ARC and BDNF expression after cocaine self-administration or cue-induced reinstatement of cocaine seeking in adolescent and adult male rats.

Recreational drug use peaks during adolescence. Our research with adolescent vs adult male rats, however, shows that rats taking cocaine as adolescents have lower levels of cue-induced reinstatement of drug-seeking than adults, despite similar levels of intravenous (i.v.) cocaine self-administration. Lower rates of reinstatement in younger rats could be explained by higher levels of brain plasticity. Two neuroplasticity-related genes, activity-regulated cytoskeletal-associated gene (Arc) and brain-derived neurotrophic factor (Bdnf), influence cocaine self-administration and cue-induced reinstatement. We tested whether reinstatement of cocaine seeking correlates with expression of these genes in reinforcement-related brain regions. Adolescent and adult male rats (postnatal day 35 or 83-95 at start) were allowed to acquire lever-pressing maintained by i.v. infusions of cocaine in daily 2-h sessions over 13 days. At one of three experimental time points, rats were sacrificed and tissue collected to analyze Arc and Bdnf mRNA by in situ hybridization in the entire medial prefrontal cortex and entire nucleus accumbens, as well as relevant subregions: prelimbic cortex, infralimbic cortex, and nucleus accumbens core and shell. Despite taking similar amounts of cocaine, adolescents reinstated less than adults. Gene expression was most notable in the prelimbic cortex, was generally higher in adolescent-onset groups, and was higher with longer abstinence. These data partially support the hypothesis that higher levels of Arc and/or Bdnf gene expression in reinforcement-related brain regions of younger animals contribute to lower rates of extinction responding and/or reinstatement. Future studies should include mechanistic analysis of Arc, Bdnf, and their signaling pathways in age-dependent effects of cocaine.

The dendritically targeted protein Dendrin is induced by acute nicotine in cortical regions of adolescent rat brain.

The response of the brain to addictive substances such as nicotine includes the rapid induction of genes that influence synaptic events. This response is different in adolescent brain, which continues to undergo synaptic remodeling in regions that include reward-associated corticolimbic areas. We report here that acute nicotine (0.4 mg/kg), but not cocaine or exposure to a novel environment, induces the expression of the dendritically targeted, corticolimbic mRNA Dendrin in specific regions of adolescent brain. Acute nicotine resulted in an increase in Dendrin mRNA levels in the adolescent prefrontal cortex that was not evident in adult animals. The induction in Dendrin mRNA was a rapid, short-lived transcriptional event that resulted in changes in Dendrin protein. For example, an increase in Dendrin protein levels following nicotine treatment paralleled enhanced Dendrin immunoreactivity in the dendrites of pyramidal neurons of somatosensory cortex. As Dendrin is an important component of cytoskeletal modifications at the synapse, these results suggest that nicotine influences unique plasticity-related changes in the adolescent forebrain that differ from the adult.

Differential behavioral effects of nicotine exposure in adolescent and adult rats.

RATIONALE: Although the detrimental effects of nicotine in early brain development and the addictive properties in adulthood are well known, little is known about the neurobiological effects of nicotine in adolescence. An important question is whether adolescents and adults differ in the development of nicotine sensitization and drug-cue conditioning. OBJECTIVE: To examine the behavioral effects of multiple, repeated injections of nicotine on both sensitization and drug-cue conditioning in the adolescent rat, and to compare this profile with the adult rat. METHODS: Sixteen male adolescent (28 day) and 16 young adult (70 day) rats were given injections of either saline or nicotine and tested for motor activity for 90 min for ten consecutive days. Following 4 days of no testing, animals were given a sham injection and placed in the testing apparatus for 90 min. A dose-response curve for nicotine was also generated using two additional groups of ten adolescent and ten adult male rats. RESULTS: Adolescent rats, unlike adults, did not exhibit signs of nicotine-cue conditioning, and displayed less robust sensitization to the locomotor effects of nicotine than adults. Dose-response testing revealed differences in adolescent responsivity to nicotine in measures of rearing, but not ambulation. Initial exposure to nicotine resulted in increased sensitivity to the motor-activating effects of nicotine but less sensitivity to the depressant effects of nicotine in rearing in adolescents. CONCLUSIONS: Adolescent animals display different long-term neuroadaptive responses to nicotine than adult animals, possibly related to immature or still-developing plasticity mechanisms in the prefrontal cortex.

Risk taking and novelty seeking in adolescence: introduction to part I.

Risk taking and novelty seeking are hallmarks of typical adolescent behavior. Adolescents seek new experiences and higher levels of rewarding stimulation, and often engage in risky behaviors, without considering future outcomes or consequences. These behaviors can have adaptive benefits with regard to the development of independence and survival without parental protection, but also render the adolescent more vulnerable to harm. Indeed, the risk of injury or death is higher during the adolescent period than in childhood or adulthood, and the incidence of depression, anxiety, drug use and addiction, and eating disorders increases. Brain pathways that play a key role in emotional regulation and cognitive function undergo distinct maturational changes during this transition period. It is clear that adolescents think and act differently from adults, yet relatively little is known about the precise mechanisms underlying neural, behavioral, and cognitive events during this period. Increased investigation of these dynamic alterations, particularly in prefrontal and related corticolimbic circuitry, may aid this understanding. Moreover, the investigation of mammalian animal models of adolescence-such as those examining impulsivity, reward sensitivity, and decision making-may also provide new opportunities for addressing the problem of adolescent vulnerability.

Elk-1 phosphorylated at threonine-417 is present in diverse cancers and correlates with differentiation grade of colonic adenocarcinoma.

Elk-1 is a member of the Ets family of transcription factors, which are identified by a conserved Ets DNA-binding domain that mediates transcriptional regulation at Ets sequence--containing promoters. The activation domain of Elk-1 is important for executing its physiologic functions and contains many phosphorylation sites targeted by various MAP kinases following exposure to cell stressors or mitogenic stimuli. The different combinations of phosphorylated sites allow specificity of cellular responses mediated through redundant signaling pathways activated by distinct stimuli. Through phosphorylation of S383, mitogen-activated protein kinase (MAPK)-activating stimuli have been shown to regulate various processes important in carcinogenesis through transcriptional regulation in various cell lines, including proliferation. Phosphorylation at the T417 site (pT417), but not the S383 site, is involved in neuronal apoptosis induced through dendritic signaling mechanisms and associates with neuronal lesions in many Lewy body diseases. This points to distinct roles for these different phosphorylation sites in pathophysiologic pathways. However, the S383 site remains the best characterized in the context of normal function and carcinogenesis in cell lines, and less is known about the biochemistry of other phosphorylation sites, particularly in more biochemically relevant models. Here, we show that Elk-1 pT417 is present in epithelial cell nuclei of various normal and cancer tissues and that the number of pT417-positive cells correlates with differentiation grade of colonic adenocarcinomas. This nuclear localization and correlation with tumor differentiation in adenocarcinoma suggests a potentially important transcriptional and biochemical role of this phosphorylation site in carcinogenesis of this tumor type.

Quantitative biology of single neurons.

The building blocks of complex biological systems are single cells. Fundamental insights gained from single-cell analysis promise to provide the framework for understanding normal biological systems development as well as the limits on systems/cellular ability to respond to disease. The interplay of cells to create functional systems is not well understood. Until recently, the study of single cells has concentrated primarily on morphological and physiological characterization. With the application of new highly sensitive molecular and genomic technologies, the quantitative biochemistry of single cells is now accessible.

A comparison of adult and adolescent rat behavior in operant learning, extinction, and behavioral inhibition paradigms.

Poor self-control, lack of inhibition, and impulsivity contribute to the propensity of adolescents to engage in risky or dangerous behaviors. Brain regions (e.g., prefrontal cortex) involved in impulse-control, reward-processing, and decision-making continue to develop during adolescence, raising the possibility that an immature brain contributes to dangerous behavior during adolescence. However, very few validated animal behavioral models are available for behavioral neuroscientists to explore the relationship between brain development and behavior. To that end, a valid model must be conducted in the relatively brief window of adolescence and not use manipulations that potentially compromise development. The present experiments used three operant arrangements to assess whether adolescent rats differ from adults in measures of learning, behavioral inhibition, and impulsivity, within the aforementioned time frame without substantial food restriction. In Experiment 1, separate squads of rats were trained to lever-press and then transitioned to two types of extinction. Relative to their baselines, adolescent rats responded more during extinction than adults, suggesting that they were less sensitive to the abolishment of the reinforcement contingency. Experiment 2 demonstrated similar age-related differences during exposure to a differential reinforcement of low rates schedule, a test of behavioral inhibition. Lastly, in Experiment 3, adolescent's responding decreased more slowly than adults during exposure to a resetting delay of reinforcement schedule, suggesting impaired self-control. Results from these experiments suggest that adolescents exhibit impaired learning, behavioral inhibition and self-control, and in concert with recent reports, provide researchers with three behavioral models to more fully explore neurobiology of risk-taking behavior in adolescence.