Effects Of mCPP Research Articles

Effect of mCPP on Cognitive Control, Appetite, and Neural Responses

Effect of mCPP on Cognitive Control, Appetite, and Neural Responses

Evaluation of Selective 5-HT2C Agonists in Acute Seizure Models.

The 5-HT releaser/reuptake inhibitor fenfluramine has been recently reported to provide benefit as an adjunctive treatment for Dravet and Lennox-Gastaut syndromes, two types of severe childhood epilepsy. Despite its enhancement of 5-HT function, many effects of fenfluramine have been demonstrated to be dependent on 5-HT2C receptor activation, suggesting that 5-HT2C receptor activation may have an anticonvulsant property. The present study was designed to evaluate fenfluramine and 5-HT agonists of varying 5-HT2C agonist selectivity, the relatively nonselective mCPP and Ro 60-0175, and the selective 5-HT2C agonists lorcaserin and CP-809101 across a variety of acute seizure tests conducted in adult rats and mice, which have been instrumental in identifying the majority of clinically efficacious antiepileptic drugs. Tests included the maximal electroshock seizure (MES), MES threshold, and 6 Hz electrical convulsive seizure models and the chemoconvulsant pentylenetetrazole test. The effect of mCPP, lorcaserin, and CP-809101 against electrically evoked seizures in amygdala kindled rats was also investigated. Overall, at doses known to interact with 5-HT2CR, there was no clear class-related effect of these agonists in any test. The only notable antiseizure effect of fenfluramine was inhibition of MES-induced tonic seizures in the rat. The current preclinical studies using the classical acute seizure tests and an amygdala kindling model do not identify a reliable antiseizure effect of fenfluramine, an agent now used in the treatment of human epilepsies, including Dravet syndrome and Lennox-Gastaut syndrome. Given the nature of these epilepsies, early life and/or genetic models may have better construct validity and be more appropriate for further study.

Pharmacological evaluation of novel 5-HT3 receptor antagonist, QCM-13 (N-cyclohexyl-3-methoxyquinoxalin-2-carboxamide) as anti-anxiety agent in behavioral test battery.

Objective:In the last few decades, serotonin type-3 (5-HT3) receptor antagonists have been identified as potential targets for anxiety disorders. In preclinical studies, 5-HT3 antagonists have shown promising antianxiety effects. In this study, a novel 5-HT3 receptor antagonist, QCM-13(N-cyclohexyl-3-methoxyquinoxalin-2-carboxamide) was evaluated for anxiolytic-like activity in rodent behavioral test battery.Materials and Methods:Mice were given QCM-13 (2 and 4 mg/kg, intraperitoneally [i.p.]) or diazepam (2 mg/kg, i.p.) or vehicle and after 30 min, mice were subjected to four validated behavioral test batteries viz. elevated plus maze, hole board, light-dark and open field tests. Interaction study of QCM-13 with m-chlorophenyl piperazine (mCPP) (mCPP, a 5-HT2A/2C receptor agonist, 1 mg/kg, i.p.) and buspirone (BUS, a partial 5-HT1A agonist, 10 mg/kg, i.p.) were performed to assess the pharmacological mechanism of the drug.Results:QCM-13 expressed potential anxiolytic effect with significant (P < 0.05) increase in behavioral parameters measured in aforementioned preliminary models. Besides, QCM-13 was unable to reverse the anxiogenic effect of mCPP, but potentiated anxiolytic affect of BUS.Conclusion:The results suggest that QCM-13 can be a potential therapeutic candidate for the management of anxiety-like disorders and combination doses of novel 5-HT3 receptor antagonist with standard anxiolytics may improve therapeutic efficacy.

Evidence for a role of 5-HT2C receptors in the motor aspects of performance, but not the efficacy of food reinforcers, in a progressive ratio schedule.

5-Hydroxytryptamine2C (5-HT2C) receptor agonists reduce the breakpoint in progressive ratio schedules of reinforcement, an effect that has been attributed to a decrease of the efficacy of positive reinforcers. However, a reduction of the breakpoint may also reflect motor impairment. Mathematical models can help to differentiate between these processes. The effects of the 5-HT2C receptor agonist Ro-600175 ((αS)-6-chloro-5-fluoro-α-methyl-1H-indole-1-ethanamine) and the non-selective 5-HT receptor agonist 1-(m-chlorophenyl)piperazine (mCPP) on rats' performance on a progressive ratio schedule maintained by food pellet reinforcers were assessed using a model derived from Killeen's Behav Brain Sci 17:105-172, 1994 general theory of schedule-controlled behaviour, 'mathematical principles of reinforcement'. Rats were trained under the progressive ratio schedule, and running and overall response rates in successive ratios were analysed using the model. The effects of the agonists on estimates of the model's parameters, and the sensitivity of these effects to selective antagonists, were examined. Ro-600175 and mCPP reduced the breakpoint. Neither agonist significantly affected a (the parameter expressing incentive value), but both agonists increased δ (the parameter expressing minimum response time). The effects of both agonists could be attenuated by the selective 5-HT2C receptor antagonist SB-242084 (6-chloro-5-methyl-N-{6-[(2-methylpyridin-3-yl)oxy]pyridin-3-yl}indoline-1-carboxamide). The effect of mCPP was not altered by isamoltane, a selective 5-HT1B receptor antagonist, or MDL-100907 ((±)2,3-dimethoxyphenyl-1-(2-(4-piperidine)methanol)), a selective 5-HT2A receptor antagonist. The results are consistent with the hypothesis that the effect of the 5-HT2C receptor agonists on progressive ratio schedule performance is mediated by an impairment of motor capacity rather than by a reduction of the incentive value of the food reinforcer.

Effects of the 5-HT2C receptor agonist meta-chlorophenylpiperazine on appetite, food intake and emotional processing in healthy volunteers.

The treatment of obesity is an increasing global health priority, yet few effective drug treatments are currently available. The discovery of novel anti-obesity therapies could be assisted by the validation of experimental (translational) medicine models in healthy volunteers that assess efficacy and safety at an early stage of drug development. The aim of this study was to examine the effects of the 5-HT2C receptor agonist meta-chlorophenylpiperazine (mCPP) in an experimental medicine model assessing both appetite and mood. Using a between-subjects, double-blind, placebo-controlled design, 24 male and 24 female participants were randomly assigned to either placebo, 15- or 30-mg mCPP treatment groups. Lunch was eaten from a Universal Eating Monitor (UEM) that measured eating rate, and the participants completed the P1vital® Oxford Emotional Test Battery (ETB) and a series of appetite and mood ratings. mCPP reduced appetite and, in women, enhanced measures of satiation. The drug also enhanced memory for emotional material in the word recall and recognition memory tasks of the ETB. The results provide new insight into the effects of mCPP on appetite, satiety and memory in humans. In addition, our data provide an illustration of the value of measuring changes in appetite and mood in healthy volunteers to determine the potential efficacy and safety of novel anti-obesity drugs.

New Findings on the Sensitivity of Free-Operant Timing Behaviour to 5-Hydroxytryptamine Receptor Stimulation

Timing performance maintained under the free-operant psychophysical procedure (FOPP) is sensitive to 5-hydroxytryptamine (5-HT)1A and 5-HT2A receptor stimulation. Agonists of these receptors displace the psychometric function towards shorter durations, reducing , the index of central tendency of timing. Here we report the effects of Ro-600175, a selective 5-HT2C receptor agonist, and mCPP, a 5-HT receptor agonist with high affinity for 5-HT2C receptors and lower affinity for 5-HT1A, 5-HT1B and 5-HT2A receptors, on timing behaviour. Rats were trained under the FOPP to press two levers (A and B) in 50-s trials in which reinforcers were provided intermittently for responding on A in the first half, and B in the second half of the trial. Percent responding on B (%B) was recorded in successive 5-s epochs of the trials; logistic psychometric curves were fitted to the data from each rat under each treatment condition for derivation of timing indices [ (time corresponding to %B = 50%), Weber fraction]. The rats received systemic treatment with Ro-600175, mCPP, and mCPP in combination with antagonists of 5-HT1A (WAY-100635), 5-HT1B (isamoltane), 5-HT2A (MDL-100907) or 5-HT2C (SB-242084) receptors. mCPP (2.5 mg kg−1 i.p.), but not Ro-600175 (1, 2, 4 mg kg−1 i.p.), reduced . SB-242084 (0.6 mg kg−1 i.p.) potentiated mCPP’s effect on . mCPP’s effect on was not altered by isamoltane (8.0 mg kg−1 i.p.), but was attenuated by MDL-100907 (1.0 mg kg−1 i.p.) and WAY-100635 (0.1 mg kg−1 s.c.). The results suggest that mCPP’s effect on timing is mediated by an agonistic action at 5-HT1A and 5-HT2A, but not 5-HT1B, receptors. The role of 5-HT2C receptors is unclear, in view of SB-242084’s ability to potentiate the effect of mCPP, while Ro-600175 had no effect on . The possibility is considered that 5-HT2C receptors may counteract 5-HT1A and/or 5-HT2A receptor-mediated effects on timing performance.

Cannabidiol reverses the mCPP‐induced increase in marble‐burying behavior

Cannabidiol (CBD), one of the main components of Cannabis sp., presents clinical and preclinical anxiolytic properties. Recent results using the marble-burying test (MBT) suggest that CBD can also induce anticompulsive-like effects. Meta-chloro-phenyl-piperazine (mCPP) is a nonspecific serotonergic agonist (acting mainly at 5HT1A, 5HT2C and 5HT1D receptors) reported to increase symptoms in OCD patients and block the anticompulsive-like effect of serotonin reuptake inhibitors (SRIs) in animal models. The aim of this study was to investigate the interference of CBD on mCPP effects in repetitive burying. Administration of mCPP showed dual effects in the MBT, increasing the number of buried marbles at lower (0.1 mg/kg) while decreasing it at higher doses (1 mg/kg), an effect not related to a general increase in anxiety-like behavior. As found previously, CBD (30 mg/kg) and the positive control fluoxetine (FLX; 10 mg/kg) decreased burying behavior without changing general exploratory activity. A similar effect was found when subeffective doses of CBD (15 mg/kg) and FLX (3 mg/kg) were administered together. These subeffective doses alone were also able to block mCPP-induced repetitive burying. The results, in addition to reinforcing a possible anticompulsive effect of CBD, also suggest that mCPP-induced repetitive burying could be a useful test for the screening of compounds with presumed anticompulsive properties.

Role of 5-HT2C receptors in the enhancement of c-Fos expression induced by a 5-HT2B/2C inverse agonist and 5-HT2 agonists in the rat basal ganglia

Some non-selective serotonin2C (5-HT2C) agonists or inverse agonists enhance the product of the proto-oncogene c-Fos within the basal ganglia, a group of brain regions involved in motor behavior and in the ability of these drugs to promote abnormal movements. The role of 5-HT2C receptors in these effects is unclear. The 5-HT2C antagonist SB243,213 (1mg/kg), which enhanced Fos per se in the striatum and the subthalamic nucleus (STN) only, was used to study the implication of 5-HT2C receptors. The agonists Ro 60-0175 (3mg/kg) and m-CPP (1mg/kg) and the inverse agonist SB206,553 (10mg/kg) enhanced Fos expression in the STN and faintly in the entopeduncular nucleus (EPN, the internal globus pallidus in primate). The effects of these drugs differed mainly in the striatum regarding the magnitude (m-CPP>Ro 60-0175>SB243,213>SB206,553) or the striatal quadrants (faint to no labeling in lateral striatum) and in the substantia nigra. None of these compounds enhanced Fos expression by themselves in the globus pallidus or in the EPN when combined with SB243,213. Their Fos effect in the STN was reduced significantly by SB243,213 only in the case of m-CPP. In the ventromedial striatum, SB243,213 reduced the effects of m-CPP while SB206,553 reduced the effects of SB243,213. The results show that opposite pharmacological agents alter similarly Fos expression in the EPN or the STN. Although some of the effects of 5-HT agents are related to targets other than 5-HT2C receptors, the study confirms the existence of multiple 5-HT2C receptor-dependent controls recruited by these drugs upon basal ganglia activity.

Effects of the serotonergic agonist mCPP on male rats in the quinpirole sensitization model of obsessive–compulsive disorder (OCD)

The serotonergic agonist, meta-chlorophenylpiperazine (mCPP), produces inconsistent effects on obsessive-compulsive disorder (OCD) symptoms, perhaps because clinical studies have not utilized a homogenous OCD subgroup of patients. This study aimed to evaluate mCPP effects on functional components of compulsive checking, using the quinpirole sensitization rat model of OCD. In study 1, the effects of mCPP were evaluated in quinpirole rats with compulsive checking. Two experimental groups were co-injected with quinpirole (0.125mg/kg) and mCPP (0.625 or 1.25mg/kg), while one control group was co-injected with quinpirole (0.125mg/kg) and saline and the other control group received co-injections of saline. In study 2, mCPP (0, 0.3125, 0.625, and 1.25mg/kg) was administered repeatedly to naïve rats and induction of compulsive checking evaluated. mCPP significantly attenuated quinpirole-induced compulsive checking behavior by reducing vigor of checking (indexed by frequency of checking and length of check) and increasing rest after a bout of checking (indexed by time to the next checking bout), but it did not affect focus on the task of checking (indexed by recurrence time of checking and number of stops before returning to check). In naïve rats, mCPP did not induce compulsive behavior, but the highest dose reduced vigor of checking performance compared to saline controls. mCPP did not exacerbate or induce compulsive checking behavior. Instead, it ameliorated compulsive checking by reducing vigor of checking and increasing post-checking satiety, without affecting focus on checking. Ameliorative effects of mCPP may involve 5HT2A/2C receptors in substantia nigra pars reticulata that inhibit expression of motor vigor.

Ritualistic Chewing Behavior induced by mCPP in the rat is an animal model of Obsessive Compulsive Disorder

Obsessive Compulsive Disorder (OCD) is characterized by recurrent, anxiety-producing thoughts accompanied by unwanted, overwhelming urges to perform ritualistic behaviors. Pharmacological treatments for this disorder (serotonin uptake inhibitors) are problematic because there is a 6–8week delayed onset and half of the patients do not adequately respond. The present study evaluated whether Ritualistic Chewing Behaviors (RCBs) induced by the serotonin agonist mCPP in the rat is a behavioral model for OCD. The effects upon the RCBs induced by mCPP (1mg/kg) were evaluated following treatments with either the serotonin antagonist mianserin (3mg/kg), the dopamine antagonist haloperidol (1mg/kg), the GABA modulator diazepam (10mg/kg), or the serotonin uptake inhibitors clomipramine and fluvoxamine (15mg/kg). The response to mCPP was blocked by acute treatment with mianserin, but not with acute haloperidol or diazepam. Further experiments revealed that the effects of mCPP were blocked by chronic, but not acute, treatment with clomipramine and fluvoxamine. A time-course demonstrated that 14days of chronic treatment were required for blockade of the mCPP-evoked response.The current study demonstrates that mCPP-evoked RCBs may be a rodent model for OCD that can be used to predict the clinical efficacy and time course of novel OCD treatment. Future investigations may be able to use the current model as a tool for bench-marking corresponding changes in other measures of neurological activity that may provide insight into the mechanisms underlying OCD.

Role of cortical reorganization on the effect of 5-HT pharmacotherapy for spinal cord injury

Cortical reorganization or expansion of the intact cortical regions into the deafferented cortex after complete spinal transection in neonatally spinalized rats was shown to be essential for increases in weight-supported stepping at adulthood. The novel somatotopic organization identified in these animals can be induced by exercise or spinal transplants that bridge the site of injury. However, the role of cortical reorganization in increased weight-supported (WS) stepping after pharmacotherapy is unknown. For the neonatally spinalized rat model, the 5-HT2C receptor agonist 1-(m-chlorophenyl)-piperazine hydrochloride (mCPP) increases the number of WS steps taken when administered to adult rats spinalized as neonates (mCPP+) though not all animals showed this effect (mCPP−). Since no differences in the behavior of the animals off-drug has been demonstrated, it is unclear why acute administration of 5-HT affects only a subset of animals. One possibility is that differences in cortical organization between mCPP+ and mCPP− may contribute to the differences in the functional effect of mCPP. To test this, we recorded from single neurons in the deafferented hindlimb sensorimotor cortex during passive sensory stimulation of the cutaneous surface of the forepaws and during active sensorimotor stimulation of the forepaws while the animals locomoted on a motorized treadmill. Our results show that neurons recorded from mCPP+ animals increased their responsiveness to both passive and active stimulation off-drug in comparison to neurons from mCPP− animals. These data suggest that differences in the cortical organization of mCPP+ compared to mCPP− animals may be at least partially responsible for the effect of a 5-HT2C receptor agonist on functional outcome.

Altered 5-HT2C receptor agonist-induced responses and 5-HT2C receptor RNA editing in the amygdala of serotonin transporter knockout mice

BackgroundThe serotonin 5-HT2C receptor (5-HT2CR) is expressed in amygdala, a region involved in anxiety and fear responses and implicated in the pathogenesis of several psychiatric disorders such as acute anxiety and post traumatic stress disorder. In humans and in rodent models, there is evidence of both anxiogenic and anxiolytic actions of 5-HT2C ligands. In this study, we determined the responsiveness of 5-HT2CR in serotonin transporter (SERT) knockout (-/-) mice, a model characterized by increased anxiety-like and stress-responsive behaviors.ResultsIn the three-chamber social interaction test, the 5-HT2B/2C agonist mCPP decreased sociability and sniffing in SERT wildtype (+/+) mice, both indicative of the well-documented anxiogenic effect of mCPP. This 5-HT2C-mediated response was absent in SERT -/- mice. Likewise, in the open field test, the selective 5-HT2C agonist RO 60-0175 induced an anxiogenic response in SERT +/+ mice, but not in SERT -/- mice. Since 5-HT2CR pre-mRNA is adenosine-to-inosine (A-to-I) edited, we also evaluated the 5-HT2CR RNA editing profiles of SERT +/+ and SERT -/- mice in amygdala. Compared to SERT +/+ mice, SERT-/- mice showed a decrease in less edited, highly functional 5-HT2C isoforms, and an increase in more edited isoforms with reduced signaling efficiency.ConclusionsThese results indicate that the 5-HT2CR in the amygdala of SERT -/- mice has increased RNA editing, which could explain, at least in part, the decreased behavioral responses to 5-HT2C agonists in SERT -/- mice. These alterations in 5-HT2CR in amygdala may be relevant to humans with SERT polymorphisms that alter SERT expression, function, and emotional behaviors.

P.2.d.012 Role of 5-HT1A receptor on extracellular 5-HT increase induced by trazodone in the rat prefrontal cortex

In the present study, we have investigated how various 5-HT agonists (m-chlorophenylpiperazine (mCPP) (0.1–1 mg/kg), 8-hydroxy 2-(di-N-propylamino) tetralin (8-OH DPAT) (0.125–2 mg/kg) and 5-HT (0.5–2 mg/kg)), the 5-HT uptake blocker sertraline (1–10 mg/kg), and the 5-HT uptake blocker and releaser dexfenfluramine (0.5–2.5 mg/kg), affect ethanol intake in a continual access paradigm using Wistar rats. By means of a drinkometer system the effect of each drug on microdrinking parameters (e.g., drink latency, number, and duration of drinking bouts) was assessed. The effect of various 5-HT antagonists (metergoline, ritanserin, ondansetron, and xylamidine) against the dexfenfluramine-induced suppression was studied. Furthermore, threshold doses for the anorectic and the suppressant effects of mCPP, sertraline and dexfenfluramine on ethanol intake were identified. From these studies, it seemed that similar mechanisms may be responsible for the suppressant effects of the various 5-HT agonists studied (direct and indirect) on ethanol and food intake. The 5-HT3 receptor antagonist, ondansetron, also reduced ethanol (but not food) intake. However, the profile of this effect may suggest an alternative means by which 5-HT3 receptors regulate ethanol intake in the rat by comparison to the various 5-HT agonists studied.

M‐chlorophenylpiperazine (mCPP) attenuates the behavioral‐stimulant effects of cocaine via activation of the 5‐HT2C receptor in nonhuman primates

Serotonin (5‐HT) indirect agonists have been shown to modulate the behavioral and neurochemical effects of cocaine in rodents and nonhuman primates, yet the specific receptors mediating these effects have not been fully elucidated. Recent evidence suggests that these actions may be partially mediated by the 5‐HT2C receptor in rodents, but this has not been systematically tested in nonhuman primates. In the present study, squirrel monkeys (n=3) were trained to lever‐press according to a fixed‐interval 300‐sec schedule of stimulus termination. Administration of cocaine (0.3 – 3.0 mg/kg) resulted in a typical inverted U‐shape dose‐response function with response rate as the dependent measure. Pretreatment with the preferential 5‐HT2C agonist mCPP (0.1 – 0.3 mg/kg) dose‐dependently and insurmountably attenuated the behavioral‐stimulant effects of cocaine, inducing a downward‐shift of the cocaine dose‐response curve. Moreover, the effects of mCPP were dose‐dependently reversed following pretreatment with the selective 5‐HT2C antagonist SB 242084 (0.01 – 0.3 mg/kg). These data are the first to demonstrate a modulatory effect of 5‐HT2C receptor activation on the behavioral effects of cocaine in nonhuman primates and warrant further investigation into the capacity of more selective compounds to alter cocaine's neurochemical and reinforcing effects. Support: F31DA026262, DA12514, DA00517 and RR00165.

S01-04 - 5-HT2C receptor activation inhibits stress-induced increase in 5-HT transmission: relevance to the effects of antidepressant drugs

Objectives5-HT2C receptors are well known to be involved in anxiety, but their implication in stress-induced changes of 5-HT transmission remained to be investigated. We thus assess the behavioral and neurochemical effects of 5-HT2C receptor activation in naïve and stressed mice, and after chronic paroxetine known to exert anxiolytic effects in humans.Methods and resultsThe effects of the preferential 5-HT2C agonists m-chlorophenylpiperazine (mCPP) and RO60-0175, the selective 5-HT2C receptor antagonist SB242,084 and restraint-stress on anxiety-like behavior in mice were assessed using the social interaction test, while the neurochemical effects of these treatments on 5-HT turnover (5-HIAA/5-HT ratio) and extracellular 5-HT were determined using HPLC and microdialysis. Both mCPP and restraint-stress increased anxiety-like behavior in the social interaction test, and these effects were blocked by pretreatment with SB242,084. Restraint-stress increased 5-HT turnover in various brain areas, and this effect could be prevented by the 5-HT2C receptor agonist RO60-0175. Acute administration of SB242,084 potentiated the stress-induced increase in 5-HT turnover and blocked the inhibitory effect of RO60-0175. Microdialysis studies in frontal cortex revealed that RO60-0175 has an inhibitory effect on the stress-induced increase in extracellular 5-HT levels, but not on basal 5-HT levels. Chronic paroxetine prevented the anxiogenic effect of mCPP and prevented the inhibitory effect of RO60-0175 on restraint-stress-induced increase in 5-HT turnover.ConclusionsThese data strongly suggest that 5-HT2C receptor activation mediates the anxiogenic effect of stress. In addition, the anxiolytic action of long term treatment with SSRIs might be causally related to a clear-cut 5-HT2C receptor desensitization.

MCPP: an undesired addition to the ecstasy market

A new ecstasy-like substance, meta-chlorophenylpiperazine (mCPP), has been detected in street drugs in the Netherlands. Theoretically, mCPP possesses the potential to become a non-neurotoxic alternative for methylenedioxymethamphetamine (MDMA), the regular psychoactive substance of ecstasy. Since its introduction on the Dutch market of synthetic drugs, the percentage of mCPP-containing tablets has increased, including both tablets that contain only mCPP and tablets containing a combination of mCPP and MDMA. These tablets occur in many different colours, shapes and sizes and with various logos, making it impossible to distinguish mCPP-containing tablets from regular MDMA tablets. In addition, the reports of users concerning the effects of mCPP are predominantly negative. All these aspects together lead to the conclusion that mCPP is an undesired addition to the ecstasy market from the user's perspective.

1-( m-Chlorophenyl)piperazine induces depressogenic-like behaviour in rodents by stimulating the neuronal 5-HT 2A receptors: Proposal of a modified rodent antidepressant assay

1-( m-Chlorophenyl)piperazine ( mCPP) has a fairly complex neuropsychopharmacological profile owing to its affinity to multiple serotonergic receptors. This investigation was designed to establish the effect of mCPP on rodent depression-like behaviour. mCPP was screened in a rodent behavioural test battery comprising of validated antidepressant assays and interaction studies with conventional antidepressants and ligands were carried out in forced swim and tail suspension test (in mice). mCPP (1 mg/kg, i.p.) exhibited depressant-like effects in forced swim and tail suspension test (in mice), without influencing the locomotor status. Potentiation of 5-hydroxytryptophan/pargyline induced head twitches (in mice) and hyperthermic effects (in rats) were observed at the same dose level. Further, the behavioural anomalies of the olfactory bulbectomised (OBX) rats were augmented by chronic mCPP (1–2 mg/kg) treatment as observed from the modified open field, elevated plus maze and social interaction paradigms. Interaction studies revealed that the mCPP induced depressant-like effects were reversed by ketanserin, escitalopram, amitriptyline, ziprasidone, venlafaxine pretreatments but not by bupropion, harmane, ondansetron, 8-hydroxy-2-(di- n-propylamino) tetralin (8-OH-DPAT) and MK-801. In conclusion, this study provided ample evidence that the stimulation of 5-HT 2A receptors underlies the depressogenic-like effect of mCPP. Finally, the mCPP induced depression-like behaviour in rodents is envisaged as a modified antidepressant assay to identify novel serotonergic antidepressants.

Trazodone generates m-CPP: In 2008 risks from m-CPP might outweigh benefits of trazodone

Since deleterious effects of m-CPP, the primary catabolic metabolite of trazodone, were last reviewed 2 years ago, research data continue to accrue showing that clinically significant levels of m-CPP (a) are generated in patients using trazodone for sleep and (b) are present 24 h a day and (c) have potentially serious ill effects. This commentary argues that the documented potential for harm and multiple risks of m-CPP outweigh potential benefits of trazodone, given the development and marketing of many safer alternatives since trazodone's introduction in the 1980s.

P03-32 Directional persistence in the rewarded alternation model of obsessive-compulsive disorder is responsive to both dopaminergic and serotonergic manipulations

Rationale:In the rewarded alternation model of obsessive compulsive disorder (OCD), the serotonin agonist m-chlorophenylpiperazine (mCPP) increases persistent behaviour, while chronic pretreatment with selective serotonin reuptake inhibitor (SSRI-fluoxetine) but not benzodiazepine or desipramine abolishes mCPP effects. However, we noted that acute SSRI administration also causes transient persistence increases, counteracted by mCPP pretreatment.Objectives:This studya.further explores the apparent cross-tolerance between fluoxetine and mCPP andb.extends the model by investigating its sensitivity to dopaminergic manipulations (D2,3 agonism - quinpirole).Methods:In both experiments, baseline and drug testing was carried out under daily T-maze alternation training.Exp.1:Matched group (n=8) pairs of rats received one of the following 20-day pretreatments (daily intraperitoneal administration):1.saline,2.low-dose fluoxetine (2.5mg/kg),3.low-dose mCPP (0.5mg/kg) or4.combined fluoxetine+mCPP.One group per pretreatment then received a 4-day challenge with high-dose fluoxetine (10mg/kg), the other with high-dose mCPP (2.5mg/kg).Exp.2:One group (n=12) of rats received 20-day treatment with saline, another with quinpirole (0.5 mg/kg).Results:Exp.1:Saline and low-dose mCPP- or fluoxetine-pretreated animals showed significant persistence increases under both challenges, while combined low-dose fluoxetine+mCPP pretreatment afforded full protection from either challenge.Exp.2:Quinpirole significantly increased directional persistence after 13 administration days.Conclusions:These results establish the sensitivity of the rewarded alternation OCD model to D2,3receptor activation, thereby extending its profile of pharmacological isomorphism with OCD. Furthermore, they suggest a common mechanism of action of an SSRI and a serotonin agonist in the control of directional persistence.

Subthalamic neurons show increased firing to 5-HT 2C receptor activation in 6-hydroxydopamine-lesioned rats

The subthalamic nucleus is innervated by 5-HT afferents from the dorsal raphe nucleus and expresses high density of 5-HT 2C receptors. However, the role of these receptors in neuronal firing of subthalamic neurons in vivo is unknown. In the present study, we examined the changes in the firing rate and firing pattern of subthalamic neurons, and the effect of the nonselective 5-HT 2C receptor agonist m-CPP and selective antagonist SB242084 on the neuronal firing of subthalamic neurons in normal rats, sham rats, and rats with 6-hydroxydopamine lesions of the substantia nigra pars compacta by using extracellular recording. Results showed an increase in the percentage of subthalamic neurons exhibiting burst-firing pattern with no change in firing rate during the third week after the lesion compared to normal rats. The systemic administration of m-CPP (20–320 μg/kg, i.v.) dose-dependently increased the firing rate of subthalamic neurons, and the local application of m-CPP, 4 μg, in the subthalamic nucleus also increased the firing rate of subthalamic neurons in the lesioned rats. Similarly, at the same doses, the systemic and local administration of m-CPP induced the excitatory effects on subthalamic neurons in normal and sham rats. The excitatory effect of m-CPP was reversed by the subsequent administration of SB242084 (200 μg/kg, i.v.). These results suggest that the response of subthalamic neurons to 5-HT 2C receptor stimulation is not altered after 6-hydroxydopamine lesions of the substantia nigra pars compacta.