Bidirectional changes in ethanol consumption in rats with site-specific antisense down-regulation of 5-hydroxytryptamine2A receptors in brain. (41/566)

The 5-hydroxytryptamine (5-HT)2A receptor is an important component of the neural substrates underlying ethanol (EtOH) intake and behaviors related to anxiety and stress. Paradoxically, both 5-HT2A agonists and antagonists have been shown to reduce EtOH intake, however the mechanisms underlying these effects are not understood. This inconsistency could possibly be explained by their chronic down-regulation of the 5-HT2A receptor. To further address these findings, the present study sought to functionally characterize the role of localized 5-HT2A receptors in regulating EtOH ingestion by producing central nervous system site-specific receptor down-regulation through infusion of antisense oligonucleotide (ASO). Rats were infused with 5-HT2A receptor ASO into the lateral ventricle (i.c.v.), prefrontal cortex (PFC), central amygdaloid nucleus, medial and lateral division (CeA/L), dorsal raphe nucleus (DRN), or hippocampus (HIP) for a period of 26 days. Subjects were tested for EtOH intake and behaviors related to anxiety and stress. ASO administration i.c.v. and into the CeA/L significantly reduced EtOH intake. PFC 5-HT2A ASO administration increased EtOH intake. Administration of 5-HT2A ASO into the DRN and HIP had no effect on EtOH intake. Intracerebroventricular ASO administration increased activity in a novel open field and increased anxiety-like behavior in the elevated plus maze. PFC ASO administration produced an anxiogenic effect in the elevated plus maze. Intracerbroventricular, PFC, and CeA/L ASO infusions altered adrenocortical function. These differential behavioral effects specific to the anatomical locations targeted for 5-HT2A receptor down-regulation may help resolve a long-standing, apparent inconsistency in the role of 5-HT2A receptors in EtOH consumption.  (+info)

RNA-editing of the 5-HT(2C) receptor alters agonist-receptor-effector coupling specificity. (42/566)

1. The serotonin(2C) (5-HT(2C)) receptor couples to both phospholipase C (PLC)-inositol phosphate (IP) and phospholipase A(2) (PLA(2))-arachidonic acid (AA) signalling cascades. Agonists can differentially activate these effectors (i.e. agonist-directed trafficking of receptor stimulus) perhaps due to agonist-specific receptor conformations which differentially couple to/activate transducer molecules (e.g. G proteins). Since editing of RNA transcripts of the human 5-HT(2C) receptor leads to substitution of amino acids at positions 156, 158 and 160 of the putative second intracellular loop, a region important for G protein coupling, we examined the capacity of agonists to activate both the PLC-IP and PLA(2)-AA pathways in CHO cells stably expressing two major, fully RNA-edited isoforms (5-HT(2C-VSV), 5-HT(2C-VGV)) of the h5-HT(2C) receptor. 2. 5-HT increased AA release and IP accumulation in both 5-HT(2C-VSV) and 5-HT(2C-VGV) expressing cells. As expected, the potency of 5-HT for both RNA-edited isoforms for both responses was 10 fold lower relative to that of the non-edited receptor (5-HT(2C-INI)) when receptors were expressed at similar levels. 3. Consistent with our previous report, the efficacy order of two 5-HT receptor agonists (TFMPP and bufotenin) was reversed for AA release and IP accumulation at the non-edited receptor thus demonstrating agonist trafficking of receptor stimulus. However, with the RNA-edited receptor isoforms there was no difference in the relative efficacies of TFMPP or bufotenin for AA release and IP accumulation suggesting that the capacity for 5-HT(2C) agonists to traffic receptor stimulus is lost as a result of RNA editing. 4. These results suggest an important role for the second intracellular loop in transmitting agonist-specific information to signalling molecules.  (+info)

Characterization of the functional heterologous desensitization of hypothalamic 5-HT(1A) receptors after 5-HT(2A) receptor activation. (43/566)

Desensitization of 5-HT(1A) receptors could be involved in the long-term therapeutic effect of anxiolytic and antidepressant drugs. Pretreatment of rats with the 5-HT(2A/2C) agonist DOI induces an attenuation of hypothalamic 5-HT(1A) receptor-G(z)-protein signaling, measured as the ACTH and oxytocin responses to an injection of the 5-HT(1A) agonist 8-OH-DPAT. We characterized this functional heterologous desensitization of 5-HT(1A) receptors in rats and examined some of the mechanisms that are involved. A time course experiment revealed that DOI produces a delayed and reversible reduction of the ACTH and oxytocin responses to an 8-OH-DPAT challenge. The maximal desensitization occurred at 2 hr, and it disappeared 24 hr after DOI injection. The desensitization was dose-dependent, and it shifted the oxytocin and ACTH dose-response curves of 8-OH-DPAT to the right (increased ED(50)) with no change in their maximal responses (E(max)). The 5-HT(2A) receptor antagonist MDL 100,907 prevented the DOI-induced desensitization, indicating that 5-HT(2A) receptors mediate the effect of DOI. Analysis of the components of the 5-HT(1A) receptor-G(z)-protein signaling system showed that DOI did not alter the level of membrane-associated G(z)-proteins in the hypothalamus. Additionally, DOI did not alter the binding of [(3)H]8-OH-DPAT or the inhibition by GTPgammaS of [(3)H]8-OH-DPAT binding in the hypothalamus. In conclusion, the activation of 5-HT(2A) receptors induces a transient functional desensitization of 5-HT(1A) receptor signaling in the hypothalamus, which may occur distal to the 5-HT(1A) receptor-G(z)-protein interface.  (+info)

The pharmacology and toxicology of "ecstasy" (MDMA) and related drugs. (44/566)

"Ecstasy" (MDMA) and related drugs are amphetamine derivatives that also have some of the pharmacological properties of mescaline. They have become popular with participants in "raves," because they enhance energy, endurance, sociability and sexual arousal. This vogue among teenagers and young adults, together with the widespread belief that "ecstasy" is a safe drug, has led to a thriving illicit traffic in it. But these drugs also have serious toxic effects, both acute and chronic, that resemble those previously seen with other amphetamines and are caused by an excess of the same sympathomimetic actions for which the drugs are valued by the users. Neurotoxicity to the serotonergic system in the brain can also cause permanent physical and psychiatric problems. A detailed review of the literature has revealed over 87 "ecstasy"-related fatalities, caused by hyperpyrexia, rhabdomyolysis, intravascular coagulopathy, hepatic necrosis, cardiac arrhythmias, cerebrovascular accidents, and drug-related accidents or suicide. The toxic or even fatal dose range overlaps the range of recreational dosage. The available evidence does not yet permit an accurate assessment of the size of the problem presented by the use of these drugs.  (+info)

Fatalities caused by the MDMA-related drug paramethoxyamphetamine (PMA). (45/566)

The past several years have seen a marked increase in the recreational use of 3,4-methylenedioxymethamphetamine (MDMA) or "Ecstasy". MDMA use is especially common among young people participating in dance parties called "raves". Paramethoxyamphetamine (PMA) exhibits both structural and pharmacological similarity to MDMA. It may, however, be a more potent central stimulant, particularly in its effects on serotonergic transmission. Several fatalities from PMA have been reported in Australia, and here we report three recent fatalities that occurred in the midwestern United States in which each of the decedents believed that they were ingesting MDMA. Symptoms observed included agitation and bruxism, progressing to severe hyperthermia, convulsions, and hemorrhage. Blood was screened for drugs of abuse by enzyme immunoassay with the presence of amphetamines indicated in each case. Confirmation and quantitation for amphetamines was performed by gas chromatography-mass spectrometry. The deceased, two males ages 19 and 24 and a female age 18, had postmortem blood PMA concentrations of 1.07, 0.60, and 1.90 mg/L, respectively. PMA is not a contaminant of MDMA, and no MDMA was found in any of these cases. The primary metabolite of PMA is produced by O-demethylation to 4-hydroxyamphetamine, a reaction catalyzed by cytochrome P450 2D6. This enzyme is noted to be genetically polymorphic. Those with the "slow metabolizer" phenotype may be likely to have higher peak blood concentrations of PMA. Whether any of the decedents described herein were of the slow metabolizer phenotype is not known. Several groups have advocated the onsite use of the Marquis Test for the purpose of pill screening in efforts to distinguish PMA from MDMA. A dark purple is consistent with MDMA, whereas PMA imparts no color change in this test. PMA is often in the form of a white pill with a Mitsubishi symbol on one side. This design has been identified in at least one of these fatalities.  (+info)

Three cases of fatal paramethoxyamphetamine overdose. (46/566)

Two recent cases of death due to paramethoxyamphetamine (PMA), a methoxylated phenylethylamine derivative, are described and compared with a previous PMA death that occurred in this province in 1985. The deceased were 18 or 19 years of age and were reported to have ingested either methylenedioxymethamphetamine (MDMA, Ecstasy) or methylenedioxyamphetamine (MDA) prior to their deaths. Concentrations of PMA were measured in both peripheral and heart blood samples using gas chromatography equipped with a nitrogen-phosphorus detector. PMA results in the most recent cases were 0.6 mg/L and 1.3 mg/L in the peripheral blood samples, and corresponding heart blood samples were 0.7 mg/L and 2.3 mg/L, respectively. In the 1985 case, the femoral blood concentration was 0.6 mg/L, and the heart blood concentration was 0.8 mg/L. Significant differences between heart and peripheral blood concentrations were observed in two of the three cases, which may indicate the potential for postmortem redistribution of PMA.  (+info)

A contemporaneous finding of fenproporex in a polydrug suicide. (47/566)

Fenproporex is a sympathomimetic agent with a pharmacological profile similar to that of amphetamine. It is available in many countries throughout the world, but it is currently not available in the United States. Because of its stimulant effects, it has a great potential for abuse. To the best of our knowledge, there have been no literature reports of blood or serum concentrations found in therapeutic, toxic, or fatal cases. We report a case where fenproporex was a finding in the death of a young adult. Blood, urine, and gastric contents were analyzed. The following drug concentrations were found: 0.90 mg/L (inferior vena cava blood), 1.2 mg/L (urine), and 120 mg total (gastric) for fenproporex and 0.084 mg/L (inferior vena cava blood), 0.94 mg/L (urine), and 0.14 mg total (gastric) for amphetamine. In addition to the fenproporex, other medications detected and their blood concentrations found in this case were H diazepam (0.54 mg/L), nordiazepam (0.46 mg/L), diphenhydramine (0.12 mg/L), and gamma hydroxybutyric acid (GHB) (1100 mg/L).  (+info)

Serotonin(2) receptors mediate respiratory recovery after cervical spinal cord hemisection in adult rats. (48/566)

The aim of the present study was to specifically investigate the involvement of serotonin [5-hydroxytryptamine (5-HT(2))] receptors in 5-HT-mediated respiratory recovery after cervical hemisection. Experiments were conducted on C(2) spinal cord-hemisected, anesthetized (chloral hydrate, 400 mg/kg ip), vagotomized, pancuronium- paralyzed, and artificially ventilated female Sprague-Dawley rats in which CO(2) levels were monitored and maintained. Twenty-four hours after spinal hemisection, the ipsilateral phrenic nerve displayed no respiratory-related activity indicative of a functionally complete hemisection. Intravenous administration of the 5-HT(2A/2C)-receptor agonist (+/-)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI) induced respiratory-related activity in the phrenic nerve ipsilateral to hemisection under conditions in which CO(2) was maintained at constant levels and augmented the activity induced under conditions of hypercapnia. The effects of DOI were found to be dose dependent, and the recovery of activity could be maintained for up to 2 h after a single injection. DOI-induced recovery was attenuated by the 5-HT(2)-receptor antagonist ketanserin but not with the 5-HT(2C)-receptor antagonist RS-102221, suggesting that 5-HT(2A) and not necessarily 5-HT(2C) receptors may be involved in the induction of respiratory recovery after cervical spinal cord injury.  (+info)