Differential effect of haloperidol on release of neurotensin in extrapyramidal and limbic systems

Abstract

The effect of the antipsychotic drug haloperidol on extracellular neurotensin-like immunoreactivity was investigated by microdialysis and compared with the time-dependent response of tissue neurotensin-like immunoreactivity content in brain structures containing dopamine nerve cell bodies and terminals. A single administration of haloperidol (1 mg/kg) increased the extracellular neurotensin-like immunoreactivity levels in nucleus accumbens as measured by microdialysis, but decreased its extracellular concentration in the caudate regions surrounding the probe. The same treatment increased the tissue content of neurotensin-like immunoreactivity in both the nucleus accumbens core and all caudate regions examined within 24 h after the injection. Interestingly, although the neurotensin-like immunoreactivity concentration in the substantia nigra was not altered by the haloperidol treatment, neurotensin-like immunoreactivity levels decreased significantly in the ventral tegmental area. These findings suggest that varied neurotensin systems are associated with nigrostriatal and mesolimbic dopamine pathways and these systems have different responses to haloperidol. The changes in the release of neurotensin may contribute to altered caudate and accumbens neurotensin-like immunoreactivity tissue content induced by haloperidol treatment, but other factors, such as variation in synthesis also likely influence these effects. Differential actions of haloperidol on neurotensin release might be due to regional differences in dopamine or sigma receptor subtypes associated with the neurotensin-containing neurons.

Introduction

Neurotensin, an endogenous tridecapeptide, is thought to be an important modulator of dopamine neurotransmission in extrapyramidal and limbic regions (Govoni et al., 1980; Kitabgi, 1989). It has been found to be colocalized with dopamine in the prefrontal cortex, but not in the caudate and nucleus accumbens (Kitabgi, 1989). Neurotensin receptors are located on dopamine terminals in both the caudate and nucleus accumbens, suggesting that neurotensin influences the release of this catecholamine (Kitabgi, 1989). Due to the presence of neurons containing mRNA for a neurotensin precursor, it is thought that this peptide originates from neurons with cell bodies in the caudate and nucleus accumbens (Alexander et al., 1989). Although the interaction between neurotensin and dopamine systems is regionally dependent (Gygi et al., 1994), neurotensin's ability to antagonize dopamine-mediated behavior has led to speculation that this neuropeptide can function as an endogenous neuroleptic (Nemeroff et al., 1982; Quirion, 1983; Nemeroff, 1986). Because of its apparent antagonism of dopamine functions, some investigators have speculated that neurotensin plays an important role in the actions of antipsychotic drugs (Govoni et al., 1980; Levant et al., 1989; Myers et al., 1992).

Haloperidol is a widely used antipsychotic drug for the treatment of psychosis such as schizophrenia. This drug has been reported to increase neurotensin concentrations in the nucleus accumbens and caudate nucleus in rats as well as elevate the expression of neurotensin mRNA in these two structures (Govoni et al., 1980; Frey et al., 1986; Merchant et al., 1991, Merchant et al., 1992). In addition, reduced neurotensin levels observed in the cerebrospinal fluid of untreated schizophrenic patients appear to return to normal after neuroleptic therapy (Widerlov et al., 1982). Nevertheless, the relationship between the synthesis, release and the tissue content of neurotensin in the presence of haloperidol treatment remains unresolved. Therefore, the precise effect of haloperidol on the neurotensin system and the contribution of this neuropeptide to the pharmacological effects of this antipsychotic require elucidation.

In the present study, we measured alterations of extracellular neurotensin in extrapyramidal and limbic terminal fields of dopaminergic pathways by microdialysis and compared the changes in neurotensin release caused by haloperidol with corresponding alterations in surrounding neurotensin tissue content 1–24 h after treatment. The effect of haloperidol treatment on neurotensin tissue levels were also determined in the ventral tegmental area and substantia nigra which contain the corresponding dopaminergic cell bodies.