Chronic haloperidol-induced changes in regional dopamine release and metabolism and neurotensin content in rats

Chronic neuroleptic administration has previously been shown to alter in vivo measures of dopaminergic function and lead to regionally selective increases in neurotensin levels. In the current study, female rats were administered chronic haloperidol for 6 months via subcutaneous silastic implants. After 24 weeks of administration, microdialysis probes were inserted into the lateral caudate putamen and the medial prefrontal cortex. Basal samples were collected prior to infusion of a high K⁺ concentration (100 mM KCI). Extracellular concentrations of dopamine, 3,4-dihydroxyphenylacetic acid, homovanillic acid, and 5-hydroxyindoleacetic acid were assessed using HPLC. Chronic haloperidol-treated rats showed increased basal dopamine metabolite levels in the caudate putamen and an altered response to the effects of high K⁺ on 3,4-dihydroxyphenylacetic acid; no significant differences were seen with other analytes in the caudate putamen. Although basal concentrations were not different between groups in the prefrontal cortex, haloperidol-treated rats showed a significant attenuation of response to the effects of high K⁺ infusion on dopamine metabolite concentrations. Radioimmunoassay measurement of tissue neurotensin content showed highly significant elevations of neurotensin concentrations in the caudate putamen and nucleus accumbens, but not in other brain regions analyzed. These results suggest a confluence of altered dopamine and neurotensin function in the caudate putamen which may be related to motor side effects of haloperidol, whereas changes in prefrontal dopamine function are not associated with altered neurotensin levels.