The Brain as a Drug Target – Herbal Supplements

Transmitters are chemicals synthesized in neurons. Two dozen or so chemical substances have been identified as brain neurotransmitters. These agents are the primary means of communication between brain cells. Transmitter vocabulary is limited, however, in that a given agent either enhances or decreases the firing of an adjacent neuron. By affecting the excitability of the neuron, transmitters influence the way the receptive cell modifies the activity of neighboring neurons. In most cases the transmitter is stored in packets, called vesicles, in the nerve terminal (refer to Figure 4.1). When the neuron is stimulated an impulse travels along the axon causing the vesicles to fuse with the presynaptic axon terminal membrane, to open, and then to discharge the stored transmitter into the synapse (refer to Figure 4.1). Once released, the transmitter diffuses across the synaptic cleft and attaches to its receptors on the adjacent postsynaptic neuron. Typically, the postsynaptic membrane is located on the dendrites of an adjacent cell. Attachment of the transmitter to its receptor enhances, in the case of excitatory neurotransmitters, or inhibits, in the case of inhibitory neurotransmitters, the activity of the postsynaptic neuron. If the neuron is stimulated, the impulse generated facilitates the release of the neurotransmitter from its axon terminals to transmit a signal, which is either excitatory or inhibitory, to adjacent neurons. By slowing the firing of the receptive neuron, inhibitory transmitters decrease transmitter release from the adjacent cell which, in turn, influences the firing of neighboring neurons. Thus, overall brain activity represents a delicate balance between excitatory and inhibitory transmitters.

Besides being localized on postsynaptic membranes, neurotransmitter receptors may be found on presynaptic terminals. When activated these presynaptic receptors slow the release of a transmitter from that terminal by causing intracellular biochemical changes that reduce vesicular attachment to the membrane. Thus, if an excessive amount of neurotransmitter is being liberated from a presynaptic nerve terminal, some will leak out of the synapse and stimulate the presynaptic receptors, slowing further transmitter release in an attempt to return the system to equilibrium. It is also possible that an axon from a neighboring neuron may synapse with a presynaptic, rather than postsynaptic, membrane. This is referred to as an axo-axonic, as opposed to axo-dendritic, synapse. If there is an axo-axonic interaction the rate of transmitter release from a terminal is regulated not only by the firing rate of that neuron, but also by the activity of an adjacent cell releasing its transmitter onto the presynaptic receptors.

Once a neurotransmitter activates its receptor it is released back into the synapse. Some transmitters are destroyed by metabolizing enzymes located at or near the synapse. Many are also transported back (reuptake) into the presynaptic terminal where they may be metabolized intracellularly or re-stored in vesicles for future use.

The elements involved in synaptic transmission provide many targets for manipulating this process pharmacologically. For example, brain neurotransmitter function can be modified by agents that inhibit the synthesis, metabolism, or storage of neurotransmitters, or their reuptake into the presynaptic terminal. Agents are also known that enhance the release of certain neurotransmitters. Commonly drugs, and possibly natural products, directly interact with neurotransmitter receptors, either activating (agonists) or blocking (antagonists) these sites. Brain neurotransmission is also affected by drugs that interact with neuronal ion channels or ion transporters. The passage of ions across the neuronal membrane is essential for transmitting nerve impulses and for maintaining a healthy intracellular environment. Activation of some receptors can affect ion channel activity or ion transport, thereby modifying cellular excitability and stability. Likewise, chemical agents can modify brain function by attaching directly to these sites.

There are many other potential drug targets in neuronal tissue besides those involved directly with chemical neurotransmission. Included are enzymes, such as kinases and phosphatases, responsible for modifying protein function, and intracellular receptor systems, such as those for certain hormones, which regulate gene expression in the cell nucleus.