Dopaminergic regulation of extrapyramidal and limbic neurotensin activity

The dopaminergic regulation of extrapyramidal and limbic neurotensin (NT) systems was examined by combining in vivo microdialysis with a sensitive radioimmunoassay. Extracellular neurotensin-like immunoreactivity (NTLI) levels were characterized as being of neuronal origin and were compared with tissue NTLI content following the administration of dopaminergic drugs. Dopamine (DA) D-2 receptors oppositely regulated both tissue NTLI content and extracellular NTLI levels in the striatum and nucleus accumbens. An inverse correlation was observed between tissue and extracellular NTLI levels after administration of a D-2 agonist. This treatment decreased tissue NTLI content and increased extracellular NTLI levels in both these regions. Blockade of D-2 receptors increased tissue NTLI content, whereas extracellular levels were diminished. These effects indicate that, in some cases, variations in tissue NTLI content may reflect changes in the release of NT and that D-2 receptors are involved in the basal regulation of NT activity. Activation of DA D-1 receptors increased tissue NTLI levels in whole striatum and nucleus accumbens. Surprisingly, extracellular NTLI levels were also elevated after a similar treatment. However, a distinct anterior/posterior delineation was observed in caudate regions following a single dose of a D-1 agonist. NTLI levels in anterior regions increased but were reduced in posterior areas. Thus, an inverse correlation between changes in NTLI content in the posterior caudate and extracellular NTLI levels occurred after D-1 stimulation. Glutamate N-methyl-D-aspartate receptors were found to mediate the effects of D-1 activation on NT release since blockade of these receptors prevented the D-1 agonist-induced increase in extracellular NTLI levels. Blockade of D-1 receptors did not alter tissue NTLI content or extracellular NTLI levels in the striatum or accumbens, implying that D-1 receptors do not regulate basal NT activity. Endogenous NT systems reduced the DA response to a low dose of methamphetamine (METH). In turn, this dose of METH stimulated NT release in both striatum and nucleus accumbens. Surprisingly, the effects on NT release were diminished with increasing doses of METH. D-2 receptors appeared to regulate the low-dose effect of METH in the accumbens, whereas the coactivation of D-1 and D-2 receptors was necessary in the striatum. These results help to elucidate the physiological relevance of the complex interactions between DA and NT pathways.