Antipsychotic Mechanisms of Action

ANTIPSYCHOTIC MECHANISMS OF ACTION

Several lines of evidence demonstrated long ago that antipsychotic drugs blocked the synaptic actions of dopamine and should be classified as dopaminergic an-tagonists. Three dopaminergic pathways in the brain serve as primary substrates for the pharmacological ef-fects of these agents. The nigrostriatal system consists of neurons with cell bodies in the substantia nigra that project to the caudate and putamen, and it is primarily involved in the coordination of posture and voluntary movement. The mesolimbic–mesocortical system pro-jects from cell bodies in the ventral mesencephalon to the limbic system and neocortex, pathways associated with higher mental and emotional functions. The tuberoinfundibular system connects arcuate and peri-ventricular nuclei of the hypothalamus to the mam-motropic cells of the anterior pituitary, thereby physio-logically inhibiting prolactin secretion. The antagonism of dopamine in the mesolimbic–mesocortical system is thought to be the basis of the therapeutic actions of the antipsychotic drugs, while antagonism of the nigrostriatal system is the major factor in the extrapyramidal side ef-fects seen with these agents. Moreover, antagonism of dopamine’s neurohormonal action in the anterior pitu-itary accounts for the hyperprolactinemia associated with antipsychotic administration. Thus, the same phar-macodynamic action may have distinct psychiatric, neu-rological, and endocrinological outcomes.

Five subtypes of dopamine receptors have been de-scribed; they are the D₁-like and D₂-like receptor groups. All have seven transmembrane domains and are G protein–coupled. The D₁-receptor increases cyclic adenosine monophosphate (cAMP) formation by stim-ulation of dopamine-sensitive adenylyl cyclase; it is lo-cated mainly in the putamen, nucleus accumbens, and olfactory tubercle. The other member of this family is the D₅-receptor, which also increases cAMP but has a 10-fold greater affinity for dopamine and is found pri-marily in limbic regions. The therapeutic potency of an-tipsychotic drugs does not correlate with their affinity for binding to the D₁-receptor.

The D₂-dopaminergic receptor decreases cAMP production by inhibiting dopamine-sensitive adenylyl cyclase and opens K⁺ channels but can also block Ca⁺⁺ channels. It is located both presynaptically and postsyn-aptically on neurons in the caudate putamen, nucleus accumbens, and olfactory tubercle. Another member of this family is the D₃-receptor, which also decreases cAMP formation but which has much lower expression, primarily in limbic and ventral striatal areas. The D₄-receptor also inhibits adenylyl cyclase and is found in frontal cortex and amygdala. The binding affinity of an-tipsychotic agents to D₂-receptors is very strongly corre-lated with clinical antipsychotic and extrapyramidal po-tency.

The antischizophrenic actions of these drugs may not consist simply of postsynaptic blockade of hyperac-tive dopamine systems. Such a blockade occurs within hours, while most symptoms improve over weeks. This discrepancy in the latency to therapeutic effect has been hypothesized to be linked to drug-induced changes in dopaminergic activity: after initiation of therapy, dopamine turnover increases, but after continued an-tipsychotic treatment, tolerance develops and dopa-mine metabolism returns to normal. This downward ad-justment of dopaminergic activity is consistent with the decreased plasma concentrations of the dopamine metabolite homovanillic acid, an observation that cor-relates temporally with the clinical response to drug treatment.

Antipsychotic drugs also affect other transmitter systems that may contribute both to their antipsychotic actions and to their adverse reactions. Until recently the main focus in drug development was to discover agents that were more potent and selective in blocking D₂-receptors. However, newer atypical antipsychotics, such as clozapine and risperidone, have a weaker affinity for D₂-receptors and bind more strongly to 5-HT₂ (5-hydroxytryptamine) serotonergic receptors. Thus, lesser activity at the D₂-receptor relative to other transmitter receptors may diminish untoward side effects such as extrapyramidal toxicity. However, the antipsychotics also have variable antagonist actions at muscarinic, α-adrenergic, and histaminergic receptors in brain and peripheral tissue. The antimuscarinic activities cause blurred vision, dry mouth, and urinary retention and may contribute to excessive sedation. Blocking α-adrenoceptors may lead to sedation, orthostatic hy-potension, and light-headedness. The antihistaminergic actions of these drugs probably contribute to drowsi-ness and sedation also.