REGIONAL EFFECTS OF AMPHETAMINE, COCAINE, NOMIFENSINE AND GBR-12909 ON THE DYNAMICS OF DOPAMINE RELEASE AND METABOLISM IN THE RAT-BRAIN

1 The effects of single-dose regimens of amphetamine, cocaine, nomifen sine and GBR 12909 on the dynamics of dopamine (DA) release and metabo lism were evaluated in the frontal cortex, hypothalamus, nucleus accum bens and striatum. The regimens selected are known to produce substant ial behavioural effects. 2 3-Methoxytyramine (3MT) and 3,4-dihydroxyph enylacetic acid (DOPAC) rates of formation were used to assess DA meta bolism by catechol-O-methyltransferase and monoamine oxidase respectiv ely. The rate of formation of 3MT was used as an index of synaptic DA. The ratio and sum, respectively, of 3MT and DOPAC rates of formation were used to assess DA reuptake inhibition and turnover. 3 The effects of amphetamine on 3MT production and DOPAC steady-state levels were s imilar in all regions, suggesting similar pharmacodynamic actions. Amp hetamine increased 3MT formation and steady-state levels, and reduced DOPAC steady-state levels. DOPAC formation was significantly reduced o nly in the nucleus accumbens and striatum. Total DA turnover remained unchanged except in the nucleus accumbens. Apparently, the amphetamine -induced increase in DA release occurred at the expense of intraneuron al DA metabolism and did not require stimulation of synthesis. 4 Nomif ensine elevated 3MT formation in all regions. A similar effect was pro duced by cocaine except in the nucleus accumbens. GBR 12909 elevated 3 MT production only in the hypothalamus, the striatum and the nucleus a ccumbens. 5 Cocaine selectively reduced DOPAC formation in the frontal cortex. Nomifensine increased and reduced, respectively, DOPAC format ion in striatum and hypothalamus. GBR 12909 elevated DOPAC formation i n all regions except the cortex, where pargyline did not reduce DOPAC levels in GBR 12909-treated rats. 6 Ratios and sum of 3MT and DOPAC ra tes of formation also exhibited wide regional variations for each drug . In contrast to the other drugs, the ratio was not increased after GB R 12909. Apparently, the DA uptake properties of this drug are poorly related to its in vivo effects on the ratio of 3MT production to that of DOPAC, which should increase when DA reuptake is inhibited. 7 Total DA turnover was increased by GBR 12909 in the hypothalamus, nucleus a ccumbens and striatum, while cocaine and nomifensine increased it only in the nucleus accumbens and striatum respectively. 8 It is concluded that: (a) 3MT and DOPAC rates of formation provide better indices of DA release and metabolism than do their steady-state concentrations. ( b) Some effects of DA uptake blockers on DA transmission, especially t hose of nomifensine and cocaine, may be attributed to increased DA rel ease. (c) Patterns of regional effects of psychostimulants on the dyna mics of DA release and metabolism may be better biochemical correlates of stimulant-induced behaviours than would changes in any single regi on.