Despite large numbers of studies describing neuroadaptations caused by chronic cocaine exposure, there remains considerable uncertainty as to whether alterations in dopamine (DA) neurotransmission are responsible for progression into an addicted state. Highintake, 24-h access cocaine self-administration (SA, 10 days) followed by an extended (7 days), but not 1 day deprivation period produces an increased motivation to SA cocaine as measured by a progressive ratio protocol. Following binge cocaine SA and deprivation, the status of DA terminals in the nucleus accumbens (NAc) was investigated using microdialysis in freely moving rats and voltammetry in brain slices. At 1 and 7 days following binge cocaine SA, baseline extracellular DA concentrations in the NAc core were decreased by 40 and 55% of control levels, in the 1 and 7 day deprivation groups, respectively. Acute cocaine (1.5 mg/kg, i.v.) administration increased extracellular DA (350%) in the NAc core of naïve animals but failed to significantly increase DA at 1 or 7 days following binge cocaine SA. The shell of the NAc showed a similar lack of effect of cocaine. Analysis of DA terminals in brain slices showed that cocaine was markedly less effective in inhibiting DA uptake at 1 and 7 days of cocaine deprivation (max. effect 40% of control). Electrically stimulated DA release was decreased at 1 day and further decreased at 7 days of deprivation (67 and 49% of control, respectively). The rate of DA uptake was increased (150% of control) following binge SA, irrespective of deprivation period. Finally, presynaptic autoreceptors were subsensitive at both time points, as measured by the ability of quinpirole, a D2-like DA receptor agonist, to inhibit DA release. Thus, the NAc was hypodopaminergic and DA terminals were less sensitive to cocaine following binge cocaine SA and deprivation.

Background Herceptin, a humanized antibody to HER‐2, is now utilized in the clinic for metastatic breast cancer treatment. The response rate for HER‐2+ patients is only 30% and little is known as to mechanisms of resistance. The mechanism of Herceptin action is also unknown but has been related to cell cycle inhibition. Methods The effects of Herceptin and other antibody treatments were determined by cell counting and cell cycle analysis. HER‐2 and p27 expression levels were analyzed by flow cytometry and levels of activated AKT were compared by Western blot analysis. Cellular HER‐2 and p27 expression was measured by immunofluorescence. Results Herceptin treatment of BT‐474 cells results in inhibition of cell growth and arrest in the G1 phase. The efficacy of growth arrest was not directly correlated to the binding affinity of antibodies to Her‐2. Our laboratory has developed cell lines that are resistant to Herceptin treatment. In resistant cell lines, binding of antibodies is not hindered. However, Herceptin has completely lost the ability to inhibit cell proliferation. Yet, the mouse isotype 4D5 maintains significant inhibitory activity upon Herceptin‐resistant clones. Conclusions Herceptin binds effectively to Her‐2 on the cell surface of Herceptin‐resistant cell lines and the level of Her‐2 expression on the cell surface is not downregulated. Herceptin resistance is not due to downregulation of levels of AKT protein expression, although, phosphorylation of AKT is enhanced in resistant lines and could have a role in resistance. Resistance appears to correlate with the loss of nuclear expression of the cyclin‐dependent kinase inhibitor, p27, as defined by immunofluorescence and flow cytometry studies and cdk‐2 binding studies. © 2004 Wiley‐Liss, Inc.

Rationale To date, there is no medication specifically approved for cocaine addiction. Agonist medications are used clinically in the treatment of other addictions, which suggests that this method of drug therapy could potentially be successful in treating cocaine addiction as well. Objectives The objective of this study was to determine the effect of extended d-amphetamine treatment on responding on a progressive ratio (PR) schedule reinforced by cocaine. Methods Rats were trained to self-administer cocaine (0.19, 0.38, 0.75, or 1.5 mg/kg/injection) or food on a PR schedule. After stable baseline breakpoints (the number of reinforcers earned in one session) were established over 3 days, animals were implanted with osmotic mini-pumps that continuously delivered d-amphetamine (5 mg/kg/day) for a duration of either 7 or 14 days. Breakpoints were then determined during and/or after this treatment period. Results Rats demonstrated dose-dependent decreases in cocaine-reinforced responding over the d-amphetamine treatment period. Breakpoints for doses of 0.75 mg/kg/injection and below decreased significantly when compared to baseline and remained decreased for up to 14 days after mini-pump removal whereas those for the highest dose of cocaine remained unchanged. Additionally, d-amphetamine treatment during a 14-day abstinence period from cocaine self-administration had no effect on breakpoints when tested the day after mini-pump removal. Conclusions These data suggest that the reduction in cocaine-reinforced responding after continuous d-amphetamine treatment cannot be accounted for by tolerance alone. Instead, the roles of learning and the interaction between cocaine and d-amphetamine must be considered and examined in future studies.

The present results demonstrate that a progressive increase in breakpoints on a PR schedule can be established in rats at a time when the ability of cocaine to increase extracellular DA levels and stimulate locomotor activity is reduced. Therefore, sensitization of the mesolimbic DA system does not account for the observed change in drug-taking behavior.

The DT5x10-day history of heroin self-administration resulted in an upward shift in the cocaine dose-effect curve, suggesting that DT5 heroin self-administration produced an increase in potency and sensitization of the maximal effectiveness with which cocaine functions as a reinforcer. The present experiments contribute to a growing amount of preclinical evidence suggesting an impact of opioid exposure on the reinforcing effects of cocaine, which may partially explain the high incidence of cocaine use in opioid-dependent individuals.

Dual-energy computed tomography (DECT) has many current and evolving applications in neuroradiology including material decomposition, improving conspicuity of iodinated contrast enhancement, and artifact reduction. However, there are multiple challenges in incorporating DECT into practice including hardware selection, postprocessing software requirements, technologist and physician training, and numerous workflow issues. This article reviews in a question-and-answer format common issues that arise when incorporating DECT into a busy neuroradiology practice.

BACKGROUND AND PURPOSE: SWI is an advanced imaging modality that is especially useful in cerebral microhemorrhage detection. Such microhemorrhages have been identified in adult contact sport athletes, and the sequelae of these focal bleeds are thought to contribute to neurodegeneration. The purpose of this study was to utilize SWI to determine whether the prevalence and incidence of microhemorrhages in adolescent football players are significantly greater than those of adolescent noncontact athletes.MATERIALS AND METHODS: Preseason and postseason SWI was performed and evaluated on 78 adolescent football players. SWI was also performed on 27 adolescent athletes who reported no contact sport history. Two separate one-tailed Fisher exact tests were performed to determine whether the prevalence and incidence of microhemorrhages in adolescent football players are greater than those of noncontact athlete controls. RESULTS:Microhemorrhages were observed in 12 football players. No microhemorrhages were observed in any controls. Adolescent football players demonstrated a significantly greater prevalence of microhemorrhages than adolescent noncontact controls (P ¼ .02). Although 2 football players developed new microhemorrhages during the season, microhemorrhage incidence during 1 football season was not statistically greater in the football population than in noncontact control athletes (P ¼ .55). CONCLUSIONS:Adolescent football players have a greater prevalence of microhemorrhages compared with adolescent athletes who have never engaged in contact sports. While microhemorrhage incidence during 1 season is not significantly greater in adolescent football players compared to adolescent controls, there is a temporal association between playing football and the appearance of new microhemorrhages. ABBREVIATION: SWI ¼ susceptibility weighted imaging M icrohemorrhages result in abnormal blood product and iron accumulation in the brain after vascular injury. Although microhemorrhages are commonly associated with hypertension, apolipoprotein E « 4 carrier status, and cerebral

Aim-To investigate the use of clinical head magnetic resonance imaging (MRI) in determining body composition and to evaluate how well it correlates with established measures based on abdominal computed tomography (CT).Materials and Methods-Ninety-nine consecutive patients were identified who had undergone both brain MRI and abdominal CT within a 2-week span. Volumes of fat and muscle in the extracranial head were measured utilising several techniques by both abdominal CT and head MRI.Results-MRI-based total fat volumes in the head correlated with CT-based measurements of fat in the abdomen using both single-section (r=0.64, p<0.01) and multisection (r=0.60, p<0.01) techniques. No significant correlation was found between muscle volumes in the abdomen and head.Conclusion-Based on the present results, head MRI-based measures may provide a useful surrogate for CT measurements of abdominal fat, particularly in patients with neurological cancers, as head MRI (and not abdominal CT) is routinely and repeatedly obtained for the purpose of clinical care for these patients.