reported to exert minimal GABAergic properties in animal models of anxiety. The strongest evidence for the anxiolytic properties of these medications includes multiple meta-analysis submissions reporting superior anxiolytic actions compared to placebo in many patients. Pregabalin has been specifically found to have potential efficacy in the treatment of social anxiety disorder. Although approved for the treatment of partial seizures, tiagabine has shown impressive results as an anxiolytic in many animal studies (Carl et al., 2020). Tiagabine’s mechanism of Antipsychotics (Neuroleptics) Antipsychotics are generally prescribed for the treatment of schizoaffective disorders, acute mania, major depressive disorder, delusional disorder, severe agitation, Tourette disorder, dementia, schizophrenia, substance-induced psychotic disorder, childhood schizophrenia, and borderline personality disorders. The antipsychotic activity of the drugs in this class reportedly correlates with their affinity to a subtype of the postsynaptic dopamine receptor, the D2 receptor. Five different subtypes of this receptor have been identified, with each receptor showing a specific difference in action mediation and coupling (Bhatia et al., 2022). For instance, the D1 and D5 receptors appear to be coupled to a stimulatory G protein that activates the adenyl cyclase enzyme. This enzyme is known for its action in converting adenosine triphosphate to the second-messenger cyclic adenosine monophosphate (CAMP). On the other hand, the D3 and D4 receptors particularly inhibit adenylyl cyclase in an action that reduces CAMP production. In addition to their different actions, these receptor subtypes are predominantly in different regions of the brain. The D3 and D4 subtypes are expressed at particularly high levels in the striatum, as well as in limbic structures such as the amygdala and the hippocampus. The D1 and D5 subtypes are expressed mainly in the neocortex and the hippocampus. Recently, new research has identified antipsychotic effects beyond the domains of dopamine receptors. It appears that typical and atypical antipsychotics interact with multiple receptors and structural complexes in the central nervous system to exert antipsychotic action. Some of the identified interactions in this regard include the following. Noradrenergic Interactions The actions of norepinephrine as both a central and peripheral neurotransmitter are well studied in psychopharmacology. In the central nervous system, norepinephrine exerts multiple neuronal signaling actions that directly influence concentration, alertness, and energy. In the context of neurology generally, drug interactions that affect the norepinephrine neurons are considered potential therapeutic options in the management of psycho-behavioral deficiencies. For instance, both citalopram and escitalopram were reported to inhibit the excitability of locus coeruleus (LC) in animal studies. This excitability is reportedly mediated in part through serotonin receptors. Considering the enormous potential of the norepinephrine neurons in the pathophysiology of mood disorders, different studies have been conducted to investigate how neurotropic drugs generally influence the biochemical activities of these neurons and their signaling pathway. Preliminary research conducted to investigate a possible interaction between these neurons and antipsychotics reported controversial results. However, subsequent studies reported different interactions based on the chemical composition, and - by extension - classification of the antipsychotic drugs. For instance, it was reported that the typical antipsychotic drug haloperidol does not alter the excitability of norepinephrine neurons of the LC in animal studies. Haloperidol also does not alter the SSRI escitalopram-induced inhibition of the firing activity of LC norepinephrine neurons. However, the reports on atypical antipsychotics were different. For instance, olanzapine, an atypical antipsychotic, reportedly stimulates the excitability of norepinephrine neurons of the LC after controlled acute administration in animal models. Additionally, increased activity of norepinephrine neurons was found after subchronic
anxiolytic action is largely unknown; however, preliminary studies indicate that it increases GABA activity by inhibiting important stages of GABA reuptake in the presynaptic neurons. In the same vein, topiramate has been demonstrated to inhibit voltage- dependent sodium channels to enhance GABA, and it also inhibits carbonic anhydrase. Valproic acid also reportedly blocks voltage-dependent sodium channels and inhibits glutamate- mediated excitation to enhance GABA action. and chronic administration of aripiprazole, quetiapine, and brexpiprazole. Brexpiprazole also increases the sensitivity of hippocampal α2-adrenoceptors to norepinephrine. In separate studies, the combination of aripiprazole and escitalopram also appear to enhance cortical norepinephrine levels was also confirmed using in vivo microdialysis (Hereta et al., 2020). Asenapine also reportedly boosts norepinephrine neuronal excitability after 14, but not after 2, days of treatment. In contrast, acute, subchronic, and chronic administration of risperidone and paliperidone do not alter the norepinephrine neuronal firing activity in the LC. Escitalopram reportedly suppresses the excitability of norepinephrine neurons of the LC. Risperidone not only reverses the escitalopram-induced excitability of norepinephrine neurons but also boosts the firing activity of norepinephrine neurons above the values recorded in control rats. Paliperidone, aripiprazole, and quetiapine also reverse the SSRI-induced inhibition of norepinephrine neurons. However, these drugs do not boost the firing of norepinephrine neurons to values higher than in control animals. Available evidence on the interactions of antipsychotics with the norepinephrine complex has not followed a particular trend. These interactions are not exactly based on the chemical nature of the class of the antipsychotic. Studies have, however, described the different interactions peculiar to different antipsychotics in this regard. In summary, it appears the beneficial effects of antipsychotics in psychopharmacology can be linked to their ability to enhance the excitability of norepinephrine neurons via an α2-adrenoceptor-mediated mechanism. This is in addition to their ability to reverse the SSRI- induced inhibition of norepinephrine neuronal firing activity. Histaminergic Interactions Some atypical antipsychotics, including clozapine, olanzapine, and quetiapine, have demonstrated antipsychotic actions by an interaction with the histamine-1 receptor. The synergy in this interaction and the strength of the bonding expressed have been compared in efficacy to that of D2 receptors and 5-HT receptors. In addition to the antipsychotic effects linked to this interaction, it also provides a logical explanation for some of the side effects linked with the long-term administration of antipsychotics, including those affecting the immune system and the sleep cycle. Because histamine receptors are generally involved in cognition, sleep, and emotion, the effects of antipsychotics on these receptors indicate their immense potential in psychopharmacology. Purinergic Interactions Purinergic receptors such as adenosine-2A receptors are involved in the pathology of both psychotic and affective disorders. This observation has prompted various research into the possible potential of these receptors being targeted in the management of psycho-behavioral disorders. They are moderately distributed in the central nervous system. A chemical moiety that can prompt the actions of these receptors is expected to have central actions in both human and animal models. In a 2001 study, a group of researchers for the first time described the antipsychotic effects of an adenosine-2A receptor agonist in laboratory research exploring the function of purinergic mechanisms in primates (Prasad et al., 2021). The antipsychotic action of this agonist was linked to its ability to attenuate the affinity of postsynaptic D2 receptors in the striatum to dopamine.
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