Unexpected inhibitory regulation of glutamate release from rat cerebrocortical nerve terminals by presynaptic 5‐hydroxytryptamine‐2A receptors

Abstract

Presynaptic 5-HT(2A) receptor modulation of glutamate release from rat cerebrocortical nerve terminals (synaptosomes) was investigated by using the 5-HT(2A/2C) receptor agonist (+/-)-1-[2,5-dimethoxy-4-iodophenyl]-2-aminopropane (DOI). DOI potently inhibited 4-aminopyridine (4AP)-evoked glutamate release. Involvement of presynaptic 5-HT(2A) receptors in this modulation of 4AP-evoked release was confirmed by blockade of the DOI-mediated inhibition by the 5-HT(2A) receptor antagonist ketanserin but not by the 5-HT(2C) receptor antagonist RS102221. Inhibition of glutamate release by DOI was associated with a reduction of 4AP-evoked depolarization and downstream elevation of cytoplasmic free calcium concentration ([Ca(2+)](C)) mediated via P/Q- and N-type voltage-dependent Ca(2+) channels (VDCCs). In contrast to the DOI effect on 4AP-evoked release, the agonist had no effect on high external [K(+)] (30 mM)-induced (KCl) stimulation of VDCCs or glutamate release. Likewise, release mediated by direct Ca(2+) entry with Ca(2+) ionophore (ionomycin) or by hypertonic sucrose was unaffected by DOI. Mechanistically, DOI modulation of 4AP-evoked glutamate release appeared to involve a phospholipase C/protein kinase C signaling cascade, insofar as pretreatment of synaptosomes with the phospholipase C inhibitor U73122 or protein kinase C inhibitors Ro320432 or GF109203X all effectively occluded the inhibitory effect of the agonist. Together, these results suggest that presynaptic 5-HT(2A) receptors present on glutamatergic terminals effect an unexpected depression of glutamate release by negatively modulating nerve terminal excitability and downstream VDCC activation through a signaling cascade involving phospholipase C/protein kinase C. These observations invoke presynaptic inhibitory 5-HT(2A) receptor function as a potential target for drugs to mitigate the effects of excessive glutamatergic transmission.

Blockade of nucleus accumbens 5-HT2A and 5-HT2C receptors prevents the expression of cocaine-induced behavioral and neurochemical sensitization in rats

“…While no published report exists concerning 5-HT 2A receptor regulation of NAC extracellular glutamate, considerable electrophysiological and neurochemical data indicate that in various frontal cortical regions, 5-HT 2A receptor activation stimulates glutamate release and/or increases glutamate neuron excitability via both pre- and postsynaptic mechanisms (Aghajanian and Marek 1997; Hasuo et al 2002; Marek and Aghajanian 1994, 1999; Marek et al 2001, 2006; Martin-Ruiz et al 2001; Scruggs et al 2000, 2003; Wang 2005; Wang et al 2006). Consistent with the possibility that 5-HT 2A receptors exert a facilitatory role also over NAC extracellular levels of glutamate, intra-NAC infusion of MDL 100907 completely blocked the expression of cocaine-induced glutamate sensitization, without influencing NAC glutamate levels in animals treated acutely with this stimulant (Fig.…”

RANTES Modulates the Release of Glutamate in Human Neocortex

“…In fact, if RANTES can activate chemokine receptors coupled to mobilization of internal Ca 2ϩ from IP 3 -sensitive stores, the depolarization-evoked exocytosis of glutamate should be potentiated. Meanwhile it is worth reminding that some receptors, like the serotonin 5-HT 2 receptors, were reported to mediate inhibition of the depolarization-evoked glutamate exocytosis, despite their positive coupling to the phosphoinositide pathway (Wang et al, 2006).…”

Metabotropic actions of kainate receptors in the CNS

“…As such, this preparation directly assays the release of neurotransmitter and only reports the modulation thereof by pre‐synaptic receptors present at the terminal itself (Sánchez‐Prieto et al. 1996; Perkinton and Sihra 1998, 1999; Wang et al. 2002, 2006; Wang and Sihra 2003, 2004).…”