Amphetamine-induced in vivo release of dopamine in the striatum is influenced by local pH

The effect of local pH on the in vivo efflux of endogenous dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) following administration of d-amphetamine (AMPH) was examined in the striatum of the anesthetized rat using two bilaterally placed push-pull cannulae. At both pH 7.3 and 6.4, the baseline efflux values for DA and DOPAC were approximately 0.2 and 25 pmoles/15 min, respectively. Subcutaneous injection of 2 mg/kg AMPH induced a 3-fold increase of DA release at pH 7.3 and a 21-fold increase of DA release at pH 6.4. In both cases, the maximum was reached at about 30 min after the drug administration. Following the administration of AMPH, the efflux of DOPAC was reduced to the same degree (20% of control values) under both pH conditions. In vitro data showed that the lower pH did not alter the recovery of DA or DOPAC. In addition, release of DA produced by local perfusion with 5 uM AMPH was also greater at the lower pH (50-fold increase over baseline) than at the physiological pH (10-fold increase over baseline). The stimulated DA release produced by local perfusion with 35 mM K+, however, was the same at both pH values. Preliminary experiments also indicated that there was a pH effect for AMPH-induced serotonin (5-HT) release but that the difference in the amount of 5-HT in the two media was not nearly as large as that obtained for DA. The markedly elevated level of extracellular DA at the lower pH might be due to a higher affinity of the DA uptake system for AMPH, thereby producing greater inhibition of DA uptake as well as enhanced DA release. The data also suggest an enhanced affinity of AMPH for 5-HT uptake sites at the lower pH.