4.1  The monoamine hypothesis of mood disorders

In the 1950s it was noticed that around 20% of those patients prescribed the drug reserpine, used at the time to control high blood pressure, developed severe depression as a side effect.

It was subsequently discovered that reserpine depletes a group of neurotransmitters called monoamines, which include serotonin, noradrenalin and dopamine. Recall from earlier in this course that neurotransmitters are chemicals that neurons use to communicate with one another. Once neurotransmitter is released into a gap between neurons it must effectively bind to (join on to) an adjacent neuron in order to pass on its message. The point where it binds is known as a ‘receptor’. Every neuron therefore has a multitude of receptors for receiving neurotransmitter molecules. These receptors are like the glucocorticoid receptors that you saw in Activity 6.

Reserpine actually works inside neurons by preventing monoamines from being taken up into vesicles, leaving them vulnerable to being broken down inside neurons. Vesicles are small ‘bubbles’ inside neurons in which neurotransmitters are stored after they are made by the neuron and before they are released into synaptic gaps, the gaps between neurons – see Figure 9.)

Around the same time it was noticed that tuberculosis patients, prescribed a different drug, isoniazid, sometimes experienced a lifting of pre-existing depression. Isoniazid inhibits (slows down or prevents the activity of) the substance monoamine oxidase (MAO). MAO is important because it breaks down monoamine neurotransmitters. As MAO destroys monoamines, inhibiting MAO would have the net effect of increasing the levels of monoamines available for neuron to neuron communication.

Such monoamine oxidase inhibitors (or MAOIs) became the first generation of antidepressants.

Subsequently it emerged that there was yet another way that available monoamine levels might increase: imipramine, another antidepressant, inhibited the reuptake of serotonin and noradrenalin that had been released into the synaptic gap (Figure 9). Reuptake is a clever process by which neurons try to reuse the neurotransmitter they have released. They simply take it back into themselves via special reuptake channels and try to package it neatly back into the vesicles (or storage bubbles) ready to be released the next time the neuron needs to signal to another neuron.

Figure 9 The serotonin synapse. Serotonin secreted by a presynaptic neuron into the synaptic gap binds to receptors on the postsynaptic neuron to affect the activity of the postsynaptic neuron. The postsynaptic neuron’s response depends on the amount of serotonin in the synaptic gap. Serotonin levels in the synaptic gap fall partly because reuptake transporters take back the neurotransmitter into the presynaptic neuron.

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The diagram shows secretion, receptor binding and reuptake of serotonin. The serotonin is contained inside a vesicle in the presynaptic neuron, the vesicle moves to the cell membrane and discharges the serotonin into the synaptic gap. Serotonin then binds to its receptors on the postsynaptic neuron. Finally the serotonin is taken back into the presynaptic neuron by the serotonin reuptake transporter.

Figure 9 The serotonin synapse. Serotonin secreted by a presynaptic neuron into the synaptic gap binds to receptors on the postsynaptic ...

These findings about monoamines caused much excitement and led to the monoamine hypothesis of mood disorders. This postulated that monoamine levels have a primary role in causing depression, as lowering the levels of monoamines causes depression, while raising them lifts depression (see Hirschfeld (2000) for an overview). The mechanism postulated for this is shown in Figure 10.

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Figure 10 The monoamine hypothesis of mood disorders. (a) In normal brain, monoamine molecules are released and bind to receptors on the neighbouring neuron; (b) In depression, fewer monoamine molecules are available for binding to receptors, leading to a mood disorder; (c) Treatment with a reuptake inhibitor (the red shape blocking the reuptake transporter channel; here the SSRI Prozac^®) increases the number of monoamine molecules in the synaptic gap, so more are available to bind to receptors on the neighbouring neuron. This corrects the mood disorder.

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All three parts of the figure show events at a monoamine synapse. In (a) the monoamine is contained in vesicles in the neuron, it emerges into the synaptic gap as the vesicles merge with the cell membrane, it binds to a proportion of the receptors on the neighbouring neuron, and move back into the original neuron through the reuptake channels, completing the cycle. In (b) there are fewer vesicles so less transmitter is released, resulting in reduced occupancy of the receptors. In (c) the reuptake channels are blocked by a reuptake inhibitor, so there is more monoamine bound to receptors on the neighbouring neuron.

Figure 10 The monoamine hypothesis of mood disorders. (a) In normal brain, monoamine molecules are released and bind to receptors on the...

ADMs that inhibit the reuptake of specific monoamines such as serotonin (SSRIs, selective serotonin reuptake inhibitors), noradrenalin (noradrenergic reuptake inhibitors, NRIs), or combinations of monoamines such as serotonin and noradrenalin (serotonin noradrenergic reuptake inhibitors, SNRIs) are nowadays amongst the most prescribed drugs in Western societies, showing that the biomedical approach, and the monoamine hypothesis, still have a powerful influence on the treatment of depression. This is, in part at least, because many people see drugs as a ‘quick fix’ for depression and there is pressure to prescribe them.