The Potential Antipsychotic Mechanism Of Serotonin 2C Receptor Agonist

Background: Antipsychotic medications are the main intervention in the treatment of schizophrenia.Although the first-generation antipsychotics?typical?are quite effective in controlling positive symptoms of schizophrenia,they also produce extra-pyramidal side effects including dystonia,akathisia,and Parkinsonism due to a preferential affinity for the dopamine D2 receptors.The second generation antipsychotics?atypical?are characterized by their lower liability to induce extra-pyramidal side effects and better tolerability.However,they also cause other side effects such as weight gain and the increased risk of diabetes.Therefore,the current drug development is aimed to identify novel drugs that are effective in treating schizophrenia without producing extra-pyramidal syndrome,weight gain,and other side effects.The researches on antipsychotic drugs have found that inhibiting the release of dopamine can suppress psychotic symptoms.Recent studies have demonstrated that 5-hydroxytryptamine 2C(5-HT_2C)receptor agonists potential antipsychotic activity in preclinical animal studies.In combination with the fact that activation of 5-HT_2C receptors decrease dopamine release in the nucleus accumbens and cell firing in the ventral tegmental area.As such,it is widely accepted that 5-HT_2C receptor agonists produce antipsychotic profiles due to reduced dopamine neurotransmission from presynaptic neurons.Nevertheless,although it is widely accepted that 5-HT_2C receptor agonists have antipsychotic profiles via reducing dopamine release from presynaptic neurons,there is no direct evidence to support the idea that the impaired release of dopamine is necessary to the antipsychotic activity of 5-HT_2C receptor agonist or there is another mechanism for the antipsychotic effect of 5-HT_2C receptor agonists.The researchers found that antipsychotics can selectively inhibit conditioned avoidance response in rats,which is dose dependently.The conditioned avoidance response paradigm is a widely used paradigm to investigate antipsychotic effect in preclinical practice.Research aim: the aim of the paper is to investigate whether 5-HT_2C receptor agonists show antipsychotic activities dependently on reducing dopamine release.Experiment method: Animals were firstly trained for conditioned avoidance response,and then rats were administrated with reserpine to deplete dopamine.Besides,we treated rats with quinpirole,and test whether it can reverse the effect of reserpine,for determining the feasibility of behavioral indicators.Experiment 1 is to make dopamine-depleted animals could perform normal conditioned avoidance response since the dopamine-depleted animals almost do not show any behavior.In experiment 2,We tested the effect to conditioned avoidance response,by combining with quinpirole?0.3,0.5,1.0 mg/kg,i.p?and MK212?0.5 mg/kg,i.p?.As such,quinpirole might reverse the disruptive effect of 5-HT_2C agonists,if 5-HT_2C agonists disrupt conditioned avoidance response via reducing dopamine release.In experiment 3,we tested the effect of MK212 in dopamine-depleted animals,excluding the possibility of dopamine release reduction,whether MK212 could display antipsychotic effect.In experiment 4,we tested the changes of glutamate level in accumbens nucleus with microdialysis in rats treated with MK212 or saline.It has been hypothesized that an imbalance in glutamatergic transmission is associated with schizophrenia.In addition,the nucleus accumbens play an important role in motivation-behavior,reward behavior and spatial memory.And mostly metabotropic glutamate receptor subtypes,which are corelated with schizophrenia,located in prefrontal cortex and nucleus accumbens.Experiment result: As shown in experiment 1,reserpine 5 mg/kg significantly disrupted conditioned avoidance response 24 h after administration?p = 0.000,n = 6?.Interestingly,quinpirole 0.3mg/kg dramatically reversed the disrupted conditioned avoidance response caused by reserpine,even very close to that in normal animals.In addition,dopamine D2 receptor play an important role in conditioned avoidance response,by the fact that haloperidol can neutralize the effect of quinpirole.Quinpirole can trigger conditioned avoidance response,although endogenous dopamine release had been depleted by reserpine.In experiment 2,quinpirole?0.3,0.5,1.0 mg/kg,i.p?failed to reverse the disrupted conditioned avoidance responses induced by MK212.These data gave us an indication that MK212 may have other way to disrupt avoidance responses rather than inhibiting dopamine release.In experiment 3,independently of reducing dopamine release,MK212 could also display antipsychotic effects.In experiment 4,compared with rats pretreated with saline or 0.1 mg/kg MK212,0.5 mg/kg MK212 can significantly reduce glutamate release in the nucleus accumbens,which indicates that MK212 may act as antipsychotics by inhibiting glutamate release.Conclusions: The present study first demonstrates that 5-HT_2C receptor agonists can disrupt conditioned avoidance responses independently of inhibiting endogenous dopamine release.Furthermore,we also determinates that 5-HT_2C receptor agonist MK212 decreases extracellular concentration of glutamate in the nucleus accumbens,which may be a critical mechanism underlying the antipsychotic effect of 5-HT_2C receptor agonist.