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[The mechanisms of morphine dependence and it's withdrawal syndrome: study in mutant mice]
Y Noda1, T Mamiya, T Nabeshima
1Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, 65, Tsuruma-cho, Showaku, Nagoya 466-8560, Japan. y-noda@med.nagoya-u.ac.jp
Abstract:
To investigate the involvement of catecholamines and/or the cyclic AMP (cAMP) systems in the development of drug dependence, we examined whether morphine dependence was developed in tyrosine hydroxylase (TH) heterozygous (TH+/-) and cAMP response element binding protein (CREB) binding protein (CBP) heterozygous (CBP+/-) mice. Morphine (10 mg/kg) induced place preference in the wild-type mice. In the TH+/- and CBP+/- mice, however, we could not find any morphine-induced place preference. When the wild-type mice pretreated with morphine (10 mg/kg) twice a day for 5 days were challenged with naloxone (5 mg/kg), they showed increased numbers of jumping, rearing and forepaw tremor as a sign of withdrawal symptom and increased level of cAMP in the thalamus/hypothalamus, but not in the striatum. However, increased numbers of jumping and forepaw tremor in the TH+/- and CBP+/- mice and increased level of cAMP in the thalamus/hypothalamus of TH+/- mice were not observed. These results suggest that catecholamines and CBP are involved in the development of morphine dependence, and that some changes in the catecholaminergic and/or cAMP system induced by repeated morphine treatment play an important role in the addiction of morphine.
Insights
Catecholamines and cAMP response element binding protein (CREB) binding protein (CBP) are crucial for developing morphine dependence. Genetic alterations in these systems prevent morphine-induced preference and withdrawal symptoms in mice.
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Context:
- Drug dependence, particularly morphine addiction, is a significant public health concern.
- The roles of catecholamines and cyclic AMP (cAMP) signaling pathways in addiction development are not fully understood.
- Investigating genetic factors influencing these pathways can reveal mechanisms of drug dependence.
Purpose:
- To determine the involvement of catecholamines and cAMP systems in morphine dependence.
- To examine if reduced levels of tyrosine hydroxylase (TH) or cAMP response element binding protein (CREB) binding protein (CBP) affect morphine-induced place preference and withdrawal symptoms in mice.
Summary:
- Wild-type mice exhibited morphine-induced place preference, while TH+/- and CBP+/- mice did not.
- Wild-type mice showed withdrawal symptoms (jumping, rearing, tremor) and increased thalamus/hypothalamus cAMP levels after chronic morphine exposure and naloxone challenge.
- TH+/- and CBP+/- mice displayed reduced withdrawal symptoms, and TH+/- mice showed no increase in cAMP levels, suggesting catecholamines and CBP are vital for morphine dependence.
Impact:
- This study highlights the critical roles of catecholamines and CBP in the neurobiological mechanisms underlying morphine addiction.
- Findings suggest that targeting catecholaminergic and/or cAMP signaling pathways could be a potential therapeutic strategy for treating opioid dependence.
- The research provides a genetic basis for understanding individual susceptibility to drug dependence.