Pharmacological and mechanistic studies of cholecystokinin-facilitated [3H]dopamine efflux from rat nucleus accumbens

doi:10.1016/0143-4179(89)90020-6

Neuropeptides

Volume 13, Issue 1, January 1989, Pages 43-50

https://doi.org/10.1016/0143-4179(89)90020-6 Get rights and content

Abstract

Cholecystokinin (CCK) is co-localized with dopamine (DA) in mesolimbic neurons of the CNS and appears to selectively regulate the output of this system. In an attempt to characterize the nature of CCK interactions with mesolimbic DA-containing nerve terminals, we have investigated CCK regulation of [³H]DA overflow from rat nucleus accumbens slices. CCK-8 produced a saturable and potent (EC₅₀ = 3nM) facilitation of KCl (35mM)-evoked [³H]DA efflux from nucleus accumbens, but failed to significantly alter [³H]DA efflux from striatum. The stimulatory action of CCK-8 was unaffected by the muscarinic antagonist atropine, the opiate antagonist naloxone, or the selective ion channel blockers tetrodotoxin and nifedipine. Pharmacological studies revealed that non-sulfated CCK-8 and CCK-4 (up to low micromolar concentrations) did not facilitate [³H]DA efflux from accumbens slices. Furthermore, the effect of CCK-8 was selectively and potently (IC₅₀= 300nM) inhibited by the Type-A-selective CCK antagonist CR-1409. Taken together, these results indicate that CCK regulates DA efflux from mesolimbic nerve terminals via a direct presynaptic action on receptors which display a pharmacological profile that is similar to Type A CCK receptors in gastrointestinal tissues.

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Cholecystokinin modulation of locomotor behavior in rats is sensitized by chronic amphetamine and chronic restraint stress exposure
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Citation Excerpt :
Evidence suggests that CCKA receptors mediate DA agonist-like effects in this region. For example, NAcc CCKA receptor activation potentiates K+-stimulated endogenous DA release [30,49] and increases extracellular concentrations of DA and its metabolites, DOPAC and HVA [23,50]. Consistent with these findings, behavioral studies have demonstrated that exogenous activation of NAcc CCKA receptors potentiates mesolimbic DA-dependent behaviors, such as hyperlocomotion induced by DA or the indirect DA agonist amphetamine (AMPH) [5,7,48].
DA release in the nucleus accumbens (NAcc) is a critical substrate mediating locomotor behavior. Cholecystokinin (CCK) is co-localized with dopamine (DA) in up to 90% of mesolimbic DA neurons. We have previously shown that while CCK_A receptor antagonists generally do not affect locomotor behaviors, systemic administration of a CCK_A receptor antagonist attenuates amphetamine (AMPH)-induced locomotion in animals previously treated chronically with AMPH, suggesting that chronic stimulant pretreatment may sensitize CCK systems. The present studies examined this issue by testing the effects of CCK_A antagonists on AMPH- and novel environment-induced locomotor activity following two manipulations which are known to alter mesolimbic system function: Chronic AMPH administration and chronic restraint stress (RS). Additionally, CCK immunoreactivity in the mesolimbic system following these manipulations was examined using immunohistochemistry. Results indicated that intra-NAcc microinjections of the selective CCK_A receptor antagonist PD-140548 attenuated AMPH-induced and novel environment-induced locomotion only in animals which had previously been exposed to chronic AMPH or chronic RS pretreatment. However, chronic AMPH and chronic RS did not produce detectable changes in the number of CCK-immunostained neurons in the ventral tegmental area (VTA) or substantia nigra (SN), or in CCK levels in any of the subregions of the NAcc. Together, these results suggest that the role of endogenous CCK in the modulation of locomotor behaviors is sensitized following chronic psychostimulant or chronic RS exposure. However, this sensitization does not appear to be accompanied by changes in the overall basal levels of CCK or in the number of CCK-positive cells within the mesoaccumbens system.
Atypical behavioural responses to CCK-B receptor ligands in Fawn-Hooded rats
2003, Life Sciences
At present there is an increasing literature demonstrating heterogeneity of the CCK-B receptor. Recent reports by our laboratory have demonstrated that the Fawn-Hooded rat demonstrates atypical neurochemical responses to CCK₄, in vitro. Since the ability of CCK-B receptor ligands to modulate affective state is dependent on the putative receptor subtype activated, the aim of the present study was to examine the behavioural effects of the CCK-B receptor agonist, t-boc-CCK₄, and the CCK-B receptor antagonist, Ci-988 in Fawn-Hooded and Wistar Kyoto rats. Interestingly, both t-boc-CCK₄ and Ci-988 produced an anxiolytic profile in FH rats as determined by an increased time spent on the open arms of an elevated plus maze, while both drugs were devoid of any behavioural effect in WKY rats, lending further support to the theory that the FH rat strain has an atypical relative proportion of these putative subtypes apparently resulting in a predominantly CCK-B₂ receptor effect.
CCK/dopamine interactions in Fawn-Hooded and Wistar-Kyoto rat brain
2000, Peptides
The aim of this study was to compare the actions of CCK neuropeptides within the nucleus accumbens (N.Acc) of alcohol preferring (Fawn-Hooded, FH) and alcohol nonpreferring (Wistar–Kyoto, WKY) rats. CCK-8S (30–300 nM) facilitated the K⁺ stimulated release of [³H]dopamine (DA) from N.Acc prisms in both rat strains, whereas CCK-4 (30 nM–1 μM) caused a significant decrease of evoked [³H]DA in the FH rat only. A scattered distribution of CCK-A and -B receptor immunopositive varicose fibers were visualized throughout the N.Acc of both rat strains along with a topographic distribution of CCK receptor positive cells throughout the ventral mesencephalon.
The expression of behavioral sensitization to amphetamine: Role of CCK(A) receptors
1999, Pharmacology Biochemistry and Behavior
These studies investigated whether endogenous activation of CCK_A receptors mediates the expression of amphetamine (AMP)-induced locomotor activity. In Experiment 1, locomotor activity was assessed in rats pretreated with the CCK_A antagonist devazepide (0.001, 0.01, and 0.1 mg/kg) and subsequently injected with AMP (1.5 mg/kg). In Experiment 2, rats were administered AMP (1.5 mg/kg) once daily for 7 days. Following a 10-day withdrawal, locomotor activity was assessed following treatment with devazepide (0.001, 0.01, and 0.1 mg/kg) and AMP (0.75 mg/kg). In both studies, rats were classified as low (LR) or high (HR) responders based upon a median split of their locomotor response to a novel environment. Results from Experiment 1 showed that AMP potentiated the expression of locomotor activity, and this effect was most pronounced in HR rats. However, devazepide did not affect AMP-induced locomotion. Results from Experiment 2 demonstrated that chronic AMP pretreatment augmented the locomotor response to subsequent AMP challenge, and this effect was most pronounced in the HR group. Further, this augmented response was blocked by devazepide in HR rats. These findings constitute the first demonstration that endogenous CCK_A receptor activation is an important substrate mediating AMP-induced locomotor activity in animals with a previous history of AMP treatment.
Individual differences in sucrose intake predict behavioral reactivity in rodent models of anxiety
1998, Pharmacology Biochemistry and Behavior
We have previously shown that individual differences in oral sucrose consumption are predictive of behavioral reactivity of rats in the elevated plus-maze (EPM). The present experiments were designed to replicate the EPM results and to extend them to another animal model of anxiety, the acoustic startle reflex (ASR) paradigm. In two experiments, sucrose consumption was assessed in separate groups of rats across eight daily 1-h feeding sessions. Animals were designated as either low (LSF) or high sucrose feeders (HSF) based on a median split of their sucrose intake on the final test day. Following this assay, animals were tested in the EPM in Experiment 1, and in the ASR paradigm in Experiment 2. Results from Experiment 1 replicated our previous findings and showed that the percentage of time spent on, and entries into, open arms was significantly lower in LSF than HSF. Further, results from Experiment 2 revealed a significantly augmented startle response to acoustic stimuli (94–108 dB SPL) in LSF compared to HSF. These data provide converging evidence to support the notion that individual differences in baseline levels of oral sucrose consumption are predictive of anxious behaviors in rats.
Cholecystokinergic innervation of nucleus accumbens subregions
1998, Peptides
Behavioral and pharmacological evidence has shown a different and opposite role of the neuropeptide cholecystokinin (CCK) on the dopamine (DA) function in the caudal versus rostral part of the nucleus accumbens. Previous reports have speculated that the caudal region of the nucleus accumbens would receive CCKergic innervation from dopaminergic neurons of the mesencephalic ventral tegmental area, whereas the CCKergic input to the rostral accumbens would originate in non-dopaminergic neurons from extra-mesencephalic areas of the brain. In the present study, this issue was addressed using retrograde tracing techniques in conjunction with immunocytochemistry. Retrograde tracers were injected in the three compartments of the accumbens (i.e., rostral pole, core and septal shell). In summary, our results demonstrate that 1) the main CCKergic input of the accumbens originates in the ventral mesencephalon; 2) the rostral pole is equally innervated by CCK neurons projecting from both substantia nigra pars compacta and ventral tegmental area; 3) the primary source of CCK innervation of the accumbal core is the substantia nigra pars compacta; and 4) whereas the CCKergic input to the septal shell originates primarily in the ventral tegmental area. Additionally, our results also showed that most of the CCKergic neurons projecting to any of the accumbal compartments also produce dopamine. These data constitute the first neuroanatomical evidence for the differential effects of CCK on dopamine actions in the different regions of the nucleus accumbens.

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Pharmacological and mechanistic studies of cholecystokinin-facilitated [3H]dopamine efflux from rat nucleus accumbens

Abstract

J. Biol. Chem.

Eur. J. Pharmacol.

Neuroscience

Neurosci. Lett.

Neuroscience

Eur. J. Pharmacol.

Brain Res.

Eur. J. Pharmacol.

Neurochem. Int.

Neurochem. Int.

Peptides

Biochem. Pharmacol.

Eur. J. Pharmacol.

Brain Res.

Brain Res.

Brain Res.

Trends Pharmacol. Sci.

Biochem. Pharmacol.

Biochem. Pharmacol.

Brain Res.

Immunochemical evidence of cholecystokinin-like peptides in brain

Nature

Cholecystokinin and its COOH-terminal octapeptide in the pig brain

Pharmacological and mechanistic studies of cholecystokinin-facilitated [³H]dopamine efflux from rat nucleus accumbens