Dopamine D2 receptors exert tonic regulation over discrete neurotensin systems of the rat brain

doi:10.1016/0006-8993(89)90295-3

Brain Research

Volume 500, Issues 1–2, 23 October 1989, Pages 21-29

https://doi.org/10.1016/0006-8993(89)90295-3 Get rights and content

Abstract

Blockade of dopamine D₂ receptors with either the selective antagonist, sulpiride, or the non-selective antagonist, haloperidol, induces 2- to 3-fold increases in the content of neurotensin-like immunoreactivity in the striatum and the nucleus accumbens of the rat brain. Quantitatively similar increases were also observed (a) in the striatum following selective degeneration of more than 85% of the nigrostriatal dopamine pathway with 6-hydroxydopamine and (b) in both the striatum and the nucleus accumbens after non-selective depletion of brain dopamine using reserpine plus α-methyl-p-tyrosine. Interestingly, treatment of animals with sulpiride or haloperidol, following the depletion of dopamine by either 6-hydroxydopamine or reserpine plus α-methyl-p-tyrosine, did not add to the elevation in neurotensin content of either structure caused by the dopamine depletion alone. These data suggest that an intact dopamine system is required for the neuroleptics to exert effects on individual neurotensin systems. In addition, the same mechanism appears to underlie the responses of the neurotensin pathways to treatments with the neuroleptics or dopamine-depleting drugs. A likely explanation for the effects of neuroleptics and dopamine-depleting drugs is that they eliminate tonic activity on D₂ receptors by basally released dopamine in the striatum and the nucleus accumbens. Supportive evidence for this hypothesis is that concurrent administration of the D₂ receptor agonist, LY 171555, with reserpine, completely blocked the effects of reserpine-induced dopamine depletion on neurotensin systems of the striatum and the nucleus accumbens.

References (36)

BradfordM.
A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding
Anal. Biochem.
(1976)
DupontA. et al.
Enzymatic inactivation of neurotensin by thalamic and brain extracts of the rat
Life Sci.
(1978)
EmsonP.C. et al.
Neurotensin in human brain: regional distribution and effects of neurological illness
Brain Research
(1985)
FreyP. et al.
Effects of acute and long-term treatment with neuroleptics on regional telencephalic neurotensin levels in the male rat
Neurochem. Int.
(1986)
FreyP. et al.
Neurotensin concentrations in rat striatum and nucleus accumbens: further studies of their regulation
Neurochem. Int.
(1988)
GehlertD.R. et al.
Dopamine receptors in the rat brain: quantitative autoradiographic localization using [³H]sulpiride
Neurochem. Int.
(1985)
LetterA.A. et al.
Characterization of dopaminergic influence on striatal-nigral neurotensin systems
Brain Research
(1987)
MerchantK.M. et al.
Role of dopamine D₁ and D₂ receptors in the regulation of neurotensin systems of the neostriatum and the nucleus accumbens
Eur. J. Pharmacol.
(1989)
NagatsuT. et al.
A rapid and simple radioassay for tyrosine hydroxylase activity
Anal. Biochem.
(1964)
NemeroffC.B. et al.
Neurotensin-dopamine interactions in the CNS
Trends Pharmacol. Sci.
(1985)

NemeroffC.B.

The interaction of neurotensin with dopaminergic pathways in the central nervous system: basic neurobiology and implications for pathogenesis and treatment of schizophrenia

Psychoneuroendocrinology

(1986)

NielsenJ.A. et al.

Measurement of metabolites of dopamine and 5-hydroxytryptamine in cerebroventricular perfusates of unanesthetized, freely moving rats: selective effects of drugs

Pharmacol. Biochem. Behav.

(1982)

QuirionR.

Interactions between neurotensin and dopamine in the brain: an overview

Peptides

(1983)

ScattonB.

Differential changes in DOPAC levels in the hippocampal formation, septum and striatum of the rat induced by acute and repeated neuroleptic treatment

Eur. J. Pharmacol.

(1981)

SchmidtC.J. et al.

In vitro and in vivo neurochemical effects of methylenedioxymethamphetamine on striatal monoaminergic systems in the rat brain

Biochem. Pharmacol.

(1987)

SonsallaP.K. et al.

Nigrostriatal dopamine actions of the D₂ receptors mediate methamphetamine actions on the striatonigral substance P system

Neuropharmacology

(1986)

SonsallaP.K. et al.

Opposite responses in the striato-nigral substance P system to D₁ and D₂ receptor activation

Eur. J. Pharmacol.

(1984)

UhlG.R. et al.

Neurotensin, a central nervous system peptide: apparent receptor binding in brain membranes

Brain Research

(1977)

Cited by (42)

Electrophysiological and behavioral effects of neurotensin in rat globus pallidus: An in vivo study
2007, Experimental Neurology
The globus pallidus plays a critical role in movement regulation. Morphological study has indicated that the globus pallidus receives neurotensinergic innervation from the striatum. The present study investigated the effects of activating neurotensin receptor in globus pallidus. In vivo single unit electrophysiological recordings showed that micro-pressure ejection of neurotensin into the globus pallidus increased spontaneous firing of pallidal neurons. The excitatory effect of neurotensin could be mimicked by the C-terminal fragment, neurotensin (8–13), but not by the N-terminal fragment, neurotensin (1–8). Local administration of both the non-selective neurotensin receptor antagonist, SR142948A, and the selective neurotensin type-1 receptor antagonist, SR48692, blocked the excitatory effect induced by neurotensin. In the behaving rats, we observed the postural effects of neurotensin in the globus pallidus. Unilateral microinjection of neurotensin into the globus pallidus induced a SR48692-sensitive contralateral dystonic posturing in the presence of systemic haloperidol administration, which could be accounted for by the electrophysiological effect of neurotensin in increasing the firing rate of pallidal neurons. Our in vivo electrophysiological and behavioral findings suggest that pallidal neurotensin receptor plays a role in the basal ganglia motor circuit by mediating an excitation of spontaneous activity in the globus pallidus.
Differential neurotensin responses to low and high doses of methamphetamine in the terminal regions of striatal efferents
2005, European Journal of Pharmacology
Neurotensin is a neuropeptide associated with basal ganglia dopaminergic neurons. Because levels of neurotensin in striatal tissue are differentially affected by low or high doses of methamphetamine, we employed microdialysis to assess the dose-dependent effects of methamphetamine on neurotensin release from the terminals of striatonigral and striatopallidal neurons. A low (0.5 mg/kg), but not high (10 mg/kg), dose of methamphetamine significantly increased nigral extracellular levels of neurotensin. The low-dose effect on extracellular nigral neurotensin levels was blocked by pretreatment with either a dopamine D1 or D2 receptor antagonist. In the globus pallidus, only half of the animals demonstrated increased neurotensin release after the low dose of methamphetamine. These findings suggest that low and high doses of methamphetamine differentially affect the release of neurotensin from the terminals of striatonigral neurons and that both dopamine D1 and D2 receptor activation contributes to the low-dose methamphetamine effects in the substantia nigra.
Altered neurotensin mrna expression in mice lacking the dopamine transporter
2004, Neuroscience
Psychostimulants and antipsychotic drugs increase mRNA expression of the neuropeptide neurotensin (NT) in the striatum and nucleus accumbens. In the present study, we used mice lacking the dopamine transporter (DAT) to investigate the consequences of a chronic hyperdopaminergic state on NT gene expression. NT mRNA expression was examined under basal conditions and after administration of haloperidol or amphetamine using in situ hybridization with a digoxigenin-labeled NT cRNA probe. DAT−/− mice exhibited a striking increase in the number of NT mRNA-expressing perikarya in the substantia nigra and ventral tegmental area, as well as a less pronounced increase in the lateral septum compared with wild-type littermates. No changes were detected in other regions expressing NT mRNA. Acute administration of haloperidol (1 mg/kg) induced a significant increase in the number of NT mRNA-expressing neurons in the dorsomedial and dorsolateral striatum of wild-type mice but failed to stimulate NT gene expression in DAT mutants. In contrast, a higher dose of haloperidol (5 mg/kg) stimulated striatal NT mRNA expression both in DAT+/+ and DAT−/− mice. Amphetamine (10 mg/kg) increased the number of hybridized neurons in the nucleus accumbens shell and fundus striati of wild-type and DAT−/− mice, indicating that the drug acted through a target other than DAT, such as the serotonin or the norepinephrine transporters. The up-regulation of NT mRNA observed in DAT−/− mice may represent an adaptive mechanism in response to constitutive hyperdopaminergia. These results illustrate the profound alterations in the NT system induced by chronic stimulation of DA receptors and underscore the potential clinical relevance of NT/DA interactions in schizophrenia and drug abuse.
A 6-Hydroxydopamine lesion of the mesostriatal dopamine system decreases the expression of corticotropin releasing hormone and neurotensin mRNAs in the amygdala and bed nucleus of the stria terminalis
2002, Brain Research
Citation Excerpt :
The differential effect of the lesion on NT mRNA expression in the caudate putamen versus CEA and BSTov may be due to a direct versus indirect effect, or may reflect a difference in the relative contribution of D1 versus D2 receptors. Indeed, D1 and D2 receptors appear to exert different effects on striatal neurotensin gene expression, with D2 receptor activation leading to a decrease and D1 receptor activation leading to an increase in levels of neurotensin in striatal tissue [21,28,29]. The lateral CEA has been reported to express D2 receptor mRNA [2] and we have observed D2 receptor mRNA within enkephalin containing neurons of the lateral part of the CEA [Day and Akil, unpublished observations].
The mesostriatal dopamine (DA) system is known to play a vital role in extrapyramidal motor responses, and animals with a unilateral 6-hydroxydopamine (6-OHDA) lesion of this system have proved useful in studying the behavioral and neurobiological effects of DA depletion. Less is known about the role of this system in modulating emotional responses, although a number of lines of evidence suggest that dopamine influences emotional behavior. During the course of a study involving rats that had a unilateral 6-OHDA lesion, we discovered a hemispheric asymmetry in the levels of corticotropin releasing hormone (CRH) mRNA in the central nucleus of the amygdala (CEA). The present study was performed in order to determine (1) if the lesion resulted in a decrease in CRH mRNA, and/or if there was upregulation on the intact side, (2) if a similar imbalance in CRH mRNA was observed in other brain regions and (3) if levels of other neuropeptide mRNAs were affected by the lesion. Adult male Sprague–Dawley rats were left unoperated or were pretreated with desipramine and then injected unilaterally with 6-OHDA into the medial forebrain bundle to lesion the ascending mesostriatal DA neurons. Animals were killed 15–31 days following surgery and brain sections processed for CRH, neurotensin and enkephalin mRNAs by in situ hybridization. Levels of CRH and neurotensin mRNAs were decreased on the lesioned side in the CEA and oval nucleus of the BST (BSTov) relative to the intact side and to unoperated controls. Levels of enkephalin mRNA in these regions were not affected by the lesion. These effects appeared specific, because the lesion did not alter CRH mRNA expression in the ventral BST, paraventricular nucleus of the hypothalamus or cortex or neurotensin mRNA expression in the CA1 region of the hippocampus. In contrast, and consistent with previous reports, levels of neurotensin and enkephalin mRNAs were upregulated on the lesioned side of the striatum. This study provides evidence that the mesostriatal DA system regulates CRH and neurotensin mRNA in the BSTov and CEA, suggesting that dopamine may be an important modulator of CRH and neurotensin function within these nuclei. Although the precise mechanisms are not clear, and the involvement of noradrenergic systems cannot be precluded, data are consistent with the idea that dopamine, released in response to a stressful experience for example, interacts with CRH and neurotensin in the extended amygdala to affect emotional responsiveness.
Effects of haloperidol and risperidone on neurotensin levels in brain regions and Neurotensin efflux in the ventral striatum of the rat
2002, Neuropsychopharmacology
Neurotensin (NT) may play a role in the pathophysiology of schizophrenia and in the mechanism of action of antipsychotic drugs. Here we studied the effects of a 30-day regimen of haloperidol (1.15 mg/100 g food) and risperidone (1.15 and 2.3 mg/100 g food) on NT-like immunoreactivity (-LI) levels in brain tissue and NT-LI efflux in the ventral striatum (VSTR) of the rat. Haloperidol, but not risperidone, increased NT-LI levels in the striatum. In the occipital cortex, risperidone, but not haloperidol, decreased levels of NT-LI. In the hippocampus and the frontal cortex both haloperidol and risperidone (the higher dose) increased NT-LI levels. In the VSTR, haloperidol and risperidone (the higher dose) decreased NT-LI efflux and abolished the stimulatory effect of d-amphetamine (1.5 mg/kg, s.c.). Thus, changes in NT occur in response to antipsychotic drugs and psychostimulants that may be relevant for the pathophysiology and treatment of schizophrenia.
Neurotensin gene expression and behavioral responses following administration of psychostimulants and antipsychotic drugs in dopamine D<inf>3</inf> receptor deficient mice
2001, Neuropsychopharmacology
Exposure to psychostimulants and antipsychotics increases neurotensin (NT) gene expression in the striatum and nucleus accumbens. To investigate the contribution of D₃ receptors to these effects we used mice with targeted disruption of the D₃ receptor gene. Basal NT mRNA expression was similar in D₃ receptor mutant mice and wild-type animals. Acute administration of haloperidol increased NT gene expression in the striatum in D₃+/+, D₃+/− and D₃−/− mice. Similarly, acute cocaine and amphetamine induced NT mRNA expression in the nucleus accumbens shell and olfactory tubercle to a comparable extent in D₃ mutants and wild-type mice. Daily injection of cocaine for seven days increased NT mRNA in a restricted population of neurons in the dorsomedial caudal striatum of D₃+/+ mice, but not in D₃−/− and D₃+/− animals. No differences were observed between D₃ receptor mutant mice and wild-type littermates in the locomotor activity and stereotyped behaviors induced by repeated cocaine administration. These findings demonstrate that dopamine D₃ receptors are not necessary for the acute NT mRNA response to drugs of abuse and antipsychotics but appear to play a role in the regulation of NT gene induction in striatal neurons after repeated cocaine. In addition, our results indicate that the acute locomotor response to cocaine and development of psychostimulant-induced behavioral sensitization do not require functional D₃ receptors.

View all citing articles on Scopus

View full text

Dopamine D2 receptors exert tonic regulation over discrete neurotensin systems of the rat brain

Abstract

Anal. Biochem.

Life Sci.

Brain Research

Neurochem. Int.

Neurochem. Int.

Neurochem. Int.

Brain Research

Eur. J. Pharmacol.

Anal. Biochem.

Trends Pharmacol. Sci.

Psychoneuroendocrinology

Pharmacol. Biochem. Behav.

Peptides

Eur. J. Pharmacol.

Biochem. Pharmacol.

Neuropharmacology

Eur. J. Pharmacol.

Brain Research

Dopamine D₂ receptors exert tonic regulation over discrete neurotensin systems of the rat brain