Dopamine Efflux from Striatum After Chronic Nicotine: Evidence for Autoreceptor Desensitization

Abstract

We examined the effect of chronic nicotine treatment on dopaminergic activity by measuring the effects of D₁ and D₂ dopamine (DA) receptor agonists and antagonists on tritium release from mouse striatum preloaded with [³H]DA. The radioactivity released during superfusion was separated on alumina columns and the distribution and efflux of [³H]DA and its main ³H‐labeled metabolites were quantified. After preloading by incubation with [³H]DA, the electrical stimulation‐evoked tritium overflow was higher in striatum prepared from nicotine‐treated mice, whereas in vitro addition of nicotine caused a similar increase in tritium release from striatum of untreated and chronic nicotine‐treated mice. The overflow of [³H]DA and its ³H‐metabolites exhibited similar distribution patterns in [³H]DA‐preloaded striatum dissected from untreated and chronic nicotine‐pretreated mice, indicating that repeated injections with nicotine did not alter the metabolism of [³H]DA taken up by the tissue. (−)‐Quinpirole, a selective agonist for D₂ DA receptors, and apomorphine, a nonselective D₁/D₂ agonist, inhibited the electrical stimulation‐induced tritium efflux from striatum of untreated mice, whereas (±)‐sulpiride, a D₂ DA receptor antagonist, enhanced the evoked release of tritium. These changes in tritium efflux effected by (−)‐quinpirole and (±)‐sulpiride reflected changes in [³H]DA release and not in DA metabolism, as shown by separation of the released radioactivity on alumina columns. The D₁ receptor agonist (±)‐SKF‐38393 did not affect the tritium overflow, whereas the D₁ receptor antagonist (+)‐SCH‐23390 exerted a stimulatory action but only at a high concentration. In contrast, neither the DA receptor agonists [(−)‐quinpirole, apomorphine, and (±)‐SKF‐38393] nor the antagonists [(±)‐sulpiride and (+)‐SCH‐23390] altered the stimulation‐evoked tritium release in striatum obtained from mice repeatedly treated with nicotine. It is concluded that chronic administration of nicotine produces an increased release of DA in the striatum with a resulting elevation of synaptic DA concentrations leading to development of D₂ DA autoreceptor subsensitivity. As a consequence, chronic nicotine may attenuate autoinhibition of dopaminergic neurotransmission in the striatum.