5-HT2a antagonism

The mechanism by which 5-HT2 antagonism could ameliorate schizophrenic symptoms and what effect 5-HT has on mesolimbic and mesocortical pathways through A10 neurons is even less certain. It is more likely that 5-HT s action occurs postsynaptically in the limbic system or PFC. The probability that neuroleptics benefit from a particular balance of DA and 5-HT2A antagonism is developed later. 

It is thought that 5-HT2a antagonism together with relatively weaker dopamine antagonism are principal features that differentiate the side-effect profile of atypical antipsychotic agents of the first generation treatments. 

The question arises whether 5-HT2A antagonism per se may be sufficient to treat positive as well as negative symptoms in schizophrenia without causing EPS. 

Fibres from 5-HT neurons in the raphe nucleus innervate and yet, despite the observed 5-HT2A receptor link with neuronal excitation, appear to inhibit DA neurons in the SN (A9). Thus antagonism of 5-HT released onto them would increase their firing and so reduce the likelihood of EPSs, although how 5-HT2A antagonists can... 

Ketanserin is an antagonist at 5-HT2A receptors and produces antihypertensive effects, as well as inhibition of thrombocyte aggregation. Whether 5-HT antagonism accounts for its antihypertensive effect remains questionable, because ketanserin also blocks a-adren-oceptors. 

Risperidone has been developed as a combined D2/5-HT2A receptor antagonist. In addition, it has a high affinity for 5-HT1A and 5-HT7 receptors. Whether such an effect has any relevance to its beneficial effects on the negative symptoms of schizophrenia, and lack of extrapyramidal side effects at moderate therapeutic doses, is unknown. An important advantage of risperidone over clozapine lies in its lack of antagonism of muscarinic receptors. 

HT2A receptors, were formerly called S-HTz receptors also 5-HT D receptors - because they were irreversibly alkylated by the p-haloalkylamine, dibenamine. They are antagonized by MDL 100907, ketanserin, ritanserin. spiperone, LY 53857, mesulergine and AMI 193. 

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