Depression monoamines, synaptic levels

In the 1960s researchers formulated, and later refined, the so-called monoamine hypothesis of depression. This hypothesis states that symptoms of depression are due to alterations in the functioning of certain neurotransmitters known as monoamines, notably norepinephrine, serotonin, and to a lesser degree, dopamine. Roles for other neurotransmitters have been identified in recent years. The foundation of this hypothesis rests on the finding that all antidepressant medications known at the time had, to some extent, the ability to increase the availability of these neurotransmitters at the synaptic level. Patients and the general public often refer to this hypothesis as chemical imbalance. ... 

Several theories have attempted to explain the pathology of depression. One of these theories is the monoamine theory of depression (Heninger et al., 1996). This theory proposes that impaired monoaminergic function is the central basis behind depression. Serotonin and norepinephrine are the two monoamines that have been primarily implicated in the disease. Pharmacological treatment of depression has focused on increasing synaptic levels of these two neurotransmitters (Table 3). 

One of the major drawbacks in the pharmacotherapy of depression has been the delay in response of 2-4 weeks between administering an antidepressive drug and the resolution of depression, despite immediate uptake blockade/reduced metabolism of monoamines at a synaptic level. The 5-HTia receptors are a subgroup of G-protein-coupled serotonergic receptors that are present postsynaptically on the soma and dendrites of serotonergic neurons. These receptors are found mainly in the mid and dorsal raphe nuclei of the midbrain and their main effect is inhibitory in nature. It has been demonstrated (mainly in rats) that repeated administration of selective serotonin reuptake inhibitors (SSRIs) and other antidepressants leads to functional desensitization of the somatodendritic 5-HTia... 

Reserpine inhibits the synaptic vesicular storage of the monoamines dopamine, serotonin and noradrenaline. As a result they leak out into the cytoplasm where they are inactivated by monoamine oxidase this causes their long-lasting depletion. The resulting low levels of dopamine underlie the antipsychotic actions of reserpine (Chapter 11), whereas the reduced noradrenaline levels underlie its antihypertensive actions. Finally, the resulting low levels of serotonin and noradrenaline mean that reserpine also induces depression. These severe side effects mean that reserpine is no longer used clinically as a treatment for schizophrenia (Chapter 11). 

Monoamine reuptake inhibitors elevate extracellular levels of serotonin (5-HT), norepinephrine (NE) and/or dopamine (DA) in the brain by binding to one or more of the transporters responsible for reuptake, namely the serotonin transporter (SERT), the norepinephrine transporter (NET) and the dopamine transporter (DAT), thereby blocking the reuptake of the neurotransmitter(s) from the synaptic cleft [1], Monoamine reuptake inhibitors are an established drug class that has proven utility for the treatment of a number of CNS disorders, especially major depressive disorder (MDD). 

It was observed (in the 1960s) that the antihistamine imipramine and the anti-tuberculosis drug iproniazid had antidepressant activities. Imipramine was found to inhibit neuronal uptake of noradrenaline and serotonin by pre-synaptic neurons in the brain. Iproniazid was found to inhibit monoamine oxidase, the enzyme that breaks down monoamines. Both these actions result in raised levels of monoamines at the synapse. In addition, drugs that reduce the availability of monoamines cause symptoms of depression. 

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