meta substituted N-ethylamphetamine self-injection responding in the rhesus monkey: structure-activity relationships

Various doses of N-ethylamphetamine and its meta-fluoro, meta-bromo, meta-methyl, meta-iodo and meta-t-butyl derivatives were substituted for response-contingent intravenous injections of cocaine (30 μg/kg/injection) to determine the potencies and maximal response rates with which these compounds maintained fixed-ratio 30 responding in rhesus monkeys. Response rate was an inverted V-shaped function of dose for N-ethylamphetamine and its fluoro-, bromo-, and methyl-substituted derivatives. During 14 sessions of stable responding, N-ethylamphetamine and its fluorinated congeners each maintained maximal rates of 0.30 responses/sec at 30 μg/kg/injection while 100 μg/kg/injection of the brominated and methylated drugs were required to maintain a similar maximal response rate (about 0.40 responses/sec). Substitution of saline resulted in an extremely low rate of responding (0.04 responses/sec). No dose of the iodo or t-butyl derivatives (10 through 300 μg/kg/injection) maintained rates of responding significantly higher than that associated with saline. The potencies with which these drugs suppressed fixed-ratio 30 food-maintained responding in other monkeys were also determined. These data suggested that the failure of the 2 previous drugs to maintain responding was not due to the use of an inappropriate range of doses. In other studies, the potencies with which these drugs released norepinephrine, but not dopamine, were inversely related to meta-substituent size. Taken together with the present study, the data suggest that norepinephrine may be a major participant in the capacity of N-ethylamphetamines to maintain self-injection responding.