Increased levels of calcium-sensitive adenylyl cyclase subtypes in the limbic system of alcoholics: evidence for a specific role of cAMP signaling in the human addictive brain

Yamamoto, Megumi; Pohli, S.; Durany, Núria; Ozawa, Hiroki; Saito, Toshikazu; Boissl, Karl W.; Zöchling, Robert; Riederer, Peter; Böning, Jobst; Götz, Mario E.

doi:10.1016/s0006-8993(00)03260-1

Cited by 22 publications

(20 citation statements)

References 13 publications

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“…Indeed, a chronic morphine-induced increase in AC activity has been associated with increased levels of ACI and ACVIII mRNAs and immunoreactivity in the locus ceruleus and of ACVIII in the dorsal raphe nucleus (Nestler and Aghajanian, 1997;Jolas et al, 2000). Interestingly, increased immunoreactivity of ACVIII has been found in the hippocampus and amygdala of the human alcoholic brain (Yamamoto et al, 2001). Mice lacking both ACI and ACVIII display no synaptic plasticity of long-term potentiation in the hippocampus (Wong et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

cAMP-Mediated Mechanisms for Pain Sensitization during Opioid Withdrawal

Bie¹,

Peng²,

Zhang³

et al. 2005

J. Neurosci.

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Chronic opioid-induced drug dependence and withdrawal syndrome after opioid cessation remain a severe obstacle in clinical treatment of chronic pain and opioid drug addiction. One of the key symptoms during opioid withdrawal is a state of sensitized pain. The most significant molecular adaptation induced by chronic opioids in the brain is upregulation of the cAMP-signaling pathway. Although the cAMP system is known to have multiple effects on central neuron functions, how its upregulation mediates behavioral opioid dependence and withdrawal-induced pain in vivo remains unclear. In this study, we demonstrate that withdrawal from chronic morphine significantly upregulates the mRNA level of adenylyl cyclase (AC) VI and VIII isoforms and immunoreactivity of ACV/VI in the nucleus raphe magnus (NRM), a brainstem site critically involved in opioid modulation of pain. In cellular studies of NRM neurons containing -opioid receptors, we show that morphine withdrawal significantly increases glutamate synaptic transmission via a presynaptic mechanism mediated by an upregulated cAMP pathway. Morphine withdrawal also enhances the hyperpolarization-activated current in these neurons by increased intracellular cAMP. Both of the withdrawal-induced cAMP actions increase the excitability of these -receptorcontaining neurons, which are thought to facilitate spinal pain transmission. Furthermore, in morphine-dependent rats in vivo, blocking the cAMP pathway significantly reduces withdrawal-induced pain sensitization. These results illustrate neurobiological mechanisms for the cAMP-mediated withdrawal pain and provide potential therapeutic targets for the treatment of opioid dependence and withdrawalrelated problems.

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Section: Discussionmentioning

confidence: 99%

cAMP-Mediated Mechanisms for Pain Sensitization during Opioid Withdrawal

Bie¹,

Peng²,

Zhang³

et al. 2005

J. Neurosci.

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“…An involvement of AC1 in the pathophysiology of alcoholism and Alzheimer's disease was proposed (Sohma et al, 1999;Yamamoto et al, 2000Yamamoto et al, , 2001, but these studies hinged on the use of commercial antibodies with questionable specificity (Göttle et al, 2009). b. Adenylyl cyclase 1 and adenylyl cyclase 8 redundancies.…”

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confidence: 99%

International Union of Basic and Clinical Pharmacology. CI. Structures and Small Molecule Modulators of Mammalian Adenylyl Cyclases

Dessauer¹,

Watts²,

Ostrom³

et al. 2017

Pharmacol Rev

172

198

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“…In heroin addicts, levels of several isoforms of adenylate cyclase protein and enzyme activity are lower in cortex but unaltered in nucleus accumbens (Shichinohe et al, 1998(Shichinohe et al, , 2001. In alcoholics, levels of various isoforms of adenylate cyclase are also lower in cortex, whereas levels are variably reported to be elevated or unaltered in nucleus accumbens and amygdala Sohma et al, 1999;Yamamoto et al, 2001a). In methamphetamine users, dopamine-stimulated adenylate cyclase activity is less in nucleus accumbens, caudate, and putamen (Tong et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Long-Term Upregulation of Protein Kinase A and Adenylate Cyclase Levels in Human Smokers

Hope¹,

Nagarkar²,

Leonard³

et al. 2007

J. Neurosci.

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Repeated injections of cocaine and morphine in laboratory rats cause a variety of molecular neuroadaptations in the cAMP signaling pathway in nucleus accumbens and ventral tegmental area. Here we report similar neuroadaptations in postmortem tissue from the brains of human smokers and former smokers. Activity levels of two major components of cAMP signaling, cAMP-dependent protein kinase A (PKA) and adenylate cyclase, were abnormally elevated in nucleus accumbens of smokers and in ventral midbrain dopaminergic region of both smokers and former smokers. Protein levels of the catalytic subunit of PKA were correspondingly higher in the ventral midbrain dopaminergic region of both smokers and former smokers. Protein levels of other candidate neuroadaptations, including glutamate receptor subunits, tyrosine hydroxylase, and other protein kinases, were within normal range. These findings extend our understanding of addiction-related neuroadaptations of cAMP signaling to tobacco smoking in human subjects and suggest that smoking-induced brain neuroadaptations can persist for significant periods in former smokers.

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Increased levels of calcium-sensitive adenylyl cyclase subtypes in the limbic system of alcoholics: evidence for a specific role of cAMP signaling in the human addictive brain

Cited by 22 publications

References 13 publications

cAMP-Mediated Mechanisms for Pain Sensitization during Opioid Withdrawal

cAMP-Mediated Mechanisms for Pain Sensitization during Opioid Withdrawal

International Union of Basic and Clinical Pharmacology. CI. Structures and Small Molecule Modulators of Mammalian Adenylyl Cyclases

Long-Term Upregulation of Protein Kinase A and Adenylate Cyclase Levels in Human Smokers

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