ISSN:
1432-1912
Keywords:
Dopamine
;
Autoreceptor
;
Agonists
;
D2 receptor
;
Cloned receptor
Source:
Springer Online Journal Archives 1860-2000
Topics:
Medicine
Notes:
Summary The biochemical, endocrine, receptor binding, and behavioral effects of the putative dopamine autoreceptor agonist, U-86170F, were evaluated in various in vivo and in vitro models. U-86170F and apomorphine were shown to cause a significant reversal of the effects of γ-butyrolactone (GBL) on dopamine accumulation in mouse striata. In contrast to apomorphine, U-86170F had a ceiling effect on the extent of the reversal of GBL effects (55%), whereas apomorphine had an 82% reversal. The effect on striatal homovanillic acid (HVA) levels was also monitored, and both compounds exerted a similar and significant reduction in striatal HVA. A comparison was made between the effects of intraperitoneal (i.p.) and oral administration of U-86170F in the α-methyl-p-tyrosine (α-MPT)/prolactin model in rats. When administered by the i.p. route, U-86170F suppressed the effects of α-MPT on prolactin level increase, having an ED50 of about 0.03 mg/kg, and when administered by the oral route, its ED50 was approximately 0.1 mg/kg. U-86170F has been shown to be a potent dopamine autoreceptor agonist in the GBL, prolactin, and HVA models, with an effective i.p. dose of approximately 0.03 mg/kg. When evaluated for postsynaptic dopaminergic activity in the reserpinized mouse model, and compared to apomorphine, U-86170F was found to increase locomotor activity, but its maximum effect was only 65% of that attained with apomorphine. Higher doses were needed for postsynaptic effects. In receptor binding studies using cloned D2 receptor preparations, U-86170F was found to exhibit agonist binding properties similar to dopamine as demonstrated by their inhibition of 3H-raclopride binding. Both compounds exhibited biphasic inhibition curves, with U-86170F having Ki values of 7.5 nM and 250 nM, and for dopamine the Ki values were 34.7 nM and 1031 nM. Binding studies conducted in the presence of GTP yielded only one site with Kis of 289 nM and 670 nM, for both U-86170F and dopamine, respectively. The results presented in this report demonstrated that U-86170F is a potent dopamine autoreceptor agonist, with limited activity at the postsynaptic receptor.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1007/BF00170644
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