Neuroscientists have taken advantage of this model to investigate the brain loci mediating the reinforcing and dependence-producing properties of morphine (Bozarth and Wise, 1984), the dopaminergic contributions to drug reinforcement, and the brain areas activated by specific drugs (Koob and Bloom, 1989; Cerruti et al., 1994; Nestler, 1994). Geneticists have used this technology to evaluate the heritability of drug abuse (e.g., Froelich et al., 1988); similarly, neurochemists have examined specific behavioral correlates in this model (Kalivas and Duffy, 1993; see Chapter 3).

Excitatory Amino Acids

Research on phencyclidine (PCP) provides a good example of the way in which behavioral studies provide a body of data for understanding the neural basis of learning and memory, as well as the development of novel medication strategies. In the early 1970s, the introduction of PCP as a drug of abuse was immediately recognized as different and potentially more devastating than abuse of other hallucinogens. Initial studies evaluated this drug and its analogues in self-administration and drug discrimination paradigms (reviewed in Balster and Willetts, 1996). It became obvious that PCP was a noncompetitive antagonist at the NMDA (N-methyl-D-aspartate) receptor. PCP became an important research tool for understanding the role of excitatory amino acid neurotransmission initiated by glutamate in the control of a variety of behaviors and in the pathophysiology of neuronal death.

Current work in this area has the potential to lead to novel treatment medication strategies for preventing neurotoxicity following brain trauma. As excitatory amino acid antagonists are developed for therapeutic uses, an important goal will be to avoid the abuse liability (the likelihood that a drug will be abused) and psychological disturbances produced by PCP; the animal models developed by drug abuse researchers are now being relied on in this area of medications development. An exciting research development suggests that excitatory amino acids may play an important role in the development of tolerance to and dependence on drugs of abuse such as the opiates, alcohol, and stimulants (Balster and Willetts, 1996). It is possible that this research will lead to completely novel strategies for the treatment of the addictions.

Development of Therapeutic Drugs Without Abuse Liability

A major concern in the development of new psychotropic medications is to maximize therapeutic efficacy while reducing the risks of abuse and dependence. In the 1920s, substitutes for morphine were sought that



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