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The atypical antipsychotics integrate with the serotonin (5-HT), norepinephrine (α, β), and dopamine (D) receptors in order to effectively treat schizophrenia.
D2 Receptor: Hyperactive dopaminergic activity on D2 receptors in the mesolimbic pathway is responsible for the positive symptoms of schizophrenia (hallucinations, delusions, paranoia). After taking an antipsychotic, antagonism of D2 receptors occurs throughout the entire brain, leading to a number of deleterious side effects from D2 receptor antagonism throughout the entire dopamine pathway system. Unfortunately, it’s not possible to affect D2 receptors only in the mesolimbic pathway.[58][Stahl AP Explained 1 - 1] Fortunately, 5-HT2A receptor antagonism reverses these side effects to some extent.[Stahl AP Explained 1 - 2] Reducing D2 dopaminergic activity in the mesolimbic pathway also results in an anhedonic effect, reducing pleasure, motivation, and the salience of one’s life experience. In the mesocortical pathway to the DLPFC and VMPFC, endogenous D2 receptor dopamine activity is sometimes low in schizophrenia, resulting in cognitive, affective, and, broadly, the negative symptoms of schizophrenia. D2 receptor antagonism here further compounds these problems. In the nigrostratial pathway, D2 receptor antagonism results in extrapyramidal symptoms. If this antagonism occurs long enough, symptoms of EPS may become permanent, even if antipsychotic use is discontinued. In the tuberoinfundibular pathway, D2 receptor antagonism results in elevated prolactin. If prolactin levels become high enough, hyperprolactinaemia may occur, resulting in sexual dysfunction, weight gain, more rapid demineralization of bones, and possibly galactorrhea and amenorrhea.[Stahl AP Explained 1 - 1]
5-HT2A Receptor: When serotonin is released on to postsynaptic 5-HT2A receptors, the dopamine neuron is inhibited, thus acting as a brake on dopamine release.[Stahl AP Explained 1 - 2] This brake is disrupted through action of a 5-HT2A antagonist, which cuts the brake cable, disinhibiting the dopamine neuron, and stimulating dopamine release. The result of this is that dopamine competes with antipsychotic D2 antagonistic action at D2 receptors, thereby reducing antagonistic binding there and eliminating or lowering D2 antagonistic effects in several pathways of the dopamine system.[Stahl AP Explained 1 - 2] In the nigrostratial pathway, it reduces EPS. In the tuberoinfundibular pathway, it reduces or eliminates prolactin elevation.[Stahl AP Explained 1 - 3] Dopamine release in the mesolimbic pathway from 5-HT2A antagonism does not appear to be as robust as in the other pathways of the dopamine system, thereby accounting for why atypical antipsychotics still retain part of their efficacy against the positive symptoms of schizophrenia through their D2 antagonism.[Stahl AP Explained 1 - 3] When 5-HT2A antagonistic agent particles occupy 5-HT2A receptors in the mesocortical pathway and in the prefrontal cortex, the negative symptoms of schizophrenia, affective symptoms, and cognitive deficits and abnormalities are treated and reduced.[Stahl AP Explained 1 - 3] Furthermore, 5-HT2A receptor antagonism blocks the serotonergic excitation of cortical pyramidal cells, reducing glutamate release, which in turn lowers hyperactive dopaminergic D2 receptor activity in the mesolimbic pathway, reducing or eliminating the positive symptoms of schizophrenia.[Stahl AP Explained 1 - 3][59][60]
Some effects of 5-HT1A receptor activation include decreased aggressive behavior/ideation,[61] increased sociability, and decreased anxiety and depression.[non-primary source needed] 5-HT2C activation blocks dopamine and inhibits norepinephrine release. Blockade of the 5-HT2C receptor increases serotonin, releasing norepinephrine and dopamine within the brain.[58] But neuronal reuptake of norepinephrine is limited sharply by some antipsychotics, for example ziprasidone. Increased norepinephrine can cause increased glucose levels, which is to say blood sugar levels.[62][63][64] Increased blood sugar levels by increased norepinephrine causes hunger in many humans, which is why weight gain occurs with some antipsychotics if the norepinephrine is not inhibited.[65][66][67][68][69] Inhibition of norepinephrine stabilizes mood in humans.[70] 5-HT6 receptor antagonists improve cognition, learning, and memory.[71] The 5-HT7 receptor is very potent for the mitigation of bipolar conditions and also yields an antidepressant effect. The antipsychotics asenapine,[72] lurasidone,[73][74] risperidone,[75] and aripiprazole[76] are very potent at the 5-HT7 receptor. Antagonistic affinity for the H1 receptor also has an antidepressant effect. H1 antagonism blocks serotonin and norepinephrine reuptake. Patients with increased histamine levels have been observed to have lower serotonin levels.[77] However, the H1 receptor is linked to weight gain. To have partial agonism at the 5-HT1A receptor can yield absence of weight gain in an antipsychotic. This is very relevant for ziprasidone,[78][79] but it creates a risk for a prolonged QTc interval.[80][81] On the other hand, blockade of the 5-HT3 receptor removes the risk for a prolonged QTc interval,[73] but then creates a larger risk for weight gain. Relation to the 5-HT3 receptor increases caloric uptake and glucose,[82] which is seen in clozapine and olanzapine.[83][84] Other ways for dopamine to resolve is to have agonism at both the D2 receptor and 5-HT1A receptor, which normalizes the dopamine level in the brain. This occurs with haloperidol and aripiprazole.
Whether the anhedonic, loss of pleasure and motivation effect resulting from dopamine insufficiency or blockade at D2 receptors in the mesolimbic pathway, which is mediated in some part by antipsychotics (and despite dopamine release in the mesocortical pathway from 5-HT2A antagonism, which is seen in atypical antipsychotics), or the positive mood, mood stabilization, and cognitive improvement effect resulting from atypical antipsychotic serotonergic activity is greater for the overall quality of life effect of an atypical antipsychotic is a question that is variable between individual experience and the atypical antipsychotic(s) being used.[58]
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