The second set of clues concerning the substrates of addiction came from more recent work which showed that each of these highly addictive drugs mimics or enhances the actions of one or more neurotransmitters in the brain that are involved in the control of the brain reward circuit (Cooper et al., 1996). The opioids mimic endogenous opioid-like compounds called endorphins; cocaine and related drugs enhance the actions of dopamine itself; nicotine mimics the action of acetylcholine (another transmitter) at its nicotinic receptors; and alcohol, among its many effects, facilitates the activation of a particular receptor for gamma-aminobutyric acid (GABA), one of the most prevalent neurotransmitters throughout the brain. Although each of these four mimicked neurotransmitters has many actions in the brain, they all share one common property: all regulate the activity of the brain reward pathway that extends from the VTA to the NAc (Di Chiara and Imperato, 1988).
Each of these abused drugs also interacts with other neurotransmitter systems and molecules within neurons that act as "second messengers" that effectively translate input to neurons into a variety of intracellular chemical and molecular changes (signal transduction), some of which affect gene expression. In addition, other types of neurotransmitters can be affected in direct and indirect ways. For example, one way neurons regulate the amount of neurotransmitter acting at a second neuron is through reuptake mechanisms, that is, the reabsorption of the transmitter into the presynaptic neuron via specialized channels called "transporters." Cocaine inhibits the neuronal reuptake of serotonin and norepinephrine, as well as dopamine, leaving these neurotransmitters in the synapse and effectively increasing their actions within the synapse by increasing their action on their receptors. These additional actions contribute to the unique properties of each class of abused agents and may enhance or reduce the behavioral