Paternal nicotine exposure alters hepatic xenobiotic metabolism in offspring

Paternal environmental conditions can influence phenotypes in future generations, but it is unclear whether offspring phenotypes represent specific responses to particular aspects of the paternal exposure history, or a generic response to paternal \u27quality of life\u27. Here, we establish a paternal effect model based on nicotine exposure in mice, enabling pharmacological interrogation of the specificity of the offspring response. Paternal exposure to nicotine prior to reproduction induced a broad protective response to multiple xenobiotics in male offspring. This effect manifested as increased survival following injection of toxic levels of either nicotine or cocaine, accompanied by hepatic upregulation of xenobiotic processing genes, and enhanced drug clearance. Surprisingly, this protective effect could also be induced by a nicotinic receptor antagonist, suggesting that xenobiotic exposure, rather than nicotinic receptor signaling, is responsible for programming offspring drug resistance. Thus, paternal drug exposure induces a protective phenotype in offspring by enhancing metabolic tolerance to xenobiotics

Habenula cholinergic neurons regulate anxiety during nicotine withdrawal via nicotinic acetylcholine receptors

Cholinergic neurons in the medial habenula (MHb) modulate anxiety during nicotine withdrawal although the molecular neuroadaptation(s) within the MHb that induce affective behaviors during nicotine cessation is largely unknown. MHb cholinergic neurons are unique in that they robustly express neuronal nicotinic acetylcholine receptors (nAChRs), although their behavioral role as autoreceptors in these neurons has not been described. To test the hypothesis that nAChR signaling in MHb cholinergic neurons could modulate anxiety, we expressed novel gain of function nAChR subunits selectively in MHb cholinergic neurons of adult mice. Mice expressing these mutant nAChRs exhibited increased anxiety-like behavior that was alleviated by blockade with a nAChR antagonist. To test the hypothesis that anxiety induced by nicotine withdrawal may be mediated by increased MHb nicotinic receptor signaling, we infused nAChR subtype selective antagonists into the MHb of nicotine naive and withdrawn mice. While antagonists had little effect on nicotine naive mice, blocking alpha4beta2 or alpha6beta2, but not alpha3beta4 nAChRs in the MHb alleviated anxiety in mice undergoing nicotine withdrawal. Consistent with behavioral results, there was increased functional expression of nAChRs containing the alpha6 subunit in MHb neurons that also expressed the alpha4 subunit. Together, these data indicate that MHb cholinergic neurons regulate nicotine withdrawal-induced anxiety via increased signaling through nicotinic receptors containing the alpha6 subunit and point toward nAChRs in MHb cholinergic neurons as molecular targets for smoking cessation therapeutics

Dementia associated with disorders of the basal ganglia

Dementia is now the leading cause of death in the United Kingdom, accounting for over 12% of all deaths and is the fifth most common cause of death world-wide. As treatments for heart disease and cancers improve and the population ages, the number of sufferers will only increase, with the chance of developing dementia doubling every 5 years after the age of 65. Finding an effective treatment is ever more critical to avert this pandemic health (and economic) crisis. To date, most dementia-related research has focused on cortex and hippocampus, however, with dementia becoming more fully recognized as aspects of diseases historically categorized as motor disorders (e.g. Parkinson’s and Huntington’s diseases), the role of the basal ganglia in dementia is coming to the fore. Conversely, it is highly likely that neuronal pathways in these structures traditionally considered as spared in Alzheimer’s disease are also affected, particularly in later stages of the disease. In this review we examine some of the limited evidence linking the basal ganglia to dementia