Reduction of [125I]Bolton Hunter CCK8 and [3H]MK-329 (devazepide) binding to CCK receptors in the substantia nigra/VTA complex and its forebrain projection areas following MPTP-induced hemi-parkinsonism in the monkey

doi:10.1016/0304-3940(91)90353-U

Neuroscience Letters

Volume 131, Issue 1, 30 September 1991, Pages 129-134

https://doi.org/10.1016/0304-3940(91)90353-U Get rights and content

Abstract

Cholecystokinin (CCK) receptors were visualized autoradiographically using [¹²⁵I]Bolton Hunter CCK8 ([¹²⁵I]BHCCK8) in the fore- and midbrain of 3 monkeys rendered hemi-parkinsonian by unilateral intra-carotid infusion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). More specifically, CCK-A receptors were detected using [³H]MK-329 (devazepide), a peripheral-type (CCK-A) receptor antagonist. In the substantia nigra pars compacta, ipsilateral to the toxin infusion, where dopamine D₂ receptors (labelled with [³H]sulpiride) were lost, there was a decrease in the binding of both [¹²⁵I]BHCCK8 and [³H]MK-329. Binding of the two CCK ligands was also reduced in the ipsilateral nucleus accumbens and most medial part of the caudate nucleus, whereas ³H-sulpiride binding was increased in the lateral caudate nucleus and putamen. These results indicate that CCK-A receptors may be located on dopaminergic cells within the substantia nigra, which are lost in the parkinsonian brain, and may also be present on dopaminergic terminals within restricted regions of nigral/ventral tegmental area projection sites.

References (24)

I.J.M. Beresford et al.
Striatal lesions and transplants demonstrate that CCK receptors are localized on intrinsic striatal neurones: a quantitative autoradiographic study
Neuropeptides
(1987)
C.E. Clarke et al.
Drug-induced dyskinesia in primates rendered hemiparkinsonian by intracarotid administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)
J. Neurol. Sci.
(1989)
A.S. Freeman et al.
Electrophysiological effects of cholecystokinin octapeptide on identified rat nigrostriatal dopaminergic neurones
Brain Res.
(1988)
P. Gaudreau et al.
Localization of CCK receptors in relation to the nigrostriatal and mesolimbic dopaminergic pathways
Neuropeptides
(1987)
W.C. Graham et al.
Autoradiographic studies in animal models of hemi-parkinsonism reveal dopamine D₂ but not D₁ receptor supersensitivity. II. Unilateral intra-carotid infusion of MPTP in the monkey (Macaca fascicularis)
Brain Res.
(1990)
D.R. Hill et al.
CCK-A receptors in the rat interpeduncular nucleus: evidence for a presynaptic location
Brain Res.
(1988)
T. Hokfelt et al.
A subpopulation of mesencephalic dopamine neurones project to limbic areas contains a CCK-like peptide: evidence from immunohistochemistry combined with retrograde tracing
Neuroscience
(1980)
D.W. Hommer et al.
Cholecystokinin-like peptides potentiate apomorphine-induced inhibition of dopamine neurones
Eur. J. Pharmacol.
(1983)
P.D. Marley et al.
Effect of 6-OHDA lesions of the MFB on the distribution of CCK in rat forebrain
Brain Res.
(1982)
T.H. Moran et al.
Two brain cholecystokinin receptors: implications for behavioural actions
Brain Res.
(1986)

D. Pelaprat et al.

Autoradiography of CCK receptors in the rat brain using [3H]Boc[Nle^28,30]CCK_27–33 and [125I]Bolton Hunter CCK₈

Functional significance of subregional distributions

Neurochem. Int.

(1987)

L.R. Skirboll et al.

Peptide-monoamine coexistence: studies of the actions of CCK-like peptide on the electrical activity of midbrain dopamine neurones

Neuroscience

(1981)

Cited by (18)

Does endogenous cholecystokinin modulate alcohol intake?
2021, Neuropharmacology
Citation Excerpt :
Studies in animals (Crespi et al., 1997, 2000; Crespi, 1998; Miyasaka et al., 2005) and genetic evidence in humans (Miyasaka et al., 2004) indicate a relationship between the CCK1 receptor and ethanol dependence. In the VTA, CCK1 receptors are localized in the somatodendritic region of DA neurons (Graham et al., 1991; Hamilton and Freeman, 1995), as well as in DAergic terminals of the caudal nucleus accumbens (Vaccarino, 1994) and striatal spiny neurons (Davidowa et al., 1995). CCK action on these receptors could enhance reward-related behaviors (Crespi et al., 2000; Rotzinger and Vaccarino, 2003).
Alcohol use disorder or alcoholism is characterized by uncontrollable alcohol use and intoxication, as well as a heightened state of anxiety after alcohol withdrawal. Ethanol-associated stimuli also drive the urge to drink by means of classical conditioning. Alcoholism has been considered a dopamine (DA) dysregulation syndrome that involves the activity of the central amygdala circuitry of anxiety. Cholecystokinin (CCK) is the most abundant neuropeptide in the mammal brain, where it activates two receptors, CCK₁ and CCK₂. Genetic evidence relates CCK₁ receptors to alcoholism in humans. CCK₂ activity has been associated with the onset of human anxiety. CCK modulates DA release in the nucleus accumbens (NAc) and it is expressed in the γ-aminobutyric acid (GABA)-expressing basket interneurons in the cerebral cortex. CCK interacts with serotonin (5-HT) neurotransmission through 5-HT₃ receptors to regulate mesocorticolimbic pathways and with GABA to attenuate anxiety in the amygdala. Finally, CCK stimulates the release of orexins and oxytocin in the hypothalamus, two relevant hypothalamic neuropeptides involved in signaling satiety for ethanol and well-being respectively. Given the “dimmer-switch” function of endogenous CCK in the neurotransmission by 5-HT, DA, GABA, and glutamate in normal and pathological behaviors (Ballaz and Bourin, 2020), we hypothesize that CCK adjusts functioning of the reward and anxiety circuitries altered by ethanol. This review gathers data supporting this hypothesis, and suggests mechanisms underlying a role for endogenous CCK in alcoholism.
Brief intermittent access to sucrose differentially modulates prepulse inhibition and acoustic startle response in obese CCK-1 receptor deficient rats
2005, Brain Research
Citation Excerpt :
Specifically, CCK stimulates DA release by acting on CCK-1 receptors [4], while activation of the CCK-2 receptor confers an inhibitory effect on DA release [22]. In contrast to the ubiquitous presence of CCK-2 receptors throughout the brain, populations of central CCK-1 receptors are only known to exist within limited regions, such as the dorsomedial hypothalamus [23,30] and striatum [10], with specifically high intensity in the caudo-medial shell of the nucleus accumbens (NAcc) [17,20]. In the caudal NAcc, DA and CCK are co-released in vivo after administration of drugs that increase DA neuronal firing rate [4,19].
Otsuka Long-Evans Tokushima Fatty (OLETF) rats lack the CCK-1 receptor and are hyperphagic and obese. CCK-1 receptors play a role in prepulse inhibition (PPI) by modulating mesolimbic dopamine transmission, a modulator of sensorimotor gating. Therefore, the present study assessed the effects of brief, daily sucrose access on PPI and acoustic startle response (ASR) in OLETF rat and age-matched non-mutant Long-Evans Tokushima Otsuka (LETO) rats. The results revealed that OLETF rats with sucrose access showed an increased ASR [F(1,16) = 6.84; P < 0.01)], relative to sucrose receiving LETO rats. No significant sucrose effect (P = 0.283) on PPI was noted in OLETF rats, whereas sucrose receiving LETO rats had a significantly lower (P < 0.05) PPI percentage than non-sucrose controls. In contrast, sucrose-receiving OLETF rats expressed significantly higher PPI percentage than LETO rats with identical sucrose presentation (P < 0.01). Taken together, these results suggest that sucrose access alters PPI and ASR in general, and the CCK-1 receptors play a modulatory role in facilitating or inhibiting these responses, respectively. A similar effect may be contributory to the hyperphagic behavioral phenotype of obese animal models with altered central dopamine regulation.
Altered extracellular dopamine concentration in the brains of cholecystokinin-A receptor deficient rats
2003, Neuroscience Letters
The gut-brain peptide cholecystokinin (CCK) has been implicated in the regulation of dopamine (DA) transmission in the brain. CCK agonists have been shown to modify baseline and stimulant-induced DA release in the brain via CCK-A mediated mechanisms. However, the role of endogenous CCK in regulating brain DA via CCK-A receptors has not been fully elucidated. Recently, a strain of rats (Otsuka Long Evans Tokushima Fatty (OLETF)), lacking the CCK-A receptor due to a genetic mutation, was discovered, providing a potentially useful tool to study the DA regulatory role of CCK-A receptors. In order to further clarify the role of CCK-A receptors in the regulation of central DA transmission, extracellular DA levels in the nucleus accumbens (NAC) and the caudate-putamen (CP) of OLETF rats, and their non-mutant counterparts, Long Evans Tokushimo Otsuka rats, was assessed by microdialysis at baseline and in response to cocaine (15 mg/kg) and amphetamine (0.5 mg/kg) administration. Baseline levels of extracellular DA were significantly elevated in the CP but not in the NAC of OLETF rats. In contrast, the NAC exhibited a greater DA response to cocaine (15 mg/kg) and amphetamine (0.5 mg/kg) in OLETF rats. This is the first direct evidence, of which we are aware, supporting altered DA regulation in OLETF rats. These findings suggest that CCK-A receptors play an important role in the regulation of central DA transmission, and support the notion that the OLETF rat is a useful model to study this regulation.
Amphetamine-induced zif268 mRNA expression in the medial posterior nucleus accumbens in cholecystokinin-A receptor mutant rats
2000, Neuroscience Letters
Converging evidence supports a role for cholecystokinin (CCK) in modulating dopamine (DA)-mediated activity in the rat mesolimbic system. In particular, CCK co-localized with mesolimbic DA cells originating in the ventral tegmental area potentiates DA function in the medial posterior nucleus accumbens (mpNA) through CCK-A receptors. Recently, a strain of rats lacking the CCK-A receptor, Otsuka Long Evans Tokushima Fatty (OLETF), has been discovered making it possible to study the mesolimbic DA regulatory role of CCK-A receptors. Previous studies have shown that OLETF rats are less sensitive to amphetamine (AMPH)-induced behavioral effects compared to controls. To determine if this altered sensitivity is associated with decreased AMPH-induced postsynaptic activation in the mpNA in OLETF rats, we performed the following experiment. OLETF (CCK-A mutants) and Long Evans Tokushima Otsuka (LETO) rats (controls) were given subcutaneous injections of either saline or AMPH (5.0 mg/kg). One hour after injection all animals were sacrificed and activation of the mpNA was assessed using in situ hybridization with antisense probes for zif 268 mRNA. AMPH treatment produced a significant up-regulation of zif 268 mRNA expression in both OLETF and LETO rats (P≤0.0002), compared to saline treatment. However, AMPH had almost an identical effect on zif 268 mRNA expression in the mpNA in both rat strains suggesting similar postsynaptic neural activation. The significance of this AMPH-induced zif 268 mRNA expression in these two rat strains and its relationship to CCK function in the nucleus accumbens are discussed.
Modulation of neurotransmitter release by cholecystokinin in the neostriatum and substantia nigra of the rat: Regional and receptor specificity
1996, Neuroscience
The effect of cholecystokinin peptides on the release of dynorphin B, aspartate, glutamate, dopamine and GABA in the neostriatum and substantia nigra of the rat was investigated using in vivo microdialysis. Sulphated cholecystokinin-8S in the dialysis perfusate (1–100 μM) induced a concentration-dependent increase in extracellular dynorphin B and aspartate levels, both in the neostriatum and substantia nigra. Striatal dopamine levels were only increased by 100 μM of cholecystokinin-8S, while in the substantia nigra they were increased by 10–100 μM of cholecystokinin-8S. Extracellular GABA and glutamate levels were increased following 100 μM of cholecystokinin-8S only. Striatal cholecystokinin-8S administration also produced a significant increase in nigral dynorphin B levels. Local cholecystokinin-4 (100 μM) produced a moderate, but significant, increase of extracellular dynorphin B and aspartate levels in the neostriatum and substantia nigra. No effect was observed on the other neurotransmitters investigated.
A 6-hydroxydopamine lesion of the nigrostriatal dopamine pathway did not affect the increases in dynorphin B and aspartate levels produced by local administration of cholecystokinin-8S. Basal extracellular GABA levels were increased significantly in both the neostriatum and substantia nigra ipsilateral to the lesion. Nigral glutamate and aspartate levels were also increased in the lesioned substantia nigra, but in the lesioned neostriatum aspartate levels were decreased. The cholecystokinin-B antagonist L-365,260 (20 mg/kg, s.c.), but not the cholecystokinin-A antagonist L-364,718 (devazepide; 20 mg/kg, s.c.), significantly inhibited the effect of cholecystokinin-8S on striatal dynorphin B and aspartate levels. In the substantia nigra, however, the effect of cholecystokinin-8S on dynorphin B and aspartate levels was inhibited to a similar extent by both L-365,260 and L-364,718. Pretreatment with L-364,718, but not with L-365,260, prevented the increase in nigral dopamine levels produced by nigral cholecystokinin-8S administration.
Taken together, these results suggest that cholecystokinin-8S modulates dynorphin B and aspartate release in the neostriatum and substantia nigra of the rat via different receptor mechanisms. In the neostriatum, the effect of cholecystokinin-8S on dynorphin B and aspartate release is mediated via the cholecystokinin-B receptor subtype, while in the substantia nigra, cholecystokinin-8S modulates dynorphin B and aspartate release via both cholecystokinin-A and cholecystokinin-B receptor subtypes. Cholecystokinin-8S modulates dopamine release mainly in the substantia nigra, via the cholecystokinin-A receptor subtype.
Effects of systematically administered ceruletide on the in vivo release, and metabolism of dopamine in the medial prefrontal cortex of awake, freely moving rats: an in vivo microdialysis study
1994, Brain Research
The effects of the cholecystokinin octapeptide-related peptide, ceruletide (CER), on the in vivo release and metabolism of dopamine (DA) in the medial prefrontal cortex were examined in awake, freely moving rats, using in vivo microdialysis. Subcutaneously administered CER (200 μg/kg) increased extracellular levels of DA, 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA), indicating that extracellular levels of DOPAC and HVA may reflect DA release in the medial prefrontal cortex. Bilateral subdiaphragmatic vagotomy markedly attenuated the CER-induced effect, but did not abolish it completely. CER (10⁻⁷ and 10⁻¹⁰ M), applied locally via the dialysis tube, had no effect on the extracellular levels of either DOPAC or HVA. The CCK-A receptor antagonist, L-364,718 (3 mg/kg, i.p.), completely prevented CER-induced increases in the extracellular levels of DOPAC and HVA. The CCK-B antagonist, L-365,260 (3 mg/kg, i.p.), however, given 1 h before the CER treatment, slightly attenuated the CER-induced increase in the extracellular levels of DOPAC, but not the CER-induced increase in HVA, 60–180 min after the treatment. These findings indicate that systematically administered CER modulates the in vivo release and metabolism of DA in the medial prefrontal cortex. We suggest that systemically administered CER exerts its action on both vagal afferent nerves and the area postrema via CCK-A receptors, thus enhancing the in vivo release and metabolism of DA in the medial prefrontal cortex.

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^∗: Present address: Parke Davis Research Unit, Addenbrookes Hospital Site, Hills Road, Cambridge, CB2 2QB, U.K.

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Neuroscience Letters

Abstract

References (24)

Striatal lesions and transplants demonstrate that CCK receptors are localized on intrinsic striatal neurones: a quantitative autoradiographic study

Neuropeptides

Drug-induced dyskinesia in primates rendered hemiparkinsonian by intracarotid administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)

J. Neurol. Sci.

Electrophysiological effects of cholecystokinin octapeptide on identified rat nigrostriatal dopaminergic neurones

Brain Res.

Localization of CCK receptors in relation to the nigrostriatal and mesolimbic dopaminergic pathways

Neuropeptides

Autoradiographic studies in animal models of hemi-parkinsonism reveal dopamine D₂ but not D₁ receptor supersensitivity. II. Unilateral intra-carotid infusion of MPTP in the monkey (Macaca fascicularis)

Brain Res.

CCK-A receptors in the rat interpeduncular nucleus: evidence for a presynaptic location

Brain Res.

A subpopulation of mesencephalic dopamine neurones project to limbic areas contains a CCK-like peptide: evidence from immunohistochemistry combined with retrograde tracing

Neuroscience

Cholecystokinin-like peptides potentiate apomorphine-induced inhibition of dopamine neurones

Eur. J. Pharmacol.

Effect of 6-OHDA lesions of the MFB on the distribution of CCK in rat forebrain

Brain Res.

Two brain cholecystokinin receptors: implications for behavioural actions

Brain Res.

Autoradiography of CCK receptors in the rat brain using [3H]Boc[Nle^28,30]CCK_27–33 and [125I]Bolton Hunter CCK₈

Functional significance of subregional distributions

Neurochem. Int.

Peptide-monoamine coexistence: studies of the actions of CCK-like peptide on the electrical activity of midbrain dopamine neurones

Neuroscience

Cited by (18)

Does endogenous cholecystokinin modulate alcohol intake?

Brief intermittent access to sucrose differentially modulates prepulse inhibition and acoustic startle response in obese CCK-1 receptor deficient rats

Altered extracellular dopamine concentration in the brains of cholecystokinin-A receptor deficient rats

Amphetamine-induced zif268 mRNA expression in the medial posterior nucleus accumbens in cholecystokinin-A receptor mutant rats

Modulation of neurotransmitter release by cholecystokinin in the neostriatum and substantia nigra of the rat: Regional and receptor specificity

Effects of systematically administered ceruletide on the in vivo release, and metabolism of dopamine in the medial prefrontal cortex of awake, freely moving rats: an in vivo microdialysis study