Among heroin addicts, alcohol abuse is a significant problem. While alcohol use is due, in part, to its reinforcing effects, this dual addiction may reflect additional factors, as suggested by recent research. Ethanol blocks the NMDA-glutamate activated ion channel, a system implicated in many neural plasticity phenomena, including responses associated with chronic drug exposure. The development of analgesic tolerance and dependence to morphine and locomotor sensitization to psychostimulants is attenuated by dizocilpine, an uncompetitive NMDA antagonist. Given that ethanol may mimic dizocilpine, it too, may attenuate plasticity effects of chronic drug use. Indeed, our preliminary data confirm that ethanol, like dizocilpine, attenuates morphine dependence. The proposed studies would extend that finding to include several behavioral plasticity phenomena associated with chronic morphine exposure, including: 1) dependence, as evaluated by naloxone-precipitated withdrawal aversion; 2) locomotor sensitization and; 3) tolerance to the place conditioning effects of morphine after chronic exposure. The ability of dizocilpine and ethanol to attenuate morphine dependence may occur via their NMDA antagonist effects, which will be assessed in another study proposed herein. Specifically, we will determine whether the ability of dizocilpine or ethanol to attenuate morphine dependence can be blocked by NMDA treatment. Finally, dizocilpine, and perhaps ethanol, may enhance the behavioral effects of morphine. Indeed, we find that dizocilpine enhances the ability of morphine to lower the threshold for brain stimulation reward. Thus, a final set of studies will investigate further whether dizocilpine and ethanol enhance the locomotor sensitizing, discriminative stimulus, and place conditioning effects of morphine. All studies will address these questions by assessing shifts in morphine dose-response functions. These preclinical studies may provide information indicating that the pharmacological interactions of these two drugs enhance their abuse potentials which may have implications for understanding and treating dual addiction to heroin and alcohol.
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