Some neurotransmitter–receptor combinations excite activity in the postsynaptic neuron, depolarizing it and making it likely to fire an AP. Other neurotransmitter–receptor combinations inhibit the responses of the postsynaptic cell. Neurons integrate information by summing excitatory and inhibitory synaptic inputs. Over- inhibition in the nervous system can arise when too much inhibitory neurotransmitter (such as GABA) is released, or if postsynaptic cells have too many receptors for inhibitory neurotransmitters. Drugs that decrease the synthesis and release of the inhibitory neurotransmitter can reduce the inhibition, as can drugs that block the receptors for such neurotransmitters. In the case of the Down syndrome model mice, drugs such as pentylenetetrazole, which blocked the GABA receptors (which function also as Cl– channels), reduced the level of inhibition in the mouse nervous system and increased the ability of the mice to learn and form memories.
Going from experiments on the effects of drugs on mice to a therapy for humans is a difficult path. To protect patients, the Federal Food and Drug Administration (FDA) has a rigorous procedure for approving drugs for human use. After a candidate drug is shown to be effective and safe in animal models, four stages of approval must be passed before a drug is allowed on the market. In Phase 0, the first in-human trials are conducted on a small group of volunteers to study how the body absorbs, distributes, metabolizes, and excretes the drug, and whether it has any obvious side effects. In Phase 1, trials are conducted in a small group of volunteers to evaluate safety and dosage, and again to look for side effects. Phase 2 involves a larger group of subjects who have the disease that the drug is expected to treat, to see if it is effective and safe. The comparison is with a placebo. In Phase 3, trials are conducted with a large group of patients to assess the drug’s effectiveness and safety, and to compare it with other commonly used treatments. Each of these phases must be reviewed by the FDA and approved before proceeding to the next phase. Pentylenetetrazole is currently in Phase 2 trials.