Demographic Analysis of Industry-Sponsored Alzheimer's Disease Trial Populations in the United States.

The Food and Drug Administration has that "sponsors should enroll participants who reflect the characteristics of clinically relevant populations". Recent reports have noted that global Alzheimer's Disease trials have enrolled predominantly White subjects. However, a thorough analysis of industry-sponsored, United States-only Alzheimer's trials has yet to be performed. A search of the clinicaltrials.gov database and PubMed identified 101 industry-sponsored Alzheimer's trials, performed solely in the United States, with gender data. The percentage of male (46%) vs. female (54%) subjects was higher than expected compared to real-world data. There were 50 Alzheimer's trials with race data. There was a significant overrepresentation of White subjects (92%) compared to all other race groups. These data suggest that significant modifications of subject recruitment methods are needed to increase the enrollment of underrepresented populations into Alzheimer's trials of potential new therapeutic agents in the United States.

Long-term antidepressant treatment decreases spiroperidol-labeled serotonin receptor binding.

Antidepressants compete at several neurotransmitter receptor binding site, but drug affinities do not correlate with clinical efficacy. Long-term, but not short-term, antidepressant treatment decreases the numbers of both serotonin and beta-adrenergic receptors. The decrease in the number of receptor sites is most marked for [3H]spiroperidol-labeled serotonin receptors and is characteristic for antidepressants of several classes.

Two distinct central serotonin receptors with different physiological functions.

Two distinct serotonin (5-hydroxytryptamine) receptors designated serotonin 1 and serotonin 2 bind tritium-labeled serotonin and tritium-labeled spiroperidol, respectively. Drug potencies at serotonin 2 sites, but not at serotonin 1 sites, predict their effects on the "serotonin behavioral syndrome," indicating that serotonin 2 sites mediate these behaviors. The limited correlation of drug effects with regulation by guanine nucleotides suggests that serotonin 1 sites might be linked to adenylate cyclase. Drug specificities of serotonin-elicited synaptic inhibition and excitation may reflect serotonin 1 and serotonin 2 receptor interactions, respectively.

Neurotransmitter receptor binding in bovine cerebral microvessels.

Purified preparations of microvessels from bovine cerebral cortex contain substantial levels of alpha-adrenergic, beta-adrenergic, and histamine 1 receptor binding sites but only negligible serotonin, muscarinic cholinergic, opiate, and benzodiazepine receptor binding. Norepinephrine and histamine may be endogenous regulators of the cerebral microcirculation at the observed receptors.

The medical utility of genomics data in neuropsychiatry: mutational genetics versus association genetics.

The long anticipated 'genetic revolution' in neuropsychiatry has yet to have an impact on the practice of clinical medicine. Excitement in the 1980s over major genetic breakthroughs in schizophrenia and manic depression, for example, has been replaced in the late 1990s by the sobering realization that most common neuropsychiatric disorders are multifactorial. Despite considerable effort and resources, no 'causative' genetic variation has been identified that plays a definitive major role in any common neuropsychiatric disorder.

Selective interaction of novel anxiolytics with 5-hydroxytryptamine1A receptors.

Radioligand binding studies were used to analyze the interactions of two novel anxiolytics, buspirone and TVX Q 7821, with a series of 10 neuronal membrane receptor sites. Buspirone (IC50 = 24 nM) and TVX Q 7821 (IC50 = 9.5 nM) display the highest affinity for 5-hydroxytryptamine1A (5-HT1A) binding sites labeled by 3H-8-hydroxy-2-(di-n-pro-pylamino) tetralin (DPAT). By contrast, buspirone is 16-fold weaker at dopamine (D2) receptors (IC50 = 380 nM), whereas TVX Q 7821 is 6-fold less potent at alpha-adrenergic1 sites (IC50 = 58 nM). At the other receptors studied, buspirone and TVX Q 7821 had similar pharmacological profiles. Both agents display moderate affinity for histamine (H1), alpha-adrenergic2, and 5-HT2 binding sites. The drugs are essentially inactive at 5-HT1B, calcium channel antagonist, muscarinic cholinergic, and benzodiazepine receptors. These results suggest that the anxiolytic effects of buspirone and TVX Q 7821 may be mediated by central 5-HT1A receptors.

1-(m-chlorophenyl)piperazine (mCPP) interactions with neurotransmitter receptors in the human brain.

The affinity of 1-(m-chlorophenyl)piperazine (mCPP) for 11 neurotransmitter receptor binding sites was determined in human brain membranes. mCPP is essentially equipotent at all 5-hydroxytryptamine (5-HT) receptor subtypes (IC50 values ranging from 360 to 1300 nM). The drug displays similar affinity (IC50 = 570 nM for alpha 2-adrenergic receptors labeled for 3H-rauwolscine. mCPP is less potent at alpha 1- and beta-adrenergic, dopamine, and muscarinic cholinergic receptors (IC50 values 2500-24,000 nM). mCPP is inactive at both benzodiazepine receptors and the 5-HT uptake sites at concentrations below 100,000 nM. These data demonstrate that mCPP displays similar potency for multiple neurotransmitter receptor binding sites in human brain.

Differential modulation of dopamine D2 receptors by chronic haloperidol, nitrendipine, and pimozide.

Chronic administration of the neuroleptic haloperidol, the calcium channel antagonist nitrendipine, and the calcium channel antagonist neuroleptic pimozide produce differential effects on rat striatal 3H-spiperone binding. Following 7 days of 10 mg/kg i.p. administration, haloperidol significantly increases (p less than 0.01) dopamine D2 receptor binding to 123% +/- 6% of control values, whereas pimozide treatment significantly reduces (p less than 0.001) striatal 3H-spiperone binding to 46% +/- 6% of control values. Chronic administration of the calcium channel antagonist nitrendipine does not alter 3H-spiperone binding relative to control values. Saturation analysis reveals an increase in Bmax following chronic haloperidol and a decrease in Bmax following chronic pimozide treatment. No alterations in muscarinic cholinergic sites, dopamine uptake sites, or calcium channel antagonist sites result following chronic drug administration. These results are the first demonstration of a decrease in dopamine D2 binding sites after chronic neuroleptic treatment.

Analysis of tandospirone (SM-3997) interactions with neurotransmitter receptor binding sites.

The interactions of tandospirone (formerly called SM-3997) with 5-HT and other neurotransmitter receptor binding sites were determined in brain homogenates. Tandospirone is most potent at the 5-HT1A receptor, displaying a Ki value of 27 +/- 5 nM. The agent is approximately two to three orders of magnitude less potent at 5-HT2, 5-HT1C, alpha 1-adrenergic, alpha 2-adrenergic, and dopamine D1 and D2 receptors (Ki values ranging from 1300 to 41000 nM). Tandospirone is essentially inactive at 5-HT1B receptors; 5-HT uptake sites; beta-adrenergic, muscarinic cholinergic, and benzodiazepine receptors. This pharmacological profile differs slightly from that of other novel anxiolytics such as buspirone, ipsapirone, and gepirone. Saturation and competition studies using 3H-tandospirone also suggest that the drug interacts with 5-HT1A receptor binding sites in rat cortical membranes (KD = 4.5 +/- 0.8 nM; Bmax = 2.2 +/- 0.6 pmol/g tissue). Based on adenylate cyclase studies which measure 5-HT1A receptor-mediated effects, tandospirone displays approximately 60% of the agonist effect of 8-OH-DPAT, a selective 5-HT1A agonist. Thus, the primary pharmacological effect of tandospirone appears to be partial agonism at the 5-HT1A receptor, an activity similar to other pyrimidinyl-piperazines which are being developed as novel anxiolytic agents.

An Alu sequence interrupts a human 5-hydroxytryptamine1D receptor pseudogene.

Molecular cloning studies have now identified six HTR genes encoding the biosynthesis of the structurally homologous human serotonin (5-hydroxytryptamine; 5-HT) receptors, namely 5-HTR1A, 5-HTR1B, 5-HTR1C, 5-HTR1D, 5-HTR2 and 5-HTRS31. Several of these receptors are encoded by intronless genes, and we now report the cloning of another intronless serotonergic HTR gene. This gene was cloned by a method using the polymerase chain reaction. The nucleotide sequence of this gene is most closely homologous to the 5-HTR1D gene; however, several stop codons, frame shifts and deletions are present in the coding region suggesting that this is a pseudogene which could not encode a functional receptor. Sequence analysis also revealed that the coding sequence of this pseudogene is disrupted by insertion of a 283-bp Alu repeat sequence.

Relationship of neuroleptic drug effects at brain dopamine, serotonin, alpha-adrenergic, and histamine receptors to clinical potency.

The authors examined the potencies of 22 neuroleptic drugs competing for binding sites associated with dopamine, serotonin, alpha-adrenergic, and histamine receptors in brain membranes. They found that although many neuroleptics are quite potent in competing at several of these receptor sites, the average antipsychotic clinical potency correlates closely only with the drug affinity for dopamine receptors labeled by 3H-spiroperidol At clinically effective doses, however, substantial occupancy of serotonin, alpha-adrenergic, and histamine receptors often occurs and may account for some of the auxiliary actions of neuroleptics.

5-Hydroxytryptamine receptor subtypes and the pharmacology of migraine.

Multiple 5-hydroxytryptamine (5-HT) receptors have been identified in the human nervous system. A subgroup of these receptors, designated 5-HT1 receptors, appears to be involved in the mechanism of action of acute antimigraine agents. This review summarizes data indicating that compounds with proven efficacy in the acute treatment of migraine are agonist at human 5-HT1 receptors. Further studies are cited to support two possible mechanisms of action for the efficacy of 5-HT1 agonists in treating migraine. It seems likely that a single 5-HT1 receptor subtype may be found in the near future to be the final common pathway in the mechanism of action of acute antimigraine agents.

Dopamine and migraine.

This review summarizes a growing body of biological, pharmacologic, and genetic data that support a role for dopamine in the pathophysiology of certain subtypes of migraine. Most migraine symptoms can be induced by dopaminergic stimulation. Moreover, there is dopamine receptor hypersensitivity in migraineurs, as demonstrated by the induction of yawning, nausea, vomiting, hypotension, and other symptoms of a migraine attack by dopaminergic agonists at doses that do not affect nonmigraineurs. Conversely, dopamine receptor antagonists are effective therapeutic agents in migraine. Recent genetic data suggest that molecular variations within dopamine receptor genes play a modifying role in the pathophysiology of migraine with aura. Therefore, modulation of dopaminergic neurotransmission should be considered in the therapeutic management of migraine.

The calcium antagonist properties of cyproheptadine: implications for antimigraine action.

Cyproheptadine is equipotent (IC50 = 41 to 45 nM) in blocking contractions of canine basilar artery segments induced by serotonin, norepinephrine, potassium, or calcium. Methysergide and amitriptyline display variable potencies in inhibiting contractions depending on the initiating agent. Propranolol, at concentrations to 10 micromolar, had minimal effect on vessel contractions. We conclude that the primary action of cyproheptadine in preventing induced contractions of the canine basilar artery is antagonism of calcium channels. This action is unique among drugs used for migraine prophylaxis and may have important implications for the treatment of headache and other neurologic disorders.

Clinical susceptibility to migraine with aura is modified by dopamine D2 receptor (DRD2) NcoI alleles.

Migraine has a major genetic component. Although most recent scientific studies have focused on the role of 5-hydroxytryptamine and neuropeptides in migraine, dopaminergic systems are also implicated in the pathogenesis. Therefore, the dopamine D2 receptor (DRD2) was analyzed as a candidate gene since antagonists of this receptor have been reported to be effective in the acute treatment of migraine. Individuals with migraine with aura (n = 52) have an increased frequency (0.84) of the DRD2 NcoI C allele (chi-square = 6.47; p < 0.005) compared with control individuals (n = 121; C allele frequency = 0.71). Individuals with migraine without aura (n = 77) showed the same DRD2 T allele frequency (0.70) as the control group. Migraine with aura was present in 27% of the C/C individuals, 16% of the C/T individuals, and 5.2% of the T/T individuals. These data suggest that activation of the DRD2 receptor plays a modifying role in the pathophysiology of migraine with aura. As a result, these data provide a molecular rationale for the documented efficacy of DRD2 antagonists in the treatment of migraine with aura.

Treatment of lethal pertussis vaccine reaction with histamine H1 antagonists.

We studied mortality after pertussis immunization in the mouse. Without treatment, 73 of 92 animals (80%) died after injection of bovine serum albumin (BSA) on day +7 of pertussis immunization. After pretreatment with 3 mg of cyproheptadine, 2 mg mianserin, or 2 mg chlorpheniramine, only 5 of 105 animals (5%) died after receiving BSA on day +7 (p less than 0.001). Blockade of histamine H1 receptors may reduce mortality in pertussis immunization-induced encephalopathy in mice.

Nifedipine in the prophylaxis of classic migraine: a crossover, double-masked, placebo-controlled study of headache frequency and side effects.

Twenty-four patients with classic migraine attacks were treated with either nifedipine or placebo for up to 12 weeks. No significant differences were observed between the nifedipine (2.1 +/- 0.2) and placebo (2.3 +/- 0.2) treatment groups in the monthly frequency of headaches. However, the incidence of side effects was significantly greater (p less than 0.001) in the nifedipine (54% of patients) than in the placebo (8% of patients) treatment groups.

Antagonist properties of d-LSD at 5-hydroxytryptamine2 receptors.

The hallucinogenic agent d-lysergic acid diethylamide (d-LSD) interacts with a number of serotonin (5-hydroxytryptamine [5-HT]) receptor subtypes in the central nervous system. It has been hypothesized that hallucinosis is produced by agonist activity at 5-HT2 receptors. There exist, however, numerous data from radioligand binding, cellular, smooth muscle, and behavioral studies that suggest that d-LSD is a potent 5-HT2 antagonist. These data are reviewed in this report. In addition, d-LSD displays agonist activity at 5-HT1A and 5-HT1C receptor subtypes, as determined in biochemical studies. At the present time, agonist interactions at 5-HT1C receptors, as opposed to 5-HT2 receptors, appears to be a more likely "common mechanism of action" of hallucinogenic agents.

Subjective effects of 3,4-methylenedioxymethamphetamine in recreational users.

3,4-Methylenedioxymethamphetamine (MDMA; Ecstasy) is a serotonergic neurotoxin in laboratory animals that has been used for recreational purposes by humans. The subjective effects of this drug were determined in recreational users at a university campus. Of individuals who had admitted to using MDMA recreationally, 100 of 143 agreed to complete a detailed questionnaire concerning the subjective effects of this Schedule I compound. The most common effect of MDMA was a heightened sense of "closeness" with other people (90% of subjects). Tachycardia, dry mouth, bruxism and/or trismus were reported by the majority of users. These effects probably result from the amphetaminelike properties of the drug. Visual hallucinations were reported by 20% of users. Untoward side effects were most common on the day following the use of MDMA, with complaints of muscle aches, fatiguability, depression, and difficulty concentrating noted by 21% to 36% of subjects. Sixty-seven percent of frequent users of the drug (six or more separate doses) reported that the "positive" effects of the drug decreased with successive doses while the "negative" effects increased. Although these observations should be considered preliminary, they represent the first documentation of the subjective effects of MDMA in recreational users and confirm previous reports obtained from patients treated with this drug.

Phylogenetic tree analysis of G protein-coupled 5-HT receptors: implications for receptor nomenclature.

The nomenclature system used to characterize 5-hydroxytryptamine receptor subtypes remains controversial. To date, the majority of nomenclature systems have been on the differential pharmacological properties of the receptors. However, the availability of molecular biological data allows for a nomenclature system based on the structural properties of the receptors. The evolutionary relationships between the known G protein-coupled 5-HT receptor subtypes were determined by a phylogenetic tree analysis. The data indicate that 2 major classes of G protein-coupled 5-HT receptors have evolved. Each of the 2 branches differentiate into additional 5-HT receptor subtypes. The most recent branching of 5-HT receptor subtypes occurs at the level of individual species. These data also indicate that the degree of structural similarity (e.g. 93% identify between human and rat 5-HT1B receptors) does not necessarily correlate with pharmacological similarity. Phylogenetic tree analysis allows for a nomenclature framework that can be easily expanded to incorporate additional 5-HT receptor subtypes that have yet to be identified.