Phospholipase C mediates (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI)-, but not lysergic acid diethylamide (LSD)-elicited head bobs in rabbit medial prefrontal cortex.

The phenethylamine and indoleamine classes of hallucinogens demonstrate distinct pharmacological properties, although they share a serotonin(2A) (5-HT(2A)) receptor mechanism of action (MOA). The 5-HT(2A) receptor signals through phosphatidylinositol (PI) hydrolysis, which is initiated upon activation of phospholipase C (PLC). The role of PI hydrolysis in the effects of hallucinogens remains unclear. In order to better understand the role of PI hydrolysis in the MOA of hallucinogens, the PLC inhibitor, 1-[6-((17ß-3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl]-1H-pyrrole-2,5-dione (U73122), was used to study the effects of two hallucinogens, the phenethylamine, (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), and the indoleamine, lysergic acid diethylamide (LSD). PI hydrolysis was quantified through release of [3H]inositol-4-phosphate from living rabbit frontocortical tissue prisms. Head bobs were counted after hallucinogens were infused into the medial prefrontal cortex (mPFC) of rabbits. Both DOI and LSD stimulated PI hydrolysis in frontocortical tissue through activation of PLC. DOI-stimulated PI hydrolysis was blocked by 5-HT(2A/2C) receptor antagonist, ketanserin, whereas the LSD signal was blocked by 5-HT(2B/2C) receptor antagonist, SB206553. When infused into the mPFC, both DOI- and LSD-elicited head bobs. Pretreatment with U73122 blocked DOI-, but not LSD-elicited head bobs. The two hallucinogens investigated were distinct in their activation of the PI hydrolysis signaling pathway. The serotonergic receptors involved with DOI and LSD signals in frontocortical tissue were different. Furthermore, PLC activation in mPFC was necessary for DOI-elicited head bobs, whereas LSD-elicited head bobs were independent of this pathway. These novel findings urge closer investigation into the intracellular mechanism of action of these unique compounds.

Effects of high ambient temperature on glow-peak fading properties of LiF:Mg,Ti thermoluminescent dosemeters.

The effects of a controlled high temperature environment on LiF:Mg,Ti thermoluminescent dosemeters (TLDs) were investigated. TLDs were exposed to ambient temperatures of 30, 40 and 50°C. Sensitivity changes before irradiation, typically called pre-irradiation fading, and signal loss after irradiation, called post-irradiation fading, were studied. Dosemeters were subjected to up to 33 d of pre-irradiation and 68 d of post-irradiation storage. For pre-irradiation fading, peak 5 showed a signal increase of ∼30 % and peak 4 showed an ∼30 % decrease in 20 d. The sum of the areas of peaks 4 and 5 remained relatively constant even for long pre-irradiation times, although at 50°C, losses in peak 5 signal were too significant to maintain the sum of peaks 4 and 5 constant. Peak 3 was still detectable even at 50°C and the longest irradiation times, but peak 2 was very difficult to detect after 15-20 d, especially with post-irradiation fading.

Serotonergic and dopaminergic distinctions in the behavioral pharmacology of (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and lysergic acid diethylamide (LSD).

RATIONALE: After decades of social stigma, hallucinogens have reappeared in the clinical literature demonstrating unique benefits in medicine. The precise behavioral pharmacology of these compounds remains unclear, however. OBJECTIVES: Two commonly studied hallucinogens, (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and lysergic acid diethylamide (LSD), were investigated both in vivo and in vitro to determine the pharmacology of their behavioral effects in an animal model. METHOD: Rabbits were administered DOI or LSD and observed for head bob behavior after chronic drug treatment or after pretreatment with antagonist ligands. The receptor binding characteristics of DOI and LSD were studied in vitro in frontocortical homogenates from naïve rabbits or ex vivo in animals receiving an acute drug injection. RESULTS: Both DOI- and LSD-elicited head bobs required serotonin(2A) (5-HT(2A)) and dopamine(1) (D(1)) receptor activation. Serotonin(2B/2C) receptors were not implicated in these behaviors. In vitro studies demonstrated that LSD and the 5-HT(2A/2C) receptor antagonist, ritanserin, bound frontocortical 5-HT(2A) receptors in a pseudo-irreversible manner. In contrast, DOI and the 5-HT(2A/2C) receptor antagonist, ketanserin, bound reversibly. These binding properties were reflected in ex vivo binding studies. The two hallucinogens also differed in that LSD showed modest D(1) receptor binding affinity whereas DOI had negligible binding affinity at this receptor. CONCLUSION: Although DOI and LSD differed in their receptor binding properties, activation of 5-HT(2A) and D(1) receptors was a common mechanism for eliciting head bob behavior. These findings implicate these two receptors in the mechanism of action of hallucinogens.

A computerized glow curve analysis (GCA) method for WinREMS thermoluminescent dosimeter data using MATLAB.

A computerized glow curve analysis (GCA) program for handling of thermoluminescence data originating from WinREMS is presented. The MATLAB program fits the glow peaks using the first-order kinetics model. Tested materials are LiF:Mg,Ti, CaF(2):Dy, CaF(2):Tm, CaF(2):Mn, LiF:Mg,Cu,P, and CaSO(4):Dy, with most having an average figure of merit (FOM) of 1.3% or less, with CaSO(4):Dy 2.2% or less. Output is a list of fit parameters, peak areas, and graphs for each fit, evaluating each glow curve in 1.5 s or less.

The effects of high ambient radon on thermoluminescence dosimetry readings.

The effect of a high level of ambient (222)Rn gas on thermoluminescence dosemeters (TLDs) is examined. Groups of LiF:Mg,Ti and CaF(2):Dy TLDs were exposed to (222)Rn under controlled environmental conditions over ∼7 d using a luminous (226)Ra aircraft dial. LiF:Mg,Ti TLDs were tested bare, and both types were tested mounted in cards used for environmental dosimetry and mounted in cards enclosed in plastic badges. A passive continuous radon monitor was used to measure the (222)Rn level in the small chamber during the experiments. The data were analysed to determine the relationship between the integrated (222)Rn level and the TLD response. Although both LiF:Mg,Ti and CaF(2):Dy TLDs showed a strong response to (222)Rn, the badges prevented measurable radon detection by the TLDs within. The TLDs were not used to directly measure the radon concentration; rather, a correction for its influence was desired.

The role of serotonin-2 (5-HT2) and dopamine receptors in the behavioral actions of the 5-HT2A/2C agonist, DOI, and putative 5-HT2C inverse agonist, SR46349B.

RATIONALE: Atypical antipsychotic efficacy is often attributed to actions at serotonin-2 (5-HT(2)) and dopamine receptors, indicating a potential benefit of understanding the interplay between these systems. Currently, it is known that 5-HT(2) receptors modulate dopamine release, although the role of specific dopamine receptors in 5-HT(2)-mediated behavior is not well understood. OBJECTIVES: We examined the role of 5-HT(2A), 5-HT(2C), and dopamine (D1 and D2) receptors in the behavioral response to a 5-HT(2A/2C) agonist (DOI) and 5-HT(2A/2C) antagonist (SR46349B). MATERIALS AND METHODS: Effects were assessed by measuring rabbit head bobs (previously characterized as 5-HT(2A) receptor-mediated) and body shakes (5-HT(2C)-mediated). RESULTS: As expected, DOI produced head bobs and body shakes, and these DOI-elicited behaviors were attenuated by the SR46349B pretreatment. Unexpectedly, SR46349B also induced head bobs when administered alone. However, SR46349B-elicited head bobs are distinguishable from those produced by DOI since the 5-HT(2A) antagonist, ketanserin, only attenuated DOI-elicited head bobs. Conversely, 5-HT(2C) ligands (SB242084 and SB206553) inhibited SR46349B but not DOI-induced head bobs. Furthermore, when administered alone, SB206553 (a 5-HT(2C) inverse agonist) produced head bobs, indicating the behavior can be either 5-HT(2A) or 5-HT(2C) mediated. Next, it was revealed that D1 and D2 receptors play a role in DOI-elicited head bobs, but only D1 receptors are required for SR46349B-elicited head bobs. CONCLUSIONS: 5-HT(2A) receptor agonism and 5-HT(2C) inverse agonism produce the same behavior, likely due to similar downstream actions at D1 receptors. Consequently, 5-HT(2C) agonism or D1 agonism may be effective therapies for disorders, such as schizophrenia, currently being treated with 5-HT(2A) antagonists.

Intrahippocampal LSD accelerates learning and desensitizes the 5-HT(2A) receptor in the rabbit, Romano et al.

RATIONALE: Parenteral injections of d-lysergic acid diethylamide (LSD), a serotonin 5-HT(2A) receptor agonist, enhance eyeblink conditioning. Another hallucinogen, (±)-1(2, 5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI), was shown to elicit a 5-HT(2A)-mediated behavior (head bobs) after injection into the hippocampus, a structure known to mediate trace eyeblink conditioning. OBJECTIVE: This study aims to determine if parenteral injections of the hallucinogens LSD, d,l-2,5-dimethoxy-4-methylamphetamine, and 5-methoxy-dimethyltryptamine elicit the 5-HT(2A)-mediated behavior of head bobs and whether intrahippocampal injections of LSD would produce head bobs and enhance trace eyeblink conditioning. MATERIALS AND METHODS: LSD was infused into the dorsal hippocampus just prior to each of eight conditioning sessions. One day after the last infusion of LSD, DOI was infused into the hippocampus to determine whether there had been a desensitization of the 5-HT(2A) receptor as measured by a decrease in DOI-elicited head bobs. RESULTS: Acute parenteral or intrahippocampal LSD elicited a 5-HT(2A) but not a 5-HT(2C)-mediated behavior, and chronic administration enhanced conditioned responding relative to vehicle controls. Rabbits that had been chronically infused with 3 or 10 nmol per side of LSD during Pavlovian conditioning and then infused with DOI demonstrated a smaller increase in head bobs relative to controls. CONCLUSIONS: LSD produced its enhancement of Pavlovian conditioning through an effect on 5-HT(2A) receptors located in the dorsal hippocampus. The slight, short-lived enhancement of learning produced by LSD appears to be due to the development of desensitization of the 5-HT(2A) receptor within the hippocampus as a result of repeated administration of its agonist (LSD).

Inverse agonism at serotonin and cannabinoid receptors.

Contemporary receptor theory was developed to account for the existence of constitutive activity, as defined by the presence of receptor signaling in the absence of any ligand. In vitro studies with a variety of cell types have revealed the existence of constitutive activity and inverse agonism at a large number of receptors and also additional complexities of ligand-receptor interactions. Thus, ligands acting at a constitutively active receptor can act as agonists, antagonists, and/or inverse agonists, and these pharmacological characteristics can differ for an individual ligand depending upon the receptor response measured and the physiological state of the system under study. Studies with a variety of cell types have established that the serotonin 5-HT(2A) and 5-HT(2C) receptors and the cannabinoid CB1 receptor demonstrate constitutive activity and inverse agonism in vitro. Serotonin and cannabinoid receptors are involved in a large number of physiological and behavioral functions. The possible existence of constitutive activity and inverse agonism at these receptors in vivo would provide new avenues for drug development. Recent studies have provided compelling evidence that both the serotonin 5-HT(2A) and 5-HT(2C) receptors and cannabinoid CB1 receptor demonstrate inverse agonism and constitutive activity also in vivo. This chapter describes our current knowledge of constitutive activity in vitro and then examines the evidence for constitutive activity in vivo.

Characterization of the glow-peak fading properties of six common thermoluminescent materials.

The pre-irradiation and post-irradiation fading rates of the thermoluminescent glow peaks of six commonly used thermoluminescent dosimeters under controlled environmental conditions over approximately 30 d are examined. Glow peaks were fit to the first-order kinetics model using a computerized glow curve deconvolution program. Dosimeters studied were LiF:Mg,Ti, CaF(2):Dy, CaF(2):Tm, CaF(2):Mn, LiF:Mg,Cu,P, and CaSO(4):Dy. LiF:Mg,Ti and LiF:Mg,Cu,P experienced significant pre-irradiation fading. All types except CaF(2):Mn experienced post-irradiation fading. Ratios of glow-peak areas were fit to exponential decay functions when possible.

Performance of vintage direct reading pocket ionization chambers.

The linearity, accuracy, and precision of each of two groups of vintage 51.6 microC-kg-1 maximum scale passive direct reading pocket ionization chambers, each from a different manufacturer and all aged at least 50 years since manufacture, were tested. The pocket ionization chambers were suspended on a phantom and exposed using a 137Cs source. Variations from trial to trial were smaller than variations from chamber to chamber. The average percent standard deviations ranged from 5.7% to 14% across all exposures. The accuracy of the dosimeter readings increased as the exposure level increased. Percent error from known exposure values decreased as exposure increased. An independent samples t test indicated there was a statistically significant difference between the two groups only at a delivered exposure of 6.45 microC-kg-1. Testing was performed in a 222Rn drum to determine the effect of Rn on the pocket ionization chambers. Exposure of five chambers to an average Rn level of 4.70 kBq m-3 and thirty chambers to 3.86 kBq m-3 over a 7-d period produced abnormally high readings at least three times background in eight of the 35 chambers tested.

Amphetamine influences conditioned response timing and laterality of anterior cingulate cortex activity during rabbit delay eyeblink conditioning.

Previous studies have shown that amphetamine can enhance learning in Pavlovian conditioning tasks, but little is known about the changes in neural activity accompanying these performance enhancements. We evaluated the effects of amphetamine (10micromol/kg) on delay eyeblink conditioning performance and single-neuron activity in the anterior cingulate cortex (area 24) of the rabbit (Oryctolagus cuniculus). Amphetamine produced little to no learning enhancement on our task but strongly influenced the conditioned response (CR), which peaked closer in time to the onset of the unconditioned stimulus (US). The overall ACC population response showed very weak stimulus-evoked modulations during the course of training, with the primary effect being an increase in inhibition. Group discrepancies in stimulus-evoked inhibition correlated with differences in learning performance, and this correlation was stronger when subjects were grouped according to learning performance, independent of drug treatment. ACC neuronal responses of both groups displayed hemispheric asymmetries (laterality), but amphetamine treatment altered this effect, in that activity within each hemisphere of the amphetamine group more closely resembled that of the contralateral hemisphere of controls. Our data suggest that amphetamine modulates CR timing, and influences the flow of sensory information to the two cortical hemispheres. Our observations are also consistent with the ACC's non-essential role in learning during delay eyeblink conditioning.

Physiological and therapeutic relevance of constitutive activity of 5-HT 2A and 5-HT 2C receptors for the treatment of depression.

Serotonin(2A) (5-HT(2A)) and 5-HT(2C) receptors are highly homologous members of the serotonin(2) family of 7-transmembrane-spanning (7-TMS) receptors. Both of these receptor subtypes have been implicated in the aetiology and/or treatment of affective disorders such as anxiety and depression. Regulation of dopaminergic neurotransmission by 5-HT(2A) and 5-HT(2C) receptor systems has been well established. In general, agonist activation of 5-HT(2A) receptors can facilitate stimulated dopamine (DA) release, whereas 5-HT(2C) agonists inhibit dopaminergic neural activity and DA release under both basal and activated conditions. However, recent experimental evidence suggests that 5-HT(2A) and 5-HT(2C) receptors can be constitutively active (agonist-independent activity) in vivo. Alterations in the constitutive activity of 5-HT(2A) and 5-HT(2C) receptor systems could be involved in the mechanisms underlying anxiety and depression or exploited for therapeutic benefit. Consequently, drugs with inverse agonist properties may have more activity in vivo to regulate DA neurotransmission than that afforded by simple competitive antagonism.

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.

5-Hydroxytryptamine (serotonin; 5-HT)2 receptor agonists such as (+/-)-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) injected systemically or directly into frontal cortex, elicit stereotyped head movements that are mediated by 5-HT2A receptors. Chronic administration of 5-HT2A receptor antagonists can produce either a down-regulation, e.g., d-2-bromolysergic acid diethylamide (BOL) or an up-regulation, e.g., alpha-phenyl-10(2-phenylethyl)-4-piperidinemethanol (MDL11,939) of cortical 5-HT2A receptors in the rabbit with no change in the density of the 5-HT2C receptor. We examined the degree to which the time course for the onset and offset of changes in cortical 5-HT2A receptor density was correlated with functional changes as measured by the magnitude of DOI elicited, 5-HT2A 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 micromol/kg), MDL11,939 (10 micromol/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, DOI-elicited head bobs were determined. Samples of frontal cortex were obtained for each animal immediately following behavioral testing, and 5-HT2A receptor density was measured using [3H]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-HT2A receptors in cortex reflects their functional status.

Physiological relevance of constitutive activity of 5-HT2A and 5-HT2C receptors.

It is generally accepted that seven-transmembrane receptors have the capacity to regulate cellular signaling systems in the absence of occupancy by a ligand (i.e. the receptors display constitutive activity). Drugs can increase (agonists), decrease (inverse agonists) or not change (antagonists) receptor activity towards a cellular effector. Moreover, some drugs (protean ligands) have multiple pharmacological properties (e.g. agonism towards one response and inverse agonism towards another response coupled to the same receptor and measured from the same cells, simultaneously). In this article, we describe response-dependent constitutive activity and ligand pharmacology for 5-HT2A and 5-HT2C receptors in vitro. Moreover, we provide evidence that 5-HT2A and 5-HT2C receptor constitutive activity is physiologically relevant in vivo and suggest that strong consideration should be given to the impact of constitutive receptor activity on disease and the therapeutic potential of inverse agonism.

Serotonin 5-HT2A receptors in the CA1 field of the hippocampus mediate head movements in the rabbit.

RATIONALE: Motor movements (head bobs) in the rabbit have been shown to be elicited by LSD-like hallucinogenic drugs through actions at central serotonin 5-HT(2A) receptors, though their central locus remains unknown. Serotonergic innervation of the hippocampus has been suggested to play an important role in motor programming including movements of the head. OBJECTIVES: We examined whether intrahippocampal injections of a 5-HT(2A) receptor agonist would elicit head bobs and whether elicitation of head bobs would be modified by increases in hippocampal 5-HT(2A) receptor density. METHODS: Animals received bilateral injections of DOI or its vehicle into the dorsal hippocampus either before or after chronic administration of MDL 11,939 or its vehicle. The number of head bobs was counted continuously for 60 min and reported in blocks of 10 min and this was compared with the density of 5-HT(2A) receptors in dorsal hippocampus. RESULTS: Infusion of DOI into the CA1 region of the dorsal hippocampus elicited head bobs that were blocked by prior intrahippocampal injection of the 5-HT(2A) receptor antagonist ketanserin. Receptor autoradiography revealed that chronic administration of MDL 11,939 produced a 2.5-fold up-regulation of 5-HT(2A) receptors in the CA1 field and dentate gyrus of the hippocampus. This 5-HT(2A) receptor up-regulation was associated with a nearly 2-fold increase in head bobs elicited by infusion of DOI into the CA1 field. CONCLUSIONS: These results indicate that 5-HT(2A) receptors located in the CA1 field of the hippocampus mediate a motor movement, head bobs, and that this mediation is functionally related to receptor density.

Cocaine effects on the developing brain: current status.

The present paper reports on the results obtained in a rabbit model of prenatal cocaine exposure that mimics the pharmacokinetics of crack cocaine in humans, and relates these findings to studies in other species including humans. A general finding is that prenatal exposure to cocaine during neurogenesis produces dysfunctions in signal transduction via the dopamine D(1) receptor and alterations in cortical neuronal development leading to permanent morphological abnormalities in frontocingulate cortex and other brain structures. Differences in the precise effects obtained appear to be due to the dose, route and time of cocaine administration. Related to these effects of in utero cocaine exposure, animals demonstrate permanent deficits in cognitive processes related to attentional focus that have been correlated with impairment of stimulus processing in the anterior cingulate cortex. The long-term cognitive deficits observed in various species are in agreement with recent reports indicating that persistent attentional and other cognitive deficits are evident in cocaine-exposed children as they grow older and are challenged to master more complex cognitive tasks.

Role of central 5-HT2 receptors in mediating head bobs and body shakes in the rabbit.

Systemic administration of the 5-HT(2A/2C) agonist DOI [(1(2,5-dimethoxy-4-iodophenyl)-2-aminopropane)hydrochloride] in rabbits elicits head bobs and body shakes, which are mediated by 5-HT(2A) and 5-HT(2C) receptors, respectively. This study was designed to determine whether the receptors mediating these behaviors are primarily located in the brain or in the periphery. Systemic administration of the peripheral 5-HT(2A/2C) antagonist xylamidine 30 min before systemic DOI challenge attenuated DOI-elicited body shakes by 50% without an effect on head bobs, suggesting a central origin for head bobs and a partial peripheral and a partial central origin for body shakes. Central administration of DOI into the lateral ventricle (ICV) elicited head bobs but not body shakes, demonstrating that the receptors mediating head bobs are centrally located. Pretreatment with ICV xylamidine blocked head bobs elicited by ICV DOI, indicating that the lack of inhibition, when systemically administered, is due to xylamidine's failure to reach central receptors. ICV pretreatment with the 5-HT(2A) receptor antagonist ketanserin inhibited ICV DOI-elicited head bobs establishing that 5-HT(2A) receptors activation elicits head bobs. In conclusion, 5-HT(2A) receptors mediating head movements are located in the brain whereas 5-HT(2C) receptors mediating the body movements appear to be located at different central sites as well as in the periphery.

Selective remodeling of rabbit frontal cortex: relationship between 5-HT2A receptor density and associative learning.

RATIONALE: Associative learning during classical trace eyeblink conditioning has been shown to be regulated by serotonin 5-HT(2A )receptors and to be critically dependent on the integrity of frontal cortex. Chronic administration of 5-HT(2A) ligands has been shown to produce a selective up- or down-regulation of 5-HT(2A) receptors in frontal cortex. OBJECTIVES: We examined whether alterations in 5-HT(2A) receptor density had a functional significance with respect to associative learning. METHODS: Animals received chronic injections of LSD, BOL or MDL11,939 and 1 day later began classical trace conditioning of the eyeblink response. RESULTS: The density of 5-HT(2A) receptors in frontal cortex was significantly increased at 1-4 days after the cessation of chronic injections of the selective 5-HT(2A) receptor ligand MDL11,939. Rabbits demonstrated an enhancement of associative learning when training began at 1 day after cessation of chronic MDL11,939 injections, but acquired at the same rate as controls when training began at 8 days after cessation of injections, a time when receptor density had returned to control levels. Animals that began training 1 day after chronic injections of BOL or LSD, drugs that produce decreases in 5-HT(2A) receptor density, demonstrated normal rates of acquisition. CONCLUSIONS: These results indicate that increases in the density of 5-HT(2A) receptors in frontal cortex are associated with increases in the rate of associative learning, and further support an important role for this receptor in cortical circuitry that mediates learning. More generally, these results suggest an approach for functional remodeling of brain regions in the adult animal.

Role of the serotonin 5-HT(2A) receptor in learning.

This study reviews the role of the serotonin 5-HT2A receptor in learning as measured by the acquisition of the rabbit's classically conditioning nictitating membrane response, a component of the eyeblink response. Agonists at the 5-HT2A receptor including LSD (d-lysergic acid diethylamide) enhanced associative learning at doses that produce cognitive effects in humans. Some antagonists such as BOL (d-bromolysergic acid diethylamide), LY53,857, and ketanserin acted as neutral antagonists in that they had no effect on learning, whereas others (MDL11,939, ritanserin, and mianserin) acted as inverse agonists in that they retarded learning through an action at the 5-HT2A receptor. These results were placed in the context of what is known concerning the anatomical distribution and electrophysiological effects of 5-HT2A receptor activation in frontal cortex and hippocampus, as well as the role of cortical 5-HT2A receptors in schizophrenia. It was concluded that the 5-HT2A receptor demonstrates constitutive activity, and that variations in this activity can produce profound alterations in cognitive states.