bw-723c86 and 6-chloro-2-(1-piperazinyl)pyrazine

Our first aim was to elucidate the mechanisms underlying the hypotensive response elicited by 5-HT(2) receptor activation in the nucleus tractus solitarius (NTS). In pentobarbitone-anaesthetized rats, intra-NTS administration of 2,5-dimethoxy-4-iodoamphetamine (DOI), a wide spectrum 5-HT(2) receptor agonist, but not an antagonist of selective 5-HT(2B) and 5-HT(2C) receptors, produced a decrease in blood pressure and heart rate. The maximal cardiovascular changes obtained by DOI (0.5 pmol) could be almost completely abolished by prior intra-NTS microinjection (10 pmol) of MDL-100907, a selective 5-HT(2A) receptor antagonist, but not by 5-HT(2B) or 5-HT(2C) receptor antagonists. In addition, using extracellular recordings we found that the large majority of identified cardiovascular rostroventrolateral medulla (RVLM) neurons were almost totally inhibited by NTS 5-HT(2A) receptor stimulation. We then investigated whether intra-NTS administration of a subthreshold dose (0.05 pmol) of DOI, known to facilitate the cardiovagal component of the baroreflex, could also modulate the sympathoinhibitory component of this reflex. These experiments showed that neither the decrease in the activity of the cardiovascular RVLM neurons and lumbar sympathetic nerve activities produced by aortic occlusion (gain of the baroreflex), nor the hypotensive response elicited by aortic nerve stimulation, were potentiated by the microinjection of DOI under such conditions. These data show that activation of 5-HT(2A), but not 5-HT(2B) or 5-HT(2C), receptors, located on NTS neurons, elicits depressor and bradycardic responses, and that this 5-HT(2A)-mediated hypotension is produced via the inhibition of RVLM cardiovascular neurons. In addition, NTS 5-HT(2A) receptor activation facilitates the cardiac but not the sympathetic baroreflex response.

Topics: Adrenergic beta-Antagonists; Animals; Atenolol; Atropine Derivatives; Baroreflex; Blood Pressure; Heart Rate; Indoles; Male; Microinjections; Pyrazines; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT2A; Serotonin Receptor Agonists; Solitary Nucleus; Sympathetic Nervous System; Thiophenes

Intrathecal administration of serotonin type 2 (5-HT(2)) receptor agonists, alpha-methyl-5-hydroxytryptamine maleate (alpha-m-5-HT) or (+/-)-1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane hydrochloride (DOI), produces antiallodynic effects in a rat model of neuropathic pain. In the present study, we examined the antiallodynic effects of intrathecally administered agents which are selective for 5-HT(2C) receptors. Allodynia was produced by tight ligation of the left L5 and L6 spinal nerves, and was measured by applying von Frey filaments to the left hindpaw. Administration of the 5-HT(2C) receptor agonist, 6-chloro-2-(1-piperazinyl)-pyrazine (MK212; 3-100 microg), 1-(m-chlorophenyl)-piperazine (mCPP; 30-300 microg), or 1-(m-trifluoromethylphenyl)-piperazine (TFMPP; 30-300 microg), produced antiallodynic effects in a dose-dependent manner with no associated motor weakness. The ED(50) values of MK212, mCPP, and TFMPP were 39.2, 119.9, and 191.9 microg, respectively. Intrathecal pretreatment with the selective 5-HT(2C) receptor antagonist RS-102221 (30 microg) diminished the effects of the highest doses of 5-HT(2C) receptor agonists. The preferential 5-HT(2A) receptor antagonist ketanserin (30 microg) did not reverse the effects. In contrast to 5-HT(2C) receptor agonists, the antiallodynic effects of intrathecally administered alpha-m-5-HT (30 microg) and DOI (100 microg) were reversed by ketanserin, but not by RS-102221. These results indicate that 5-HT(2C) receptors have a role in spinal inhibition of neuropathic pain, and the effects produced by intrathecal administration of 5-HT(2C) receptor agonists are mediated by a mechanism different from that of alpha-m-5-HT or DOI, which seem to produce their effects through 5-HT(2A) receptors.

Topics: Amphetamines; Animals; Indoles; Injections, Spinal; Ketanserin; Ligation; Lumbar Vertebrae; Male; Neuralgia; Nociceptors; Piperazines; Pyrazines; Rats; Rats, Wistar; Receptor, Serotonin, 5-HT2C; Serotonin; Serotonin 5-HT2 Receptor Agonists; Serotonin 5-HT2 Receptor Antagonists; Serotonin Antagonists; Serotonin Receptor Agonists; Spinal Nerves; Spiro Compounds; Sulfonamides; Thiophenes

The role of serotonin (5-hydroxytryptamine; 5-HT) 5-HT2 receptor subtypes (5-HT2AR, 5-HT2BR, and 5-HT2CR) in acute cocaine-evoked hyperactivity was compared with their contribution to the development and expression of locomotor sensitization upon repeated, intermittent treatment with cocaine (10 mg/kg/day for 5 days) in male Wistar rats. Cocaine-evoked hyperactivity was significantly enhanced by pretreatment with the preferential 5-HT2AR agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and the 5-HT2CR antagonist SDZ SER-082 [(+)-cis-4,5,7a,8,9,10,11,11a-octahydro-7H-10-methylindolo(1,7-BC)(2,6) naphthyridine fumarate]. The 5-HT2AR antagonist SR 46349B [1(Z)-[2-(dimethylamino)ethoxyimino]-1(2-fluorophenyl)-3-(4-hydroxyphenyl)-2(E)-propene] and the preferential 5-HT2CR agonist MK 212 [6-chloro-2-(1-piperazinyl)pyrazine HCl] (2 mg/kg) significantly attenuated acute cocaine-evoked hyperactivity; however, a lower dose of MK 212 (0.3 mg/kg) enhanced cocaine-evoked hyperactivity. The 5-HT2BR agonist BW 723C86 (1-[5-(2-thienylmethoxy)-1H-3-indolyl]propan-2-amine HCl) and the 5-HT2BR antagonist SB 204741 [N-(1-methyl-5-indolyl)-N'-(3-methyl-5-isothiazolyl) urea] had no effect on cocaine-evoked hyperactivity. Repeated treatment with cocaine alone resulted in a 2-fold increase in hyperactivity upon challenge with cocaine 5 days after termination of the cocaine regimen (sensitization). The 5-HT2AR antagonist SR 46349B also blocked cocaine-evoked hyperactivity following repeated cocaine treatment, whereas the other 5-HT2R ligands were ineffective. When any of the 5-HT2R ligands was coadministered with cocaine during the treatment regimen (10 mg/kg/day for 5 days), the development of sensitization was unchanged as measured by the level of cocaine-evoked hyperactivity upon challenge 5 days after termination of the treatment. The present study implies that 5-HT2AR and 5-HT2CR exert oppositional influence upon hyperactivity evoked by acute administration of cocaine; this balance is altered following repeated cocaine administration.

Topics: Amphetamines; Animals; Cocaine; Drug Interactions; Fluorobenzenes; Hyperkinesis; Indoles; Male; Phenols; Pyrazines; Rats; Rats, Wistar; Receptor, Serotonin, 5-HT2A; Receptor, Serotonin, 5-HT2B; Receptor, Serotonin, 5-HT2C; Serotonin Antagonists; Serotonin Receptor Agonists; Thiophenes

The role of serotonin 5-HT2 receptors (5-HT2R) in the discriminative stimulus effects of fenfluramine was investigated. Male Sprague-Dawley rats were trained to discriminate (+/-)-fenfluramine (2 mg/kg ip) from saline using a 2-lever, water-reinforced paradigm. Drug-lever responding after fenfluramine was dose-dependent. The 5-HT(2C/1B)R agonist mCPP and the 5-HT(2C)R agonist MK 212 fully substituted, whereas the 5-HT(2A/2C)R agonist DOI partially substituted, for the training drug. The 5-HT(2B)R agonist BW 723C86 engendered saline-lever responding. The 5-HT(2C/2B)R antagonist SB 206553 completely antagonized the fenfluramine discrimination a well as the full substitutions of mCPP and MK 212 and the partial substitution of DOI. The selective 5-HT(2A)R antagonist M100907 partially suppressed the stimulus effects of fenfluramine, mCPP, and MK 212 and almost fully attenuated the partial substitution of DOI. RS 102221, a selective 5-HT(2C)R antagonist that does not cross the blood-brain barrier, did not alter the fenfluramine cue. Results demonstrate that the discriminative stimulus effects of fenfluramine are centrally mediated by 5-HT(2C)R and to some extent by 5-HT(2A)R.

Topics: Animals; Discrimination Learning; Dose-Response Relationship, Drug; Drug Combinations; Drug Interactions; Fenfluramine; Fluorobenzenes; Indoles; Ketanserin; Male; Piperidines; Pyrazines; Pyridines; Rats; Receptor, Serotonin, 5-HT2A; Receptors, Serotonin; Reinforcement, Psychology; Serotonin Antagonists; Serotonin Receptor Agonists; Spiro Compounds; Sulfonamides; Thiophenes

1. In in vivo experiments, DOI (a 5-HT(2) receptor agonist), MK-212 (a 5-HT(2C) receptor agonist), and BW-723C86 (a 5-HT(2B) receptor agonist) were applied by ionophoresis to neurones in the rat nucleus tractus solitarius (NTS) receiving vagal afferent input. 2. The majority of the putative 'monosynaptically' vagal activated cells were inhibited by both MK-212 (4/6) and DOI (2/4), but unaffected by BW-723C86 (12/14). In contrast, 'polysynaptically' activated NTS cells were excited by both BW-723C86 (13/19) and DOI (9/10). Inactive 'intermediate' cells were inhibited by BW-723C86 (9/12), MK-212 (5/6) and DOI (3/4), whilst active cells of this group were excited by BW-723C86 (7/13) and DOI (5/5). 3. The selective 5-HT(2B) receptor antagonist LY-202715 significantly reduced the excitatory actions of BW-723C86 on 'intermediate' and 'polysynaptic' cells (13/13), but not the inhibitory effects observed on inactive Group 2 cells (n=5) whereas the selective 5-HT(2C) receptor antagonist RS-102221 reversed the inhibitory effects of MK-212 and DOI on 'monosynaptic and 'intermediate' neurones. 4. Cardio-pulmonary afferent stimulation inhibited two of four putative 'monosynaptically' activated calls and all four inactive intermediate cells. These were also inhibited by DOI and MK-212. In contrast, cardio-pulmonary afferents excited all five active intermediate cells and all six putative 'polysynaptically' activated NTS cells, while all were also previously excited by BW-723C86 and/or DOI. 5. In conclusion, these data demonstrate that neurones in the NTS are affected differently by 5-HT(2) receptor ligands, in regard of their vagal postsynaptic location, the type of cardio-pulmonary afferent they receive and the different 5-HT(2) receptors activated.

Topics: Afferent Pathways; Amphetamines; Animals; Antihypertensive Agents; Electric Conductivity; Evoked Potentials; Heart; Indoles; Lung; Male; Medulla Oblongata; Nerve Fibers, Myelinated; Neurons; Organic Chemicals; Pyrazines; Rats; Rats, Sprague-Dawley; Receptors, Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Solitary Nucleus; Spiro Compounds; Sulfonamides; Thiophenes; Vagus Nerve

Employing a Fixed-Ratio 10, food-reinforced protocol, rats were trained to recognize the discriminative stimulus (DS) properties of the novel, potent, 5-HT2C agonist, Ro 60-0175 (2.5 mg/kg, i.p.). This schedule generated appropriate drug versus vehicle responding after 50 + 5 training sessions and Ro 60-0175 elicited full (100%) drug selection with an effective dose50 (ED50) of 0.6 mg/kg, i.p.. The 5-HT2C receptor agonists, mCPP and MK 212, fully generalized to Ro 60-0175 with ED50s of 0.8 and 0.4 mg/kg, s.c., respectively, whereas the preferential 5-HT2B agonist, BW 723C86 ( > 10.0 mg/kg, s.c.) and the 5-HT2A agonist, DOI ( > 2.5 mg/kg, s.c.), were ineffective. The 5-HT2A/2B/2C receptor antagonist, mianserin, dose-dependently blocked the DS properties of Ro 60-0175 with an ED50 of 0.7 mg/kg, s.c. This action was mimicked by the novel, 5-HT2B/2C antagonist, SB 206,553 (ED50 = 0.3 mg/kg, s.c.), whereas the selective 5-HT2A antagonist, MDL 100,907 ( > 0.63 mg/kg, s.c.), was ineffective. Further, the selective 5-HT2C antagonist, SB 242,084, dose-dependently and fully blocked drug selection (ED50 = 0.2 mg/kg, i.p.), whereas the selective 5-HT2B antagonist, SB 204,741, was not active ( > 0.63 mg/kg, i.p.). In conclusion, these data demonstrate that Ro 60-0175 generates a robust DS and suggest that activation of 5-HT2C receptors is the principal mechanism underlying its DS properties.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Aminopyridines; Animals; Conditioning, Operant; Ethylamines; Fluorobenzenes; Indoles; Male; Mianserin; Piperazines; Piperidines; Pyrazines; Rats; Rats, Wistar; Receptor, Serotonin, 5-HT2C; Receptors, Serotonin; Reinforcement, Psychology; Serotonin Antagonists; Serotonin Receptor Agonists; Thiophenes