Biochemistry of Methamphetamine

Serotonin

Serotonin is a monoamine neurotransmitter. 5-HT is the chemical abbreviation for serotonin, and the chemical formula is C10H12N2O. It is believed to play a central role in the modulation of anger, aggression, body temperature, mood, sleep, sexuality, and appetite as well as stimulation of vomiting reflex.


Biosynthesis

The synthesis of serotonin is similar in some ways to the synthesis of dopamine and norepinephrine. Tryptophan is also the precursor to serotonin. Tryptophan is taken up by serotonergic neurons in restricted brain areas such as the raphe nucleus. Once it enters the neurons, an enzyme called tryptophan hydroxylase adds the hydroxyl group and produces 5-HTP (short for 5-hydroxytryptophan). 5-HTP is further decarboxylated by aromatic L-amino acid decarboxylase to produce serotonin. Serotonin is then stored in synaptic vesicles and docked at the nerve terminals, where it awaits an action potential. Release of serotonin into the synaptic cleft activates serotonergic receptors in the post-synaptic neurons.


Where are serotonergic neurons found in the brain?

Serotonergic neurons are found primarily in nine clusters located mostly in the raphe nuclei of the midbrain, pons, and medulla. The two most important clusters are found in the dorsal and medial raphe nuclei. Both the dorsal and medial raphe nuclei send axons of serotonergic neurons to the cerebral cortex. But the neurons in the dorsal raphe nuclei also project to the basal ganglia while the neurons in the medial raphe nuclei project to the dendate gyrus.


How does methamphetamine affect serotonergic systems?

Because of the widespread circuirtry, activation of the serotonin system affects large areas of the brain. Methamphetamine affects the serotonin systems in several different ways. Some research indicates that serotonin levels increase, some say serotonin levels decrease. One study found that methamphetamine promoted the increase of serotonin at a rate of three times greater than amphetamine, its parent compound (Kuczenski et al., 1995). Serotonin in the synaptic cleft builds up in two ways: 1) inhibiting the reuptake process and 2) reversing the transport of serotonin. Elevated levels of serotonin result in increased feelings of empathy and closeness as well as a generalized state of well being.


How are these effects on serotonin related to dopamine activity?

Research has shown that the release of dopamine may be an intermediate step in the cause of serotonin degeneration (Nordahl et al., 2003). Sonsalla et al. (1986) found that multiple administrations of methamphetamine in the striatal serotonergic system on rats was partially related to the increased activity of dopamine receptors, in particular, the D1type. This finding has further support in other research that has found that blocking dopamine synthesis prevents serotonin degeneration (Schmidt et al., 1985). The effect of methamphetamine on the dopamine and serotonin systems seems to be a complex process and may even involve other neurotransmitter systems.

Other research has found that long-term use of methamphetamine may decrease serotonin levels (Seiden et al., 1975/1976). Introducing methamphetamines into the serotonergic neurons may eventually disrupt the synthesis and release of serotonin into the synaptic cleft. There may be no postsynaptic potential produced and thus serotonin system is inhibited.. Decreased levels of serotonin correspond to a decreased amount of activation of serotonergic neurons and results in changes in behavior. Because of the decreased levels of serotonin, a person is likely to exhibit violent behavior, anxiety, depression, impulsiveness, and could have a propensity towards drug and alcohol abuse.

Furthermore, methamphetamine kills serotonergic neurons and thus a methamphetamine userís brain may forever be lacking or have decreased levels of serotonin, which may certainly affect various aspects of normal functioning. A person needs a relatively high level of serotonin to maintain a manageable level of aggressiveness as well as an overall feeling happiness. Because of a decreased amount of serotonergic neurons, a methamphetamine user will always have an inadequate amount of serotonin levels. This will results in permanent changes in behavior and mood, such as feelings of depression and guilt.


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