Mechanism of the 5-hydroxytryptamine 2A receptor-mediated facilitation of synaptic activity in prefrontal cortex

Abstract

Classic hallucinogens such as lysergic acid diethylamide are thought to elicit their psychotropic actions via serotonin receptors of the 5-hydroxytryptamine 2A subtype (5-HT 2AR). One likely site for these effects is the prefrontal cortex (PFC). Previous studies have shown that activation of 5-HT2ARs in this region results in a robust increase in spontaneous glutamatergic synaptic activity, and these results have led to the widely held idea that hallucinogens elicit their effect by modulating synaptic transmission within the PFC. Here, we combine cellular and molecular biological approaches, including single-cell 5-HT 2ARs inactivation and 5-HT2AR rescue over a 5-HT 2AR knockout genetic background, to distinguish between competing hypotheses accounting for these effects. The results from these experiments do not support the idea that 5-HT 2ARs elicit the release of an excitatory retrograde messenger nor that they activate thalamocortical afferents, the two dominant hypotheses. Rather, they suggest that 5-HT 2ARs facilitate intrinsic networks within the PFC. Consistent with this idea, we locate a discrete subpopulation of pyramidal cells that is strongly excited by 5-HT 2AR activation.gene gun ͉ in vitro electrophysiology ͉ organotypic slices ͉ serotonin ͉ hallucinogen T he idea that classic hallucinogens such as lysergic acid diethylamide and psylocibin act by interfering with serotonergic neurotransmission can be traced to the middle of the 20th century (1). It was, however, not until the 1980s that serotonin receptors of the 5-hydroxytryptamine 2A subtype (5-HT 2A R) were identified as the molecular target for these agents (refs. 2, 3; reviewed in refs. 4, 5). Subsequent brain imaging studies in human subjects have extended these findings to identify the prefrontal cortex (PFC), which is highly enriched in these receptors, as a key brain region in mediating the effects of hallucinogens (6, 7). These findings have led to the now widely accepted view that activation of 5-HT 2A R in the prefrontal is a key biological step leading to the psychological effects of hallucinogens (5, 8).Our understanding of the mechanisms by which 5-HT 2A R activation elicits the sensory and behavioral manifestation of hallucinogens would be enriched by a precise understanding of how these receptors modulate cellular and network excitability in the PFC. To that effect, a number of studies have addressed the electrophysiological effects signaled by 5-HT 2A Rs in this region. There is general concordance that the most robust cellular effect observed in pyramidal cell of the PFC on stimulation of 5-HT 2A Rs involves an increase in both the frequency and amplitude of glutamatergic spontaneous excitatory postsynaptic potentials/spontaneous excitatory postsynaptic currents (sEPSCs) (9)(10)(11)(12)(13)(14). This observation thus points to 5-HT 2A Rs as powerful modulators of the excitability of PFC networks and reconciles evidence implicating both glutamatergic and serotonergic systems in the actions of hallucinogens (15).Although multiple ...

Prefrontal/Amygdalar System Determines Stress Coping Behavior Through 5-HT/GABA Connection

“…Activation of 5-HT2a receptors in mpFC results in increased glutamatergic synaptic activity (Beique et al, 2007). Some authors have proposed that the excitatory action of this receptor 5-HT2a may be particularly prominent under conditions of high 5-HT release (Sharp et al, 2007), and a growing body of clinical psychopharmacological evidence is consistent with the hypothesis that blockade of 5-HT2a receptors might enhance the therapeutic effectiveness of SSRIs in depression patients (Marek et al, 2005).…”

Regulation of rat cortical 5-hydroxytryptamine2A receptor-mediated electrophysiological responses by repeated daily treatment with electroconvulsive shock or imipramine

“…Recent work has suggested that a retrograde influence of apical dendritic 5-HT 2A receptors in pyramidal cells does not lead to glutamate release in the prefrontal cortex (Beique et al, 2007). Other work involving rescue of cerebral cortical 5-HT 2A receptors in mice with a global disruption of 5-HT 2A receptors has seemingly suggested that cortical 5-HT 2A receptors are sufficient to induce 5-HT-induced excitatory synaptic currents (Weisstaub et al, 2006).…”

Stress blunts serotonin- and hypocretin-evoked EPSCs in prefrontal cortex: Role of corticosterone-mediated apical dendritic atrophy

“…As subcortical structures such as thalamus and basolateral amgdala that project to prefrontal cortex were devoid of 5-HT 2A receptors in the rescue mice (9), these subcortical inputs do not appear to play a primary role in mediating 5-HT 2A -induced responses. Although typical layer V pyramidal cells are not directly induced to fire by 5-HT beyond the first 2-3 weeks of postnatal development (25), it has been reported recently that 5-HT strongly depolarizes and initiates spiking activity in a special subpopulation of large ''deep layer'' pyramidal cells in the mPFC (26). These results suggest that recurrent collaterals from this deep layer subset rather than typical layer V pyramidal cells may be a source for the 5-HTevoked EPSCs.…”