reinforcement associated with activation of dopamine pathways (Koob, 1996).

As described, the major neurotransmitter released by VTA neurons in the NAc is dopamine. Experiments in which dopamine neurons are destroyed, or other experiments in which dopamine receptors are blocked, confirm that this neurotransmitter is necessary for significant brain reward. Cocaine and the related synthetic compound, amphetamine, both facilitate the action of dopamine while also affecting the balance of other neurotransmitters.

DRUG EFFECTS ON BRAIN REWARD SYSTEMS

Normally, following the release of dopamine, its action is terminated by a presynaptic reuptake transporter that takes the dopamine back into the neuron that released it (the presynaptic neuron). Cocaine mimics dopamine enough to bind to the dopamine reuptake transporter, but not enough to be taken up. Hence, cocaine blocks the transporter, causing a buildup of dopamine in the synapse because it is not inactivated by reuptake. Amphetamine causes the presynaptic neuron to release more dopamine, essentially by putting the transporter into "reverse." Thus, both cocaine and amphetamine produce strong stimulation of the dopamine pathway leading to the brain reward centers (Hyman, 1996) (Figure 3.2).

Opioids are hypothesized to act on the brain reward circuitry in at least two ways. There are opioid receptors on neurons in the limbic system, including the NAc; thus opioids may act on these brain regions directly. In addition, opioids can indirectly cause VTA neurons to release more dopamine. The firing rate of VTA dopamine neurons is held at a certain "tonic" or stable level by inhibitory neurons. These inhibitory neurons, in turn, possess opioid receptors. Because opioids are inhibitory, endogenous opioids (e.g., enkephalins) or opioid drugs (e.g., morphine) essentially turn off or decrease the action of these inhibitory neurons (Nicoll et al., 1980) and thereby disinhibit the midbrain dopamine neurons. This results in enhanced release of dopamine and a stronger stimulation of the brain reward centers and imbalance with other neurotransmitters (Johnson and North, 1992; Izenwasser et al., 1993).

Although less well understood, both alcohol (ethanol) (Tabakoff and Hoffman, 1996) and nicotine (Dani and Heinemann, 1996) appear to disinhibit VTA neurons and to cause dopamine release in this same circuit. Ethanol increases the firing of dopamine neurons in the ventral tegmental area (VTA) and increases extracellular dopamine levels in the nucleus accumbens (NAc). The sites at which ethanol exerts it action may be multiple and include a number of modulators of dopaminergic activity in the VTA and the NAc (See Box 3.2). These (and other) neurotransmitter systems and sites may also be involved in mediating negative reinforcement by ethanol, as with drinking for relief of withdrawal symptoms and anxiety (Koob, 1992a).



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