nAChR dysfunction as a common substrate for schizophrenia and comorbid nicotine addiction: Current trends and perspectives

Brain-derived neurotrophic factor (BDNF) promotes maturation of cholinergic neurons. However, how activity-dependent BDNF expression affects specific cholinergic gene expression remains unclear. This study addressed this question by determining mRNA levels of 22 acetylcholine receptor subunits, the choline transporter (CHT), and the choline acetyltransferase (ChAT) in mice deficient in activity-dependent BDNF via promoter IV (KIV) and control wild-type mice. Quantitative RT-PCR revealed significant reductions in nicotinic acetylcholine receptor alpha 5 (CHRNA5) in the frontal cortex and hippocampus and M5 muscarinic acetylcholine receptor (CHRM5) in the hippocampus, but significant increases in M2 muscarinic acetylcholine receptor (CHRM2) in the frontal cortex of KIV mice compared to wild-type mice. Three-week treatments with fluoxetine, phenelzine, duloxetine, imipramine, or an enriched environment treatment (EET) did not affect the altered expression of these genes except that EET increased CHRNA5 levels only in KIV frontal cortex. EET also increased levels of CHRNA7, CHT, and ChAT, again only in the KIV frontal cortex. The imipramine treatment was most prominent among the four antidepressants; it upregulated hippocampal CHRM2 and frontal cortex CHRM5 in both genotypes, and frontal cortex CHRNA7 only in KIV mice. To our knowledge, this is the first evidence that BDNF deficiency disturbs expression of CHRNA5, CHRM2, and CHRM5. Our results suggest that promoter IV-BDNF deficiency – which occurs under chronic stress – causes cholinergic dysfunctions via these receptors. EET is effective on CHRNA5, while its compensatory induction of other cholinergic genes or drugs targeting CHRNA5, CHRM2, and CHRM5 may become an alternative strategy to reverse these BDNF-linked cholinergic dysfunctions.

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“…; Parikh et al . ), while both CHRNA7‐ and BDNF‐mutant mice show cognitive inflexibility (Sakata et al . ; Parikh et al .…”

Section: Discussionmentioning

confidence: 99%

“…; Lewis and Picciotto ; Parikh et al . ). Previous studies have shown reciprocal regulation between acetylcholine and BDNF.…”

mentioning

confidence: 97%

Promoter IV‐BDNF deficiency disturbs cholinergic gene expression of CHRNA5, CHRM2, and CHRM5: effects of drug and environmental treatments

Sakata

Overacre

2017

Journal of Neurochemistry

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“…In line with this interpretation is the self-medication hypothesis of addiction, which states that one of the major contributors to addiction is the drive to reduce the negative symptoms that arise during drug withdrawal (Khantzian 1985). In support, nicotine has been shown to alleviate cognitive deficits in various mental disorders such as schizophrenia (Adler et al 1993; for review, see Parikh et al 2016) and attention deficit/ hyperactivity disorder (ADHD, Potter and Newhouse 2008; Evans and Drobes 2009; for review, see Kutlu et al 2015b), two populations that show higher rates of smoking (38%-42% of ADHD population, Pomerleau et al 1995;80%-90% in schizophrenia, George and Krystal 2000;de Leon and Diaz 2005). Also in support of the self-medication hypothesis, there is evidence showing that cognitive deficits during nicotine withdrawal predict future relapse to nicotine use (Rukstalis et al 2005;Patterson et al 2010).…”

Section: Nicotinementioning

confidence: 99%

Effects of drugs of abuse on hippocampal plasticity and hippocampus-dependent learning and memory: contributions to development and maintenance of addiction

2016

Self Cite

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It has long been hypothesized that conditioning mechanisms play major roles in addiction. Specifically, the associations between rewarding properties of drugs of abuse and the drug context can contribute to future use and facilitate the transition from initial drug use into drug dependency. On the other hand, the self-medication hypothesis of drug abuse suggests that negative consequences of drug withdrawal result in relapse to drug use as an attempt to alleviate the negative symptoms. In this review, we explored these hypotheses and the involvement of the hippocampus in the development and maintenance of addiction to widely abused drugs such as cocaine, amphetamine, nicotine, alcohol, opiates, and cannabis. Studies suggest that initial exposure to stimulants (i.e., cocaine, nicotine, and amphetamine) and alcohol may enhance hippocampal function and, therefore, the formation of augmented drug-context associations that contribute to the development of addiction. In line with the self-medication hypothesis, withdrawal from stimulants, ethanol, and cannabis results in hippocampus-dependent learning and memory deficits, which suggest that an attempt to alleviate these deficits may contribute to relapse to drug use and maintenance of addiction. Interestingly, opiate withdrawal leads to enhancement of hippocampus-dependent learning and memory. Given that a conditioned aversion to drug context develops during opiate withdrawal, the cognitive enhancement in this case may result in the formation of an augmented association between withdrawalinduced aversion and withdrawal context. Therefore, individuals with opiate addiction may return to opiate use to avoid aversive symptoms triggered by the withdrawal context. Overall, the systematic examination of the role of the hippocampus in drug addiction may help to formulate a better understanding of addiction and underlying neural substrates.Addiction is a major worldwide health problem that results in maladaptive behavioral changes, some that can last a lifetime. This behavioral plasticity, often times maladaptive, must be associated changes in neural plasticity. In fact, it has been noted multiple times that there is a high degree of overlap between the neurobiology of learning and memory and the neurobiology of addiction

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“…There are several possible reasons why people living with severe mental disorders smoke more than those without mental disorders, including: social determinants of health [5,6]; neurobiological links between addiction and mental illness which cause a shared vulnerability [6,7,8,9]; and possibly therapeutic benefits to smoking such as alleviating symptoms of mental illness and side-effects of psychotropic medications, although this is disputed [8,10,11]. …”

Section: Introductionmentioning

confidence: 99%

Views and Preferences for Nicotine Products as an Alternative to Smoking: A Focus Group Study of People Living with Mental Disorders

Ford

Sharma

Fitzgerald

et al. 2016

IJERPH

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Aims and Background: People living with mental disorders experience a disproportionately higher burden of tobacco-related disease than the general population. Long-term substitution with less harmful nicotine products could reduce the tobacco-related harm among this population. This study investigated the views and preferences of people with mental health disorders about different nicotine products and their use as long-term substitutes for cigarettes. Methods: Semi-structured focus group discussion followed by a brief questionnaire. The discussion transcripts were analysed for content and themes and quantitative data summarised with descriptive statistics. Results: Twenty-nine participants took part in four focus groups. Vaping devices were the most acceptable nicotine products discussed; however preferences for nicotine products were individual and varied along aesthetic, pragmatic, sensory and symbolic dimensions. The concept of tobacco harm reduction was unfamiliar to participants, however they generally agreed with the logic of replacing cigarettes with less harmful nicotine products. Barriers to activating tobacco harm reduction included the symbolism of smoking and quitting; the importance placed on health; the consumer appeal of alternatives; and cost implications. Discussion and Conclusions: Engaging this population in tobacco harm reduction options will require communication that challenges black and white thinking (a conceptual framework in which smoking cigarettes or quitting all nicotine are the only legitimate options) as in practice this serves to support the continuance of smoking. Consumers should be encouraged to trial a range of nicotine products to find the most acceptable alternative to smoking that reduces health harms. Providing incentives to switch to nicotine products could help overcome barriers to using less harmful nicotine products among mental health consumers.

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nAChR dysfunction as a common substrate for schizophrenia and comorbid nicotine addiction: Current trends and perspectives

Cited by 78 publications

References 274 publications

Promoter IV‐BDNF deficiency disturbs cholinergic gene expression of CHRNA5, CHRM2, and CHRM5: effects of drug and environmental treatments

Promoter IV‐BDNF deficiency disturbs cholinergic gene expression of CHRNA5, CHRM2, and CHRM5: effects of drug and environmental treatments

Effects of drugs of abuse on hippocampal plasticity and hippocampus-dependent learning and memory: contributions to development and maintenance of addiction

Views and Preferences for Nicotine Products as an Alternative to Smoking: A Focus Group Study of People Living with Mental Disorders

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