Substance P in the ventral pallidum: Projection from the ventral striatum, and electrophysiological and behavioral cinsequences of pallidal substance P

doi:10.1016/0306-4522(95)00218-8

Neuroscience

Volume 69, Issue 1, November 1995, Pages 59-70

https://doi.org/10.1016/0306-4522(95)00218-8 Get rights and content

Abstract

The ventral pallidum of the basal forebrain contains a high concentration of substance P and receives a massive projection from the nucleus accumbens. The present study was designed to determine whether the accumbens serves as a source for substance P-containing fibers in the ventral pallidum and characterize the function of this tachykinin peptide within the ventral pallidum.

By combining in situ hybridization for messengerRNA of the substance P prohormone, β-preprotachykinin, with Fluoro-Gold retrograde labeling from iontophoretic deposits in the ventral pallidum, a population of substance P-containing neurons was demonstrated in the shell and core components of the nucleus accumbens and the ventromedial striatum. The function of substance P within the ventral pallidum was characterized at the level of the single neuron, and the behaving animal. Electrophysiological assessment revealed that approximately 40% of the 97 ventral pallidal neurons tested were readily excited by microiontophoretic applications of substance P or a metabolically stable agonist analog, DiMeC7 [(pGlu5, MePhe8, MeGly9)-substance P5-11]. Response characteristics were distinguished from glutamate-induced excitations by a slower onset and longer duration of action. Recording sites of tachykinin-sensitive neurons were demonstrated to be located throughout the ventral pallidum and within high densities of fibers exhibiting substance P-like immunoreactivity. When behaving rats received microinjections of DiMeC7 into this same region, the animals displayed an increase in motor activity, with a response threshold of 0.1 nmol per hemisphere.

These results verify the existence of a substantial substance P-containing projection from the nucleus accumbens to the ventral pallidum. The projection likely serves to excite ventral pallidal neurons for these neurons readily increased firing following local exposure to tachykinins. Furthermore, an increase in motor behavior appears to be a consequence of this neuronal response.

References (85)

AltierN. et al.
Intra-VTA infusions of the substance P analogue, DiMeC7, and intra-accumbens infusions of amphetamine induce analgesia in the formalin test for tonic pain
Brain Res.
(1993)
BaudP. et al.
Locomotor hyperactivity in the rat after infusion of muscimol and [d-Ala²]Met-enkephalin into the nucleus basalis magnocellularis. Possible interaction with cortical cholinergic projections
Brain Res.
(1988)
BeachT.G. et al.
The distribution of substance P in the primate basal ganglia: an immunohistochemical study of baboon and human brain
Neuroscience
(1984)
BeachT.C. et al.
Light microscopic evidence for a substance P-containing innervation of human nucleus basalis of Meynert
Brain Res.
(1987)
BiellaG. et al.
Facilitatory role of calcitonin gene-related peptide (CGRP) on excitation induced by substance P (SP) and noxious stimuli in rat spinal dorsal horn neurons. An iontophoretic study in vivo
Brain Res.
(1991)
BiglV. et al.
Cholinergic projections from the basal forebrain to frontal, parietal, temporal, occipital, and cingulate cortices: a combined fluorescent tracer and acetylcholinesterase analysis
Brain Res. Bull.
(1982)
BolamJ.P. et al.
Substance P-containing terminals in synaptic contact with cholinergic neurons in the neostriatum and basal forebrain: a double immunocytochemical study in the rat
Brain Res.
(1986)
CooperP.E. et al.
The regional distribution of somatostatin, substance P and neurotensin in human brain
Brain Res.
(1981)
DanksJ.A. et al.
A comparative autoradiographic study of the distributions of substance P and eledoisin binding sites in rat brain
Brain Res.
(1986)
EisonA.S. et al.
The behavioural effects of a novel substance P analogue following infusion into the ventral tegmental area or substantia nigra of rat brain
Brain Res.
(1982)

ElliottP.J. et al.

Behavioural effects of tachykinins and related peptides

Brain Res.

(1986)

GerfenC.R.

Substance P (neurokinin-1) receptor mRNA is selectively expressed in cholinergic neurons in the striatum and basal forebrain

Brain Res.

(1991)

GuyenetP.G. et al.

Excitation of neurons in the nucleus locus coeruleus by substance P and related peptides

Brain Res.

(1977)

HaberS.N. et al.

Correlation between met-enkephalin and substance P immunoreactivity in the primate globus pallidus

Neuroscience

(1981)

HaberS.N. et al.

Ramifications of the globus pallidus in the rat as indicated by patterns of immunohistochemistry

Neuroscience

(1983)

HaberS.N. et al.

The comparative distribution of enkephalin, dynorphin and substance P in the human globus pallidus and basal forebrain

Neuroscience

(1985)

HeimerL. et al.

Specifictty in the projection patterns of accumbal core and shell in the rat

Neuroscience

(1991)

HoffmanD.C. et al.

Ventral pallidal microinjections of receptor-selective opioid agonists produce differential effects on circling and locomotor activity in rats

Brain Res.

(1991)

Holzhauer-OitzlM.S. et al.

Reinforcing properties of substance P in the region of the nucleus basalis magnocellularis in rats

Neuropharmacology

(1988)

HubnerC.B. et al.

The ventral pallidum plays a role in mediating cocaine and heroin self-administration in the rat

Brain Res.

(1990)

HustonJ.P. et al.

Lateralized functional relationship between the preoptic area and lateral hypothalamic reinforcement

Brain Res.

(1987)

JohnsonP.I. et al.

Regional reward differences within the ventral pallidum are revealed by microinjections of amu opiate receptor agonist

Neuropharmacology

(1993)

KalivasP.W.

Neurotransmitter regulation of dopamine neurons in the ventral tegmental area

Brain Res. Rev.

(1993)

KalivasP.W. et al.

GABA and enkephalin projection from the nucleus accumbens and ventral pallidum to the ventral tegmental area

Neuroscience

(1993)

KanazawaI. et al.

On the origin of substance P-containing fibres in the entopeduncular nucleus and the substantia nigra of the rat

Brain Res.

(1980)

Le Gal La SalleG. et al.

Microiontophoretic effects of substance P on neurons of the medial amygdala and putamen of the rat

Brain Res.

(1977)

LjungdahlA. et al.

Distribution of substance P-like immunoreactivity in the central nervous system of the rat—I. Cell bodies and nerve terminals

Neuroscience

(1978)

MarksteinerJ. et al.

Comparative distribution of neurokinin B-, substance P- and enkephalin-like immunoreactivities and neurokinin B messenger RNA in the basal forebrain of the rat: evidence for neurochemical compartmentation

Neuroscience

(1992)

McAlonanG.M. et al.

Effects of medial dorsal thalamic and ventral pallidal lesions on the acquisition of a conditioned place preference: further evidence for the involvement of the ventral striatopallidal system in reward-related processes

Neuroscience

(1993)

MogensonG.J. et al.

Evidence that an accumbens to subpallidal GABAergic projection contributes to locomotor activity

Brain Res. Bull.

(1983)

MogensonG.J. et al.

Evidence that projections from substantia innominata to zona incerta and mesencephalic locomotor region contribute to locomotor activity

Brain Res.

(1985)

MogensonG.J. et al.

Subpallidal projections to the mesencephalic locomotor region investigated with a combination of behavioral and electrophysiological recording techniques

Brain Res. Bull.

(1986)

MogensonG.J. et al.

Subpallidal-penunculopontine projections but not subpallidal-mediodorsal thalamus projections contribute to spontaneous exploratory locomotor activity

Brain Res.

(1989)

NapierT.C.

Dopamine receptors in the ventral pallidum regulate circling induced by opioids injected into the ventral pallidum

Neuropharmacology

(1992)

PomeroyS.L. et al.

Response of nucleus raphe magnus neurons to iontophoretically applied substance P in rats

Brain Res.

(1980)

RothmanR.B. et al.

Visualization of rat brain receptors for the neuropeptide, substance P

Brain Res.

(1984)

SalterM.W. et al.

Responses of functionally identified neurons in the dorsal horn of the cat spinal cord to substance P, neurokinin A and physalaemin

Neuroscience

(1991)

SaperC.B. et al.

A cytoarchitectonic and histochemical study of nucleus basalis and associated cell groups in the normal human brain

Neuroscience

(1984)

SembaK. et al.

Brainstem projecting neurons in the rat basal forebrain: neurochemical, topographical, and physiological distinctions from cortically projecting cholinergic neurons

Brain Res. Bull.

(1989)

ShuS.Y. et al.

High density of zinc-containing and dynorphin B- and substance P-immunoreactive terminals in the marginal division of the rat striatum

Brain Res. Bull.

(1990)

ShultsC.W. et al.

A comparison of the anatomical distribution of substance P and substance P receptors in the rat central nervous system

Peptides

(1984)

SwansonL.W. et al.

Anatomical and electrophysiological evidence for a projection from the medial preoptic area to the “mesencephalic and subthalamic locomotor regions” in the rat

Brain Res.

(1987)

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^§: Present address: Division of Neurological Sciences, Department of Psychiatry, The University of British Columbia, Vancouver, B.C., Canada.

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