Prior to the 1950s, opioids, amphetamines, and St John's wort were used as antidepressants.
In the 1950s, isoniazid and iproniazid were antibiotics used to treat tuberculosis and were found to have antidepressant effects. The mechanism was later found to be inhibition of monoamine oxidase (MAO).
MAO is the enzyme that breaks down monoamines like dopamine and norepinephrine. Hence, the idea that depression involved monoamine neurotransmitters began.
As these discoveries were unfolding, a Swiss psychiatrist named Roland Kuhn was working with phenothiazines and antihistamines as sedatives for surgery.
Interest in phenothiazines had started with methylene blue, an anti-malarial drug and staining agent which was known to be sedating due to its antihistamine effects.
Chlorpromazine (Thorazine), a tricyclic antihistamine and phenothiazine antipsychotic, was used as a sedative during surgery for many years before it was serendipitously found to improve behavioral symptoms in psychotic patients. These observations were instrumental in the initial discovery and later development of antipsychotic drugs.
In addition to his work on phenothiazines, Roland Kuhn also discovered imipramine, a tricyclic compound that had potent antidepressant effects.
Eventually, imipramine was found to primarily target receptors for monoamines such as serotonin and norepinephrine, as well as acetylcholine and histamine. More specifically, imipramine was an inhibitor of the serotonin and norepinephrine reuptake pumps (also called the serotonin and norepinephrine transporters).
The prevailing hypothesis at the time was that depression resulted from abnormalities in the neurotransmission of monoamines--also called the monoamine hypothesis of depression.
The monoamine hypothesis dominated psychopharmacological research for over 30 years and the first selective serotonin reuptake inhibitor, fluoxetine (Prozac), was developed and then approved for depression in 1987.
Since the approval of fluoxetine (Prozac), numerous medications have been developed with similar mechanisms.
More recently, other neurotransmitter systems. such as the glutamate and GABA systems, have been implicated in the pathogenesis of depression. Glutamatergic drugs such as ketamine are being investigated as antidepressants.
Monoamines
Monoamines have an aromatic ring attached to two carbon atoms with an amino group (see structure below).
In the brain, monoamines act as neurotransmitters. Examples of monoamine neurotransmitters include serotonin, norepinephrine, epinephrine, dopamine, histamine, and melatonin.
All monoamine neurotransmitters are synthesized from aromatic amino acids such as tyrosine, tryptophan, and phenylalanine. It isn't surprising that the enzymes that synthesize monoamines are called aromatic amino acid decarboxylases (AADC).
The synthetic pathways for classic monoamines are illustrated below.
Although monoamine neurotransmitters represent a very small fraction of neurotransmitters in the brain, they have very important roles in the modulation and regulation of glutamate and GABA neurotransmission in a variety of neurocircuits.
After released from presynaptic nerve terminals, monoamines like serotonin, dopamine, and norepinephrine must be rapidly removed from the synaptic cleft to prepare for the next action potential. The rapid removal of monoamines from the synaptic cleft occurs via three main mechanisms:
Reuptake into the presynaptic nerve terminal by monoamine transporters
Enzymatic degradation by Monoamine oxidase (MAO) and/or Catechol-o-methyltransferase (COMT)
Passive diffusion away from the synapse.
Monoamine transporters located at the presynaptic nerve terminals are named after the specific monoamine they remove from the synaptic cleft. However, the specificity of monoamine transporters is variable. That is, multiple monoamines may be taken up by a single monoamine transporter. For example, norepinephrine transporters (NETs) show specificity for both norepinephrine and dopamine. This may be important for the removal of both norepinephrine and dopamine in regions of the brain where dopamine transporters are sparse, such as the prefrontal cortex (PFC).
Blocking monoamine transporters causes accumulation of monoamines in the synaptic cleft and theoretically contributes to the therapeutic and adverse effects of many antidepressant medications.
Norepinephrine
Norepinephrine (NE) is a catecholamine synthesized from tyrosine and stored in synaptic vesicles located at the nerve terminal of norepinephrine neurons. Once release, norepinephrine acts on post synaptic receptors.
Like all monoamines, norepinephrine is rapidly removed from the synaptic cleft by three major mechanisms:
Reuptake into the presynaptic nerve terminal by monoamine transporters
Enzymatic degradation by Monoamine oxidase (MAO) and/or Catechol-o-methyltransferase (COMT)
Passive diffusion away from the synapse.
Most of the norepinephrine neurons (also called noradrenergic neurons) that project widely throughout the cortex and subcortex originate in a region of the brainstem called the locus coeruleus. A minority of norepinephrine (and serotonergic) neurons descend down the spinal cord and synapse in the dorsal horn where they modulate afferent pain signals from the periphery.
FIGURE BELOW: Norepinephrine Projections and Norepinephrine synapse
Dopamine
Dopamine (DA) is a monoamine derived from L-tyrosine. L-Tyrosine is converted to L-DOPA by Tyrosine Hydroxylase which is the rate limiting step.
L-DOPA is converted to dopamine by an amino acid decarboxylase (AADC).
Dopamine neurons project to specific areas within distinct pathways
The dopaminergic system plays a major role in initiating movements, motivation, compulsive drug abuse, working memory, selective attention, sustained attention, and the coordination of goal-directed behaviors.
Dopamine transporters (DATs) are located on the somatodendritic and nerve terminal regions of dopamine neurons. There are very few DATs in the prefrontal cortex (PFC). Dopamine transporters are responsible for the reuptake of dopamine from the synaptic cleft after a nerve impulse. Blocking DATs in the nucleus accumbens can be reinforcing and lead to addictive behaviors (Cocaine, methylphenidate, bupropion, and amphetamines all block DATs to varying degrees in the nucleus accumbens).
Monoamine Hypothesis of Depression
The monoamine hypothesis of depression proposes that monoamines like serotonin, dopamine, and norepinephrine may be at low levels at both the cell body region (i.e., somatodendritic region) and the nerve terminal region (i.e., synaptic cleft) of neurons.
The monoamine receptor hypothesis of depression proposes that monoamine receptors such as serotonin receptors may be upregulated in specific areas of the depressed brain.
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