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Antagonism of the effects of (+)‐PD 128907 on midbrain dopamine neurones in rat brain slices by a selective D 2 receptor antagonist L‐741,626
Author(s) -
Bowery B.J.,
Razzaque Z.,
Emms F.,
Patel S.,
Freedman S.,
Bristow L.,
Kulagowski J.,
Seabrook G.R.
Publication year - 1996
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1996.tb16063.x
Subject(s) - ventral tegmental area , pars compacta , substantia nigra , dopamine , chemistry , agonist , striatum , endocrinology , medicine , dopamine receptor d2 , receptor , biology , biochemistry , dopaminergic
1 The ability of PD 128907 to activate dopamine receptors in the ventral tegmental area, substantia nigra pars compacta, and striatum was investigated by use of in vitro electrophysiological recording and fast cyclic voltammetry. The affinity of a novel D 2 selective antagonist L‐741,626 for receptors activated by this agonist was measured to determine if its effects were mediated by D 2 or D 3 receptors. 2 The active (+) enantiomer of PD 128907 bound with high affinity and selectivity to rat D 3 dopamine receptors. The K i values for (+)‐PD 128907 were 620 nM at D 2 , 1 nM at D 3 and 720 nM at D 4 receptors. 3 (+)‐PD 128907 inhibited cell firing in both the ventral tegmental area and substantia nigra pars compacta with EC 50 values of 33 nM (pEC 50 = 7.48 ± 0.10, n = 10) and 38 nM (pEC 50 = 7.42 ± 0.15, n = 5), respectively. No effects of (+)‐PD 128907 (100 nM) were observed on glutamate or GABA‐mediated synaptic potentials elicited by focal bipolar stimulation. 4 L‐741,626 antagonized these effects of (+)‐PD 128907 in a concentration‐dependent and surmountable manner with an affinity, determined from Schild analysis, of 20 nM (p K B = 7.71 ± 0.14) in the ventral tegmental area and 11 nM (p K B = 7.95 ± 0.18) in the substantia nigra pars compacta. 5 (+)‐PD 128907 also inhibited dopamine release in the caudate‐putamen with an EC 50 of 66 nM ( n = 5). The affinity of L‐741,626 for these nerve terminal autoreceptors (p K B = 7.71 ± 0.06; =20 nM) was identical to that observed on midbrain dopamine neurones. 6 These data demonstrate that the D 3 receptor ligand (+)‐PD 128907 is a potent agonist on rat midbrain dopamine neurones. However, its lack of regional selectivity, and the high affinity of the selective D 2 receptor antagonist L‐741,626 for receptors activated by (+)‐PD 128907, was more consistent with an action on D 2 autoreceptors rather than upon a D 3 dopamine receptor subtype.