Stimulation of adenylate cyclase activity by benzazepine D-1 dopamine agonists with varying efficacies in the 6-hydroxydopamine lesioned rat—relationship to circling behaviour

doi:10.1016/0006-2952(95)00035-X

Biochemical Pharmacology

Volume 49, Issue 9, 11 May 1995, Pages 1185-1193

https://doi.org/10.1016/0006-2952(95)00035-X Get rights and content

Abstract

The ability of benzazepine D-1 dopamine agonists with varying efficacies in stimulating adenylate cyclase and to induce contralateral circling was investigated in rats with unilateral 6-hydroxydopamine lesions of the medial forebrain bundle. In the 6-hydroxydopamine lesioned rats, the benzazepines SKF 38393 (7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine), SKF 75670 (3-CH₃ analogue), SKF 80723 (6-Br analogue), SKF 83959 (6-Cl, 3-CH₃, 3′-CH₃ analogue), SKF 83565 (6-Cl, 3-CH₃, 3′-Cl analogue) and SKF 82958 (6-Cl, 3-C₃H₅ analogue), all produced contralateral circling. The rank order of efficacies (maximal effect, E_max) being, SKF 83565 = SKF 75670 = SKF 83959 = SKF 80723 > SKF 38393 ⪢ SKF 82958. In striatal slices from the intact hemisphere, dopamine, SKF 82958, SKF 80723 and SKF 75670 stimulated adenylate cyclase activity. The rank order of efficacies being SKF 82958 (109%) = dopamine (100%) = SKF 80723 (98%) > SKF 75670 (72%). Although, SKF 38393 (67%), SKF 83565 (64%) and SKF 83959 (59%) tended to stimulate adenylate cyclase activity, this effect did not reach statistical significance. In the 6-hydroxydopamine lesioned hemisphere, basal levels of adenylate cyclase activity were lower (−25%) than in the intact hemisphere. The maximal stimulation of adenylate cyclase activity (expressed as % basal levels) produced by dopamine and the benzazepines in the denervated striatum was greater than observed in the intact striatum. The rank order of efficacies in the dopamine denervated striatum being SKF 82958 (124%) > SKF 80723 (109%) = dopamine (100%) > SKF 38393 (82%) = SKF 83959 (77%) = SKF 83565 (70%) > SKF 75670 (55%). Moreover, dopamine stimulated adenylate cyclase activity in the denervated striatum with greater potency than in the intact side. The ability of the benzazepine derivatives to induce circling in the 6-hydroxydopamine lesioned rat is consistent with the general increase in the efficacies of dopamine and benzazepine stimulated adenylate cyclase activity in the dopamine denervated striatum. However, the maximal effects for inducing circling and stimulating adenylate cyclase activity do not correspond (e.g. SKF 82958 and SKF 75670). This discrepancy may reflect the involvement of other factors including a behavioural role for extrastriatal D-1 dopamine receptors and/or transduction systems other than adenylate cyclase.

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Intriguingly, in contrast to the classic cAMP-dependent signal transduction of the D1R, a study has indicated that D1R agonists do not stimulate adenylate cyclase in homogenates of the amygdaloid complex, suggesting that D1Rs in the amygdala may not be coupled to cAMP (Leonard et al., 2003). In the past two and a half decades, a D1-like receptor-dependent PI signal pathway involving activation of the Gq protein has been proposed by pharmacological evidence with an atypical D1R agonist (Andersen and Jansen, 1990; Sahu et al., 2009) that can penetrate the brain-blood barrier (Gnanalingham et al., 1995), SKF83959 (3-methyl-6-chloro-7, 8-hydroxy-1- (3-methylphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine). SKF83959 exerts various biological functions via D1-like receptor-dependent PI signaling (Andersen and Jansen, 1990; Sahu et al., 2009), such as neuroprotection (Yu et al., 2008), promotion of spontaneous glutamate release (Chu et al., 2010), modulation of Ca2+ signals (Ming et al., 2006) and antidepressant effects (Jiang et al., 2014).
Fear-related anxiety disorders, such as social phobia and post-traumatic stress disorder, are partly explained by an uncontrollable state of fear. An emerging literature suggests dopamine receptor-1 (D₁ receptor) in the amygdala is involved in the regulation of fear memory. An early study has reported that amygdaloid D₁ receptor (D₁R) is not coupled to the classic cAMP-dependent signal transduction. Here, we investigated whether SKF83959, a typical D₁R agonist that mainly activates a D₁-like receptor-dependent phosphatidylinositol (PI) signal pathway, facilitates fear extinction and reduces the return of extinguished fear. Interestingly, long-term loss of fearful memories can be induced through a combination of SKF83959 (1 mg/kg/day, i.p., once daily for one week) pharmacotherapy and extinction training. Furthermore, sub-chronic administration of SKF83959 after fear conditioning reduced fear renewal and reinstatement in the mice. We found that the activation D₁R and PI signaling in the amygdala was responsible for the effect of SKF83959 on fear extinction. Additionally, SKF83959 significantly promoted the elevation of brain-derived neurotrophic factor (BDNF) expression, possibly by the cAMP response element binding protein (CREB) -directed gene transcription. Given the beneficial effects on extinction, SKF83959 may emerge as a candidate pharmacological approach for improving cognitive-behavioral therapy on fear-related anxiety disorders.
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If a D1 agonist with high bias for different D1-mediated signaling pathways were available, it would be a useful research tool that also might overcome some of the possible limitations associated with current D1 agonists. SKF-83959 is purported to be such a ligand, highly-biased towards D1 stimulation of phosphoinositide hydrolysis (via a D1-GαQ mechanism), but with no intrinsic activity at GαOLF/S mechanisms that stimulate adenylate cyclase (Undie and Friedman, 1992; Undie et al., 1994; Gnanalingham et al., 1995b; Arnt et al., 1992). The literature is consistent with our finding that SKF-83959 has nanomolar affinity for the dopamine D1 receptor in rat brain and the human D1 receptor expressed heterologously (Table 1), and micromolar affinity for the cloned D2L and rat brain D2-like receptor.
SKF-83959 [6-chloro-7,8-dihydroxy-3-methyl-1-(3-methylphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine] is reported to be a functionally selective dopamine D₁ receptor ligand with high bias for D₁-mediated phospholipase C (PLC) versus D₁-coupled adenylate cyclase signaling. This signaling bias is proposed to explain behavioral activity in both rat and primate Parkinson's disease models, and a D₁-D₂ heterodimer has been proposed as the underlying mechanism. We have conducted an in-depth pharmacological characterization of this compound in dopamine D₁ and D₂ receptors in both rat brain and heterologous systems expressing human D₁ or D₂ receptors. Contrary to common assumptions, SKF-83959 is similar to the classical, well-characterized partial agonist SKF38393 in all systems. It is a partial agonist (not an antagonist) at adenylate cyclase in vitro and ex vivo, and is a partial agonist in D₁-mediated β-arrestin recruitment. Contrary to earlier reports, it does not have D₁-mediated effects on PLC signaling in heterologous systems. Because drug metabolites can also contribute, its 3-N-demethylated analog also was synthesized and tested. As expected from the known structure-activity relationships of the benzazepines, this compound also had high affinity for the D₁ receptor and somewhat higher intrinsic activity than the parent ligand, and also might contribute to in vivo effects of SKF-83959. Together, these data demonstrate that SKF-83959 is not a highly-biased functionally selective D₁ ligand, and that its reported behavioral data can be explained solely by its partial D₁ agonism in canonical signaling pathway(s). Mechanisms that have been proposed based on the purported signaling novelty of SKF-83959 at PLC should be reconsidered.
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Dopamine D₁-like receptors consisting of D₁ and D₅ subtypes are intimately implicated in dopaminergic regulation of fundamental neurophysiologic processes such as mood, motivation, cognitive function, and motor activity. Upon stimulation, D₁-like receptors initiate signal transduction cascades that are mediated through adenylyl cyclase or phosphoinositide metabolism, with subsequent enhancement of multiple downstream kinase cascades. The latter actions propagate and further amplify the receptor signals, thus predisposing D₁-like receptors to multifaceted interactions with various other mediators and receptor systems. The adenylyl cyclase response to dopamine or selective D₁-like receptor agonists is reliably associated with the D₁ subtype, while emerging evidence indicates that the phosphoinositide responses in native brain tissues may be preferentially mediated through stimulation of the D₅ receptor. Besides classic coupling of each receptor subtype to specific G proteins, additional biophysical models are advanced in attempts to account for differential subcellular distribution, heteromolecular oligomerization, and activity-dependent selectivity of the receptors. It is expected that significant advances in understanding of dopamine neurobiology will emerge from current and anticipated studies directed at uncovering the molecular mechanisms of D₅ coupling to phosphoinositide signaling, the structural features that might enhance pharmacological selectivity for D₅ versus D₁ subtypes, the mechanism by which dopamine may modulate phosphoinositide synthesis, the contributions of the various responsive signal mediators to D₁ or D₅ interactions with D₂-like receptors, and the spectrum of dopaminergic functions that may be attributed to each receptor subtype and signaling pathway.
Chronic SKF83959 induced less severe dyskinesia and attenuated L-DOPA-induced dyskinesia in 6-OHDA-lesioned rat model of Parkinson's disease
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SKF83959, a recently identified selective agonist of putative phosphoinositide-linked (PI-linked) D₁ dopamine (DA) receptor, is found to elicit excellent anti-parkinsonism effects in monkeys and rodents. In the present study, the effects of SKF83959 on l-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia (LID) were assessed in a unilateral 6-hydroxydopamine (6-OHDA) lesioned rat model of Parkinson's disease (PD). The results indicated that chronic L-DOPA (6 mg/kg) induced a progressive dyskinesia-like behavior in PD rats, whereas SKF83959 (0.5 mg/kg) elicited significantly less severe dyskinesia while exerts its anti-parkinsonian action effectively. Application of D₁ receptor, but not D₂, α or 5-HT receptor antagonist attenuated SKF83959-induced dyskinesia, indicating that a D₁ receptor-mediated events, assumedly via PI-linked D₁ receptor. Interestingly, chronic co-administration of SKF83959 significantly reduced LID at no expanse of reduction in the anti-parkinsonian potency in PD rats. However, this anti-dyskinesia effect was not observed while SKF83959 was acutely administered in rats with established LID. This implies that chronic SKF83959 attenuated the development of dyskinesia. Immediate early gene FosB is previously reported to positively associate with dyskinesia. However, we found that the anti-dyskinesia effect of chronic SKF83959 was independent of FosB since SKF83959 produced stronger FosB expression in the lesioned striatum than that of L-DOPA while exerting its anti-dyskinesia action. The present data demonstrated that SKF83959 reduces LID by attenuating the development of dyskinesia; the underlying signaling pathway for the anti-dyskinesia action of SKF83959 appears not to depend on FosB.
Behavioral effects of the R-(+)- and S-(-)-enantiomers of the dopamine D<inf>1</inf>-like partial receptor agonist SKF 83959 in monkeys
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Dopamine D₁-like partial receptor agonists such as SKF 83959 have been proposed as potential candidates for the treatment of cocaine addiction. The present studies were conducted to further characterize SKF 83959 by pharmacologically evaluating effects of its R-(+)- and S-(−)-enantiomers, MCL 202 and MCL 201, respectively, on overt behavior (eye blinking) and schedule-controlled performance in squirrel monkeys. MCL 202, like the D₁ full receptor agonist SKF 82958, produced dose-related increases in eye blinking and decreases in rates of fixed-ratio responding. However, the magnitude of effects of MCL 202 on eye blinking was less than observed with SKF 82958. In contrast to the effects of its R-(+) enantiomer, MCL 201 was relatively devoid of behavioral activity up to doses that were approximately 10-fold greater than MCL 202. Pretreatment with the selective D₁-like receptor antagonist SCH 39166 dose-dependently antagonized increases in eye blinking produced by MCL 202, confirming the involvement of D₁ mechanisms in its effects. A dose-ratio analysis of the antagonism of effects of MCL 202 by SCH 39166 revealed an apparent pA₂ value of 7.675 with a slope of − 0.78 ± 0.04. In further studies, pretreatment with MCL 202 antagonized the effects of SKF 82958 on eye blinking and, like SCH 39166, schedule-controlled behavior in a dose-related manner. A dose-ratio analysis of the antagonist effects of MCL 202 on the SKF 82958-induced increases in eye blinking revealed ratios of 2.7, 4.8 and 31.1 for 0.1, 0.3 and 1.0 mg/kg dose of the antagonist, respectively, indicative of a significant change in the potency of SKF 82958. These results suggest that MCL 202, like its parent compound SKF 83959, has both D₁ receptor-mediated agonist and antagonist properties, consistent with its characterization as a partial agonist at the D₁-like receptor. In addition, the inactivity of MCL 201, the S-(−)-enantiomer, suggests that the behavioral effects of SKF 83959 can be attributed primarily to the activity of its R-(+)-enantiomer.
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Research paperStimulation of adenylate cyclase activity by benzazepine D-1 dopamine agonists with varying efficacies in the 6-hydroxydopamine lesioned rat—relationship to circling behaviour

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Research paper
Stimulation of adenylate cyclase activity by benzazepine D-1 dopamine agonists with varying efficacies in the 6-hydroxydopamine lesioned rat—relationship to circling behaviour