This dissertation examined the role of nitric oxide (NO) in cocaine reinforcement processes by using the NO synthesis inhibitor Nw-nitro-L-arginine methyl ester (L-NAME). L-NAME administration failed to significantly alter frequency thresholds for brain stimulation reward (BSR). The failure of L-NAME to affect BSR thresholds suggests that NO is not directly involved in modulating the electrically stimulated release of dopamine from brain dopamine systems involved in mediating the rewarding effects of lateral hypothalamic stimulation. L-NAME pretreatment also failed to attenuate cocaine’s lowering of reward thresholds for BSR. However, L-NAME pretreatment was effective in shifting the entire time course of cocaine’s threshold-lowering effect in BSR to the right by 15 minutes.
In the intravenous self-administration method, L-NAME pretreatment produced a dose-dependent decrease in the mean number of self-administered cocaine injections and a dose-dependent increase in the mean time between successive cocaine injections. It is suggested that L-NAME’s vasoconstrictor action may change the pharmacokinetic profile of cocaine by delaying drug onset and elimination from the central nervous system.
Locomotor activity (LMA) studies revealed that L-NAME pretreatment attenuated the development of sensitization to cocaine’s locomotor-stimulating effect and that L-NAME’s attenuation was not due to a sedative or motor depressant effect produced by residual L-NAME. The finding that L-NAME administered after the cocaine conditioning trial was also effective in attenuating the development of cocaine sensitization suggests that L-NAME is disrupting some neurophysiological process (e.g., memory consolidation) that occurs after cocaine’s pharmacological effect has largely dissipated.
Results from another LMA study showed that L-NAME pretreatment attenuated the development of haloperidol-induced supersensitivity to cocaine. This suggests that NO formation is involved in the development of neuroleptic-induced supersensitivity.
These experiments show that NO has two important effects relevant to psychopharmacology. First, these studies support a role for NO’s involvement in the neuroadaptive responses (i.e., sensitization, supersensitivity) that develop from repeated drug use. Second, it was shown that acute NOS inhibition alters the reinforcement profile of cocaine and the suggestion was made that pharmacokinetic alterations may abate cocaine’s high addiction liability.
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