Aripiprazole and its human metabolite OPC14857 reduce, through a presynaptic mechanism, glutamate release in rat prefrontal cortex: Possible relevance to neuroprotective interventions in schizophrenia

Abstract

Aripiprazole is a novel atypical antipsychotic drug with neuroprotective properties. As excessive glutamate release is now considered to be part of the pathophysiology of schizophrenia, the objective of this study was to use an in vitro assay system to investigate the effect of aripiprazole and its human metabolite OPC14857 on the release of endogenous glutamate from isolated nerve terminals (synaptosomes), freshly prepared from rat prefrontal cortex. Both aripiprazole and OPC13857 potently inhibited 4-aminopyridine (4-AP)-evoked glutamate release in a concentration-dependent manner. Inhibition of glutamate release by aripiprazole and OPC13857 was associated with a reduction of 4AP-evoked Na+ influx and depolarization, as well as downstream elevation of cytoplasmic free calcium concentration mediated via N- and P/Q-type voltage-dependent Ca2+ channels (VDCCs). Release induced by direct Ca2+ entry with Ca2+ ionophore (ionomycin) was unaffected by aripiprazole or OPC13857, indicating that the inhibitory effect of aripiprazole or OPC13857 is not due to directly interfering with the release process at some point subsequent to Ca2+ influx. In addition, the dopamine D2 receptor antagonist haloperidol and the 5-HT 1A receptor antagonist WAY100635 all effectively blocked the aripiprazole or OPC13857-mediated inhibition of 4-AP-evoked glutamate release. Moreover, aripiprazole or OPC13857 modulation of 4-AP-evoked glutamate release appears to involve a protein kinase A (PKA) signaling cascade, insofar as pretreatment of synaptosomes with the PKA inhibitor H89 suppressed the inhibitory effect of aripiprazole or OPC13857. Together, these results suggest that aripiprazole and its human metabolite OPC14857 inhibit glutamate release from rat prefrontocortical nerve terminals, likely by the activation of dopamine D2 and 5-HT 1A receptors, which subsequently results in the reduction of nerve terminal excitability and downstream VDCC activation through a signaling cascade involving PKA. These actions of aripiprazole may contribute to its neuroprotective effect in excitotoxic injury.

Effects of aripiprazole, olanzapine, and haloperidol in a model of cognitive deficit of schizophrenia in rats: relationship with glutamate release in the medial prefrontal cortex

“…A pattern of effects in the 5-CSRTT similar to those seen here with aripiprazole was observed after intracortical injection of 8-OH-DPAT , which also suppressed the CPP-induced rise of extracellular GLU (Calcagno et al 2006). In addition, aripiprazole suppressed GLU release induced by the potassium channel blocker 4-aminopyridine in synaptosomes of the rat mPFC, and WAY100635 abolished this effect (Yang and Wang 2008).…”

Repeated aripiprazole administration attenuates cocaine seeking in a rat model of relapse

“…Despite evidence for 5-HT 2A antagonist reduction of cocaine seeking (Filip 2005; Fletcher et al 2002), 5-HT 2A receptor occupancy by aripiprazole does not exceed 50%, even at doses as high as 30 mg/kg, while D 2 receptor occupancy shows an ED 50 of 0.7 mg/kg (Natesan et al 2006). It would be premature to rule out a role for other receptor targets of aripiprazole, however, as some of the effects of aripiprazole on DA may involve interactions with 5-HT 1A receptors (Bortolozzi et al 2007), as well as modulation of glutamate activity in the prefrontal cortex (Yang and Wang 2008), a pathway well implicated in relapse (Kalivas et al 2005). …”

Neurobehavioral and genotoxic parameters of antipsychotic agent aripiprazole in mice

“…Another study has suggested that aripiprazole inhibits glutamate release from rat prefrontocortical nerve terminals, probably by the activation of dopamine D 2 and 5-HT 1A receptors, which subsequently results in the reduction in nerve terminal excitability and downstream activation of voltage-dependent Ca 2+ channels through a signaling cascade involving PKA. These actions of aripiprazole may contribute to its neuroprotective effect in excitotoxic injury [29] . In SH-SY5Y human neuroblastoma cells, aripiprazole increased the levels of brain-derived neurotrophic factor (BDNF)-mediated signaling, suggesting that aripiprazole offers neuroprotective effects on human neuronal cells [30] .…”