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At least 721 records · Page 40Linked to original sources
PubMed2002

Differential involvement of 5-HT(2A) receptors in the discriminative-stimulus effects of cocaine and methamphetamine.

Involvement of 5-HT(2A) receptors in the discriminative-stimulus effects of cocaine versus methamphetamine was studied in Sprague Dawley rats (n=10) trained to discriminate 10 mg/kg cocaine, i.p., from saline under a fixed-ratio 10 (FR10) schedule of food presentation. The ability of (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), a 5-HT(2A) receptor agonist, and ketanserin, a 5-HT(2A) receptor antagonist, to either substitute for or block the discriminative-stimulus effects of cocaine, or to shift the cocaine dose-response curve, was evaluated. DOI (0.18-1.0 mg/kg) partially substituted for the training dose of 10 mg/kg cocaine, but only at doses that decreased rates of responding. At the highest dose of DOI tested (1.0 mg/kg), there was about 65% cocaine-appropriate responding. Substitution of DOI for cocaine and DOI-induced decreases in rates of responding were completely reversed by ketanserin (3.0 mg/kg). Ketanserin (3.0 mg/kg) also produced a significant shift to the right of the cocaine dose-response curve and antagonized increases in rates of responding produced by lower doses of cocaine. Ketanserin (1.0-10.0 mg/kg), however, did not block the discriminative-stimulus effects of the training dose of cocaine. When DOI (0.3 mg/kg) was co-administered with different doses of cocaine, there was a slight leftward shift in the cocaine dose-response curve, which was not significant and appeared to reflect simple additive effects of DOI and cocaine. In contrast, the same dose of DOI (0.3 mg/kg) produced a marked and highly significant shift to the left of the methamphetamine (0.18-1.0 mg/kg) dose-response curve in the same subjects and the effects of DOI and methamphetamine were clearly more than additive. The present findings provide new evidence that there is some serotonergic modulation of cocaine's discriminative-stimulus actions, which appears to involve stimulation of 5-HT(2A) receptors. However, involvement of 5-HT(2A) receptor activity in the discriminative-stimulus actions of cocaine appears to be less pronounced than in similar actions of methamphetamine.

Analysis of Variance↗
PubMed2002

DOI, a 5-HT2 receptor agonist, induces renal vasodilation via nitric oxide in anesthetized dogs.

We have previously reported that (+/-)-1-(2.5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), a 5-HT2 receptor agonist, induced renal vasodilation in anesthetized dogs. The present study was designed to investigate whether DOI-induced renal vasodilation might be mediated by increased nitric oxide (NO) release/production in renal tissue. The experiments were performed in anesthetized dogs. A 23-gauge needle was inserted into the left renal artery for infusion of drug solutions. Renal blood flow was measured with an electromagnetic flowmeter. The microdialysis probes were implanted into the renal cortex to collect the dialysate for measurement of guanosine 3',5'-cyclic monophosphate (cGMP) and nitrite/nitrate (NO2/NO3) concentration. Intrarenal infusion of DOI at a rate of 5 microg/kg/min resulted in a significant increase, by 30 +/- 4%, in renal blood flow, indicating renal vasodilation. The renal interstitial concentrations of NO2/NO3 and cGMP also increased by 70 +/- 6% and 60 +/- 6%, respectively. These changes induced by DOI were completely abolished by the intrarenal pretreatment with N(w)-nitro-L-arginine methyl ester (L-NAME, a NO synthase inhibitor, 100 microg/kg/min) or sarpogrelate (100 microg/kg/min, a highly selective 5-HT2 receptor antagonist). DOI infusion increased urine volume and urinary excretion of Na+, which were also blocked by L-NAME or sarpogrelate. These results suggest that DOI caused renal vasodilation due to increased NO release/production by stimulation of 5-HT2 receptors in the kidney. The natriuretic effect of DOI might also be related to increased intrarenal NO production.

Anesthesia↗
PubMed2003

Tricyclic analogs cyclobenzaprine, amitriptyline and cyproheptadine inhibit the spinal reflex transmission through 5-HT(2) receptors.

The centrally acting muscle relaxant cyclobenzaprine decreases the amplitude of monosynaptic reflex potentials by inhibiting the facilitatory descending serotonergic influences in the spinal cord. Interestingly, the structure of cyclobenzaprine is much similar to those of amitriptyline and cyproheptadine. In the present study, we attempted to elucidate the relationship between 5-HT(2) receptor antagonistic and inhibitory effects of cyclobenzaprine, amitriptyline, cyproheptadine and ketanserin on the spinal reflexes. Cyclobenzaprine, amitriptyline, cyproheptadine, and ketanserin significantly inhibited facilitatory effects of 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) on flexor reflexes and mono- and polysynaptic spinal reflex potentials in spinalized rats. In intact rats, these drugs significantly reduced the mono- and polysynaptic reflex potentials. 5-HT depletion significantly prevented the depression of the spinal reflex potentials induced by these drugs. These results suggest that the inhibitory effects of cyclobenzaprine, amitriptyline, and cyproheptadine on mono- and polysynaptic reflex potentials are due to the inhibition of descending serotonergic systems through 5-HT(2) receptors in the spinal cord.

Amitriptyline↗
PubMed2003

Activation of 5-HT2 receptors induces glycogenolysis in the rat brain.

The effect of 5-HT(2) receptor activation on brain glycogen and the extracellular concentration of glucose was investigated in the present study. An injection of 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) (2 mg/kg, i.p.) or mescaline (10 mg/kg, i.p.) at an ambient temperature of 29 degrees C produced a 35-45% decrease in brain glycogen that persisted for at least 2 h. DOI also increased the extracellular concentration of glucose in the striatum by 60%. Maintenance of rats at 22 degrees C significantly attenuated DOI-induced glycogenolysis, as well as DOI-induced hyperthermia, and the increase in the extracellular concentration of glucose in the striatum. DOI-induced hyperthermia, glycogenolysis and increase in the extracellular concentration of glucose also were attenuated in rats treated with the 5-HT(2) receptor antagonist, 6-methyl-1-(methylethyl)-ergoline-8beta-carboxylic acid 2-hydroxy-1-methylpropyl ester maleate (LY-53,857) (3 mg/kg, ip). These results support the conclusion that 5-HT(2) receptor activation promotes glycogenolysis and that hyperthermia exerts a prominent role in this process.

Animals↗
PubMed2000

The ontogeny of induction of c-fos in the rat SCN by a 5-HT(2A/2C) agonist.

The induction of c-fos in the suprachiasmatic nucleus (SCN) by the 5-HT(2A/2C) agonist, DOI was studied at mid-dark in neonatal rats. The number of cells expressing c-FOS immunoreactivity following DOI was low 3 days after birth, but increased rapidly over the next 3 days. By contrast, light exposure stimulated cells throughout this period. These results are consistent with the arrival of serotonergic afferents at the SCN and their role in the entrainment of rhythms.

Animals↗
PubMed2003

Evidence for a 5-HT2A receptor mode of action in the anxiolytic-like properties of DOI in mice.

DOI [(+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane] displays a high affinity for the rat 5-HT2A, 5-HT2B and 5-HT2C receptors (pKi 7.3, 7.4 and 7.8, respectively) and acts as an agonist. DOI (0.5-4 mg/kg, i.p. 30 min pre-test) increased the number of punished passages in the mouse four plates test (FPT). The anti-punishment action of DOI (1 mg/kg, i.p. 30 min pre-test) was abolished by prior treatment with the selective 5-HT2A receptor antagonist SR 46949B (0.1 and 1 mg/kg, i.p. 45 min pre-test) but not by the selective 5-HT2C receptor antagonist RS 10-2221 (0.1 and 1 mg/kg, i.p. 45 min pre-test) nor the selective 5-HT2C/2B receptor antagonist SB 206553 (0.1 and 1 mg/kg, i.p. 45 min pre-test). An anxiolytic-like action was also observed for DOI (1 mg/kg) in the elevated plus maze (EPM). The anxiolytic-like action of DOI (1 mg/kg, i.p. 30 min pre-test) was antagonised by pre-treatment with SR 46949B (0.125 and 0.5 mg/kg, i.p. 45 min pre-test) but not by RS 10-2221 (0.1 and 1 mg/kg, i.p. 45 min pre-test) nor SB 206553 (0.1 and 1 mg/kg, i.p. 45 min pre-test). In conclusion, DOI produced an anxiolytic-like profile in the mouse FPT and EPM. These effects are likely to be 5-HT2A receptor mediated.

Animals↗
PubMed1999

NH4+ utilization and regeneration rates in freshwater lakes determined by GC-MS of derivatised dihydroindophenol.

A new gas chromatographic-mass spectrometric method was established that is applicable for the determination of NH4+ utilization and regeneration rates in freshwater. Hollow-fibre modules were used to stop the biogenic nitrogen-fluxes by separating the particulate from the dissolved matter. Incubations were performed in Tedlar bags (polyvinylfluoride), which enabled repeated sample removals through Teflon tubes, making the calculation of nitrogen-fluxes in accordance to Blackburn and Caperon much more reliable. The Berthelot reaction was performed with ammonium and a fragment ion (base peak) of tris-(trifluoroacetyl) 4,4'-dihydroxydiphenylamine was used to determine the at% excess 15N by gas chromatography-mass spectrometry. Nitrogen-flux measurements were made in the epilimnion of the deep, stratified, mesotrophic Lake Zürich, in which the cyanobacterium Planktothrix rubescens was the dominating photoautotrophic micro-organism. The size fraction <20 microm that consisted of heterotrophic bacterioplankton and nanoflagellates, and photoautotrophic pico- and nanoplankton accounted only for a minor part of the ammonium utilization (<25%) and regeneration (< or =25%) rates, whereas the size fraction >20 microm which primarily consisted of Planktothrix rubescens was responsible for the major part. In the eutrophic Lake Au, which is connected to Lake Zürich through a canal, utilization and regeneration rates as high as 700 and 482 nM h(-1) were measured.

Animals↗
PubMed2003

A genetic screen for mouse mutations with defects in serotonin responsiveness.

The serotonergic system plays a key role in regulating basic behaviors. Deficits in serotonergic neurotransmission have been implicated in psychiatric disorders, such as schizophrenia and depression. Here we have optimized a behavioral screen and performed a small scale genetic screen to identify genes involved in serotonin responsiveness in the mouse. Treatment of mice with serotonin, serotonin precursors, or serotonin agonists results in a quantifiable head twitch response (HTR), which is drug dosage-dependent and dependent on the 5-HT2A receptor system. This assay can uncover variation in serotonin responsiveness as shown by our identification of inbred strains with high, medium, and low head twitch responses to administration of the serotonin agonist DOI (+-1-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane). We chose C57Bl/6J mice for our mutagenesis screen, because of their robust HTR and because of the availability of their complete genomic sequence. We optimized this assay by examining dose and age dependence of DOI-induced HTR in 6-week and 3-month-old C57BL/6J mice. HTR decreases only slightly in 3-month-old mice, and a substantial but submaximal HTR is induced by 0.75-1 mg/kg of DOI. We assayed HTR in response to DOI of 247 G1 C57BL/6J progeny from C57BL/6J males, which had been mutagenized with ethylnitrososurea (ENU), and recovered one provisionally heritable hyper-responsive mutation. This and future mutations recovered via this protocol may provide ideal subjects for the study of human psychiatric disorders, such as depression and schizophrenia, and thereby aid in the development of better therapeutic strategies for these disorders. Thus, it is well worth expanding on this genetic screen in its current form and by addition of further pharmacologic assays in the future.

Alkylating Agents↗
PubMed2001

Nicotine attenuates DOI-induced head-twitch response in mice: implications for Tourette syndrome.

Tourette syndrome (TS), a chronic neuropsychiatric disorder, is characterized by motor and vocal tics. Preliminary clinical studies indicate possible therapeutic benefits of nicotine in the treatment of Tourette's syndrome (TS). It has been proposed that twitches of the head in mice or twitches of head and shoulders in rats following administration of the selective 5HT(2A/C) agonist DOI (1-)2,5-dimethoxy-4-iodophenyl-2-aminopropane, can serve as an animal model of tics in TS. In this study, the effects of acute and chronic administration of nicotine on DOI-induced head twitch response (HTR) in male albino ICR mice were evaluated. Both acute and chronic nicotine (daily injections for 10 days) reduced the DOI-induced HTR. Moreover, chronic administration of DOI (1 mg/kg/day for 10 days) resulted in 65% increase in [125I]alpha-bungarotoxin binding in cerebellum and 41% increase in striatal [3H]cytisine binding. However, the acute inhibitory effects of nicotine were not blocked by pretreatment with the nicotinic antagonist, mecamylamine. Indeed, at higher doses, mecamylamine also reduced the DOI-induced HTR. The data suggest that both nicotine and mecamylamine may be of therapeutic potential in the treatment of some symptoms of TS.

Animals↗
PubMed1999

Selectivity of action of typical and atypical anti-psychotic drugs as antagonists of the behavioral effects of 1-[2,5-dimethoxy-4-iodophenyl]-2-aminopropane (DOI).

1. There has been considerable research in the field of schizophrenia over the past few years with emphasis on the discovery of better drugs, particularly those with 5-HT2 antagonist activity. 2. In an effort to enhance identification of such compounds and to further understand the contribution of 5-HT2 activity to the effects of antipsychotic drugs, a series of conventional, atypical and purported antipsychotic compounds were assessed as antagonists of DOI-induced behaviors in rats. 3. DOI (1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride) is an hallucinogen having high affinity and selectivity as an agonist at 5-HT2A/2C receptors. Over a 30-min period after injection, DOI (0.3-10.0 mg/kg; i.p.) produced dose-related behavioral effects including head-and-body shakes, forepaw tapping and skin-jerks. Effects of the antipsychotic drugs and other compounds (30 min pretreatment; i.p.) were examined against a fixed dose of DOI (3.0 mg/kg). 4. In a dose-dependent manner, M100907 (MDL 100,907), risperidone, haloperidol, clozapine, iloperidone, olanzapine, amperozide, remoxipride, ritanserin and the neurotensin agonist NT1 (N alpha MeArg-Lys-Pro-Trp-Tle-Leu) antagonized each of the three behavioral effects of DOI. Drugs attenuating the head-and-body shakes were equally effective in blocking both forepaw tapping and skin-jerks indicating that these behaviors are mediated by similar mechanisms. The following compounds had either inconsistent or no effect on the DOI-induced behaviors: SB 200646A, citalopram, imipramine, fluoxetine, morphine, CP 99994, diazepam, ondansetron and SKF 97541. 5. The data show that antipsychotic agents, as a drug class, effectively block the effects of DOI. These actions are selective, as a series of nine non-antipsychotic and centrally-acting drugs were generally inactive in the procedure.

Animals↗
PubMed1998

Serotonin induces an increase in D-myo-inositol (1,4,5)-trisphosphate 3-kinase activity in rat brainstem slices.

Serotonin robustly potentiated the activity of the InsP3 3-kinase in rat brainstem slices. This potentiation was mediated through activation of 5-HT2 receptors since it was only retrieved with the selective 5-HT2 agonist DOI but not with the 5-HT1A agonist 8OHDPAT. The enhancement of the InsP3 3-kinase activity by serotonin is positively modulated by pretreatment of the slices with the phosphatase inhibitor okadaic acid. Moreover, the specific CaMKII antagonists KN-62 and KN-93 dramatically reduced the serotonin-evoked increase in the InsP3 3-kinase activity. It is thus concluded that InsP3 3-kinase up-regulation occurs through activation of PLC-coupled serotoninergic receptors and requires the phosphorylation of the enzyme by the ubiquitous multimeric protein kinase CaMKII.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1999

Serotonin depolarizes hippocampal interneurones in the rat stratum oriens by interaction with 5HT2 receptors.

Patch-clamp recording techniques were used to examine the effect of serotonin (5HT) upon interneurones contained in the stratum oriens layer of hippocampal slices. Bath application of 1-20 microM 5HT depolarized neurones by the induction of an inward current at -60 mV. This inward current was Na+-dependent in nature, was mimicked by the 5HT2 receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and was inhibited by pre-incubation with the 5HT2 receptor antagonist ritanserin.

Animals↗
PubMed2001

Adenosine preferentially suppresses serotonin2A receptor-enhanced excitatory postsynaptic currents in layer V neurons of the rat medial prefrontal cortex.

Serotonin induces 'spontaneous' (non-electrically evoked) excitatory postsynaptic currents in layer V pyramidal neurons in the prefrontal cortex. This is likely due to a serotonin2A receptor-mediated focal release of glutamate onto apical dendrites. In addition, activation of the serotonin2A receptor selectively enhances late components of electrically evoked excitatory postsynaptic currents. In this study, using in vitro intracellular and whole-cell recording in rat brain slices, we examined the role of adenosine in modulating serotonin2A-enhanced 'spontaneous' and electrically evoked excitatory postsynaptic currents in layer V pyramidal neurons in the medial prefrontal cortex. Adenosine and N6-cyclopentyladenosine, an A1 adenosine agonist, markedly suppressed the serotonin2A-induced ('spontaneous') excitatory postsynaptic currents. However, adenosine had no effect on spontaneous miniature (tetrodotoxin-insensitive) postsynaptic potentials. Adenosine also blocked the late excitatory postsynaptic currents induced by the serotonin2A/2C agonist R(-)-2,5-dimethoxy-4-iodoamphetamine hydrochloride. Surprisingly, in contrast to other regions, adenosine had a relatively small effect on electrically evoked fast excitatory postsynaptic currents. These findings represent a novel demonstration of adenosine's ability to preferentially modulate serotonin2A-mediated synaptic events in the medial prefrontal cortex. As the serotonin2A receptor is closely linked with the effects of atypical antipsychotics and hallucinogens, further understanding of the modulators of this receptor such as adenosine may provide useful therapeutic applications.

Adenosine↗
PubMed2003

5-hydroxytryptamine(2A) receptors regulate sympathetic nerves constricting the cutaneous vascular bed in rabbits and rats.

Hyperthermia induced by 3,4-methylenedioxymethamphetamine (MDMA) is partially due to sympathetically-mediated cutaneous vasoconstriction that impairs normal heat dissipation. MDMA acts by releasing monoamines, including 5-hydroxytryptamine (5-HT), but receptor mechanisms underlying MDMA-elicited hyperthermia and cutaneous vasoconstriction are not known. The specific 5-HT2A agonist (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) is a potent hallucinogen that also causes marked hyperthermia, suggesting the possibility that DOI, via stimulation of 5-HT2A receptors, might also cause sympathetically mediated cutaneous vasoconstriction. We tested this hypothesis in conscious unrestrained rabbits and rats. Blood flow was assessed by chronically implanted Doppler ultrasonic flow probes. Body temperature was measured by i.p. telemetric probes. We compared effects of DOI on cutaneous blood flow (ear pinna in rabbits, tail in rats) with effects on mesenteric blood flow and arterial pressure.Hyperthermia induced by DOI (5-100 microgram/kg i.v. in rabbits and 100 microgram/kg s.c. in rats) was preceded and accompanied by markedly reduced blood flow to the cutaneous bed, with no change in flow to the mesenteric bed. In rabbits, DOI (5 microgram/kg i.v.) did not affect arterial pressure or heart rate. DOI (100 microgram/kg i.v.) caused a moderate rise in arterial pressure. In rabbits, the 5-HT2A receptor antagonists ketanserin (0.3 mg/kg i.v.) and AC90179 (0.5 mg/kg i.v.) reversed the ear pinna vasoconstriction induced by DOI (5 microgram/kg i.v.). In rats, ketanserin (3 mg/kg s.c.) reversed tail vasoconstriction and hyperthermia induced by DOI (100 microgram/kg s.c.). In rabbits, the cutaneous vasoconstricting effect of DOI (5 microgram/kg i.v.) was substantially abolished in the ipsilateral ear pinna after interruption of preganglionic sympathetic nerve activity by unilateral section of the cervical sympathetic trunk. Thus hyperthermia evoked by direct stimulation of 5-HT2A receptors is associated with marked sympathetically mediated vasoconstriction, selective for the cutaneous bed. Impairment of the ability to dissipate heat following drug-induced stimulation of 5-HT2A receptors is likely to contribute to hyperthermia induced by MDMA and by hallucinogenic drugs such as LSD.

Animals↗
PubMed2003

Serotonin type II receptor activation facilitates synaptic plasticity via N-methyl-D-aspartate-mediated mechanism in the rat basolateral amygdala.

The modulation of synaptic plasticity by serotonin type II (5-hydroxytryptamine type II (5-HT(2)))-receptor stimulation was explored using intracellular, field potential and Fura-2 fluorescence image recordings in a rat amygdala slice preparation. Bath application of 5HT(2) receptor agonist 1-(2,5)-dimethoxy-4-iodophen-2-aminopropane (DOI) transformed theta-burst-stimulated (TBS) synaptic plasticity from short-term potentiation to long-term potentiation. DOI enhanced N-methyl-D-aspartate (NMDA) receptor-mediated potentials and calcium influx without affecting the resting membrane potential or input resistance of the neurons. In contrast, alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA)/kainate receptor-mediated excitatory synaptic responses were unaffected by DOI. The facilitating effects of DOI were blocked by the 5-HT(2) receptor antagonist, ketanserin, and by the 5-HT(2C)-receptor selective antagonist, RS102221. These results indicate that 5-HT(2)-receptor activation enhances NMDA receptor-mediated synaptic function in the basolateral amygdala (BLA).

Amygdala↗