In the inaugural issue, in Lesson 1 of the Psychopharmacology Course, PL suggested we think about drugs clinically, more than biologically. An example is shown in the articles this month on suicide prevention based on clinical randomized trials. Nonetheless, biology is relevant, when seen as secondary to the clinical research evidence. In that sense, there is some basic neuroanatomy that can be helpful in the practice of clinical psychopharmacology.
One basic observation has to do with the distribution of two major groupings of neurotransmitters. The monoamines - serotonin, dopamine, and norepinephrine - are specifically distributed, mostly in the midbrain. In contrast, the inhibitory agent GABA and the excitatory agent glutamate – which are not monoamines – are nonspecifically distributed throughout the neocortex. So the monoamine system has just a few tracts of connections, which involve the limbic system, the main area of the brain that regulates emotion. In contrast, GABA and glutamate are present in the entire surface of the neocortex and affect higher cognitive functions, as well as motor and sensory activity.
A key point is that the median forebrain bundle (MFB) mediates all three major monoamine neurotransmitter projections to limbic and frontal regions. Since those projections are closely intermingled in the MFB, they interdigitate and have multiple interaxonal connections. In other words, they communicate with each other in the MFB, before they reach their ultimate limbic destinations.
Hence it’s impossible to affect one of the monoamines without affecting others. Noradrenergic neurons will communicate with serotonergic neurons in the MFB, and cause changes in serotonergic activity. And vice versa. This is a major reason why there is no truly “selective” serotonin reuptake inhibitor, and hence the acronym “SSRI” is a marketing tool which has no valid scientific meaning. These drugs are “SRIs”, but they are not selective, because they produce changes in noradrenergic and dopaminergic function, indirectly, through the MFB. (Further, as explained on the PL website, most “SSRIs” aren’t selective because they directly affect other neurotransmitter systems, besides serotonin, in the synapse).
In contrast, the glutamate and gabaergic systems are distributed throughout the neocortex, not just in the deep midbrain nuclei, as with dopamine and serotonin and norepinephrine. That’s why if you prescribe a benzodiazepine (which is gabaergic) or topiramate (which is anti-glutamtergic), you can get widespread cognitive or sedating effects: the whole brain is being affected. For the same reason, at least with gabaergic agents, you can get widespread anxiolytic effects: again, the whole brain is being affected.