ro-60-0175 and 6-chloro-2-(1-piperazinyl)pyrazine

The role of 5-HT2C receptors (5-HT2CRs) in the regulation of anxiety has been widely acknowledged. However, conflicting results have been reported on whether stimulation of these receptors increases or decreases anxiety. We here investigated the role of 5-HT2CRs of the dorsal hippocampus (DH) in the mediation of anxiety- or panic-associated defensive behaviors and in the anxiolytic effect of the tricyclic antidepressant imipramine. In the Vogel conflict test, administration of the mixed 5-HT2CR agonist mCPP into the DH of male Wistar rats was anxiogenic, whereas infusions of the more selective agonists MK-212 and RO-600175 were anxiolytic. The 5-HT2CR antagonist SB-242084, on the other hand, was anxiogenic. A sub-effective dose of this antagonist blocked the anxiolytic effect of RO-600175, but not the increase in anxiety observed with mCPP, indicating that the latter effect was not due to 5-HT2CR activation. In full agreement with these findings, MK-212 and RO-600175 in the DH also inhibited inhibitory avoidance acquisition in the elevated T-maze, whereas SB-242084 caused the opposite effect. None of these drugs interfered with escape expression in this test, which has been associated with panic. Chronic administration of imipramine (15 mg/kg, ip, 21 days) caused an anxiolytic effect in the elevated T-maze and light-dark transition tests, which was not blocked by previous infusion of SB-242084 into the DH. Therefore, facilitation of 5-HT2CR-mediated neurotransmission in the DH decreases the expression of anxiety-, but not panic-related defensive behaviors. This mechanism, however, is not involved in the anxiolytic effect caused by imipramine.

Topics: Aminopyridines; Animals; Anti-Anxiety Agents; Anxiety; Avoidance Learning; Ethylamines; Hippocampus; Imipramine; Indoles; Male; Maze Learning; Microinjections; Panic; Piperazines; Punishment; Pyrazines; Rats; Receptor, Serotonin, 5-HT2C; Serotonin 5-HT2 Receptor Agonists

Peripheral branches of the trigeminal nerve may be damaged during maxillofacial injury or surgical procedures and trigeminal trauma may induce severe pain that is very challenging to treat. Chronic constriction injury to the infraorbital nerve (ION-CCI) by loose ligatures has proven a useful model for some types of trigeminal neuropathic pain disorder. Using ION-CCI rats, we examined the antiallodynic effects of intrathecally administered agents which are selective for 5-HT2C receptors. Allodynia was evaluated by applying von Frey filaments to skin innervated by the injured ION. Dose-dependent antiallodynic effects followed administration of three 5-HT2C receptor agonists, 6-chloro-2-(1-piperazinyl)-pyrazine (MK212: 10, 30, and 100 μg); (S)-2-(chloro-5-fluoro-indol-l-yl)-1-methyamine fumarate (RO 60-0175: 10, 30, and 100 μg); (AaR)-8,9-dichloro-2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one (WAY-161503: 10, 30, and 100 μg). ED50 values for antiallodynic effects of MK212, RO 60-0175, and WAY-161503 were 39.62, 46.67, and 51.22 μg, respectively. Intrathecal administration of the 5-HT2C receptor antagonist, 8-[5-2,4-dimethoxy-5-(4-trifluoromethylphenylsulphonamido)phenyl-5-oxopentyl]-1,3,8-triazaspiro[4,5]decane-2,4-dione (RS-102221: 30 μg) did not alter the mechanical threshold. Intrathecal pretreatment with RS-102221 (10 and 30 μg) reduced the antiallodynic effects of the highest dose of 5-HT2C agonists. These results indicated that, in this rat model, the 5-HT2C receptor plays a role in spinal inhibition of trigeminal neuropathic pain.

Topics: Animals; Behavior, Animal; Dose-Response Relationship, Drug; Ethylamines; Indoles; Injections, Spinal; Male; Neuralgia; Pain Measurement; Pain Threshold; Physical Stimulation; Pyrazines; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT2C; Serotonin Antagonists; Serotonin Receptor Agonists; Spiro Compounds; Sulfonamides; Trigeminal Neuralgia

5-HT(2C) receptor agonists have considerable therapeutic potential, however there is little in vivo data to compare the potency and selectivity of 5-HT(2C) receptor agonists. Since 5-HT(2C) receptor agonists reduce locomotor activity and food intake, changes in these drug-induced behaviours in 5-HT(2C) receptor knockout mice could provide a means to examine receptor selectivity in-vivo. Initially this study compared older 5-HT(2C) agonists mCPP and MK212, to newer, apparently more selective compounds: Ro 60-0175, WAY161503, CP809,101 and lorcaserin (APD356) on motor activity in wild-type, and 5-HT(2C) receptor knockout mice. Two 5-HT(2C) receptor antagonists SB242084 and SDZ SER 082 were also examined. mCPP did not significantly alter activity in wild-type mice, but enhanced activity in knockout animals. MK212 (3 and 10 mg/kg) and Ro 60-0175 (1 and 3 mg/kg) reduced activity in wild-type but not knockout animals. At 10 mg/kg, Ro 60-0175 reduced activity in knockout animals, suggesting loss of 5-HT(2C) receptor selectivity. CP809,101 and lorcaserin reduced activity in wild-type but not knockout mice. In subsequent feeding studies, Ro 60-0175 and lorcaserin reduced food intake in wild-type animals only. Selectivity of effect for mCPP was marginal. The antagonist SB242084 increased activity in wild-type animals but not in knockout mice; SB242084 did not alter feeding in either genotype. SDZ SER 082 reduced activity in both genotypes implying poor selectivity for 5-HT(2C) receptors. The data demonstrate that studying food intake, and particularly motor behaviour, in the 5-HT(2C) receptor knockout mouse is a useful and relatively simple approach for screening 5-HT(2C) receptor ligands in vivo.

Topics: Aminopyridines; Animals; Benzazepines; Dexfenfluramine; Eating; Ethylamines; Feeding Behavior; Indoles; Ligands; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Motor Activity; Naphthyridines; Piperazines; Pyrazines; Quinoxalines; Receptor, Serotonin, 5-HT2C; Serotonin Antagonists; Serotonin Receptor Agonists

The serotonin 5-HT(2C) receptor (5-HT(2C)R) is abundant in the nucleus accumbens (NAc) shell and is considered an important target for 5-HT to modulate the dopamine (DA) mesoaccumbens circuit, which plays a prominent role in the behavioral effects of cocaine. The present study analyzed the ability of intra-NAc shell infusions of the 5-HT(2C)R agonists, MK 212 and RO 60-0175, or the 5-HT(2C)R antagonist, RS 102221, to alter either spontaneous or cocaine-evoked activity as well as the discriminative stimulus properties of cocaine. In male Sprague--Dawley rats implanted with bilateral cannulae aimed at the NAc shell, locally injected MK 212 (0.05--0.5 microg/side) or RO 60-0175 (0.5--5 microg/side) did not alter spontaneous activity, but dose-dependently enhanced hyperactivity evoked by cocaine (10 mg/kg ip). In rats trained to discriminate cocaine (10 mg/kg ip) from saline (ip) in a two-lever, water-reinforced FR 20 task, intra-NAc microinfusion of MK 212 (0.05 microg/side) or RO 60-0175 (0.5 microg/side) evoked 37% or 48% cocaine lever responding, respectively. Both MK 212 (0.05 microg/side) and RO 60-0175 (0.5 microg/side) enhanced the discriminability of submaximal doses of cocaine (0.625--2.5 mg/kg). Moreover, intra-NAc infusion of RS 102221 (0.05--1.5 microg/side) dose-dependently attenuated the stimulus effects of cocaine. These data reinforce the hypothesis that 5-HT(2C)R plays a role in the regulatory neurochemistry of the NAc shell that is important to the full expression of the behaviors evoked by cocaine.

Topics: Animals; Cocaine; Discrimination, Psychological; Dopamine Uptake Inhibitors; Dose-Response Relationship, Drug; Ethylamines; Hyperkinesis; Indoles; Male; Microinjections; Motor Activity; Nucleus Accumbens; Pyrazines; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT2C; Receptors, Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Spiro Compounds; Sulfonamides

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