Clozapine

Clozapine

Clozapine is an atypical anti-psychotic medication that

acts as an antagonist (a drug that blocks the effects of a

neurotransmitter), thus producing an inhibitory effect, at a

variety of neurotransmitter receptors in the brain. The exact

site and action by which Clozapine produces its therapeutic

effects is difficult to locate due to the complexity of its

interactions with several neurotransmitters. It is believed that

the two key neurotransmitters that Clozapine interacts with are

serotonin (5-HT) and dopamine (DA), particularly at 5-HT2, D2,

and D4 receptors (Brenner, H.D., BÖker, W., Genner, R., 2001).

Serotonin is a biogenic amine derived from tryptophan that

generally produces inhibitory postsynaptic potentials (meaning

that it causes hyperpolarization of the postsynaptic cell

membrane).Functions of serotonin include regulation of sleep and

emotions. Dopamine is a monoamine catecholamine derived from the

amino acid tyrosine. Receptors that bind dopamine are termed

dopaminergic. Dopamine is one of the principal modulatory

neurotransmitters in the brain and may have inhibitory or

excitatory effects depending upon the response of the

postsynaptic receptor (King, www.indstate.edu). Clozapine also

has effects at muscarinic M1 receptors, adrenergic receptors,

cholinergic receptors, and histamine receptors (Brenner, et al).

There are many disputed theories of the biological causes

of schizophrenia. One of the most prominent ideas is the

"dopamine hypothesis." The dopamine hypothesis attributes

hyperdopaminergic function, meaning an excess of dopamine at

certain synapses, as a possible cause of schizophrenia (Fann,

W.E., Karacan, I., Pokorney, A.D., & Williams, R.L., 1978).

Dopamine systems arise from two primary midbrain clusters, the

ventral tegmental area and the substantia nigra which have

discrete projections to mesolimbic, mesocortical, and striatal

regions of the brain. The neurochemical anatomy of dopamine

differs in cortical and striatal regions, and it appears that

dopamine concentration, receptor regulation, and D2 receptor

density varies greatly between striatal and extrastriatal

regions (Jones, & Pilowsky, 2002). It is supposed that the

therapeutic actions of antipsychotic drugs are exerted via the

mesolimbic and mesocortical dopamine pathways in the brain

(Hyman et. al., 1995). According to the dopamine hypothesis for

schizophrenia, limbic D2 receptor blockade is essential for a

drug to have antipsychotic activity. It is believed that the

therapeutic actions of antipsychotic drugs are exerted via the

mesolimbic and mesocortical dopamine pathways in the brain by

acting as D2 receptor antagonists (Hyman et al.)Without

exception, effective antipsychotic drugs have at least some

degree of antagonism of the dopamine D2 receptors. (Breier, A.,

Tran, P.