The dopaminergic stabilizers (−)-OSU6162 and ACR16 reverse (+)-MK-801-induced social withdrawal in rats

Rung, Johan P.; Carlsson, Arvid; Markinhuhta, Katarina Rydén; Carlsson, Maria

doi:10.1016/j.pnpbp.2005.03.003

Cited by 42 publications

(29 citation statements)

References 26 publications

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“…First, pridopidine exhibits certain effects not typical of D2R antagonists, such as procognitive and prosocial effects (41). Second, pridopidine treatment does not elicit certain behaviors expected of D2R antagonists, such as catalepsy (42).…”

Section: Discussionmentioning

confidence: 99%

Early pridopidine treatment improves behavioral and transcriptional deficits in YAC128 Huntington disease mice

et al. 2017

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Section: Discussionmentioning

confidence: 99%

Early pridopidine treatment improves behavioral and transcriptional deficits in YAC128 Huntington disease mice

et al. 2017

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“…Recently, a mechanism by which these compounds exert their stabilizing properties based on differences in extrasynaptic versus synaptic dopamine neurotransmission has been proposed (Carlsson and Carlsson, 2006). In addition, a recent study of these compounds showed reversal of (ϩ)-MK-801-induced behavioral impoverishment in mice and social withdrawal in rats Rung et al, 2005). This suggests that the compounds may possess activity against negative symptoms, including social withdrawal.…”

Section: Pharmacology Of Dopamine Stabilizers 815mentioning

confidence: 91%

“…Thus, optimal treatment for these conditions may not rely solely on dopamine blockade but may also include a dopamine tone-dependent modulation or "stabilization" of the dopaminergic system. There is now a class of drugs that has been suggested to possess such properties, exemplified by (Ϫ)-OSU6162 and ACR16 (Sonesson et al, 1994;Ekesbo et al, 1997;Tedroff et al, 1998;Nichols et al, 2002;Carlsson et al, 2004;Nilsson et al, 2004;Rung et al, 2005). These compounds are reported to lack high in vitro affinity for various neuroreceptors.…”

mentioning

confidence: 99%

The Dopamine Stabilizers (S)-(-)-(3-Methanesulfonyl-phenyl)-1-propyl-piperidine [(-)-OSU6162] and 4-(3-Methanesulfonylphenyl)-1-propyl-piperidine (ACR16) Show High in Vivo D₂Receptor Occupancy, Antipsychotic-Like Efficacy, and Low Potential for Motor Side Effects in the Rat

Natesan¹,

Svensson²,

Reckless³

et al. 2006

J Pharmacol Exp Ther

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Hence, we evaluated in vivo D 2 occupancy of these agents in rats and correlated it to observed effects in a series of behavioral, neurochemical, and endocrine models relevant to the dopamine system and antipsychotic effect. Both (Ϫ)-OSU6162 and ACR16 showed robust dose-dependent striatal D 2 occupancy with ED 50 values of 5.27 and 18.99 mg/kg s.c., respectively, and functional assays showed no partial agonism. Over an occupancy range of 37 to 87% (3-60 mg/kg) for (Ϫ)-OSU6162 and 35 to 74% (10 -60 mg/kg) for ACR16, we observed both inhibitory (amphetamine-induced locomotor activity) and stimulatory effects (in habituated rats). Haloperidol, over a similar occupancy range (33-78%), potently inhibited psychostimulant activity and induced catalepsy, but it failed to activate habituated animals. In the conditioned avoidance response assay, ACR16 was clearly more efficacious than (Ϫ)-OSU6162. In addition, both these compounds demonstrated significant preferential Fos induction in the nucleus accumbens compared with the dorsolateral striatum, a strong predictor of atypical antipsychotic efficacy. The results suggest that dopamine stabilizers exhibit locomotor stabilizing as well as antipsychoticlike effects, with low motor side effect liability, in a dose range that corresponds to high D 2 in vivo occupancy.

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“…It has been demonstrated that mice with reduced NMDA receptor expression avoided contacts with cage mates as well as with unfamiliar mice (Duncan et al, 2004;Mohn et al, 1999). Furthermore, atypical antipsychotic drugs, which are the most effective currently available medications in treating the negative symptoms in schizophrenic patients, have been shown to improve the social deficits displayed by either the NMDA receptor knockdown mice or NMDA receptor antagonist-treated animals (Becker and Grecksch, 2004;Mohn et al, 1999;Rung et al, 2005b;SamsDodd, 1996SamsDodd, , 1997.…”

Section: Introductionmentioning

confidence: 99%

The Selective mGlu5 Receptor Antagonist MTEP, Similar to NMDA Receptor Antagonists, Induces Social Isolation in Rats

Koroś

Rosenbrock

Birk

et al. 2006

Neuropsychopharmacol

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It has repeatedly been shown that uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists can mimic certain aspects of positive and negative symptoms of schizophrenia in human volunteers and laboratory animals. The purpose of the present study was to expand these findings and to determine whether the selective metabotropic glutamate receptor subtype 5 (mGluR5) antagonist, MTEP (3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine), could induce similar effects in Wistar rats. First, MTEP (1.0-10.0 mg/kg; intraperitoneally) after acute and subchronic (daily for 5 days) administration as well as the uncompetitive antagonists of the NMDA receptor of either high affinity, phencyclidine (0.5-4.0 mg/kg; subcutaneously (s.c.)) and ( + )-MK-801 (0.03-0.25 mg/kg; s.c.), or low-moderate affinity, ketamine (2.0-16.0 mg/kg; s.c.) and memantine (0.15-20.0 mg/kg; s.c.), following daily administration for 3 days were tested in the social interaction test to determine their ability to reproduce the negative and positive symptoms measured by social isolation and stereotyped behavior, respectively. Second, the compounds were tested in the motility test following acute administration to determine their ability to induce locomotor hyperactivity reflecting the positive symptoms. In line with previous findings, all examined NMDA receptor antagonists produced social interaction deficits, locomotor hyperactivity, and stereotypy except memantine. Notably, this study found that MTEP following both acute and subchronic administration dose-dependently induced social isolation, but did not cause either locomotor hyperactivity or stereotypy. These data demonstrate that social behavior deficits in rats can be caused by both the blockade of the NMDA receptor and the inhibition of mGluR5, whereas mGluR5 antagonists may not independently be able to mimic the positive symptoms.

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The dopaminergic stabilizers (−)-OSU6162 and ACR16 reverse (+)-MK-801-induced social withdrawal in rats

Cited by 42 publications

References 26 publications

Early pridopidine treatment improves behavioral and transcriptional deficits in YAC128 Huntington disease mice

Early pridopidine treatment improves behavioral and transcriptional deficits in YAC128 Huntington disease mice

The Dopamine Stabilizers (S)-(-)-(3-Methanesulfonyl-phenyl)-1-propyl-piperidine [(-)-OSU6162] and 4-(3-Methanesulfonylphenyl)-1-propyl-piperidine (ACR16) Show High in Vivo D₂Receptor Occupancy, Antipsychotic-Like Efficacy, and Low Potential for Motor Side Effects in the Rat

The Selective mGlu5 Receptor Antagonist MTEP, Similar to NMDA Receptor Antagonists, Induces Social Isolation in Rats

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The dopaminergic stabilizers (−)-OSU6162 and ACR16 reverse (+)-MK-801-induced social withdrawal in rats

Cited by 42 publications

References 26 publications

Early pridopidine treatment improves behavioral and transcriptional deficits in YAC128 Huntington disease mice

Early pridopidine treatment improves behavioral and transcriptional deficits in YAC128 Huntington disease mice

The Dopamine Stabilizers (S)-(-)-(3-Methanesulfonyl-phenyl)-1-propyl-piperidine [(-)-OSU6162] and 4-(3-Methanesulfonylphenyl)-1-propyl-piperidine (ACR16) Show High in Vivo D2Receptor Occupancy, Antipsychotic-Like Efficacy, and Low Potential for Motor Side Effects in the Rat

The Selective mGlu5 Receptor Antagonist MTEP, Similar to NMDA Receptor Antagonists, Induces Social Isolation in Rats

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The Dopamine Stabilizers (S)-(-)-(3-Methanesulfonyl-phenyl)-1-propyl-piperidine [(-)-OSU6162] and 4-(3-Methanesulfonylphenyl)-1-propyl-piperidine (ACR16) Show High in Vivo D₂Receptor Occupancy, Antipsychotic-Like Efficacy, and Low Potential for Motor Side Effects in the Rat