Effects of (−)-OSU6162 and ACR16 on motor activity in rats, indicating a unique mechanism of dopaminergic stabilization

Abstract

Dopaminergic stabilizers can be defined as drugs that stimulate or inhibit dopaminergic signalling depending on the dopaminergic tone. (-)-OSU6162 and ACR16 appear to possess such a profile. They have been proposed to act as partial dopamine receptor agonists or as antagonists with preferential action on dopaminergic autoreceptors. Previous studies have shown either stimulation or inhibition of behaviour in response to (-)-OSU6162 and ACR16, which has been suggested to reflect their dual effects on dopaminergic signalling. The aims of the present work are to (1) examine the relation between behavioural response to these drugs and activity baseline, and (2) test the suggested mechanisms of action by means of close comparisons with the known partial D2-receptor agonists (-)-3-PPP and aripiprazole, and the D2 autoreceptor preferring antagonist amisulpride with respect to effects on behaviour. From the results of these experiments it can be concluded that: (1) The direction of the response to (-)-OSU6162 and ACR16 is dependent on activity baseline, which in turn, under physiological conditions, is determined primarily by test arena size of and degree of habituation to the environment. (2) The effects of (-)-OSU6162 and ACR16 cannot be explained on the basis of either partial dopamine receptor agonism or preferential dopamine autoreceptor antagonism. Nevertheless, the current data suggest at least two different D2-receptor-associated targets which mediate opposite effects on activity. This result fits in with a mechanism proposed from a recent in vitro study, according to which (-)-OSU6162 has a dual action on dopamine D2 receptors, (a) an allosteric effect causing an enhanced response to dopamine, and (b) the previously proposed orthosteric effect antagonizing the action of dopamine.

The Tetrahydroisoquinoline Derivative SB269,652 Is an Allosteric Antagonist at Dopamine D3 and D2 Receptors

“…Two recently developed compounds, (Ϫ)-OSU6162 and ACR16, were also suggested to act allosterically at D 2 receptors, although data were complex and supporting evidence limited (Tamminga and Carlsson, 2002;Rung et al, 2008). The stimulation of dopamine-induced […”

“…More recently, the distinctive in vivo profiles of (3S)-3-[3-(methylsulfonyl)phenyl]-1-propylpiperidine hydrochloride [(Ϫ)-OSU6162] and ACR16 (pridopidine) were suggested to involve allosteric actions at D 2 receptors, although supporting data are limited (Tamminga and Carlsson, 2002;Rung et al, 2008). In general, allosteric modulators are well tolerated and can fine-tune pharmacological responses to endogenous neurotransmitters and exogenous agents, underpinning interest in their clinical application either alone or as adjunctive treatments (Christopoulos and Kenakin, 2002;May et al, 2007).…”

“…In general, allosteric modulators are well tolerated and can fine-tune pharmacological responses to endogenous neurotransmitters and exogenous agents, underpinning interest in their clinical application either alone or as adjunctive treatments (Christopoulos and Kenakin, 2002;May et al, 2007). Accordingly, (Ϫ)-OSU6162 displayed antipsychotic-like properties in rats in the absence of extrapyramidal motor effects and with little induction of dyskinesia (Tamminga and Carlsson, 2002;Natesan et al, 2006;Rung et al, 2008), and PLG potentiated the induction of contralateral rotation by L-DOPA in unilateral 6-hydroxydopamine lesioned rats without exacerbating the induction of dyskinesia (Ott et al, 1996). These observations support the notion that, in addition to orthosteric agents, positive and negative allosteric modulators at D 2 and/or D 3 receptors could be therapeutically useful agents, used either alone or as adjunctive therapy.…”

Dopamine and Alcohol Dependence: From Bench to Clinic

“…The mechanism of action is, however, not completely understood, and although in vitro studies indicate that OSU6162, like aripiprazole, acts as a partial agonist at D2 receptors [191,192], behavioural studies have failed to demonstrate any intrinsic activity of the compound ( [195]). Instead it has been suggested that OSU6162 produces functionally opposite effects by acting as an antagonist at both presynaptic autoreceptors and postsynaptic D2 receptors [189,[193][194][195]. Based on the hypothesis that OSU6162 can counteract both hyper-and hypo-dopaminergic states, the compound has recently been evaluated in both animal models modulating alcohol-mediated behaviours as well as in a placebo-controlled human laboratory study in alcohol-dependent patients.…”

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

“…In addition, we have shown that corresponding doses of OSU6162 and ACR16, apart from stimulating inactive rats, inhibit activity in drug-naive active rats studied in a stimulating environment. Therefore, we have suggested that these drugs have stabilizing effects on dopaminergic tone (Rung et al 2005(Rung et al , 2008.…”