Cocaine has multiple central and peripheral pharmacological actions. The action responsible for the rewarding property, and hence the abuse liability, of cocaine is an action in the dopaminergic synapse; in the rat the major set of critical dopaminergic synapses appears to be in the nucleus accumbens. Cocaine prolongs the activity of dopamine in the synapse by blocking the dopamine reuptake mechanism (which usually inactivates the transmitter by removing it from the proximity of its synaptic targets). This is an action shared with amphetamine; in addition to blocking the dopamine reuptake mechanism, amphetamine also augments dopaminergic function by augmenting dopamine release directly into the synapse. While amphetamine and cocaine have discriminable subjective effects, perhaps due to differences in rate of onset and metabolism or perhaps due to different side effects, cocaine shares its rewarding impact and abuse liability very closely with amphetamine. When drug access is unlimited, cocaine and amphetamine have the same ability to dominate behavior, reducing other behaviors such as feeding and sleeping and, in the process, reducing stress resistance to life-threatening levels. Opiates also owe their reinforcing properties to their ability to activate dopaminergic synapses in brain reward circuitry, though they activate the system at a different site and by a different local mechanism than those of amphetamine and cocaine. Where amphetamine and cocaine activate dopaminergic activity in the dopaminergic synapse, opiates activate dopaminergic activity by activating (or disinhibiting) the dopaminergic cell bodies. The site of rewarding action of opiates is the ventral tegmental area, where the dopaminergic cells projecting to the nucleus accumbens (as well as other targets) are located. Opiate actions that are restricted to this mechanism do not include opiate physical dependence; the dependence syndrome involves anatomically distinct systems in the brain, systems not activated by amphetamine or cocaine. While opiate physical dependence may contribute to the motivation for opiate intake in dependent subjects, it is not necessary for opiates to be habit-forming. The neural circuitry involved in the rewarding actions of cocaine, amphetamine, and the opiates is circuitry thought to be specialized for natural reward function. The circuit activated by these drugs is also activated by some cases of rewarding brain stimulation.(ABSTRACT TRUNCATED AT 400 WORDS)