Selective Dopamine D1 Agonists Research Articles

Neonatal tactile stimulation enhances spatial working memory, prefrontal long-term potentiation, and D1 receptor activation in adult rats

Environmental stimuli during neonatal periods play an important role in the development of cognitive function. In this study, we examined the long-term effects of neonatal tactile stimulation (TS) on spatial working memory (SWM) and related mechanisms. We also investigated whether TS-induced effects could be counteracted by repeated short periods of maternal separation (MS). Wistar rat pups submitted to TS were handled and marked transiently per day during postnatal days 2–9 or 10–17. TS/MS pups were stimulated in the same way as TS pups and then individually separated from their mother for 1 h/day. Their nontactile stimulated (NTS) siblings served as controls. In adulthood, TS and TS/MS rats showed better performance in two versions of the delayed alternation task and superior in vivo long-term potentiation of the hippocampo–prefrontal cortical pathway when compared with controls. Furthermore, there were more doses of A77636 (a selective dopamine D1 agonist) to significantly improve SWM performance in TS and TS/MS rats than in NTS rats, suggesting that activation of prefrontal D1 receptors in TS and TS/MS rats is more optimal for SWM function than in NTS rats. MS did not counteract TS-induced effects because no significant difference was found between TS/MS and TS animals. These data indicate that in early life, external tactile stimulation leads to long-term facilitative effects in SWM-related neural function.

Role of dopamine in prepulse inhibition of acoustic startle.

Prepulse inhibition of acoustic startle is the reduction in startle response to an intense auditory stimulus when this stimulus is immediately preceded by a weaker prestimulus. Prepulse inhibition occurs normally in humans and experimental animals, but schizophrenic persons often exhibit a marked impairment in this measure. Previous studies have shown that dopamine (DA)-dependent neuronal mechanisms are involved in the modulation of prepulse inhibition. Experiments were conducted in rats to elucidate further the involvement of DA-ergic mechanisms in prepulse inhibition. In line with previous studies, the indirect DA agonist, amphetamine, was shown to decrease prepulse inhibition. A close reverse relationship over time between DA overflow in the nucleus accumbens and prepulse inhibition was obtained using a technique allowing concomitant measurement of these parameters in awake, freely moving rats. This effect was more pronounced in amphetamine-treated rats compared to rats treated with equimolar doses of cocaine, which increased DA overflow without affecting prepulse inhibition. In other experiments, the combined treatment with subthreshold doses of the selective DA D1 agonist, SKF 38393, and the selective DA D2 agonist, quinpirole, was also shown to decrease prepulse inhibition. Finally, the selective DA D2 antagonist, raclopride, was shown to enhance prepulse inhibition. In line with previous studies, it is concluded that DA neurotransmission is involved in the modulation of prepulse inhibition and that the ventral part of the mesostriatal DA system may serve an important role in this modulation. Furthermore, the possibility is discussed that the discrepant results on prepulse inhibition obtained with amphetamine and cocaine may disclose functionally relevant differences in their mechanisms of action, and that the enhancement of prepulse inhibition induced by some antipsychotics in rats may reflect their propensity to induce adverse mental effects in humans.

An Efficient Enantioselective Synthesis of the D1 Agonist (5aR,11bS)-4,5,5a,6,7,11b-Hexahydro-2-propyl-3-thia- 5-azacyclopenta[c]phenanthrene-9,10-diol (A-86929).

(5aR,11bS)-4,5,5a,6,7,11b-Hexahydro-2-propyl-3-thia-5-azacyclopenta[c]phenanthrene-9,10-diol (A-86929, 1), a potent selective dopamine D1 agonist, was synthesized enantioselectively from D-aspartic acid. Key features of the 10-step synthesis are the following: (1) there is no chromatography required; (2) formation of 15 occurs in >99% ee; (3) the electrophilic cyclization to provide the desired trans stereochemisry in 18 is achieved with no loss of enantiomeric integrity.

The effect of dopamine D1 receptor stimulation on the up-regulation of histamine H3-receptors following destruction of the ascending dopaminergic neurones.

1. The binding of [3H]-(R)alpha-methylhistamine and [3H]-N alpha-methylhistamine to histamine H3-receptors, [3H]-SCH23390 to dopamine D1-receptors, and [3H]-YM09151-2 to dopamine D2-receptors was investigated by quantitative receptor autoradiography in the rat brain following 6-hydroxydopamine injection into the substantia nigra. 2. The levels of [3H]-(R)alpha-methylhistamine binding sites in the denervated striatum and substantia nigra were significantly higher than those in the contralateral side from 1 week to 12 weeks after nigral lesions. The H3-receptor binding was maximal at 3 weeks after nigral lesions and maintained until 12 weeks. 3. The increased number of histamine H3-receptors was decreased to the level of the contralateral side by chronic treatment with a selective dopamine D1 agonist, SKF38393, but not modified by a selective dopamine D2 agonist, quinpirole. 4. Dopamine D1- and D2-receptors in the striatum were similarly up-regulated after unilateral nigral lesion. On the other hand, the number of dopamine D2-receptors in the substantia nigra was markedly decreased after administration of 6-hydroxydopamine. 5. The treatment with (S)alpha-fluoromethylhistidine increased the H3-receptor binding in both the ipsilateral and contralateral sides. As a result, the magnitude of the ratio of the H3-receptor binding between ipsilateral and contralateral sides was partially attenuated by treatment with (S)-alpha-fluoromethylhistidine. 6. These results strongly suggest that the expression of histamine H3-receptors in the striatum and substantia nigra is influenced through D1-receptors by tonic nigrostriatal dopaminergic inputs.

(5aR,11bS)-4,5,5a,6,7,11b-Hexahydro-2-propyl-3-thia-5-azacyclopent-1-ena[c]phenanthrene-9,10-diol (A-86929): a potent and selective dopamine D1 agonist that maintain behavioral efficacy following repeated administration and characterization of its diacetyl prodrug (ABT-431)

(5aR,11bS)-4,5,5a,6,7,11b-Hexahydro-2-propyl-3-thia-5-azacyclopent-1-ena[c]phenanthrene-9,10-diol (A-86929): a potent and selective dopamine D1 agonist that maintain behavioral efficacy following repeated administration and characterization of its diacetyl prodrug (ABT-431)

The discriminative properties of the D1 dopamine agonist dihydrexidine in the rat.

The objective of this study was to train rats to discriminate the interoceptive stimuli produced by a selective dopamine D1 agonist. Fourteen male Sprague-Dawley rats acquired the discrimination of the fully effective, high potency, D1 agonist dihydrexidine (DHX) within 20 sessions using a training dose of 3.0 mg/kg. DHX (0.75-4.5 mg/kg) dose-dependently increased DHX-appropriate responding with an ED50 = 1.44 mg/kg. The selective D1 agonist SKF 38398 (2.0-8.0 mg/kg) dose-responsively generalized with an ED50 = 3.54 mg/kg; significantly less potent than DHX. The selective D1 antagonist SCH 23390 (0.06-0.12 mg/kg) dose-responsively decreased DHX-appropriate discriminative performance. These data would indicate that DHX is a selective D1 agonist that may allow for testing of the selectivity of other putative D1 agonists in this experimental procedure. Administration of non-selective dopaminergically active drugs, including apomorphine, amphetamine and cocaine, were each shown to produce intermediate DHX-appropriate discriminative performance.

In Vivo Evidence that Nonneuronal β‐Adrenoceptors as Well as Dopamine Receptors Contribute to Cyclic AMP Efflux in Rat Striatum

We applied in vivo microdialysis to assess the effects of dopaminergic and beta-adrenergic receptor stimulation on cyclic AMP efflux in rat striatum under chloral hydrate anesthesia. Dopamine (up to 1 mM) infused for 20 min through the probe did not increase cyclic AMP, whereas both the selective dopamine D1 agonist SKF 38393 and D2 antagonist sulpiride produced modest increases. It is interesting that the beta-adrenoceptor agonist isoproterenol produced a marked increase (204.7% of basal level at 1 mM) which was antagonized by the beta-adrenoceptor antagonist propranolol. Pretreatment with a glial selective metabolic inhibitor, fluorocitrate (1 mM), by a 5-h infusion through the probe attenuated basal cyclic AMP efflux by 30.3% and significantly blocked the response to isoproterenol. By contrast, striatal injection of a neurotoxin, kainic acid (2.5 micrograms), 2 days before the dialysis experiment did not affect basal cyclic AMP or the response to isoproterenol, but blocked the response to SKF 38393. These data demonstrate the beta-adrenoceptors as well as dopamine receptors contribute to cyclic AMP efflux in rat striatum in vivo. They also suggest that basal and beta-adrenoceptor-stimulated cyclic AMP efflux are substantially dependent on intact glial cells.

Structure-activity relationships in the trans-hexahydroindolo[4,3-ab]phenanthridine ("benzergoline") series. 2. Resolution, absolute configuration, and dopaminergic activity of the selective D1 agonist CY 208-243 and its implication for an "extended rotamer-based dopamine receptor model".

4,6,6a,7,8,12b-Hexahydroindolo[4,3-ab]phenanthridines ("benzergolines") was the first structural class of potent and selective dopamine D1 agonists lacking a catechol group. In order to determine the enantioselectivity of the 7-methyl derivative in the adenylate cyclase assay, its 5,5a-dihydro precursor was resolved and both enantiomers oxidized to the final products. The biological activity was found to reside entirely in the (-)-enantiomer, (-)-1 (CY 208-243). An X-ray study of its (-)-mandelic acid salt revealed a 6aR,12bR absolute configuration, which, in confirmation of the structure hypothesis, corresponds to that of the ergolines. Unexpectedly, an axial conformation of the N-methyl group was observed in the crystal structure. In contrast, subsequently analyzed crystals of the free base of (-)-1 revealed an equatorial conformation of the N-methyl group, which, we assume, represents the bioactive conformation. Based on the determined absolute configuration, (-)-1 could be oriented in a previously described "rotamer-based dopamine receptor model", which allowed the localization of a "subtype selectivity-inducing site" (aryl binding site at the D1 receptor, steric barrier at the D2 receptor), marked by the conformationally fixed "additional" phenyl group of the benzergoline molecule.