As a resident trudging five miles in the snow to and from Duke University Medical Center (uphill both ways), I was taught one neuron, one neurotransmitter; one neurotransmitter, one medication. Later as an instructor at Duke, I taught Charlie Nemeroff, MD, PhD (then a resident, now the premier neurobiologist in the country) how to walk in snow, or at least how to make walking in snow sound interesting.
Now Charles has taught all of us that chemical neurotransmission sometimes requires more than one neurotransmitter for each neuron. He divides chemical neurotransmission, the foundation of psychopharmacology, into three dimensions:
1. Space: Anatomically, the brain consists of an estimated 100 billion neurons (telephone wires) with over 100 trillion axons (cables) and 100 trillion synapses (plugs). Electrical impulses travel down the wires and cables to the plugs. These plugs manufacture biochemical signals that travel to biochemical receptor sites of other neurons. Chemical messeges sent by one neuron to another can also transmit to sites distant from the initial synapse by diffusion (similar to transmission with cellular telephones). Thus, the brain consists of a collection of wires and cables simmering in a sophisticated “neurotransmitter soup.”
2. Time: Some neurotransmitter impulses travel from one neuron to another in milliseconds while some signals cause biochemical cascades that last for days. Speed of transmission depends on the neurotransmitter. Pioneer neurobiologists identified half a dozen neurotransmitters. Scientists have now recognized several dozen neurotransmitters ranging from the slow-onset, long-acting neuropeptides to the fast acting amino acids such as glutamate (that universally stimulates almost any neuron) and GABA (that universally inhibits almost any neuron). Based on the amount of genetic material in neurons, several hundred neurotransmitters—some slow, others fast—may be identified upon completion of the Human Genome Project.
3. Function: Chemical neurotransmission alters the function of target neurons, creating cellular action and biological effects. Neurotransmission also regulates genetic expression. Experiences, education, physiological adaptations, disease, drugs, psychotherapy, and medications enhance or alter our genetic traits or tendencies through neurotransmission. Thus, genetics modify neurotransmission and neurotransmission modify genes.
The neuron and its synapses are changeable and malleable. Synaptic connections, formed at a furious rate between birth and age 6, are eliminated and restructured during pubescence and adolescence, allowing two-thirds of the synapses present in childhood to survive into adulthood. Neurodevelopmental experiences and genetic programming determine which connections are kept and which are destroyed. Thinking and learning provoke the release of neurotropic factors, which promote synaptic connections. Brain activity stimulates synaptic transmission.
CNS drugs replicate or mimic the actions of the brain itself. For example, the brain makes its own morphine (beta endorphin) and its own marijuana (anandamide). The brain has its own benzodiazepine receptor sites. Elavil and Prozac were being used as antidepressants before neurobiologists discovered the serotonin transporter site. God had His own pharmacopoeia before we had ours.
Because many neurons have more than one neurotransmitter, God also uses a certain “polypharmacy” of His own. Advanced clinical psychopharmacology consists of developing a rationale for specific multiple drug use based on dual transmission factors. Using drugs with multiple mechanisms or multiple drugs in combination will be the therapeutic rule rather than the exception—and that’s an idea that will turn your walk in the snow into a high-speed ski lift ride.
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