It has been found that 5-HT2A-receptor blockade is a key factor in the mechanism of action of the main class of second-generation antipsychotic drugs, of which clozapine is the prototype and which includes, in order of their introduction around the world, melperone, risperidone, zotepine, blonanserin, olanzapine, quetiapine, ziprasidone, aripiprazole, sertindole, paliperidone, iloperidone, asenapine, lurasidone, cariprazine, and brexpiprazole. These drugs are inverse agonists of the 5-HT2A receptor; that is, they block the constitutive activity of these receptors. These receptors modulate the release of dopamine, norepinephrine, glutamate, GABA, and acetylcholine, among other neurotransmitters in the cortex, limbic region, and striatum. Stimulation of 5-HT2A receptors leads to depolarization of glutamate neurons, but also stabilization of N-methyl-d-aspartate (NMDA) receptors on postsynaptic neurons. It has been found that hallucinogens can modulate the stability of a complex consisting of 5-HT2A and NMDA receptors.
5-HT2C-receptor stimulation provides a further means of modulating cortical and limbic dopaminergic activity. Stimulation of 5-HT2C receptors leads to inhibition of cortical and limbic dopamine release. Many atypical antipsychotic drugs, eg, clozapine, asenapine, and olanzapine, are 5-HT2C inverse agonists. 5-HT2C agonists are currently being studied as antipsychotic agents.
The dopamine hypothesis for schizophrenia was the second neurotransmitter-based concept to be developed but is no longer considered adequate to explain all aspects of schizophrenia, especially the cognitive impairment. Nevertheless, it is still highly relevant to understanding the major dimensions of schizophrenia, such as positive (hallucinations, delusions) and negative symptoms (emotional blunting, social withdrawal, lack of motivation), cognitive impairment, and possibly depression. It is also essential to understanding the mechanisms of action of most and probably all antipsychotic drugs.
Several lines of evidence suggest that excessive limbic dopaminergic activity plays a role in psychosis. (1) Many antipsychotic drugs strongly block postsynaptic D2 receptors in the central nervous system, especially in the mesolimbic and striatal-frontal system; this includes partial dopamine agonists, such as aripiprazole, brexpiprazole, and bifeprunox. (2) Drugs that increase dopaminergic activity, such as levodopa, amphetamines, and bromocriptine and apomorphine, either aggravate schizophrenia psychosis or produce psychosis de novo in some patients. (3) Dopamine-receptor density has been found postmortem to be increased in the brains of schizophrenics who have not been treated with antipsychotic drugs. (4) Some but not all postmortem studies of schizophrenic subjects have reported increased dopamine levels and D2-receptor density in the nucleus accumbens, caudate, and putamen. (5) Imaging studies have shown increased amphetamine-induced striatal dopamine release, increased baseline occupancy of striatal D2 receptors by extracellular dopamine, and other measures consistent with increased striatal dopamine synthesis and release.