Effects of the dopamine stabilizers (S)-(-)-OSU6162 and ACR16 on prolactin secretion in drug-naive and monoamine-depleted rats

Abstract

Dopaminergic stabilizers may be conceptualized as drugs with normalizing effects on dopamine-mediated behaviours and neurochemical events. (S)-(-)-OSU6162 (OSU6162) and ACR16 are two structurally related compounds ascribed such properties, principally because of their stabilizing effects on motor activity in rodents. Reports in the literature indicate possible partial D2 receptor agonist effects using various in vitro systems. This study aimed to measure D2 receptor antagonist and agonist effects of OSU6162 and ACR16 in vivo. To address this, we have studied the effects of both compounds on prolactin secretion in drug-naive and dopamine-depleted rats; dopamine depletion was induced by pretreatment with reserpine plus α-methyl-DL: -p-tyrosine. We find that OSU6162 and ACR16 both stimulate prolactin secretion in drug-naive rats with OSU6162 being considerably more potent and efficacious. Both compounds show a non-significant trend towards reversal of the increased secretion caused by dopamine depletion, whereas the D2 receptor antagonist haloperidol further increased prolactin secretion. Thus, this study suggests that OSU6162 and ACR16 act as D2 receptor antagonists under normal conditions in vivo, possibly with minor agonist effects in a state of dopamine depletion.

The effect of taxifolin on oxidative ovarian damage and reproductive dysfunctions induced by antipsychotic drugs in female rats

“…These adverse effects limit the use of TAPs in treatment 2 . For this reason, less toxic and prolactin‐sparing atypical antipsychotic (AAP) drugs such as clozapine (CLN) have been developed 4 . However, these prolactin‐sparing drugs have been found to cause reproductive dysfunction at the same level of TAPs, which induce hyperprolactinemia in women 5 .…”

The Dopamine Stabilizer (−)-OSU6162 Occupies a Subpopulation of Striatal Dopamine D2/D3 Receptors: An [11C]Raclopride PET Study in Healthy Human Subjects

“…In vitro, the compound shows moderate (micromolar) affinity for D2/D3 receptors with very low intrinsic activity (Burstein et al, 2011). In vivo, however, it appears to be an antagonist devoid of intrinsic activity over a wide range of doses (Carlsson et al, 2011;Rung et al, 2011). Evidence in humans of a dopamine D2 antagonistic action of ( À )-OSU6162, at the level of the pituitary, was demonstrated indirectly by a dose-dependent elevation in serum prolactin (Rodriguez et al, 2004).…”

The effects of the dopamine stabilizer (−)-OSU6162 on aggressive and sexual behavior in rodents

“…Although the mechanisms underlying the unique profile of (−)-OSU61612 remains to be clarified, one explanation might be that it is a D2 antagonist with fast dissociation properties acting predominantly on extrasynaptic D2 receptors, including both D2 receptors serving as autoreceptors, brain D2 receptors situated extrasynaptically at non-dopaminergic neurons and prolactin-regulating D2 receptors in the pituitary. 11 , 14 , 17 In line with this, PET studies suggest (−)-OSU61612 to antagonize only a subset of D2 receptors in the human striatum. 18 Other mechanisms may, however, also be of importance for its unique behavioral profile, such as an alleged allosteric influence on the D2 receptor; the literature on this possibility is, however, conflicting.…”