Developmental Sex Differences in Nicotinic Currents of Prefrontal Layer VI Neurons in Mice and Rats

There is a large sex difference in the prevalence of attention deficit disorder; yet, relatively little is known about sex differences in the development of prefrontal attention circuitry. In male rats, nicotinic acetylcholine receptors excite corticothalamic neurons in layer VI, which are thought to play an important role in attention by gating the sensitivity of thalamic neurons to incoming stimuli. These nicotinic currents in male rats are significantly larger during the first postnatal month when prefrontal circuitry is maturing. The present study was undertaken to investigate whether there are sex differences in the nicotinic currents in prefrontal layer VI neurons during development.Using whole cell recording in prefrontal brain slice, we examined the inward currents elicited by nicotinic stimulation in male and female rats and two strains of mice. We found a prominent sex difference in the currents during the first postnatal month when males had significantly greater nicotinic currents in layer VI neurons compared to females. These differences were apparent with three agonists: acetylcholine, carbachol, and nicotine. Furthermore, the developmental sex difference in nicotinic currents occurred despite male and female rodents displaying a similar pattern and proportion of layer VI neurons possessing a key nicotinic receptor subunit.This is the first illustration at a cellular level that prefrontal attention circuitry is differently affected by nicotinic receptor stimulation in males and females during development. This transient sex difference may help to define the cellular and circuit mechanisms that underlie vulnerability to attention deficit disorder

Nicotinic Receptors Underlying Nicotine Dependence: Evidence from Transgenic Mouse Models.

Nicotine underlies the reinforcing properties of tobacco cigarettes and e-cigarettes. After inhalation and absorption, nicotine binds to various nicotinic acetylcholine receptor (nAChR) subtypes localized on the pre- and postsynaptic membranes of cells, which subsequently leads to the modulation of cellular function and neurotransmitter signaling. In this chapter, we begin by briefly reviewing the current understanding of nicotine's actions on nAChRs and highlight considerations regarding nAChR subtype localization and pharmacodynamics. Thereafter, we discuss the seminal discoveries derived from genetically modified mouse models, which have greatly contributed to our understanding of nicotine's effects on the reward-related mesolimbic pathway and the aversion-related habenulo-interpeduncular pathway. Thereafter, emerging areas of research focusing on modulation of nAChR expression and/or function are considered. Taken together, these discoveries have provided a foundational understanding of various genetic, neurobiological, and behavioral factors underlying the motivation to use nicotine and related dependence processes, which are thereby advancing drug discovery efforts to promote long-term abstinence

Heterogeneity and selective targeting of nAChR subtypes expressed on retinal afferents of the superior colliculus and lateral geniculate nucleus. Identification of a new native nAChR subtype alpha3beta2(alpha5 or beta3) enriched in retinocollicular afferents

The activation of neuronal nicotinic acetylcholine receptors (nAChRs) has been implicated in the activity-dependent development and plasticity of retina and the refinement of retinal projections. Pharmacological and functional studies have also indicated that different presynaptic nAChRs can have a modulatory function in retinotectal synapses. We biochemically and pharmacologically identified the multiple nAChR subtypes expressed on retinal afferents of the superior colliculus (SC) and lateral geniculate nucleus (LGN). We found that the alpha 6 beta 2* and alpha 4(non alpha 6) beta 2* nAChRs are the major receptor populations expressed in both SC and LGN. In addition, the LGN contains two minor populations of alpha 2 alpha 6 beta 2* and alpha 3 beta 2* subtypes, whereas the SC contains a relatively large population of a new native subtype, the alpha 3 beta 2(alpha 5/beta 3) nAChR. This subtype binds the alpha-conotoxin MII with an affinity 50 times lower than that of the native alpha 6 beta 2* subtype. Studies of tissues obtained from eye-enucleated animals allowed the identification of nAChRs expressed by retinal afferents: in SC alpha 6 beta 2*, alpha 4 alpha 6 beta 2*, and alpha 3 beta 2* (approximately 45, 35, and 20%, respectively), in LGN, alpha 4 alpha 6 beta 2*, alpha 6 beta 2*, alpha 4 beta 2*, alpha 2 alpha 6 beta 2*, and alpha 3 beta 2* ( approximately 40, 30, 20, 5, and 5%, respectively). In both regions, more than 50% of nAChRs were not expressed by retinal afferents and belonged to the alpha 4 beta 2* (90%) or alpha 4 alpha 5 beta 2* (10%) subtypes. Moreover, studies of the SC tissues obtained from wild-type and alpha 4, alpha 6, and beta 3 knockout mice confirmed and extended the data obtained in rat tissue and allowed a comprehensive dissection of the composition of nAChR subtypes present in this retinorecipient area

Kinetics of brain nicotine accumulation in dependent and nondependent smokers assessed with PET and cigarettes containing 11C-nicotine

Tobacco smoking is a chronic, relapsing disorder that constitutes one of the primary preventable causes of death in developed countries. Two of the popular hypotheses to explain the development and maintenance of strong nicotine dependence in cigarette smokers posit (i) a rapid brain nicotine accumulation during cigarette smoking and/or (ii) puff-associated spikes in brain nicotine concentration. To address these hypotheses, we investigated the dynamics of nicotine accumulation in the smoker's brain during actual cigarette smoking using PET with 3-s temporal resolution and 11C-nicotine loaded into cigarettes. The results of the study, performed in 13 dependent smokers (DS) and 10 nondependent smokers (NDS), suggest that puff-associated spikes in the brain nicotine concentration do not occur during habitual cigarette smoking. Despite the presence of a puff-associated oscillation in the rate of nicotine accumulation, brain nicotine concentration gradually increases during cigarette smoking. The results further suggest that DS have a slower process of brain nicotine accumulation than NDS because they have slower nicotine washout from the lungs and that DS have a tendency to compensate for their slower rate of brain nicotine accumulation compared with NDS by inhaling a larger volume of smoke. For these reasons, smokers’ dependence on cigarette smoking, or the resistance of NDS to becoming dependent, cannot be explained solely by a faster brain nicotine accumulation