New medications development for smoking cessation.

Diseases associated with nicotine dependence in the form of habitual tobacco use are a major cause of premature death in the United States. The majority of tobacco smokers will relapse within the first month of attempted abstinence. Smoking cessation agents increase the likelihood that smokers can achieve long-term abstinence. Nevertheless, currently available smoking cessation agents have limited utility and fail to prevent relapse in the majority of smokers. Pharmacotherapy is therefore an effective strategy to aid smoking cessation efforts but considerable risk of relapse persists even when the most efficacious medications currently available are used. The past decade has seen major breakthroughs in our understanding of the molecular, cellular, and systems-level actions of nicotine in the brain that contribute to the development and maintenance of habitual tobacco use. In parallel, large-scale human genetics studies have revealed allelic variants that influence vulnerability to tobacco use disorder. These advances have revealed targets for the development of novel smoking cessation agents. Here, we summarize current efforts to develop smoking cessation therapeutics and highlight opportunities for future efforts.

Glucocorticoid Receptor Overexpression in the Dorsal Hippocampus Attenuates Spatial Learning and Synaptic Plasticity Deficits after Pediatric Traumatic Brain Injury.

Traumatic brain injury (TBI) in children <4 years of age leads to long-term deficits in cognitive and learning abilities that can persist or even worsen as these children age into adolescence. In this study, the role of glucocorticoid receptor (GR) function in the dorsal hippocampus (DH) in hippocampal-dependent cognitive function and synaptic plasticity were assessed following injury to the 11-day-old rat. Brain injury produced significant impairments in spatial learning and memory in the Morris water maze in male and female rats at 1-month post-injury (adolescence), which was accompanied by impairments in induction and maintenance of long-term potentiation (LTP) in the CA1 region of the DH. Brain injury resulted in a significant decrease in the expression of the glucocorticoid-inducible gene, serum- and glucocorticoid-kinase 1 (sgk1), suggestive of an impairment in GR transcriptional activity within the hippocampus. Lentiviral transfection of the human GR (hGR) in the DH improved spatial learning and memory in the Morris water maze and attenuated LTP deficits following TBI. GR overexpression in the DH was also associated with a significant increase in the mRNA expression levels of sgk1, and the glutamate receptor subunits GluA1 and GluA2 within the hippocampus. Overall, these findings support an important role for dorsal hippocampal GR function in learning and memory deficits following pediatric TBI and suggest that these effects may be related to the regulation of glutamate receptor subunit expression in the DH.

Intranasal Administration of Oxytocin Attenuates Social Recognition Deficits and Increases Prefrontal Cortex Inhibitory Postsynaptic Currents following Traumatic Brain Injury.

Pediatric traumatic brain injury (TBI) results in heightened risk for social deficits that can emerge during adolescence and adulthood. A moderate TBI in male and female rats on postnatal day 11 (equivalent to children below the age of 4) resulted in impairments in social novelty recognition, defined as the preference for interacting with a novel rat compared with a familiar rat, but not sociability, defined as the preference for interacting with a rat compared with an object in the three-chamber test when tested at four weeks (adolescence) and eight weeks (adulthood) postinjury. The deficits in social recognition were not accompanied by deficits in novel object recognition memory and were associated with a decrease in the frequency of spontaneous inhibitory postsynaptic currents (IPSCs) recorded from pyramidal neurons within Layer II/III of the medial prefrontal cortex (mPFC). Whereas TBI did not affect the expression of oxytocin (OXT) or the OXT receptor (OXTR) mRNAs in the hypothalamus and mPFC, respectively, intranasal administration of OXT before behavioral testing was found to reduce impairments in social novelty recognition and increase IPSC frequency in the mPFC in brain-injured animals. These results suggest that TBI-induced deficits in social behavior may be linked to increased excitability of neurons in the mPFC and suggests that the regulation of GABAergic neurotransmission in this region as a potential mechanism underlying these deficits.

Stem Cell Therapy for Pediatric Traumatic Brain Injury.

There has been a growing interest in the potential of stem cell transplantation as therapy for pediatric brain injuries. Studies in pre-clinical models of pediatric brain injury such as Traumatic Brain Injury (TBI) and neonatal hypoxia-ischemia (HI) have contributed to our understanding of the roles of endogenous stem cells in repair processes and functional recovery following brain injury, and the effects of exogenous stem cell transplantation on recovery from brain injury. Although only a handful of studies have evaluated these effects in models of pediatric TBI, many studies have evaluated stem cell transplantation therapy in models of neonatal HI which has a considerable overlap of injury pathology with pediatric TBI. In this review, we have summarized data on the effects of stem cell treatments on histopathological and functional outcomes in models of pediatric brain injury. Importantly, we have outlined evidence supporting the potential for stem cell transplantation to mitigate pathology of pediatric TBI including neuroinflammation and white matter injury, and challenges that will need to be addressed to incorporate these therapies to improve functional outcomes following pediatric TBI.

Progesterone treatment following traumatic brain injury in the 11-day-old rat attenuates cognitive deficits and neuronal hyperexcitability in adolescence.

Traumatic brain injury (TBI) in children younger than 4 years old results in cognitive and psychosocial deficits in adolescence and adulthood. At 4 weeks following closed head injury on postnatal day 11, male and female rats exhibited impairment in novel object recognition memory (NOR) along with an increase in open arm time in the elevated plus maze (EPM), suggestive of risk-taking behaviors. This was accompanied by an increase in intrinsic excitability and frequency of spontaneous excitatory post-synaptic currents (EPSCs), and a decrease in the frequency of spontaneous inhibitory post-synaptic currents in layer 2/3 neurons within the medial prefrontal cortex (PFC), a region that is implicated in both object recognition and risk-taking behaviors. Treatment with progesterone for the first week after brain injury improved NOR memory at the 4-week time point in both sham and brain-injured rats and additionally attenuated the injury-induced increase in the excitability of neurons and the frequency of spontaneous EPSCs. The effect of progesterone on cellular excitability changes after injury may be related to its ability to decrease the mRNA expression of the ß3 subunit of the voltage-gated sodium channel and increase the expression of the neuronal excitatory amino acid transporter 3 in the medial PFC in sham- and brain-injured animals and also increase glutamic acid decarboxylase mRNA expression in sham- but not brain-injured animals. Progesterone treatment did not affect injury-induced changes in the EPM test. These results demonstrate that administration of progesterone immediately after TBI in 11-day-old rats reduces cognitive deficits in adolescence, which may be mediated by progesterone-mediated regulation of excitatory signaling mechanisms within the medial PFC.