Morphine place conditioning is differentially affected by CCKA and CCKB receptor antagonists

doi:10.1016/0006-8993(92)90471-K

Brain Research

Volume 572, Issues 1–2, 14 February 1992, Pages 208-215

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Abstract

In the present study we have examined the interaction between the selective cholecystokinin (CCK)_A and CCK_B receptor antagonists, devazepide and L365-260 on morphine conditioned place preference (CPP). Using an unbiased procedure, morphine (1.5 mg/kg) produced a reliable CPP which was observed irrespective of the conditioning compartment type. Pretreatment with devazepide (0.001–0.01 mg/kg s.c.) produced a dose related attenuation of this response. At higher doses (0.1–1 mg/kg) this antagonism became variable and dependent on the training compartment with blockade only observed when conditioning was to the white/rough textured environment. This profile has also been reported for the serotonin (5-HT)₃ receptor antagonist ondansetron. The CCK_B antagonist L365-260 (0.000001–0.01 mg/kg) failed to antagonize the morphine CPP, if anything a mild potentiation was observed. To study this further we examined the interaction between L365-260 (0.01 mg/kg) and a subthreshold dose of morphine (0.3 mg/kg). At these doses neither drug elicited CPP, however when co-administered a significant CPP was recorded. Finally, L365-260 at 1 mg/kg induced a mild but significant CPP when administered alone. These results suggest a differential role of CCK receptor subtypes on reward-related behaviour and complement previous studies suggesting bimodal effects of CCK systems on mesolimbic dopamine function.

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Cholecystokinin-octapeptide (CCK-8), which is a typical brain-gut peptide, exerts a wide range of biological activities on the central nervous system. We have previously reported that CCK-8 significantly alleviated morphine-induced amnesia and reversed spine density decreases in the CA1 region of the hippocampus in morphine-treated animals. Here, we investigated the effects of CCK-8 on long-term potentiation (LTP) in the lateral perforant path (LPP)-granule cell synapse of rat dentate gyrus (DG) in acute saline or morphine-treated rats. Population spikes (PS), which were evoked by stimulation of the LPP, were recorded in the DG region. Acute morphine (30 mg/kg, s.c.) treatment significantly attenuated hippocampal LTP and CCK-8 (1 μg, i.c.v.) restored the amplitude of PS that was attenuated by morphine injection. Furthermore, microinjection of CCK-8 (0.1 and 1 μg, i.c.v.) also significantly augmented hippocampal LTP in saline-treated (1 ml/kg, s.c.) rats. Pre-treatment of the CCK2 receptor antagonist L-365,260 (10 μg, i.c.v) reversed the effects of CCK-8, but the CCK1 receptor antagonist L-364,718 (10 μg, i.c.v) did not. The present results demonstrate that CCK-8 attenuates the effect of morphine on hippocampal LTP through CCK2 receptors and suggest an ameliorative function of CCK-8 on morphine-induced memory impairment.
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For example, it has been shown that the coadministration of a CCK antagonist with a subthreshold dose of morphine induces CPP (Valverde et al., 1996). There are other studies indicating that a CCKA receptor antagonist attenuates CPP but a CCKB receptor antagonist does not modify morphine-induced CPP, indicating a differential role of CCK receptor subtypes on morphine (Higgins et al., 1992) and cocaine (Lu et al., 2002) induced CPP. Pretreatment with the gut peptide ghrelin enhances the rewarding properties of cocaine.
There are different physiological processes that influence behavior. One of this processes that produces approach behavior to a stimuli that induces a positive affective (PA) state, commonly known as reward, plays an important role in modulating behavior. There is an extensive literature in which the rewarding effects of drugs have been investigated. Less research has been devoted to the study of naturally occurring behaviors that produce a PA or reward state. Hormones modulate different behaviors, including sex. However, little attention has been devoted to study the possible role of hormones in reward states. One of the methods most frequently used to study reward or PA states is the conditioned place preference (CPP) paradigm. Hopefully this review will encourage researchers to directly address the effects of hormones on reward, research that is much needed.
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Morphine place conditioning is differentially affected by CCKA and CCKB receptor antagonists

Abstract

Brain Research

Life Sci.

Life Sci.

Pharmacol. Biochem. Behav.

Physiol. Behav.

Brain Research

Pharmacol. Biochem. Behav.

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Eur. J. Pharmacol.

Eur. J. Pharmacol.

Life Sci.

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Physiol. Behav.

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Pharmacol. Biochem. Behav.

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Trends Pharmacol. Sci.

Eur. J. Pharmacol.

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Neuropeptides

Neurosci. Lett.

Neurosci. Lett.

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Brain Research

Morphine place conditioning is differentially affected by CCK_A and CCK_B receptor antagonists