sb-242084 and 6-chloro-2-(1-piperazinyl)pyrazine

Prepulse inhibition (PPI) is disrupted in many neuropsychiatric diseases. Molecules such as 5-HT

Topics: Aminopyridines; Animals; Brain; Dizocilpine Maleate; Hippocampus; Indoles; Mice; Prefrontal Cortex; Prepulse Inhibition; Pyrazines; Receptor, Serotonin, 5-HT2C; Receptors, N-Methyl-D-Aspartate

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

The confinement of rodents to the open arm of the elevated-plus maze provokes antinociception (OAA). As a type of defensive reaction, the OAA has been investigated through systemic and intramesencephalic (e.g., dorsal portion of the periaqueductal gray - dPAG) injections of anxiolytic-like drugs [e.g., serotonergic (5-HT) receptor agonists or antagonists]. Here we investigated the effects of (i) intra-dPAG injections of a 5HT

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Aminopyridines; Animals; Dose-Response Relationship, Drug; Drug Interactions; Fear; Indoles; Male; Mice; Microinjections; Nociception; Pain Measurement; Periaqueductal Gray; Pyrazines; Receptor, Serotonin, 5-HT1A; Receptor, Serotonin, 5-HT2C; Serotonin 5-HT2 Receptor Agonists; Serotonin 5-HT2 Receptor Antagonists

A growing body of evidence indicates that facilitation of serotonin-2C receptor (5-HT2CR)-mediated neurotransmission in the basolateral nucleus of the amygdala (BLA) is involved in anxiety generation. We investigated here whether BLA 5-HT2CRs exert a differential role in the regulation of defensive behaviours related to generalized anxiety (inhibitory avoidance) and panic (escape) disorders. We also evaluated whether activation of BLA 5-HT2CRs accounts for the anxiogenic effect caused by acute systemic administration of the antidepressants imipramine and fluoxetine. Male Wistar rats were tested in the elevated T-maze after intra-BLA injection of the endogenous agonist 5-HT, the 5-HT2CR agonist MK-212 or the 5-HT2CR antagonist SB-242084. This test allows the measurement of inhibitory avoidance acquisition and escape expression. We also investigated whether intra-BLA administration of SB-242084 interferes with the acute anxiogenic effect caused by imipramine and fluoxetine in the Vogel conflict test, and imipramine in the elevated T-maze. While intra-BLA administration of 5-HT and MK-212 facilitated inhibitory avoidance acquisition, suggesting an anxiogenic effect, SB-242084 had the opposite effect. None of these drugs affected escape performance. Intra-BLA injection of a sub-effective dose of SB-242084 fully blocked the anxiogenic effect caused either by the local microinjection of 5-HT or the systemic administration of imipramine and fluoxetine. Our findings indicate that 5-HT2CRs in BLA are selectively involved in the regulation of defensive behaviours associated with generalized anxiety, but not panic. The results also provide the first direct evidence that activation of BLA 5-HT2CRs accounts for the short-term aversive effect of antidepressants.

Topics: Aminopyridines; Animals; Anti-Anxiety Agents; Antidepressive Agents, Second-Generation; Antidepressive Agents, Tricyclic; Anxiety Disorders; Avoidance Learning; Basolateral Nuclear Complex; Exploratory Behavior; Fluoxetine; Imipramine; Indoles; Male; Maze Learning; Neuropsychological Tests; Pyrazines; Rats, Wistar; Receptor, Serotonin, 5-HT2C; Serotonin; Serotonin 5-HT2 Receptor Agonists; Serotonin 5-HT2 Receptor Antagonists

Serotonin 2C receptor (5-HT(2C)R) agonists administered systemically attenuate both cocaine-primed and cue-elicited reinstatement of extinguished cocaine-seeking behavior. To further elucidate the function of these receptors in addiction-like processes, this study examined the effects of microinfusing the 5-HT(2C)R agonist MK212 (0, 10, 30, 100 ng/side/0.2 microl) into the medial prefrontal cortex (mPFC) on cocaine self-administration and reinstatement of extinguished cocaine-seeking behavior. Male Sprague-Dawley rats were trained to self-administer cocaine (0.75 mg/kg, i.v.) paired with light and tone cues. Once responding stabilized, rats received MK212 microinfusions before tests for maintenance of cocaine self-administration. Next, extinction training to reduce cocaine-seeking behavior, defined as responses performed without cocaine reinforcement available, occurred until low extinction baselines were achieved. Rats then received MK212 microinfusions before tests for reinstatement of extinguished cocaine-seeking behavior elicited by cocaine-priming injections (10 mg/kg, i.p.) or response-contingent presentations of the cocaine-associated cues; operant responses during cocaine-primed reinstatement tests produced no consequences. MK212 microinfusions into the prelimbic and infralimbic, but not anterior cingulate, regions of the mPFC dose-dependently attenuated both cocaine-primed and cue-elicited reinstatement of extinguished cocaine-seeking behavior, but did not reliably affect cocaine self-administration. A subsequent experiment showed that the effects of MK212 (100 ng/side/0.2 microl) on reinstatement of extinguished cocaine-seeking behavior were blocked by co-administration of the 5-HT(2C)R antagonist SB242084 (200 ng/side/0.2 microl). MK212 administered alone into the mPFC as a drug prime produced no discernable effects on cocaine-seeking behavior. These findings suggest that stimulation of 5-HT(2C)Rs in the mPFC attenuates the incentive motivational effects produced by sampling cocaine or exposure to drug-paired cues.

Topics: Aminopyridines; Animals; Cocaine-Related Disorders; Conditioning, Operant; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Interactions; Extinction, Psychological; Indoles; Male; Prefrontal Cortex; Pyrazines; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT2C; Reinforcement, Psychology; Self Administration; Serotonin Antagonists; Serotonin Receptor Agonists

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 extinction/reinstatement model has been used in this study to examine the role of 5-HT2C receptors in cocaine-seeking behavior elicited by cocaine-associated cues and cocaine-priming injections. Rats that had been trained to press a lever for cocaine (0.75 mg/kg/0.1 ml, intravenously) paired with light and tone cues underwent daily extinction sessions, during which responding had no consequences. After responding diminished, rats were tested for reinstatement of responding by either response-contingent presentations of the cues or a cocaine-priming injection (10 mg/kg, intraperitoneal, i.p.), with and without pretreatment with the 5-HT2C/2B receptor agonist, MK 212 (0.0-1.0 mg/kg, i.p.). MK 212 attenuated cue and cocaine-primed reinstatement, as well as spontaneous and cocaine-induced locomotion at all doses tested. These effects were reversed by coadministration of the 5-HT2C-selective receptor antagonist, SB 242 084 (3.0 mg/kg, i.p.), suggesting they are 5-HT2C receptor-mediated. Although we cannot rule out the possibility that motor impairment might have been involved in the MK 212 effects on cocaine-seeking behavior, some aspects of the data favor the explanation that MK 212 decreases the motivational effects of cocaine and cocaine cues. The latter interpretation is consistent with a growing body of literature suggesting that 5-HT2C receptors play a role in motivated behaviors in general.

Topics: Aminopyridines; Animals; Behavior, Addictive; Cocaine; Cues; Dose-Response Relationship, Drug; Extinction, Psychological; Indoles; Male; Motor Activity; Pyrazines; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT2C; Self Administration

Electrophysiological and in vivo microdialysis were used to investigate and compare the effect of tonic activation of serotonin(2C/2B) (5-HT(2C/2B)) receptors on nigrostriatal and mesolimbic dopaminergic (DA) function. Thus, extracellular single unit recordings of neurochemically-identified DA neurons in the SNc and the VTA, as well as simultaneous monitoring of striatal and accumbal DA release were performed following the administration of the unselective 5-HT(2C/2B) agonists, mCPP (m-chlorophenylpiperazine) and MK 212 [6-chloro-2-(1-piperazinyl)piperazine]. Both mCPP (5-320 microg/kg i. v.) and MK 212 (5-320 microg/kg i.v.) dose-dependently decreased the firing rate of VTA DA neurons. The maximal effect was reached at the cumulative dose of 320 microg/kg mCPP and MK 212, which caused a decrease of 42.6 +/- 12.8% and 56.4 +/- 12.6%, respectively. In addition, the total number of events in bursts and the number of bursts of VTA DA cells were significantly reduced by both mCPP and MK 212. On the other hand, mCPP (5-320 microg/kg i.v.) and MK 212 (5-320 microg/kg i.v.) induced a slight decrease in the basal firing rate, but not in bursting activity of SNc DA neurons. Consistent with electrophysiological data, dialysate DA levels in the nucleus accumbens decreased significantly, reaching the maximum of 26.6 +/- 9.6% below baseline levels 120 min after mCPP (1 mg/kg i.p.) administration, and of 25.2 +/- 5.5% 140 min after MK 212 (1 mg/kg i. p.) injection. DA outflow in the striatum was unaffected by both drugs. The inhibitory effect of both mCPP and MK 212 on VTA DA cell activity was blocked completely by pretreatment with the selective 5-HT(2C) antagonist SB 242084 ¿6-chloro-5-methyl-1-[2-(2-methylpyridyl-3-oxy)-pyrid-5-yl carbamoyl] indoline¿ (200 microg/kg), given intravenously 10 min before the first injection of the 5-HT(2C/2B) agonists. SB 242084 (2. 5 mg/kg i.p.) antagonized also the decrease in DA release induced by mCPP and MK 212 in the nucleus accumbens. Taken together, these data indicate that mCPP and MK 212 selectively inhibit mesolimbic dopaminergic function by acting on 5-HT(2C) receptors. Therefore, selective 5-HT(2C) receptor agonists might be useful in clinical conditions where it is necessary to reduce the mesolimbic dopaminergic activity without affecting the nigrostriatal function.

Topics: Aminopyridines; Animals; Dopamine; Indoles; Male; Neostriatum; Neurons; Nucleus Accumbens; Piperazines; Pyrazines; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT2B; Receptor, Serotonin, 5-HT2C; Receptors, Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Substantia Nigra; Ventral Tegmental Area

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