Presynaptic Control of the Synthesis and Release of Dopamine from Striatal Synaptosomes: A Comparison Between the Effects of 5‐Hydroxytryptamine, Acetylcholine, and Glutamate

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Abstract
The effects of 5‐HT and glutamate on dopamine synthesis and release by striatal synaptosomes were investigated and compared with the action of acetylcholine, which acts presynaptically on this system. 5‐HT inhibited (28%) synthesis of [14C]dopamine from L‐[U‐14C]tyrosine, at 10‐5M and above. This contrasts with the action of acetylcholine, which stimulated [14C]‐dopamine synthesis by 24% at 10‐4 M. Tissue levels of GABA were unaffected by either 5‐HT or acetylcholine up to concentrations of 10‐4 M. The inhibitory action of 5‐HT (5 × 10−5 M and 2 × 10−4 M) on [19C]dopamine synthesis was completely abolished by methysergide (2 × 10−6 M). Higher concentrations of methysergide (10−4 M) or cyproheptadine (10−5 M) inhibited [14C]dopamine synthesis by 28% and 25%, respectively, when added alone to synaptosomes. However, only methysergide prevented the further inhibition of synthesis caused by 5‐HT.At concentrations of 2 × 10−5 M and above, 5‐HT stimulated [14C]dopamine release. This releasing action differed from that of acetylcholine, which occurred at lower concentrations (e.g., 10−6 M). Methysergide (up to 10−4 M) or cyproheptadine (2 × 10−4 M) did not reduce the 5‐HT (5 × 10−5 M)‐induced release of [14C]dopamine, but methysergide (10−4 M) showed a potentiation (49%) of this increased release. The stimulatory effects of 5‐HT (2 × 10−5 M) and K+ (56 mM) on [14C]dopamine release were additive, indicating that two separate mechanisms were involved. However, when both agents were present the stimulatory effect of K+ (56 mM) on [14C]dopamine synthesis was not seen above the inhibitory effect of 5‐HT. Glutamate (0.1‐5 mM) did not affect [4C]dopamine release or its synthesis from L‐[U‐14C]tyrosine.It is concluded that 5‐HT modulates the synthesis of dopamine in striatal nerve terminals through a presynaptic receptor mechanism, an action antagonised by methysergide. The releasing action of 5‐HT apparently occurs through a separate mechanism which is also distinct from that involved in the response to K+ depolarisation.