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Biomedical subjects

David E Nichols

Publications and source records attributed to David E Nichols.

At least 19 recordsLinked to original sources
PubMed2006

trans-2,3-dihydroxy-6a,7,8,12b-tetrahydro-6H-chromeno[3,4-c]isoquinoline: synthesis, resolution, and preliminary pharmacological characterization of a new dopamine D1 receptor full agonist.

We report the synthesis of trans-2,3-dihydroxy-6a,7,8,12b-tetrahydro-6H-chromeno[3,4-c]isoquinoline hydrochloride 6 and the resolution of its enantiomers. This new compound is an oxygen bioisostere of the potent dopamine D1-selective full agonist dihydrexidine. The initial synthetic approach involved, as a key step, a Suzuki coupling between a chromene triflate and a boronate ester, followed by isoquinoline formation and reduction of the resulting isoquinoline. Subsequently, a more efficient route was developed that involved conjugate addition of an aryl Grignard reagent to a 2-nitrochromene. The title compound possessed high affinity (Ki=20-30 nM) for porcine D1-like receptors in native striatal tissue and full intrinsic activity at cloned human dopamine D1 receptors but had much lower affinity at dopamine D2-like receptors (Ki=3000 nM). The binding and functional properties of this compound illustrate again the utility of constructing dopamine D1 agonist ligands around the beta-phenyldopamine pharmacophore template.

Animals↗
PubMed2006

1-Methylpyridinium-4-(4-phenylmethanethiosulfonate) iodide, MTS-MPP+, a novel scanning cysteine accessibility method (SCAM) reagent for monoamine transporter studies.

A novel substituted cysteine accessibility method (SCAM) reagent was developed for monoamine uptake transporters. The new reagent, MTS-MPP(+), was a derivative of the neurotoxin and transporter substrate MPP(+). MTS-MPP(+) labeled cysteine residues introduced into the serotonin transporter protein. Although it did not prove to be a substrate, as is MPP(+), it appears to label cysteine residues lining the permeation pore of the transporter more readily than currently available nonspecific SCAM reagents.

Cell Line↗
PubMed2006

Serotonin 5-HT(2A) receptor activation induces 2-arachidonoylglycerol release through a phospholipase c-dependent mechanism.

To date, several studies have demonstrated that phospholipase C-coupled receptors stimulate the production of endocannabinoids, particularly 2-arachidonoylglycerol. There is now evidence that endocannabinoids are involved in phospholipase C-coupled serotonin 5-HT(2A) receptor-mediated behavioral effects in both rats and mice. The main objective of this study was to determine whether activation of the 5-HT(2A) receptor leads to the production and release of the endocannabinoid 2-arachidonoylglycerol. NIH3T3 cells stably expressing the rat 5-HT(2A) receptor were first incubated with [(3)H]-arachidonic acid for 24 h. Following stimulation with 10 mum serotonin, lipids were extracted from the assay medium, separated by thin layer chromatography, and analyzed by liquid scintillation counting. Our results indicate that 5-HT(2A) receptor activation stimulates the formation and release of 2-arachidonoylglycerol. The 5-HT(2A) receptor-dependent release of 2-arachidonoylglycerol was partially dependent on phosphatidylinositol-specific phospholipase C activation. Diacylglycerol produced downstream of 5-HT(2A) receptor-mediated phospholipase D or phosphatidylcholine-specific phospholipase C activation did not appear to contribute to 2-arachidonoylglycerol formation in NIH3T3-5HT(2A) cells. In conclusion, our results support a functional model where neuromodulatory neurotransmitters such as serotonin may act as regulators of endocannabinoid tone at excitatory synapses through the activation of phospholipase C-coupled G-protein coupled receptors.

Animals↗
PubMed2006

Molecular interaction of serotonin 5-HT2A receptor residues Phe339(6.51) and Phe340(6.52) with superpotent N-benzyl phenethylamine agonists.

Experiments were conducted to examine the molecular basis for the high affinity and potency of a new class of 5-HT(2A) receptor agonists, N-benzyl phenethylamines. Competition binding assays at several serotonin receptors confirmed that an N-arylmethyl substitution was necessary for affinity increases up to 300-fold over simple N-alkyl homologs, as well as enhanced selectivity for 5-HT(2A) versus 5-HT(2C) and 5-HT(1A) receptors. PI hydrolysis functional assays confirmed that these N-benzyl phenethylamines are potent and highly efficacious agonists at the rat 5-HT(2A) receptor. Virtual docking of these compounds into a human 5-HT(2A) receptor homology model indicated that the N-benzyl moiety might be interacting with Phe339((6.51)), whereas the phenethylamine portion was likely to be interacting with Phe340((6.52)). Experiments in h5-HT(2A) receptors with Phe339((6.51))L and Phe340((6.52))L mutations seem to support this hypothesis. Dramatic detrimental effects on affinity, potency, and intrinsic activity were observed with the Phe339((6.51))L mutation for all N-benzyl analogs, whereas most N-unsubstituted phenethylamines and traditional agonists were only weakly affected, if at all. Consistent with other published studies, the Phe340((6.52))L mutation detrimentally affected affinity, potency, and intrinsic activity of nearly all compounds tested, although a strong change in intrinsic activity was not seen with most N-aryl analogs. These data further validate the topology of our h5-HT(2A) receptor homology model. It is noteworthy that this study is the first to identify a hitherto unrecognized role for residue 6.51 in agonist activation of a serotonin G protein-coupled receptor (GPCR), whereas most previous reports have suggested a varied and sometimes contradictory role in homologous GPCRs.

Animals↗
PubMed2006

1-Aminomethylbenzocycloalkanes: conformationally restricted hallucinogenic phenethylamine analogues as functionally selective 5-HT2A receptor agonists.

A series of conformationally restricted analogues of the hallucinogenic phenethylamine 1 (2,5-dimethoxy-4-bromophenethylamine, 2C-B) was synthesized to test several hypotheses concerning the bioactive conformation of phenethylamine ligands upon binding to the 5-HT(2A) receptor. These benzocycloalkane analogues were assayed for their receptor binding affinity and ability to activate downstream signaling pathways, and one exceptional compound was selected for testing in an in vivo drug discrimination model of hallucinogenesis. All compounds were examined in silico by virtual docking into a homology model of the 5-HT(2A) receptor. On the basis of these docking experiments, it was predicted that the R enantiomer of benzocyclobutene analogue 2 would be the most potent. Subsequent chemical resolution and X-ray crystallography confirmed this prediction, as (R)-2 proved to be equipotent to LSD in rats trained to discriminate LSD from saline. Thus, we propose that the conformation of 2 mimics the active binding conformation of the more flexible phenethylamine type hallucinogens. In addition, (R)-2 is one of the most potent and selective compounds yet discovered in the in vivo drug discrimination assay. Further, 2 was found to be a functionally selective agonist at the 5-HT(2A) receptor, having 65-fold greater potency in stimulating phosphoinositide turnover than in producing arachidonic acid release. If hallucinogenic effects are correlated with arachidonic acid production, such functionally selective 5-HT(2A) receptor agonists may lack the intoxicating properties of hallucinogens such as LSD.

Animals↗
PubMed2006

WAY-100635 is a potent dopamine D4 receptor agonist.

RATIONALE AND OBJECTIVES: WAY-100635 is a prototypical 5-HT1A receptor antagonist and has been used widely as a pharmacological probe to investigate the distribution and function of 5-HT1A receptors. Results from our studies suggested that WAY-100635 was potently inducing effects unrelated to its 5-HT1A receptor affinity. In the present work, we evaluated the in vitro pharmacology of this compound at two D2-like receptor subtypes. METHOD: The functional properties and binding affinities of WAY-100635 were evaluated in HEK 293 cells stably expressing dopamine D2L or D4.4 receptors. RESULTS: Initial screens performed by the NIMH Psychoactive Drug Screening Program indicated that WAY-100635 displayed 940, 370, and 16 nM binding affinities at D2L, D3, and D4.2 receptors, respectively. Subsequent saturation analyses demonstrated that the Kd of [3H]WAY-100635 at D4.2 receptors was 2.4 nM, only tenfold higher than 5-HT1A. WAY-100635 and its major metabolite, WAY-100634, were potent agonists in HEK-D4.4 cells (EC50=9.7+/-2.2 and 0.65+/-0.2 nM, respectively). WAY-100635 behaved as a full agonist, and WAY-100634 was a nearly full agonist. In HEK-D2L cells, WAY-100635 weakly antagonized the effects of 300 nM quinpirole. Subsequent radioligand binding studies confirmed that WAY-100635 possesses high affinity for D4.4 receptors but binds weakly to D2L receptors (3.3+/-0.6 and 420+/-11 nM, respectively). CONCLUSIONS: This study demonstrates that WAY-100635 is not a "selective" 5-HT1A receptor antagonist, as previously reported, and conclusions drawn from studies that employed WAY-100635 as a selective 5-HT1A antagonist may need to be reevaluated.

Animals↗
PubMed2006

C-(4,5,6-trimethoxyindan-1-yl)methanamine: a mescaline analogue designed using a homology model of the 5-HT2A receptor.

A conformationally restricted analogue of mescaline, C-(4,5,6-trimethoxyindan-1-yl)-methanamine, was designed using a 5-HT(2A) receptor homology model. The compound possessed 3-fold higher affinity and potency than and efficacy equal to that of mescaline at the 5-HT(2A) receptor. The new analogue substituted fully for LSD in drug discrimination studies and was 5-fold more potent than mescaline. Resolution of this analogue into its enantiomers corroborated the docking experiments, showing the R-(+) isomer to have higher affinity and potency and to have efficacy similar to that of mescaline at the 5-HT(2A) receptor.

Animals↗
PubMed2006

Functional selectivity and classical concepts of quantitative pharmacology.

The concept of intrinsic efficacy has been enshrined in pharmacology for half of a century, yet recent data have revealed that many ligands can differentially activate signaling pathways mediated via a single G protein-coupled receptor in a manner that challenges the traditional definition of intrinsic efficacy. Some terms for this phenomenon include functional selectivity, agonist-directed trafficking, and biased agonism. At the extreme, functionally selective ligands may be both agonists and antagonists at different functions mediated by the same receptor. Data illustrating this phenomenon are presented from serotonin, opioid, dopamine, vasopressin, and adrenergic receptor systems. A variety of mechanisms may influence this apparently ubiquitous phenomenon. It may be initiated by differences in ligand-induced intermediate conformational states, as shown for the beta(2)-adrenergic receptor. Subsequent mechanisms that may play a role include diversity of G proteins, scaffolding and signaling partners, and receptor oligomers. Clearly, expanded research is needed to elucidate the proximal (e.g., how functionally selective ligands cause conformational changes that initiate differential signaling), intermediate (mechanisms that translate conformation changes into differential signaling), and distal mechanisms (differential effects on target tissue or organism). Besides the heuristically interesting nature of functional selectivity, there is a clear impact on drug discovery, because this mechanism raises the possibility of selecting or designing novel ligands that differentially activate only a subset of functions of a single receptor, thereby optimizing therapeutic action. It also may be timely to revise classic concepts in quantitative pharmacology and relevant pharmacological conventions to incorporate these new concepts.

Animals↗
PubMed2006

Engineered zinc-binding sites confirm proximity and orientation of transmembrane helices I and III in the human serotonin transporter.

The human serotonin transporter (hSERT) regulates neurotransmission by removing released serotonin (5-HT) from the synapse. Previous studies identified residues in SERT transmembrane helices (TMHs) I and III as interaction sites for substrates and antagonists. Despite an abundance of data supporting a 12-TMH topology, the arrangement of the TMHs in SERT and other biogenic amine transporters remains undetermined. A high-resolution structure of a bacterial leucine transporter that demonstrates homology with SERT has been reported, thus providing the basis for the development of a SERT model. Zn2+-binding sites have been utilized in transporters and receptors to define experimentally TMH proximity. Focusing on residues near the extracellular ends of hSERT TMHs I and III, we engineered potential Zn2+-binding sites between V102 or W103 (TMH I) and I179-L184 (TMH III). Residues were mutated to either histidine or cysteine. TMH I/III double mutants were constructed from functional TMH I mutants, and Zn2+ sensitivity was assessed. Dose-response assays suggest an approximately twofold increase in sensitivity to Zn2+ inhibition at the hSERT V102C/M180C and approximately fourfold at the V102C/I179C mutant compared to the hSERT V102C single mutant. We propose that the increased sensitivity to Zn2+ confirms the proximity and the orientation of TMHs I and III in the membrane. Homology modeling of the proposed Zn2+-binding sites using the coordinates of the Aquifex aeolicus leucine transporter structure provided a structural basis for interpreting the results and developing conclusions.

Amino Acid Substitution↗
PubMed2005

Differential phospholipase C activation by phenylalkylamine serotonin 5-HT 2A receptor agonists.

Experiments compared a series of phenethylamine hallucinogens with their phenylisopropylamine analogues for binding affinity and ability to stimulate serotonin 5-HT 2A receptor-mediated hydrolysis of phosphatidyl inositol in cells expressing cloned rat and human 5-HT 2A receptors. The (+/-)phenylisopropylamine analogues had significantly higher intrinsic activities for 5-HT 2A receptor-mediated hydrolysis of phosphatidyl inositol compared to their phenethylamine analogues. With respect to the effects of the stereochemistry of the phenylisopropylamines, those with the (R) absolute configuration at the alpha carbon had higher intrinsic activities for hydrolysis of phosphatidyl inositol in a cell line expressing the human 5-HT 2A receptor compared to those with the (S) absolute configuration. In virtual docking studies comparing the (R)- and (S)-phenylisopropylamines with their phenethylamine analogues, there were distinct differences in the orientations of key ligand binding domain residues that have been identified as important by previous mutagenesis studies. In conclusion, our data support the hypothesis that phenylisopropylamines have higher hallucinogenic potency than their phenethylamine analogues primarily because they have higher intrinsic activities at 5-HT 2A receptors. Although virtual ligand binding led to significant perturbations of certain key residues, our results emphasize the conclusion reached by others that overall three-dimensional structural microdomains within the receptor must be considered.

Animals↗
PubMed2005

Differential activation of adenylate cyclase and receptor internalization by novel dopamine D1 receptor agonists.

Structurally dissimilar dopamine D(1) receptor agonists were compared with dopamine in their ability to activate adenylate cyclase and to internalize hemagglutinin-tagged human D(1) receptors in a stably transfected human embryonic kidney cell line. Thirteen dopamine D(1) receptor agonists were selected rationally from three different structural classes: rigid fused ring compounds [dihydrexidine, dinapsoline, dinoxyline, apomorphine, and (5aR,11bS)-4,5,5a,6,7,11b-hexahydro-2-propyl-3-thia-5-azacyclopent-1-ena[c]-phenanthrene-9,10-diol (A86929)]; isochromans [(1R,3S)-3-(1'adamantyl)-1-aminomethyl-3,4-dihydo-5,6-dihydroxy-1H-2-benzopyran (A77636) and (1R,3S)-3-phenyl-1-aminomethyl-3,4-dihydo-5,6-dihydroxy-1H-2-benzopyran (A68930)]; and benzazepines [7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SKF38393), (+/-)-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SKF77434), 6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SKF82958), 3-methyl-6-chloro-7,8-hydroxy-1-[3-methylphenyl]-2,3,4,5-tetrahydro-]H-3-benzazepine (SKF83959), R(+)-6-chloro-7,8,-dihydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SKF82957), and R(+)-6-chloro-7,8,-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SKF81297)]. The working hypothesis was that some agonists have differential effects on adenylate cyclase versus receptor internalization that could be correlated to the structural class of the agonist. First, the affinity for the hemagglutinin-hD(1) receptor and the intrinsic activity and potency of adenylate cyclase activation were determined for each compound. The internalization time course and internalization efficacy were then determined for each agonist. It was surprising that internalization efficacy was found to be independent of either agonist structural class or affinity. Only agonists that had both high adenylate cyclase functional potency and high intrinsic activity caused internalization. In addition, four agonists from two structural classes were identified that were capable of fully activating adenylate cyclase without eliciting an internalization response. This study provides the first extensive characterization of D(1) receptor internalization in response to structurally diverse agonists and, at least for the D(1) receptor, shows that functional selectivity is not predictable by simple structural examination. These data are consistent with the hypothesis that functional selectivity reflects subtle ligand-induced conformational changes as opposed to simple agonist trafficking among discrete receptor active states.

Adenylyl Cyclases↗
PubMed2005

Sulfur-substituted alpha-alkyl phenethylamines as selective and reversible MAO-A inhibitors: biological activities, CoMFA analysis, and active site modeling.

A series of phenethylamine derivatives with various ring substituents and with or without N-methyl and/or C-alpha methyl or ethyl groups was synthesized and assayed for their ability reversibly to inhibit monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B). Several compounds showed potent and selective MAO-A inhibitory activity (IC(50) in the submicromolar range) but none showed appreciable activity toward MAO-B. A three-dimensional quantitative structure-activity relationship study for MAO-A inhibition was performed on the series using comparative molecular field analysis (CoMFA). The resulting model gave a cross-validated q(2) of 0.72 and showed that in this series of compounds steric properties of the substituents were more important than electrostatic effects. Molecular modeling based on the recently published crystal structure of inhibitor-bound MAO-A provided detailed evidence for specific interactions of the ligands with the enzyme, supported by previous references and consistent with results from the CoMFA. On the basis of these results, structural determinants for selectivity of substituted amphetamines for MAO-A are discussed.

Animals↗
PubMed2005

Distinct temporal phases in the behavioral pharmacology of LSD: dopamine D2 receptor-mediated effects in the rat and implications for psychosis.

RATIONALE: The effect of LSD in humans has been described as occurring in two temporal phases. The behavioral effects in rats also occur in two temporal phases: an initial suppression of exploration followed by increased locomotor activity. OBJECTIVES: We decided to investigate this phenomenon from the perspective that the pharmacology might have relevance to the neurochemical mechanisms underlying psychosis. METHODS: Twenty-five male Sprague-Dawley rats were trained to discriminate LSD (186 nmol/kg, 0.08 mg/kg, i.p.) with a 30-min preinjection time (LSD-30, N=12) and LSD (372 nmol/kg, 0.16 mg/kg, i.p.) with a 90-min preinjection time (LSD-90, N=13) from saline, using a two-lever, food-reinforced operant conditioning task. RESULTS: LSD (186 or 372 nmol/kg, 0.08 or 0.16 mg/kg) given 30 min prior to training produced a cue that was completely antagonized by 5-HT2A antagonists and lasted no longer than 1 h. LSD (372 nmol/kg, 0.16 mg/kg) injected 90 min before training produced a cue that was not fully blocked by 5-HT2A antagonists, but instead was significantly inhibited by haloperidol. In these rats, substitution no longer occurred with the 5-HT2 agonists DOI or LSD (30 min preinjection), but full substitution was obtained with the D2 agonists apomorphine, N-propyldihydrexidine, and quinelorane. CONCLUSION: The discriminative stimulus effect of LSD in rats occurs in two phases, and these studies provide evidence that the later temporal phase is mediated by D2 dopamine receptor stimulation. A second temporal phase that involves dopaminergic pathways would be consistent with the widespread belief that excessive dopaminergic activity may be an underlying cause of paranoid psychosis.

Amphetamine↗
PubMed2004

3,4-methylenedioxymethamphetamine (MDMA, ecstasy)-mediated production of hydrogen peroxide in an in vitro model: the role of dopamine, the serotonin-reuptake transporter, and monoamine oxidase-B.

3,4-methylenedioxymethamphetamine (MDMA, ecstasy) has been shown to induce long-term deficits in serotonergic function in animal models. Several studies have suggested that dopamine (DA) uptake into serotonin (5-HT) terminals by the 5-HT reuptake transporter (SERT) and subsequent deamination by monoamine oxidase-B (MAO-B) leads to the formation of hydrogen peroxide and may be major contributors to this serotonergic toxicity. In the present study, when human choriocarcinoma (JAR) cells were exposed to MDMA (1.2 mM) for 6h, followed by treatment with DA (0.1 mM), hydrogen peroxide production increased over a 24 h period, peaking at 420% over baseline and decreasing cell viability by 30%. DA alone increased hydrogen peroxide production 84% over baseline, but did not significantly decrease cell viability. Incubation of MDMA treated cells with the SERT inhibitor, fluoxetine (500 nM) or the MAO-B inhibitor, L-deprenyl (0.1 mM) for 30 min prior to DA, significantly blocked free radical production and cell death. These findings support the hypothesis that the deamination of DA by MAO-B within the serotonergic cell can lead to hydrogen peroxide formation and ultimately cell death.

Cell Line, Tumor↗
PubMed2004

8,9-dihydroxy-1,2,3,11b-tetrahydrochromeno[4,3,2,-de]isoquinoline (dinoxyline), a high affinity and potent agonist at all dopamine receptor isoforms.

The synthesis and preliminary pharmacological evaluation of 8,9-dihydroxy-1,2,3,11b-tetrahydrochromeno[4,3,2,-de]isoquinoline (5, now named dinoxyline) is described. This molecule was designed as a potential bioisostere that would conserve the essential elements of our beta-phenyldopamine D(1) pharmacophore (i.e., position and orientation of the nitrogen, hydroxyls, and phenyl rings). Previously, we have rigidified these elements using alkyl bridges, as exemplified in the dopamine D(1) full agonist molecules dihydrexidine (1) and dinapsoline (2). This approach has been modified and we now show that it is possible to tether these elements using an ether linkage. Preliminary pharmacology has revealed that 5 is a potent full D(1) agonist (K(0.5) <10 nM; EC(50)=30 nM), but also has high affinity for brain D(2)-like and cloned D(2) and D(3) receptors. Interestingly, whereas 1 and 2 and their analogues have only moderate affinity for the human D(4) receptor, 5 also has high affinity for this isoform. Moreover, although N-alkylation of 1 and 2 increases D(2) affinity, the N-allyl (15) and N-n-propyl (17) derivatives of 5 had decreased D(2) affinity. Therefore, 5 may be engaging different amino acid residues than do 1 and 2 when they bind to the D(2) receptor. This is the first example of a ligand with high affinity at all dopamine receptors, yet with functional characteristics similar to dopamine. These rigid ligands also will be useful tools to determine specific residues of the receptor transmembrane domains that are critical for agonist ligand selectivity for the D(4) receptor.

Animals↗
PubMed2004

Synthesis and SAR exploration of dinapsoline analogues.

Dinapsoline is a full D(1) dopamine receptor agonist that produces robust rotational activity in the unilateral 6-OHDA rat model. This compound is orally active, and shows a low tendency to cause tolerance in rat models. The active enantiomer was determined to have the S-(+) configuration, and the opposite enantiomer is essentially devoid of biological activity. Taken together, dinapsoline has significant metabolic and pharmacological advantages over previous D(1) agonists. In an attempt to define the structure-activity relationships (SARs) and to map out the key elements surrounding the unique structure of dinapsoline, core analogues and substitution analogues of the parent tetracyclic condensed ring structure were prepared. Based on a recently developed synthesis of dinapsoline and its enantiomers, both core and substitution analogues on all four rings (A, B', C and D ring) of dinapsoline were synthesized. It was found that affinity for both D(1)and D(2) receptors was decreased by most substituents on the A, B', and C rings, whereas D ring substitutions preserved much of the dopamine receptor binding activity.

Adenylyl Cyclases↗
PubMed2004

Hallucinogens.

Hallucinogens (psychedelics) are psychoactive substances that powerfully alter perception, mood, and a host of cognitive processes. They are considered physiologically safe and do not produce dependence or addiction. Their origin predates written history, and they were employed by early cultures in a variety of sociocultural and ritual contexts. In the 1950s, after the virtually contemporaneous discovery of both serotonin (5-HT) and lysergic acid diethylamide (LSD-25), early brain research focused intensely on the possibility that LSD or other hallucinogens had a serotonergic basis of action and reinforced the idea that 5-HT was an important neurotransmitter in brain. These ideas were eventually proven, and today it is believed that hallucinogens stimulate 5-HT(2A) receptors, especially those expressed on neocortical pyramidal cells. Activation of 5-HT(2A) receptors also leads to increased cortical glutamate levels presumably by a presynaptic receptor-mediated release from thalamic afferents. These findings have led to comparisons of the effects of classical hallucinogens with certain aspects of acute psychosis and to a focus on thalamocortical interactions as key to understanding both the action of these substances and the neuroanatomical sites involved in altered states of consciousness (ASC). In vivo brain imaging in humans using [(18)F]fluorodeoxyglucose has shown that hallucinogens increase prefrontal cortical metabolism, and correlations have been developed between activity in specific brain areas and psychological elements of the ASC produced by hallucinogens. The 5-HT(2A) receptor clearly plays an essential role in cognitive processing, including working memory, and ligands for this receptor may be extremely useful tools for future cognitive neuroscience research. In addition, it appears entirely possible that utility may still emerge for the use of hallucinogens in treating alcoholism, substance abuse, and certain psychiatric disorders.

Alcoholism↗