Medscape Special Session Coverage on the 2008 American Psychiatric Association Annual Meeting: May 5, 2008

Andrew N. Wilner, MD, FAAN, FACP


May 06, 2008

In This Article

Neurotransmitters, Drugs, and the Brain: Historical Perspectives

Solomon Snyder, MD, Distinguished Service Professor of Neuroscience, Pharmacology, and Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland, provided a sweeping, historical overview of some of the scientific advances that have led to pharmacologic treatments of important diseases such as diabetes and schizophrenia as well as pain control.[4]

Dr. Snyder emphasized that molecular structure is critical to the function of specific molecules. For example, codeine does not react with the opiate receptor. However, codeine is metabolized to morphine in the liver by demethylating enzymes. This slowed transformation to morphine prevents the "rush" of euphoria and limits the addictive potential of codeine.

Dr. Snyder observed that tiny variations in a molecule can change the molecule from an agonist to an antagonist. In addition, some molecules may have both agonistic and antagonistic properties. For example, nalorphine and pentazocine are both mixed agonists and antagonists.

The identification of receptors and receptor binding assays led to much more precise strategies for drug discovery. The development of neuroleptics, for example, was expedited when dopamine receptors could be identified by ligand binding. It became apparent that clinical potency of antipsychotic drugs correlated with the relative binding potency of dopamine receptors.

Dr. Snyder explained that nitric oxide, carbon monoxide, and hydrogen sulfide are all brain neurotransmitters. Nitric oxide, for example, is a gas that stimulates cyclic guanosine monophosphate (GMP) to mediate blood vessel relaxation. This pathway has important effects outside the brain as well. Cyclic GMP is normally degraded by phosphodiesterase. Consequently, inhibition of phosphodiesterase prevents degradation of cyclic GMP and prolongs blood vessel relaxation. One result of phosphodiesterase inhibition is sustained penile erections. This clinical phenomenon has been commercialized as sildenafil citrate (Viagra), a phosphodiesterase inhibitor.

The characterization of the NMDA receptor has revealed that it requires 2 neurotransmitters for activation: glycine (or D-serine) and glutamate. The fact that NMDA receptors blocked by phencyclidine (PCP) results in psychotic behavior has led to an NMDA hypothesis for the pathogenesis of schizophrenia. This hypothesis is supported by the observation that D-serine may alleviate schizophrenic symptoms. D-serine is needed for normal NMDA transmission and is found predominantly in the glia and astrocytes that ensheath the synapse.

Neurochemistry also explains the stimulatory effect of caffeine. Adenosine is a neuromodulator in the brain. Caffeine blocks adenosine receptors, which results in brain stimulation.

In conclusion, Dr. Snyder emphasized that neuroscientists should always keep potential clinical applications of new discoveries in mind while pursuing deeper understanding of the human nervous system.


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.