The antipsychotic potential of l-stepholidine—a naturally occurring dopamine receptor D1 agonist and D2 antagonist

Natesan, Sridhar; Reckless, Greg E.; Barlow, Karen; Odontiadis, J.; Nóbrega, José N.; Baker, Glen B.; George, Susan R.; Mamo, David C.; Kapur, Shitij

doi:10.1007/s00213-008-1172-1

Cited by 51 publications

(37 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thus, we can argue that the suppression of locomotion by antipsychotics is specific to hyperactivity induced by MK-801 and is not a consequence of motor impairment due to ataxia/sedation. Although a comprehensive evaluation of antipsychotics in a single model has been lacking, the most commonly prescribed compounds (haloperidol, clozapine, olanzapine, risperidone, ziprasidone and aripiprazole) have been well characterised in several rodent models of positive symptoms of schizophrenia, including those that are based on locomotor hyperactivity induced by the NMDA receptor antagonists in rats and in mice (Castellani and Adams 1981;Kitaichi et al 1994;Maurel-Remy 1995;Ninan and Kulkarni 1999;Nilsson et al 1997;Natesan et al 2008;Leite et al 2008;Nordquist et al 2008). It should be noted, that unlike the present findings, effects of antipsychotics on locomotor hyperactivity from earlier reports are often confounded by non-specific reduction of spontaneous locomotor activity Andiné et al 1999;Zocci et al 2005;Nordquist et al 2008).…”

Section: Discussionmentioning

confidence: 99%

Validation and pharmacological characterisation of MK-801-induced locomotor hyperactivity in BALB/C mice as an assay for detection of novel antipsychotics

et al. 2010

View full text Add to dashboard Cite

show abstract

Section: Discussionmentioning

confidence: 99%

Validation and pharmacological characterisation of MK-801-induced locomotor hyperactivity in BALB/C mice as an assay for detection of novel antipsychotics

et al. 2010

View full text Add to dashboard Cite

show abstract

“…Compounds with mixed D1 agonist/D2 antagonist profiles have also been suggested as potential antipsychotics effective in treating a broader range of symptoms of schizophrenia (Natesan et al 2008), including negative symptoms (e.g. anhedonia, asociality, blunted affect) and/or cognitive disruptions, which are not well treated by current antipsychotic medications (Young et al 2012).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of phosphodiesterase 10A has differential effects on dopamine D1 and D2 receptor modulation of sensorimotor gating

et al. 2013

View full text Add to dashboard Cite

Rationale Inhibitors of phosphodiesterase 10A (PDE10A), an enzyme highly expressed in medium spiny neurons of the mammalian striatum, enhance activity in direct, dopamine D1 receptor-expressing and indirect, D2 receptor-expressing striatal output pathways. The ability of such agents to act to potentiate D1 receptor signaling while inhibiting D2 receptor signaling suggest that PDE10A inhibitors may have a unique antipsychotic-like behavioral profile differentiated from the D2 receptor antagonist-specific antipsychotics currently used in the treatment of schizophrenia. Objectives To evaluate the functional consequences of PDE10A inhibitor modulation of D1 and D2 receptor pathway signaling, we compared the effects of a PDE10A inhibitor (TP-10) on D1 and D2 receptor agonist-induced disruptions in prepulse inhibition (PPI), a measure of sensorimotor gating disrupted in patients with schizophrenia. Results Our results indicate that in rats: 1) PDE10A inhibition (TP-10, 0.32-10.0 mg/kg) has no effect on PPI disruption resulting from the mixed D1/D2 receptor agonist apomorphine (0.5 mg/kg), confirming previous report; 2) Yet, TP-10 blocked the PPI disruption induced by the D2 receptor agonist quinpirole (0.5 mg/kg); and attenuated apomorphine-induced disruptions in PPI in the presence of the D1 receptor antagonist SCH23390 (0.005 mg/kg). Conclusions These findings indicate that TP-10 cannot block dopamine agonist-induced deficits in PPI in the presence of D1 activation and suggest that the effect of PDE10A inhibition on D1 signaling may be counterproductive in some models of antipsychotic activity. These findings, and the contribution of TP-10 effects in the direct pathway on sensorimotor gating in particular, may have implications for the potential antipsychotic efficacy of PDE10A inhibitors.

show abstract

“…L-stepholidine, one such compound, has been the focus of interest as a putative antipsychotic because of its combined DA D2 antagonist/DAD1 agonist properties [124]. Interestingly, it was recently reported that l-stepholidine (0.1, 0.3 or 1 mg/kg) produced selective suppression of CAR in rats with a favorable EPS liability profile, as well as showing effects in an animal model of negative symptoms [125]. Striatal D2 and D1 receptor occupancy following l-stepholidine 1 mg/kg (estimated from D2 occupancy graphics by l-stepholidine in [125]) seems to be around 45-50 % and 12 %, respectively, and the ED50 dose in the CAR test was reported to be 0.27 mg/kg.…”

Section: Da D2 Antagonist/dad1 Agonist -L-stepholidinementioning

confidence: 99%

Conditioned Avoidance Response in the Development of New Antipsychotics

Wadenberg¹

2010

CPD

View full text Add to dashboard Cite

Schizophrenia presents with positive/psychotic, negative and cognitive symptoms. Positive symptoms seems due to a dopamine mesolimbic overreactivity, while negative/cognitive symptoms may conversely be due to mesocortical hypo-dopaminergia. Traditional dopamine D2 receptor blocking antipsychotics (e.g. haloperidol) are effective against psychotic/positive symptoms, but less so against negative/cognitive symptoms. Some D2 receptor blockage, however, seems necessary for efficacy against psychotic symptoms. Therefore, current antipsychotic drug improvement strategies include modest D2 receptor blockage, or partial D2 stimulation, combined with adjunct pharmacological properties that may enhance: i) D2 blockage efficacy; and ii) cognitive functioning. There are also strategies with no direct D2 blockage. Clinical activity is often tested in animal screening tests (so called animal models). The screening test conditioned avoidance response in rats has shown particular sensitivity, with high predictive validity, for detection of drug antipsychotic activity. The present review assessed the significance, accuracy and use of the conditioned avoidance response test as a screening tool in current antipsychotic drug development. It was found that: i) the conditioned avoidance response test holds a strong position, is frequently used in current antipsychotic drug development, and is commonly considered a reliable screening tool, with high predictive validity, for the detection of potential antipsychotic activity; ii) in current antipsychotic drug development, the conditioned avoidance response test is able to detect pharmacological properties contributing to antipsychotic activity in the presence of sub-therapeutic D2 receptor blockade, as well as detecting antipsychotic activity of compounds having no direct D2 blocking properties.

show abstract

The antipsychotic potential of l-stepholidine—a naturally occurring dopamine receptor D1 agonist and D2 antagonist

Cited by 51 publications

References 43 publications

Validation and pharmacological characterisation of MK-801-induced locomotor hyperactivity in BALB/C mice as an assay for detection of novel antipsychotics

Validation and pharmacological characterisation of MK-801-induced locomotor hyperactivity in BALB/C mice as an assay for detection of novel antipsychotics

Inhibition of phosphodiesterase 10A has differential effects on dopamine D1 and D2 receptor modulation of sensorimotor gating

Conditioned Avoidance Response in the Development of New Antipsychotics

Contact Info

Product

Resources

About