely parallels their rank order affinity for binding to either the D2 or the D3 receptor. Pretreatment with the non‐DA receptor antagonists ritanserin (serotonin 5HT2), scopolamine (muscarinic cholinergic), propranolol (betaadrenergic), or naltrexone (opiate), each at relevant pharmacological doses, failed to reduce 7‐OH‐DPAT rotation. Taken together, these results are consistent with mediation of 7‐OH‐DPAT‐induced rotational behavior via an agonist interaction with one or more DA receptors. ©1995 Wiley‐Liss, Inc.

Receptor systems involved in norepinephrine release in heart failure: focus on dopaminergic systems.

The sympathetic nervous system is under extraordinarily complex modulation, involving numerous presynaptic and postsynpatic control mechanisms. These highly conserved and very redundant control mechanisms allow for the sympathetic nervous system to adapt quickly and precisely to altered environmental stress or conditions. Heart failure (HF) is characterized by excessive sympathetic activity, with both enhanced "spillover" and reduced clearance of norepinephrine (NE). The normal inhibitor control mechanisms appear faulty, with unleashed sympathetic activity likely contributing to the pathophysiology of the clinical syndrome and being associated with excessive mortality. Attempts to attenuate pharmacologically the release or "spillover" of NE from sympathetic neurons in HF has remained an attractive therapeutic strategy, and various alpha 2 adrenergic agonists and dopaminergic agents have been studied in several small clinical trials. Agents designed to activate both presynaptic (DA2) and postsynaptic or vascular (DA1) receptors have demonstrated promise. Ibopamine, a prodrug that is converted metabolically to epinine, a DA1 > DA2 agonist, has potential for selective vasodilation of mesenteric, renal, cerebral, and coronary vascular beds while reducing NE release and aldosterone activity. Preliminary clinical trials with ibopamine are encouraging, but placebo-controlled multicenter studies will be necessary to establish its role in the treatment of HF.

Selective dopamine antagonist pretreatment on the antiparkinsonian effects of benzazepine D1 dopamine agonists in rodent and primate models of Parkinson's disease--the differential effects of D1 dopamine antagonists in the primate.

In rats with unilateral 6-hydroxydopamine (6-OHDA) lesions of the medial forebrain bundle, pretreatment with the D1 DA antagonists, SCH 23390 (7-chloro-8-hydroxy-2,3,4,5-tetrahydro-3-methyl-1-phenyl-1H-3-benzazepin e) and A66359 (1- 2-bromo-4,5-dimethoxybenzyl]-7-hydroxy-6-methoxy-2-methyl- 1,2,3,4 tetrahydroisoquinoline), but not the D2 DA antagonist raclopride inhibited the contralateral circling induced by the benzazepine D1 DA agonists SKF 38393 (7-H, 3-H analogue of SCH 23390), SKF 80723 (7-H, 3-H, 6-Br analogue) and SKF 83959 (7-H, 6-Cl, 3'-CH3 analogue). In MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) treated common marmosets, administration of SKF 80723 and SKF 83959 increased locomotor activity and reversed the motor disability. Grooming and oral activities were also increased. Pretreatment with SCH 23390 and A66359 inhibited all the behavioural changes induced by both D1 DA agonists. In general, higher doses of A66359 and more especially SCH 23390 were needed to inhibit SKF 83959 and SKF 80723 induced increases in oral activity and grooming than locomotor activity. Raclopride pretreatment did not affect SKF 83959 and SKF 80723 induced oral activity and grooming, though it reduced the duration of the locomotor changes induced by the D1 DA agonists. These findings demonstrate that the behavioural effects of benzazepine D1 DA agonists in the 6-OHDA lesioned rat and MPTP-treated marmoset are mediated by D1 DA receptor sites, although in the primate, stimulation of D2 DA receptors by endogenous DA may be necessary in facilitating the antiparkinsonian effects of D1 DA agonists. The differential sensitivities of locomotor/motor disability and oral/grooming behaviours to antagonism by D1 DA antagonists may indicate the involvement of multiple D1 DA receptor subtypes in mediating benzazepine D1 DA agonist induced behaviours in the MPTP-treated marmoset.

Effects of dopaminergic drugs on the sympathoadrenal system.

Several studies have suggested that dopamine (DA) plays a major role in cardiovascular functions. Dopaminergic receptors have been found on sympathetic nerve terminals (DA2), kidney (DA1, DA2), vascular smooth muscle (DA1) as well as on sympathetic ganglia (DA1, DA2) and adrenal gland (DA1, DA2). Previous studies have shown that DA2 receptor stimulation by a specific DA2 agonist, quinpirole (1) elicits a peripheral depressor action (decreased blood pressure) and a central pressor component involving an increase in both sympathetic tone and vasopressin release and (2) does not affect under in vivo conditions adrenal catecholamine release. The present study investigates the effects of fenoldopam, a specific DA1 receptor agonist on both cardiovascular responses and catecholamine release from the adrenal medulla. In conscious normal dogs, fenoldopam (10, 20 and 40 micrograms/kg i.v.) elicited a decrease in blood pressure and a marked increase in heart rate associated with a rise in plasma catecholamine levels. The increase in heart rate is only due to baroreflex mechanism since fenoldopam (conversely to DA2 receptor agonists like quinpirole) does not exert a central excitatory component (as shown by the absence of cardiovascular effects after intracisternal injection). Moreover, in sinoaortic denervated dogs (i.e. animals deprived from baroreflex pathways), the decrease in arterial blood pressure was more important than in normal dogs. Heart rate was unchanged. In these animals, DA1 stimulation induced a decrease in sympathetic tone, as shown by the significant fall in plasma noradrenaline levels. These "in vivo" data clearly demonstrate the inhibitory role of ganglionic DA1 receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Ontogeny of behavioral sensitization in the rat: effects of direct and indirect dopamine agonists.

In the present study, the abilities of NPA (a direct DA receptor agonist) and amphetamine (an indirect DA receptor agonist) to induce short- and long-term behavioral sensitization were assessed in 11- and 17-day-old rats (age at initial injection). Rats were injected on 4 consecutive days with amphetamine (1.0, 2.5, or 5.0 mg/kg), NPA (1.0 mg/kg), or saline. A final test day occurred either 2 days (experiment 1) or 8 days (experiment 2) later. On the test day, rats given successive agonist injections received a single injection of the same agonist again; whereas rats given successive saline injections received either amphetamine or NPA for the first time. Five minutes after injection, locomotor activity (line-crosses), stereotyped sniffing, and vertical activity were measured during a 30-min testing session. The results showed that 11- and 17-day-old rats exhibited behavioral sensitization when tested with NPA or amphetamine after a 2-day interval. In contrast, neither NPA nor amphetamine was able to sensitize the behaviors of preweanling rats when measured 8 days after initial drug treatments. Therefore, these results show that both direct and indirect DA agonists are able to induce short-term behavioral sensitization in preweanling rats, but that the mechanisms responsible for mediating long-term behavioral sensitization have not yet matured.

Studies of the active conformation of a novel series of benzamide dopamine D2 agonists.

Analogs of dopamine D2 agonist 11 were prepared in which a rigid trans decalin ring system was used to mimic various conformations of 11. The four rigid analogs where compared for their ability to bind to the DA D2 receptor and to inhibit forskolin-stimulated cAMP formation, a measure of DA agonist activity. Of the four rigid analogs of compound 11, only compound 12b had significant activity in both assays. Molecular modeling studies of 12a-d showed each had a single conformation with regard to the distance between the benzamide aryl-centroid and the 4-nitrogen atom of the pyridylpiperazine. Compound 12b was shown to have a greater distance between these functionalities (11.8 A) as compared to the other isomers (9.8-10.4 A). The distance between these two functionalities in 12b was similar to that of a conformer of 11 which has an extended conformation. This suggest that 11 is likely in an extended conformation when bound to the DA D2 receptor.

The preferential dopamine autoreceptor antagonist (+)-UH232 antagonizes the positive reinforcing effects of cocaine and d-amphetamine in the ICSS paradigm

The dopamine autoreceptor and D 3 preferring antagonist [ cis-(+)-5-methoxy-1-methyl-2-(di-n-propylamino)tetralin] (+)-UH232, exerts weak stimulatory effects when tested in locomotor activity experiments using habituated animals. (+)-UH232 also blocks d-amphetamine-, cocaine-, and apomorphine-induced hyperactivity, but fails to induce catalepsy. Thus, the behavioral effects of (+)-UH232 appear to be dependent upon the baseline activity of the animal. The antagonistic properties of (+)-UH232 were studied in the intracranial self-stimulation (ICSS) technique in the rat. (+)-UH232 and haloperidol produced inhibitory effects over a wide dose range. Cocaine, GBR12909 and d-amphetamine clearly lowered ICSS thresholds, indicating stimulatory effects. (+)-UH232 antagonized the stimulatory effects of cocaine, GBR12909, and d-amphetamine, whereas haloperidol, at a dose producing an inhibition similar to (+)-UH232, was significantly weaker in antagonizing cocaine- or d-amphetamine-induced stimulation. This difference between (+)-UH232 and haloperidol with respect to stimulant-blocking ability, support the concept that the effects of (+)-UH232 are not representative of either classical DA agonists or DA antagonists.

Effects of catechol ring fluorination on cardiovascular and renal activities of fenoldopam enantiomers

SK&F 87516 is a potent DA1 receptor agonist with demonstrated renal vasodilator activity. SK&F 87516 is the 6-fluoro analog of another DA1 agonist/renal vasodilator agent, fenoldopam. SK&F 87516 is a racemic mixture of two enantiomers, SK&F(R)-87516 and SK&F(S)-87516, and like fenoldopam, the (R)-enantiomer is responsible for the biological activities of the racemate. SK&F(R)-87516 is diuretic in spontaneously hypertensive rats and in dogs, whereas its enantiomer, SK&F(S)-87516 is inactive. SK&F(R)-87516 increases glomerular filtration rate, an effect which may account, in part, for its diuretic activity. Unlike fenoldopam, SK&F(R)-87516 is not associated with acute hypotensive activity, tachycardia, or stimulation of the renin-angiotensin-aldosterone system. The activity differences between SK&F(R)-87516 and fenoldopam are not related to differences in DA1 agonist potency. The activity differences may be due to the differing effects of fluorine and chlorine on the electron distribution in the catechol ring, resulting in an enhanced effect of SK&F(R)-87516 at alpha 2-adrenoceptors.

Effects of remoxipride's metabolites on dopamine D2 receptors and receptor functions in the rat.

The main metabolites of remoxipride formed in rat and man were examined for their affinities for the [3H] SCH 23390-labelled DA D1 and [3H]-raclopride-labelled D2 receptors in rat striatal homogenates. In addition, their effectiveness in blocking postsynaptic DA receptor activity in vivo was measured by the use of several different test models in the male rat. Phenolic metabolites formed mainly in the rat retained (similar to remoxipride) their selectivity for the D2 receptor with very low affinities for the D1 receptor. The pyrrolidone metabolites formed mainly in man showed very low affinities for both the D1 and D2 receptors. The ability of the metabolites to block postsynaptic DA receptor activity in vivo correlated with their affinities for the D2 receptor. Among the metabolites tested, the phenolic compounds FLA 797 (-) and FLA 908 (-) were much more effective than remoxipride in inducing catalepsy, which is consistent with a higher affinity for [3H] raclopride labelled striatal D2 receptors. However, analysis of the effectiveness of the DA receptor blockade (blockade of d-amphetamine locomotion or DA agonist hypothermia) after intraperitoneal or subcutaneous administration suggested that FLA 797 (-)/FLA 908 (-) may only contribute marginally to the D2 receptor-blocking activity of remoxipride in the rat. This conclusion was further supported by the observation that the atypical antipsychotic profile of remoxipride was not mimicked by the active metabolites. The weak DA D2 blocking effect of the pyrrolidone metabolites indicated that remoxipride is responsible for the clinical action.

Behavioural effects induced in rats and chicks by D 2 dopamine agonists

In a first series of experiments, different selective dopamine D 2 receptor agonists (B-HT 920, B-HT 958, SND 919, CQ 32-084, CQP 201–403, and lisuride) and the D 1 D 2 agonist apomorphine were IP injected into adult male rats. At low doses, they elicited repeated episodes of penile erection and stretching-yawning; at all doses tested, B-HT 920, B-HT 958, and CQ 32-084 also induced hypomotility, a sign that, in the case of high doses of SND 919, CQP 201–403, lisuride, and apomorphine, was replaced by stereotyped behaviour. In a second series of experiments, the same D 2 agonists and the mixed D 1 D 2 agonist apomorphine were IP injected at the same doses into chicks. The following behavioural signs were observed: hypomotility, sleep-like state, and stereotyped pecking. The results show that: 1. there are similarities between the behavioural effects induced by the DA agonists in rats and chicks; and 2. in both species some behavioural signs elicited by the DA ergic compounds are useful pointers to their specific neurochemical activity.