Antagonist properties of LY 165,163 at pre- and postsynaptic dopamine D2, D3 and D1 receptors: modulation of agonist actions at 5-HT1A receptors in vivo.
In this study, we examined the influence of the actions of the halogenated phenylpiperazine LY 165,163 at dopamine D1, D2 and D3 receptors on its 5-HT1A agonist properties in vivo. LY 165,163 displayed marked affinity at striatal rat (r)D2 (pKi = 7.0), cloned rD2 (pKi = 7.3), cloned rD3 (pKi = 8.0), cloned human (h)D2 (pKi = 7.2) and cloned hD3 (pKi = 7.8) receptors, whereas its affinity at striatal rD1 receptors was weak (pKi = 5.7). In contrast, the prototypical 5-HT1A agonist 8-OH-DPAT displayed low affinity at each of these sites (pKi < 5.5). In vivo, LY 165,163 behaved as an antagonist at D2 autoreceptors in enhancing the synthesis of dopamine throughout the brain. Consistently with antagonist properties at postsynaptic D2 receptors, in unilateral substantia nigra-lesioned rats, the rotation elicited by the D2 agonist quinpirole was potently blocked by LY 165,163, whereas that elicited by the D1 agonist SKF 38393 was only weakly inhibited. In addition, LY 165,163 potently evoked prolactin secretion in rats and abolished apomorphine-induced climbing in mice. At native rat 5-HT1A receptors and cloned human 5-HT1A receptors, LY 165,163 (pKi values of 8.7 and 8.9, respectively) mimicked the high affinity of 8-OH-DPAT (pKi values of 9.0 and 9.2). Further, like 8-OH-DPAT, LY 165,163 acted as an agonist in inhibiting the firing of dorsal raphé nucleus neurons, in reducing striatal turnover of 5-HT and in eliciting both hypothermia and corticosterone secretion. However, in contrast to 8-OH-DPAT, LY 165,163 failed to evoke spontaneous tail-flicks (STFs). This difference probably reflects its D2 antagonist properties because the induction of STFs by 8-OH-DPAT was, in contrast to its induction of hypothermia and corticosterone secretion, blocked by the preferential D2 antagonist haloperidol. Moreover, in the presence of quinpirole and in the presence of a further dopaminergic agonist, apomorphine, LY 165,163 did elicit STFs. Further, STFs evoked by LY 165,163 in the presence of apomorphine were abolished by the 5-HT1A antagonists (-)-alprenolol, BMY 7378 and NAN-190. We conclude that LY 165,163 exhibits marked activity at both pre- and postsynaptic dopaminergic D2 (D3 and D1) receptors.(ABSTRACT TRUNCATED AT 400 WORDS)
Millan
M J
MJ
Institut de Recherches Servier, Psychopharmacology Department, Croissy-sur-Seine, France.
Rivet
J M
JM
Audinot
V
V
Gobert
A
A
Lejeune
F
F
Brocco
M
M
Newman-Tancredi
A
A
Maurel-Remy
S
S
Bervoets
K
K
D000818:Animals; D003345:Corticosterone / Q000494:pharmacology; D018491:Dopamine Agonists / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology*; D006220:Haloperidol / Q000494:pharmacology; D006801:Humans; D008297:Male; D010879:Piperazines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011954:Receptors, Dopamine / Q000187:drug effects / Q000378:metabolism; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D013569:Synapses / Q000187:drug effects* / Q000378:metabolism
D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D010879:Piperazines; D011954:Receptors, Dopamine; D011985:Receptors, Serotonin; D011994:Recombinant Proteins; D017366:Serotonin Receptor Agonists; C044643:LY 165163; D006220:Haloperidol; D003345:Corticosterone