Partial and full deletion of nicotinic acetylcholine receptor α4 and ß2 subunits reduces sensitivity to acute nicotine administration and development of tolerance following chronic nicotine administration.

The diversity of nicotinic cholinergic receptor (nAChR) subunits underlies the complex responses to nicotine. Mice differing in the expression of α4 and ß2 subunits, which are most widely expressed in brain, were evaluated for the responses to acute nicotine administration on Y-maze crossings and rears, open-field locomotion and body temperature following chronic treatment with nicotine (0, 0.25, 1.0 and 4.0 mg/kg/h). Deletion or partial deletion of the α4, ß2 or both nAChR subunits reduced the sensitivity of mice to acute nicotine administration. This reduced sensitivity was gene dose-dependent. Modification of α4 subunit expression elicited a greater reduction in sensitivity than the modification of ß2 subunit expression. No measurable tolerance was observed for mice of any genotype following chronic treatment with 0.25 mg/kg/h nicotine. Modest tolerance was noted following treatment with 1.0 mg/kg/h. Greater tolerance was observed following treatment with 4.0 mg/kg/h. The extent of tolerance differed among the mice depending on genotype: wild-type (α4 and ß2) developed measurable tolerance for all four tests. Heterozygotes (α4, ß2 and α4/ß2) developed tolerance for only Y-maze crossings and body temperature. Null mutants (α4 and ß2) did not become tolerant. However, following chronic treatment with 4.0 mg/kg/h nicotine, wild type, α4 and α4 mice displayed increased Y-maze crossings following acute administration of 0.5 mg/kg nicotine that may reflect the activity of α6ß2*-nAChR. These results confirm the importance of the α4 and ß2 nAChR subunits in mediating acute and chronic effects of nicotine on locomotion and body temperature in the mouse.

Neuropsychosocial profiles of current and future adolescent alcohol misusers.

A comprehensive account of the causes of alcohol misuse must accommodate individual differences in biology, psychology and environment, and must disentangle cause and effect. Animal models can demonstrate the effects of neurotoxic substances; however, they provide limited insight into the psycho-social and higher cognitive factors involved in the initiation of substance use and progression to misuse. One can search for pre-existing risk factors by testing for endophenotypic biomarkers in non-using relatives; however, these relatives may have personality or neural resilience factors that protect them from developing dependence. A longitudinal study has potential to identify predictors of adolescent substance misuse, particularly if it can incorporate a wide range of potential causal factors, both proximal and distal, and their influence on numerous social, psychological and biological mechanisms. Here we apply machine learning to a wide range of data from a large sample of adolescents (n = 692) to generate models of current and future adolescent alcohol misuse that incorporate brain structure and function, individual personality and cognitive differences, environmental factors (including gestational cigarette and alcohol exposure), life experiences, and candidate genes. These models were accurate and generalized to novel data, and point to life experiences, neurobiological differences and personality as important antecedents of binge drinking. By identifying the vulnerability factors underlying individual differences in alcohol misuse, these models shed light on the aetiology of alcohol misuse and suggest targets for prevention.

Varenicline blocks ß2*-nAChR-mediated response and activates ß4*-nAChR-mediated responses in mice in vivo.

INTRODUCTION: The smoking cessation aid, varenicline, has higher affinity for the alpha4beta2-subtype of the nicotinic acetylcholine receptor (α4ß2*-nAChR) than for other subtypes of nAChRs by in vitro assays. The mechanism of action of acute varenicline was studied in vivo to determine (a) subtype activation associated with physiological effects and (b) dose relationship as an antagonist of nicotine. METHODS: Acute doses of saline, nicotine, and varenicline were given to mice, and locomotor depression and hypothermia were measured. Subunit null mutant mice as well as selective antagonists were used to study mode of action of varenicline as an agonist. Varenicline as an antagonist of nicotine was also investigated. RESULTS: Varenicline evokes locomotor depression and hypothermia at higher doses than necessary for nicotine. Null mutation of the α7- or ß2-nAChR subunit did not decrease the effectiveness of varenicline; however, null mutation of the ß4 subunit significantly decreased the magnitude of the varenicline effect. Effects of the highest dose studied were blocked by mecamylamine (general nAChR antagonist) and partially antagonized by hexamethonium (largely peripheral nAChR antagonist). No significant block was seen with ondansetron antagonist of 5-hydroxytryptamine 3 receptor. Using a dose of nicotine selective for ß2*-nAChR subtype effects with these tests, dose-dependent antagonism by varenicline was seen. Effective inhibitory doses were determined and appear to be in a range consistent with binding affinity or desensitization of ß2*-nAChRs. CONCLUSIONS: Varenicline acts as a functional antagonist of ß2*-nAChRs, blocking certain effects of nicotine. At higher doses, varenicline is an agonist of ß4*-nAChRs producing physiological changes in mice.

Bone tissue engineering techniques, advances and scaffolds for treatment of bone defects.

Bone tissue engineering (BTE) aims to develop strategies to regenerate damaged or diseased bone using a combination of cells, growth factors, and biomaterials. This article highlights recent advances in BTE, with particular emphasis on the role of the biomaterials as scaffolding material to heal bone defects. Studies encompass the utilization of bioceramics, composites, and myriad hydrogels that have been fashioned by injection molding, electrospinning, and 3D bioprinting over recent years, with the aim to provide an insight into the progress of BTE along with a commentary on their scope and possibilities to aid future research. The biocompatibility and structural efficacy of some of these biomaterials are also discussed.

Decreased frontal, striatal and cerebellar activation in adults with ADHD during an adaptive delay discounting task.

An important characteristic of childhood attention-deficit/hyperactivity disorder (ADHD) is a bias towards small immediate versus larger delayed rewards, but it is not known if this symptom is also a feature of adult ADHD. A delay-discounting task was administered to participants with adult ADHD and a comparison group in conjunction with functional magnetic resonance imaging. Participants responded to a series of questions that required judgments between small sums of money available immediately and larger sums obtained after a temporal delay. Question parameters were adjusted by an adaptive algorithm designed to converge on each participant's discounting indifference point, an individual set point at which there is equal valuation of both choices. In all participants, robust task activation was observed in regions previously identified in functional imaging studies of delay discounting. However, adults with ADHD showed less task activation in a number of regions including the dorsolateral prefrontal cortex, superior frontal gyrus, anterior cingulate, caudate nucleus and declive of the cerebellum. Additionally, the degree to which a participant discounted delayed rewards was inversely related to task activation in the cerebellum. The results suggest that the bias towards immediate rewards in childhood ADHD may not persist behaviorally, but instead present in adulthood as alterations in frontostriatal and frontocerebellar networks.

Chronic treatment with varenicline changes expression of four nAChR binding sites in mice.

INTRODUCTION: Chronic treatment with nicotine is known to increase the α4ß2-nAChR sites in brain, to decrease α6ß2-nAChR sites and to have minimal effect on α3ß4-and α7-nAChR populations. Varenicline is now used as a smoking cessation treatment, with and without continued smoking or nicotine replacement therapy. Varenicline, like nicotine, upregulates the α4ß2-nAChR sites; however, it is not known whether varenicline treatment changes expression of the other nAChR subtypes. METHODS: Using a mouse model, chronic treatments (10 days) with varenicline (0.12  mg/kg/h) and/or nicotine (1 mg/kg/hr), alone or in combination, were compared for plasma and brain levels of drugs, tolerance to subsequent acute nicotine and expression of four subtypes of nAChR using autoradiography. RESULTS: The upregulation of α4ß2-nAChR sites elicited by chronic varenicline was very similar to that elicited by chronic nicotine. Treatment with both drugs somewhat increased up-regulation, indicating that these doses were not quite at maximum effect. Similar down-regulation was seen for α6ß2-nAChR sites. Varenicline significantly increased both α3ß4-and α7-nAChR sites while nicotine had less effect on these sites. The drug combination was similar to varenicline alone for α3ß4-nAChR sites, while for α7 sites the drug combination was less effective than varenicline alone. Varenicline had small but significant effects on tolerance to acute nicotine. CONCLUSIONS: Effects of varenicline in vivo may not be limited to the α4ß2*-nAChR subtype. In addition, smoking cessation treatment with varenicline may not allow receptor numbers to be restored to baseline and may, in addition, change expression of other receptor subtypes.