Evidence for the Preferential Involvement of 5-HT2A Serotonin Receptors in Stress- and Drug-Induced Dopamine Release in the Rat Medial Prefrontal Cortex

Abstract

The mechanism(s) by which serotonin modulates dopamine release in the medial prefrontal cortex is not known, although studies suggest an involvement of 5-HT2 family receptors. We employed in vivo microdialysis and putatively selective 5-HT2A antagonists (M100907, MDL 11,939, SR46349B) to determine if 5-HT2A receptors are responsible for both drug-and stress-induced DA release in the medial prefrontal cortex. MDL 11,939 and SR46349B receptor-binding studies indicated, for the first time, that only MDL 11,939 had greater selectivity for the 5-HT2A vs the 5-HT2C receptor subtypes similar to M100907, and that both showed low or no affinity for non-5-HT2 receptors. Reverse dialysis with 5-HT2A antagonists had little or no effect on basal dopamine efflux. However, intracortical administration of MDL 11,939 or M100907 attenuated dopamine release induced by systemic administration of the 5-HT2 agonist DOI. Dual-probe microdialysis demonstrated that systemic DOI also increased glutamate concentrations in the ventral tegmental area (VTA). This was blocked by intracortical M100907. Cortical perfusion with M100907, or the atypical antipsychotic drug risperidone, but not the 5-HT2B/C ligand SB 206553, also decreased dopamine release induced physiologically by stress. These results indicate that stimulation of cortical 5-HT2A receptors increases the release of dopamine from the mesocortical system. They suggest that this effect may be mediated by increases in glutamate release from corticotegmental projections to the VTA. Additionally, they indicate that cortical 5-HT2A receptors modulate evoked dopamine release, such as that observed physiologically following mild stress. These findings may have implications for the pharmacological treatment of disorders resulting from or exacerbated by stress.

Pharmacologic mechanisms of serotonergic regulation of dopamine neurotransmission

“…Thus, 5-HT2A receptor agonism may increase the activity of corticotegmental glutamatergic projection neurons. This suggestion is supported by our recent finding that systemic administration of the 5-HT2 receptor agonist DOI increased glutamate efflux in the VTA (Pehek et al, 2006). Infusions of M100907, directly into the PFC, blocked this increase, implying that the relevant 5HT2A receptors were localized in the PFC (Pehek et al, 2006).…”

“…We have demonstrated that intracortical infusions of the 5-HT2A receptor antagonists M100907 or MDL 11,939 blocked the increases in cortical DA produced by the systemic administration of the 5-HT2 receptor agonist DOI (Pehek et al, 2001;Pehek et al, 2006). Furthermore, infusions of M100907 blocked physiologically-induced DA release in the PFC, namely that produced by a mild stressor (gentle handling; Pehek et al, 2006).…”

“…These studies suggest that prefrontocortical 5-HT2A receptors are localized postsynaptically on excitatory amino acid efferents or GABAergic interneurons. Recent work indicates that 5-HT2A receptors may regulate the activity of corticotegmental projection neurons which, in turn, regulate the activity of DA neurons (Pehek et al, 2006;see below). There is also evidence that some 5-HT2A receptors are localized on axonal fibers of pyramidal cells in the monkey (Jakab and Goldman-Rakic, 1998) and that 5-HT stimulates glutamate release from these fibers in the rat (Aghajanian and Marek, 1997).…”

The Effect of Acute Tryptophan Depletion on the Neural Correlates of Emotional Processing in Healthy Volunteers

“…In humans, one study suggested that during amphetamine challenge the magnitude of DA release in the ventral striatum correlated inversely with anxiety ratings in healthy humans (Drevets et al, 2001). Moreover, the magnitude of dopamine release in the striatum has been shown to be modulated by 5-HT 2A receptor stimulation (Pehek et al, 2006;Porras et al, 2002;Yan, 2000), suggesting a mechanism through which the altered serotonergic function associated with tryptophan depletion may exert secondary effects on other neurotransmitter systems and thereby influence anxiety symptoms. Finally, the caudate responds preferentially to salient stimuli, whether or not such stimuli are associated with reward (Knutson et al, 2003;Schultz et al, 2003;Zink et al, 2006Zink et al, , 2004.…”

Dopamine D4 receptor involvement in the discriminative stimulus effects in rats of LSD, but not the phenethylamine hallucinogen DOI

“…Hallucinogens may activate dopaminergic pathways either directly, as with LSD, or indirectly by compounds that lack significant dopamine receptor affinity (Bortolozzi et al 2005;Ichikawa and Meltzer 1995;Pehek et al 2006;Vollenweider et al 1999). For example, it is well documented that activation of the 5-HT 2A receptor can modulate dopamine levels or physiological responses mediated by dopaminergic systems (Alex and Pehek 2007;Lucas and Spampinato 2000;Pehek et al 2001;Vollenweider et al 1999;Yan 2000).…”