Chlorpromazine little or no effect on the negative symptoms

Chlorpromazine  is a typicsal
phenothiazine antipsychotic drug, which act as antagonist to dopamine D2
receptor that used to treat schizophrenia.

Ø  Normally, dopamine is released by the
presynaptic neuron in the mesolimbic pathway of the brain and binds to dopaminergic D2 receptors,
which are the GPCR coupled to inhibitory G-protein (G?i). G?i ? inhibit AC ? inhibits
cAMP ? inhibit PKA from being stimulated ? less Ca release (Tritsch et al., 2015). In schizophrenic brain, the receptors on the postsynaptic neuron
are too sensitive to its effect, resulting in an over receptivity to dopamine. Chlorpromazine
acts as an antagonist on dopamine receptors, therefore, preventing the over
activity of dopamine, which leads to the blocking of the positive symptoms of schizophrenia (e.g., delusions, hallucinations and disorganized speech) However,
there is little or no effect on the negative symptoms of schizophrenia (e.g., lack
of emotion and apathy).  (Bernard et al., 2008).

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For the short
term management of anxiety, agitation or disturbed behavior of psychiatric
conditions, chlorpromazine antagonizes two receptors: 5HT-2 receptor and H1

v  Serotonin binds to (5HT-2) receptors which are GPCR coupled to Gq/11 proteins, then PIP2 is cleaved by PLC to DAG and IP3 (results in release of Ca) and then mediate excitatory neurotransmission ( Roth,
 2015).Serotonin participates in
modulating glutamate release(Ciranna,
2006).Moreover, it  mediate the neurogenic activation of CRF
production, CRF then stimulates stress hormone release (ACTH), that consequence in anxiogenic
effects (Ranabir, 2011). Chlorpromazine blocks the serotonin receptors, subsequently,
lowering glutamate and stress hormone release, which results in reducing
aggression, anxiety and disturbed behaviors (Ansah et al., 2011).


v  Histamine (H1) receptors, activation of H1 receptor lead
to stimulation in most brain regions (such as thalamus, brain stem, and
amygdala) over coupled to Gq/11proteins,
and then PIP2 is split into IP3and DAG by PLC, IP3 releases Ca (Billington
et al., 2003). Moreover, it result in direct block of K channel, Ca -dependent
K channels can be activated, leading to depolarization and thus ?neural
excitation. Chlorpromazine acts as histamine antagonist, subsequently, decrease
histamine effects and k channels are no longer inhibited and no neuronal
excitation, which results in reducing aggression, anxiety and disturbed behaviors
(Sergeeva, 2009).