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.
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