The Time-Course for Up- and Down-Regulation of the Cortical 5-Hydroxytryptamine (5-HT)2A Receptor Density Predicts 5-HT2A Receptor-Mediated Behavior in the Rabbit

Abstract

5-Hydroxytryptamine (serotonin; 5-HT) 2 receptor agonists such as (Ϯ)-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) injected systemically or directly into frontal cortex, elicit stereotyped head movements that are mediated by 5-HT 2A receptors. Chronic administration of 5-HT 2A receptor antagonists can produce either a down-regulation, e.g., d-2-bromolysergic acid diethylamide (BOL) or an up-regulation, e.g., ␣-phenyl-10(2-phenylethyl)-4-piperidinemethanol (MDL11,939) of cortical 5-HT 2A receptors in the rabbit with no change in the density of the 5-HT 2C receptor. We examined the degree to which the time course for the onset and offset of changes in cortical 5-HT 2A receptor density was correlated with functional changes as measured by the magnitude of DOI elicited, 5-HT 2A receptor-mediated head movements (head bobs). First, the magnitude of DOI-elicited head bobs was measured over 1 to 8 days after chronic BOL (5.8 mol/kg), MDL11,939 (10 mol/ kg), or vehicle administration. Second, rabbits were injected with BOL, MDL11,939, or vehicle once daily for 8 days, and then, 1 to 8 days after the cessation of drug or vehicle, DOIelicited head bobs were determined. Samples of frontal cortex were obtained for each animal immediately following behavioral testing, and 5-HT 2A receptor density was measured using [ 3 H]ketanserin. Thus, each animal provided a value for receptor density and number of head bobs, and these two measures showed a high degree of correlation between 0.94 for BOL and 0.95 for MDL11,939. This study establishes that the density of 5-HT 2A receptors in cortex reflects their functional status.Perturbations in neurotransmission can lead to adaptations at the receptor level, resulting in a change in the functional status of an organism. These adaptations may include changes in receptor density and/or the receptor's interaction with its cognate second messenger system. For G proteincoupled receptors, chronic activation with agonists produces down-regulation of the receptor, whereas inactivation with antagonists results in up-regulation. Studies investigating the in vivo regulation of the 5-HT 2A receptor have shown that the adaptive changes are different from those in other receptor systems. The expected adaptive change after chronic administration of antagonists, i.e., an increase in the density of receptors (Creese and Sibley, 1981), was not observed. Unlike most G protein-coupled receptors (Tsao and von Zastrow, 2000), numerous studies demonstrated that chronic treatment with 5-HT 2A/2C antagonists down-regulated 5-HT 2A receptor density (for reviews see Roth et al., 1998;Gray and Roth, 2001). However, recently, up-regulation of cortical 5-HT 2A receptors has been reported for two 5-HT 2A antagonists, SR 46349B in the rodent (Rinaldi-Carmena et al., 1993a,b) and MDL11,939 in the rabbit (Aloyo et al., 2001). Although the mechanisms underlying 5-HT 2A receptor up-or down-regulation by antagonists are unknown, parallel changes in receptor-mediated behaviors have been demonstrated, suggesti...

Psychedelics

“…In another study, Dave et al (2007) were able to relate the production of head bobs to 5-HT 2A receptor density in the cortex. DOI was infused bilaterally into the mPFC.…”

Intrahippocampal LSD accelerates learning and desensitizes the 5-HT2A receptor in the rabbit, Romano et al.

“…The affinity for these receptors (Kd) was not altered (Aloyo et al 2001). In addition, it has been shown that downregulation of the 5-HT 2A receptor is associated with decreases in the ability of DOI to elicit head bobs (Aloyo et al 2001;Dave et al 2007). Similarly, upregulation of the 5-HT 2A receptor with no change in the density of the 5-HT 2C receptor resulted in an enhancement of trace eyeblink conditioning (Harvey et al 2004).…”

Atypical antipsychotics and inverse agonism at 5-HT₂ receptors

“…Moreover, these studies established the rabbit eyeblink model as a tool for monitoring inverse agonism at a systems level. Further studies by the Harvey group characterized the effects of chronic inverse agonist treatment on 5-HT 2A receptor density [47, 48]. When rabbits were repeatedly administered the inverse agonists MDL11939 and M100, 907, there was a resultant increase in 5-HT 2A receptor expression as measured by radioligand binding [47, 48].…”

“…Further studies by the Harvey group characterized the effects of chronic inverse agonist treatment on 5-HT 2A receptor density [47, 48]. When rabbits were repeatedly administered the inverse agonists MDL11939 and M100, 907, there was a resultant increase in 5-HT 2A receptor expression as measured by radioligand binding [47, 48]. Moreover, there were corresponding behavioral effects as a consequence of the receptor up-regulation.…”