*4.4. Mechanism of Action*

The first-generation, or typical, antipsychotic drugs are high-affinity antagonists of the dopamine D2 receptor. However, the extrapyramidal symptoms (EPSs), such as involuntary movement and muscle control, caused by typical antipsychotics have been attributed to potent dopamine antagonism [31]. The second-generation, atypical, anti-psychotic drugs such as clozapine have less affinity for the D2 receptors and result in reduced EPS side effects. Atypical drugs also target other dopamine receptors (D1, D3, D4), the 5-HT1A, 5-HT2A, 5-HT2C, 5-HT6, and 5-HT7 receptors for serotonin (5-hydroxytryptamine), as well as muscarinic, adrenergic, and histamine receptors [32]. Clozapine has a high affinity for the serotonin 5-HT2A receptor [33,34]. A theory on the effectiveness of atypical antipsychotics relates a higher ratio of a drug's affinity for the 5-HT2A receptor compared to the dopamine D2 receptor. The 5-HT1A receptor may also play a role in the antipsychotic effect, as the receptor is stimulated by clozapine and other antipsychotic drugs [35]. Serotonin is not only active in the nervous system, but also affects the immune system. Serotonin increases the mitogen-stimulated proliferation of B-cells, which is dependent on the serotonin 5-HT1A receptor [36]. The 5-HT3A receptor is expressed on B-cells and is differentially expressed in diffuse large B-cell lymphomas (DLBCL) compared to non-neoplastic B cells [37]. The serotonin transporter (SERT) is also expressed on B cells. Culturing Burkitt lymphoma cell lines with serotonin leads to increased serotonin uptake by SERT, decreased DNA synthesis, and apoptosis of Burkitt lymphoma cells, including in EBV-positive cells [38].

The mechanism of action of VPA as an inhibitor of EBV lytic reactivation in lymphoma cells is not known [4,39]. VPA is known to have a number of effects in neurons, however, which of these roles is responsible for the clinical effects of this drug in neurological disorders is uncertain [40]. The proposed mechanisms of VPA and clozapine are not similar, and they do not have a similar chemical structure, so it is possible that the two drugs affect EBV lytic reactivation in different ways. The cellular targets of antipsychotic, anti-epileptic, and mood-stabilizing drugs will continue to be explored in cells infected by EBV.
