What is it about drugs that allows them to alter the workings of the mind, manipulating moods and perceptions, lifting depression, even enhancing memory? According to neuroscientists, these mental phenomena result from the electrical activity in the circuits of the neural computer between our ears. How then do drugs cause selective changes in the activity in these circuits? What gives the neural computer its chemical dimension?
These questions have been thrown into sharp relief by the recently reported deaths of night club revellers thought to be caused by Ecstasy. And although neuroscientists can answer them, and can even explain why Ecstasy has such dangerous side-effects, it is still impossible to predict either the efficacy or the side-effects of new drugs.
The chemical dimension of neural activity starts from the fact that the electrical currents in neurones (nerve cells) are carried not by electrons, as in a computer, but by ions (electrically charged particles produced when salts dissolve in water). Ions carry electric current much less efficiently than electrons because they are bigger and heavier, but they have the advantage that ionic currents can be switched on and off by chemical switches.
The brain compensates for the inefficiency of ions as current carriers by using the same technique as modern communication engineers, digital transmission. Information is coded and transmitted by neurones in the form of a stream of identical pulses, called action potentials.
Action potentials are electrical pulses controlled by chemical switches. The chemical switches themselves are operated by changes in voltage (voltage-gated). The action potential travels down a neurone by operating the voltage-gated switches just ahead of it, and “switching on” an action potential there, which then repeats the process. This is exactly the way that relays enable man-made cables to transmit long distances without losing signal strength.
Drugs that impair the actions of the switches can suppress the transmission of information. This is how some nerve poisons, like tetrodotoxin which is secreted by the Japanese puffer fish, and anaesthetics work.
Any drug that acts on the voltage-gated switches that control the action potential will affect the whole brain. To affect our moods a drug must modulate the activity of different brain circuits selectively. It must act on a process that works differently in brain circuits controlling different functions.
The synapse, which is the device that transmits information between neurones, is a promising target for selective drug action. When an action potential arrives at a synapse, it releases a minute quantity of a chemical called a neurotransmitter. The neurotransmitter acts on the next cell in the chain by reacting with a special molecule, a receptor, to operate a chemical switch and turn an ionic current on or off.
There are many different neurotransmitters, and each may act on several different types of receptor. Different brain circuits differ in the transmitters they use. The same transmitter may also differ from circuit to circuit.This give drug designers an opportunity to devise chemicals that will have very specific effects on the brain.
Chemicals that influence the interactions of neurotransmitters with their receptors, for example by altering the amount of transmitter released or the duration of its interaction with the receptor, have the potential to alter the operation of specific brain circuits. This is the way drugs alter the workings of the mind.
Drugs can also affect the function of other brain circuits, and of cells throughout the whole body, causing side-effects
Unfortunately there is much, not only about transmitters, receptors and brain circuitry, but also about general physiology that is not understood. It is impossible to predict the effect of new drugs either on the body or on the brain. Potential drugs still have to be identified by trial and error, and rigorously tested for safety.
Ecstasy is the classic case of a drug with a wide range of effects. It acts by suddenly increasing the release of the neurotransmitter Serotonin, which is used by neurones in circuits controlling mood, particularly reactions to unpleasant stimuli. Serotonin is also associated with the brain circuits that control body temperature, and those that select which of the millions of sensory signals available at any one time we attend to.
Ecstasy’s popularity as a dance drug stems partly from its effect on mood, but also from the fact that serotonin shuts out unpleasant sensory signals caused by thirst and high body temperature. It enables people to dance until they collapse from heatstroke.
Tragically, this effect of serotonin is compounded by the way it acts outside the brain. It causes massive and widespread blood clotting, which could be fatal even in people not suffering from heatstroke.
Thus Ecstasy (3,4 methylenedioxymethamphetamine) which was originally patented for use as an appetite suppressant, is an object-lesson in the difficulties that face the pharmaceutical industry in their search for new drugs.