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Cocaine Marijuana Heroin Stimulants

FIGURE 36-2. Rates of emergency department visits involving selected illicit drugs: 2006. (From Ref. 4.)

O Virtually all abused substances appear to activate the same brain reward pathway. Key components of the reward pathway are the dopamine (DA) mesocorti-colimbic system that projects from the ventral tegmental area (VTA) and the nucleus accumbens (NA) to the prefrontal cortex, the amygdala, and the olfactory tubercle (see Figs. 36-3 and 36-4)5 Animal studies indicate that ablation of DA neurons in the NA results in decreases in cocaine self-administration. Although many other neurotransmitters can be involved in activation of the reward system, DA appears to be a final common neurotransmitter of this pathway.6

Cocaine and stimulants, such as amphetamines, probably activate reward circuits by blocking the DA reuptake transporter. Additionally, amphetamines also cause the reverse transport of DA into the extracellular space.6 Although opioids eventually utilize the same circuitry as stimulants, initially they activate p-opioid receptors, in the NA or VTA, which ultimately results in an increase DA release in the NA. However, reinforcement of opioid use may derive from two mechanisms because in





animal studies, when the DA fibers are destroyed, the reinforcing effects of opioids remain.6 Ethanol probably produces its effects through multiple neurotransmitter pathways. Antagonists of y-amino butyric acid (GABA) reverse some of the behavioral effects of ethanol, suggesting that there may be cross-reactivity between benzo-diazepines and alcohol, and that alcohol may somehow modulate GABA receptors. Ethanol may activate the DA system indirectly by facilitating the activity of GABA neurons in the pars reticulata, ultimately disinhibiting the VTA DA neurons, resulting in an increase in DA in the NA6 There also may be an interaction between serotonin (5-HT) and the reinforcing effects of ethanol, because both 5-HT reuptake inhibitors and 5-HT2C receptor antagonists decrease ethanol intake in animals. However, studies of these drugs in alcohol-dependent humans have not been very promising. Animal studies indicated that when opioid antagonists were administered to the central nucleus of the amygdala, oral ethanol self-administration decreased. Studies in humans showed a modest decrease in alcohol consumption in alcoholics who took a long-acting opioid antagonist (naltrexone) following detoxification. Finally, small doses of ethanol inhibit N-methyl-D-aspartate (NMDA) glutamate receptors, and animals will substitute glutamate receptor antagonists for ethanol, suggesting that they find the effects of the two drugs to be similar. Nicotine also affects the reward pathways by more than one mechanism. In animal studies, either DA antagonists or destruction of DA neurons in the NA decreased nicotine self-administration. Nicotine also interacts with the opioid pathway, because opioid antagonists can precipitate nicotine withdrawal in animals. Finally, marijuana's main active component, tetrahydrocannabinol (THC), binds to cannabinoid-1 (CB)1 receptors resulting in activation of DA neurons in the mesocorticolimbic system. THC also increases the release of DA into the shell of the NA.6

FIGURE 36-3. Location of the dopamine neural tracts associated with the reward system in the brain. (From Ref. 5.)

FIGURE 36-4. Locations where different abused substances interact with the reward system in the brain. (From Ref. 5.)

FIGURE 36-4. Locations where different abused substances interact with the reward system in the brain. (From Ref. 5.)

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