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  • 1
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: CB1 cannabinoid and A2a adenosine receptors are highly expressed in the central nervous system where they modulate numerous physiological processes including emotional behaviour and the responses of several drugs of abuse. To investigate the contribution of these receptors in emotional-like responses and opioid dependence we have generated CB1/A2a double deficient mice (\mathrm{CB}^{-/-}_{1}/\mathrm{A}^{-/-}_{2\mathrm{a}}). The spontaneous locomotor activity was reduced in double knockout as compared to wild-type animals. Emotional-like responses of \mathrm{CB}^{-/-}_{1}/\mathrm{A}^{-/-}_{2\mathrm{a}} mice were investigated using the elevated plus-maze and the lit-dark box. Mutant mice exhibited an increased level of anxiety in both behavioural models. The specific involvement of CB1 and A2a receptors in morphine dependence was evaluated by using A2a knockout mice and CB1/A2a double mutant mice. The severity of naloxone-precipitated morphine withdrawal syndrome was significantly increased in the absence of A2a adenosine receptors whereas no modifications were observed in the double knockout mice. These results suggest that both receptors participate in the control of emotional behaviour and seem to play an opposite role in the expression of opioid physical dependence.
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  • 2
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Anandamide (N-arachidonoylethanolamine, AEA) and 2-arachidonoylglycerol (2-AG) are the most active endocannabinoids at brain (CB1) cannabinoid receptors. CD1 mice lacking the CB1 receptors (‘knockout’[KO] mutants) were compared with wildtype (WT) littermates for their ability to degrade AEA through an AEA membrane transporter (AMT) and an AEA hydrolase (fatty acid amide hydrolase, FAAH). The age dependence of AMT and FAAH activity were investigated in 1- or 4-month-old WT and KO animals, and found to increase with age in KO, but not WT, mice and to be higher in the hippocampus than in the cortex of all animals. AEA and 2-AG were detected in nmol/mg protein (µm) concentrations in both regions, though the hippocampus showed approximately twice the amount found in the cortex. In the same regions, 2-AG failed to change across groups, while AEA was significantly decreased (≈ 30%) in hippocampus, but not in cortex, of old KO mice, when compared with young KO or age-matched WT animals. In the open-field test under bright light and in the lit-dark exploration model of anxiety, young KO mice, compared with old KO, exhibited a mild anxiety-related behaviour. In contrast, neither the increase in memory performance assessed by the object recognition test, nor the reduction of morphine withdrawal symptoms, showed age dependence in CB1 KO mice. These results suggest that invalidation of the CB1 receptor gene is associated with age-dependent adaptive changes of endocannabinoid metabolism which appear to correlate with the waning of the anxiety-like behaviour exhibited by young CB1 KO mice.
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  • 3
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: The involvement of cannabinoid CB1 receptors in morphine and cocaine motivational effects was investigated using CB1 knockout mice. For this purpose, we evaluated the rewarding effects in the place conditioning paradigm and the sensitization to the locomotor responses induced by these drugs. The hyperlocomotion induced by acute morphine administration (15 mg/kg, s.c.) was preserved, but the sensitization to this locomotor response induced by chronic morphine treatment was abolished in CB1 mutant mice. Morphine (5 mg/kg, s.c.) induced conditioned place preference in wild-type mice but failed to produce any response in knockout mice, indicating the inability of morphine to induce rewarding effects in the absence of CB1 cannabinoid receptors. When the aversive effects of morphine withdrawal were investigated using the place aversion paradigm, no differences between genotypes were observed. Acute cocaine (10 mg/kg, i.p.) induced hyperlocomotor responses in wild-type and knockout mice and a chronic cocaine treatment produced a similar sensitization to this response in both genotypes. In the conditioning place preference paradigm, cocaine (20 mg/kg, i.p.) produced rewarding responses in both wild-type and knockout mice. These results demonstrate that CB1 receptors are essential for adaptive responses produced by chronic morphine but not by chronic cocaine treatment.
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  • 4
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: The specific participation of protein kinases in the expression of the somatic signs of morphine withdrawal has been previously demonstrated, suggesting that changes in intracellular signalling systems are involved in opioid addiction. In the present study, the involvement of protein kinases in the aversive/dysphoric effects of morphine abstinence has been investigated in the nucleus accumbens, because of the critical role played by the mesolimbic system in the rewarding effects of opioids. Rats were chronically treated with morphine, twice a day for 5 days, with doses progressively increased from 5 to 30 mg/kg (i-p.). In addition, microinjections into the nucleus accumbens of the serine-threonine kinase inhibitors H7 or H8 (1 or 10 nmol per side) or saline once daily were also given, both in control and in morphine-treated animals. After these chronic treatments, withdrawal syndrome was induced by naloxone administration (0.1 mg/kg, s. c.), and the motivational component of morphine abstinence was studied using the place aversion paradigm. When administered at the highest dose (10 nmol), H7 and H8 strongly reduced the place aversion induced by naloxone in morphine dependent animals. Protein kinase inhibitors did not induce significant behavioural responses in non-dependent animals. Chronic morphine treatment induced a selective up-regulation of adenylate cyclase activity in the amygdala, without affecting other brain regions. The morphine-increased adenylate cyclase activity in amygdala was reversed by the chronic intra-accumbens microinjection of H7 or H8. These results suggest that serine-threonine kinases in the nucleus accumbens play an important role in the emotional/dysphoric properties which characterize opiate withdrawal.
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  • 5
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: CB1 cannabinoid receptors are widely distributed in the central nervous system where they mediate most of the cannabinoid-induced responses. Here we have evaluated the interactions between the CB1 cannabinoid receptors and the endogenous opioid system by assaying a number of well-characterized opioid responses, e.g. antinociception and stress-mediated effects, on mutant mice in which the CB1 receptor gene was invalidated. The spontaneous responses to various nociceptive stimuli (thermal, mechanical and visceral pain) were not changed in mutant CB1 mice. Furthermore, the absence of the CB1 cannabinoid receptor did not modify the antinociceptive effects induced by different opioid agonists: morphine (preferential mu opioid agonist), d-Pen2- d-Pen5-enkephalin (DPDPE) and deltorphin II (selective delta opioid agonists), and U-50,488H (selective kappa opioid agonist) in the hot-plate and tail-immersion tests. In contrast, the stress-induced opioid mediated responses were modified in CB1 mutants. Indeed, these mutants did not exhibit antinociception following a forced swim in water at 34 °C and presented a decrease in the immobility induced by the previous exposure to electric footshock. However, the antinociception induced by a forced swim in water at 10 °C was preserved in CB1 mutants. These results indicate that CB1 receptors are not involved in the antinociceptive responses to exogenous opioids, but that a physiological interaction between the opioid and cannabinoid systems is necessary to allow the development of opioid-mediated responses to stress.
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  • 6
    ISSN: 1476-4687
    Source: Nature Archives 1869 - 2009
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Notes: [Auszug] The u,-opioid-receptor (MOR) gene was inactivated in PI embryonic stem (ES) cells from the 129/Sv mouse line by insertion of a neomycin-resistance (neor) cassette in the gene coding region (Fig. la). Gene targeting was identified by Southern blotting using a 5' probe (Fig. Ib), giving 7 positives ...
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  • 7
    ISSN: 1476-4687
    Source: Nature Archives 1869 - 2009
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Notes: [Auszug] Dopamine receptors have been implicated in the behavioural response to drugs of abuse. These responses are mediated particularly by the mesolimbic dopaminergic pathway arising in the ventral tegmental area and projecting to the limbic system. The rewarding properties of opiates and the somatic ...
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  • 8
    ISSN: 1546-1718
    Source: Nature Archives 1869 - 2009
    Topics: Biology , Medicine
    Notes: [Auszug] The role of the opioid system in controlling pain, reward and addiction is well established, but its role in regulating other emotional responses is poorly documented in pharmacology. The μ-, δ- and κ- opioid receptors (encoded by Oprm, Oprd1 and Oprk1, respectively) mediate ...
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  • 9
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: A2A adenosine and CB1 cannabinoid receptors are highly expressed in the central nervous system, where they modulate numerous physiological processes including adaptive responses to drugs of abuse. Both purinergic and cannabinoid systems interact with dopamine neurotransmission (through A2A and CB1 receptors, respectively). Changes in dopamine neurotransmission play an important role in addictive-related behaviours. In this study, we investigated the contribution of A2A adenosine receptors in several behavioural responses of Δ9-tetrahydrocannabinol (THC) related to its addictive properties, including tolerance, physical dependence and motivational effects. For this purpose, we first investigated acute THC responses in mice lacking A2A adenosine receptors. Antinociception, hypolocomotion and hypothermia induced by acute THC administration remained unaffected in mutant mice. Chronic THC treatment developed similar tolerance to these acute effects in wild-type and A2A-knockout mice. However, differences in the body weight pattern were found between genotypes during such chronic treatment. Interestingly, the somatic manifestations of SR141716A-precipitated THC withdrawal were significantly attenuated in mutant mice. The motivational responses of THC were also evaluated by using the place-conditioning paradigm. A significant reduction of THC-induced rewarding and aversive effects was found in mice lacking A2A adenosine receptors in comparison with wild-type littermates. Binding studies revealed that these behavioural changes were not associated with any modification in the distribution and/or functional activity of CB1 receptors in knockout mice. Therefore, this study shows, for the first time, a specific involvement of A2A receptors in the addictive-related properties of cannabinoids.
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  • 10
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Recent studies have suggested that cannabinoids might initiate the consumption of other highly addictive substances, such as opiates. In this work, we show that acute administration of Δ9-tetrahydrocannabinol in mice facilitates the antinociceptive and antidepressant-like responses elicited by the endogenous enkephalins protected from their degradation by RB 101, a complete inhibitor of enkephalin catabolism. This emphasizes the existence of a physiological interaction between endogenous opioid and cannabinoid systems. Accordingly, Δ9-tetrahydrocannabinol increased the release of Met-enkephalin-like material in the nucleus accumbens of awake and freely moving rats measured by microdialysis. In addition, this cannabinoid agonist displaced the in vivo[3H]diprenorphine binding to opioid receptors in total mouse brain. The repetitive pretreatment during 3 weeks of Δ9-tetrahydrocannabinol in mice treated chronically with morphine significantly reduces the naloxone-induced withdrawal syndrome. However, this repetitive administration of Δ9-tetrahydrocannabinol did not modify or even decrease the rewarding responses produced by morphine in the place preference paradigm. Taken together, these behavioural and biochemical results demonstrate the existence of a direct link between endogenous opioid and cannabinoid systems. However, chronic use of high doses of cannabinoids does not seem to potentiate the psychic dependence to opioids.
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