At synapses, an electrical impulse triggers the release of a chemical messenger, called neurotransmitter, from the ending of one neuron (a nerve terminal). This neurotransmitter passively diffuses across the space to the next neuron where it binds to specialized receptor proteins. Most of these receptor sites are present on dendrites, the portion of neurons that receive incoming signals. The binding of neurotransmitter to the receptor then triggers changes in that neuron, including changes in other specialized proteins called ion channels that lead to electrical changes in that next neuron. The neurotransmitter signal is turned off in most cases by still other types of specialized proteins, called transporters, that literally pump the neurotransmitter back into its nerve terminals for subsequent release.

All drugs of abuse affect the brain initially by influencing synaptic transmission: in other words, each drug of abuse binds to its specific protein target all of which are at the synapse. As depicted in the figure , many drugs of abuse (opiates, nicotine, marijuana) mimic several of the brain’s normal neurotransmitter substances. Other drugs, in particular, the stimulants (cocaine, amphetamine, methamphetamine) target the dopamine transporter in different ways but all of which lead to increases in dopamine signals at the synapse. Still other drugs, such as alcohol and phencyclidine, target the brain’s ion channels to directly affect the excitability of neurons.

However, these acute actions of drugs per se do not explain the long-term effects seen with repeated exposures, which are required to induce a state of addiction. To understand such long-term effects, it is necessary to move beyond the classical view of a synapse to a more sophisticated view, which considers post-receptor, intracellular messenger pathways.

This means that, despite the initial actions of a drug on the activity of a neurotransmitter or receptor system, the many actions of drugs on brain function are achieved ultimately through the complex network of intracellular messenger pathways that mediate physiological responses to neurotransmitter-receptor interactions. These intracellular pathways consist of G proteins, second messenger systems, protein kinases, and protein phosphatases, among many others. Repeated exposure to drugs thus produces molecular and cellular adaptations as a result of repeated perturbation of these intracellular pathways, which ultimately influence gene expression. We believe that these lasting adaptations are ultimately responsible for many features of addiction.