Central stress regulatory pathways utilize various neuropeptides, such as urocortin-1 (Ucn1) and cocaine- and amphetamine-regulated transcript peptide (CART). Ucn1 is most abundantly expressed in the non-preganglionic Edinger-Westphal nucleus (npEW). In addition to Ucn1, CART and nesfatin-1 are highly expressed in neurons of the npEW, but the way these three neuropeptides act together in response to acute stress is not known. We hypothesized that Ucn1, CART and nesfatin-1 are colocalized in npEW neurons and that these neurons are recruited by acute stress. Using quantitative immunocytochemistry and the reverse transcriptase polymerase chain reaction (RT-PCR), we support this hypothesis, by showing in B6C3F1/Crl mice that Ucn1, CART and nesfatin-1 occur in the same neurons of the npEW nucleus. More specifically, Ucn1 and CART revealed a complete colocalization in the same perikarya, while 90% of these neurons are also nesfatin-1-immunoreactive. Furthermore, acute (restraint) stress stimulates the general secretory activity of these npEW neurons (increased presence of Fos) and the production of Ucn1, CART and nesfatin-1: Ucn1, CART and nesfatin-1(NUCB2) mRNAs have been increased compared to controls by x1.8, x2.0 and x2.6, respectively (p<0.01). We conclude that Ucn1, CART and nesfatin-1/NUCB2 are specifically involved in the response of npEW neurons to acute stress in the mouse. less...

Sensation-seeking is a personality trait that is linked to use and abuse of drugs. Laboratory studies have established that high sensation seekers, as measured by different instruments, are more likely to report abuse liability-related subjective effects from drugs such as nicotine, alcohol, and d-amphetamine than low sensation seekers. One class of drugs that has not been studied to date in this fashion is opioids. Accordingly, a retrospective analysis encompassing five studies that examined oxycodone effects, including its abuse liability-related effects, was conducted in subjects categorized as high or low sensation seekers. In addition, because there appear to be sex differences in how males and females respond to opioids, this factor was taken into account in the analysis. Seventy one subjects who scored on the lower end (15 and 19 low sensation-seeking males and females, respectively) or the higher end (23 and 14 high sensation-seeking males and females) of the Disinhibition subscale of the Sensation-Seeking Scale-Form V were studied for their responses to 0, 10, and 20mg of oral oxycodone. Ratings of "pleasant bodily sensations" were significantly higher after oxycodone administration than placebo only in male and female high sensation seekers. Ratings of "take again," "drug liking," "carefree," and "elated (very happy)" also tended to differentiate high from low sensation seekers although GroupxDose interactions were only marginally significant with the latter three ratings. Male and female low sensation seekers and female high sensation seekers reported dysphoric effects (e.g., ratings of nauseated) particularly after administration of the 20mg oxycodone dose. The results of this analysis provide suggestive evidence that high sensation seekers are more likely to experience greater positive subjective effects from oxycodone than low sensation seekers, but likelihood of experiencing negative effects is more complex (involving both sensation-seeking status and sex). less...

Increased sensitivity to the locomotor-activating effects of amphetamine in rats with a history of early-life social isolation is commonly attributed to alteration of the dopamine system. The locomotor response to amphetamine may also be due to effects on the noradrenergic system and particularly alpha-adrenergic receptors The present study examined whether noradrenergic neurotransmission mediates the increased sensitivity to the locomotor effects of amphetamine resulting from early social isolation and whether this effect can be reversed by later-life social housing experience. Rats reared in complete social isolation (artificially reared, AR) exhibited higher levels of locomotor activity than maternally reared (MR) rats in response to amphetamine (0.25mg/kg) Increased sensitivity to the locomotor effects of amphetamine in AR rats was reduced by the alpha-adrenergic receptor antagonist prazosin (0.5mg/kg). Prazosin alone reduced activity in AR rats to the level of MR rats. Group housing in cages that were more complex than standard laboratory cages reduced activity in both AR and MR rats. Group housing did not decrease the sensitivity of AR rats to the locomotor effects of either amphetamine or prazosin. Differences in activity between rats in standard and complex housing conditions were not altered by drug treatments. These findings indicate that pre-weaning social experience alters the responsiveness of the noradrenergic system to drug challenges, whereas post-weaning housing experience may not, even though ongoing activity is affected. Increased activity and sensitivity to amphetamine resulting from social isolation in early life may be mediated by changes in noradrenergic alpha-receptor mediated neurotransmission. less...

A study of tetrahydrocannabinol and amphetamine. AIM: To study several methods for estimating the prevalence of high blood concentrations of tetrahydrocannabinol and amphetamine in a population of drug users by analysing oral fluid (saliva). METHODS: Five methods were compared, including simple calculation procedures dividing the drug concentrations in oral fluid by average or median oral fluid/blood (OF/B) drug concentration ratios or linear regression coefficients, and more complex Monte Carlo simulations. Populations of 311 cannabis users and 197 amphetamine users from the Rosita-2 Project were studied. RESULTS: The results of a feasibility study suggested that the Monte Carlo simulations might give better accuracies than simple calculations if good data on OF/B ratios is available. If using only 20 randomly selected OF/B ratios, a Monte Carlo simulation gave the best accuracy but not the best precision. Dividing by the OF/B regression coefficient gave acceptable accuracy and precision, and was therefore the best method. None of the methods gave acceptable accuracy if the prevalence of high blood drug concentrations was less than 15%. CONCLUSION: Dividing the drug concentration in oral fluid by the OF/B regression coefficient gave an acceptable estimation of high blood drug concentrations in a population, and may therefore give valuable additional information on possible drug impairment, e.g. in roadside surveys of drugs and driving. If good data on the distribution of OF/B ratios are available, a Monte Carlo simulation may give better accuracy. less...

The atypical antipsychotic aripiprazole has been demonstrated to reduce symptoms of bipolar mania. To further profile the antimanic-like properties of aripiprazole in relevant preclinical models, we examined its efficacy in d-amphetamine-based behavioural models of acute mania in rats. The effects of acute and repeated administration of aripiprazole were assessed in the facilitation of intracranial self-stimulation (ICSS) and hyperlocomotion after acute d-amphetamine, and in the sensitized facilitation of ICSS function and hyperlocomotion after repeated d-amphetamine. Acutely, aripiprazole (0.75, 1.5 and 2.5 mg/kg i.p.) increased ICSS thresholds, attenuated the reward-facilitating effects of d-amphetamine (0.5 mg/kg i.p.), decreased motor activity and prevented d-amphetamine-induced hyperlocomotion. Co-administration of aripiprazole and d-amphetamine for 7 d resulted in aripiprazole counteracting the d-amphetamine-induced sensitization in facilitation of brain reward function and hyperlocomotion. These results indicate the efficacy of aripiprazole in d-amphetamine-based preclinical models of acute mania that are characterized by increased motivational drive and/or hyperfunction of brain reward. less...

Amphetamine and amphetamine-like drugs are popular recreational drugs of abuse because they are powerful stimulants of the central nervous system. Due to a dramatic increase in the abuse of methylenedioxylated derivatives, individually and/or in a mixture, and to the incoherent and contradictory interpretation of the electrochemical data available on this subject, a comprehensive study of the redox properties of amphetamine-like drugs was accomplished. The oxidative behaviour of amphetamine (A), methamphetamine (MA), methylenedioxyamphetamine (MDA) and methylenedioxymethamphetamine (MDMA) was studied in different buffer systems by cyclic, differential pulse and square-wave voltammetry using a glassy carbon electrode. A quantitative electroanalytical method was developed and successfully applied to the determination of MDMA in seized samples and in human serum. Validation parameters, such as sensitivity, precision and accuracy, were evaluated. The results found using the developed electroanalytical methodology enabled to gather some information about the content and amount of MDMA present in ecstasy tablets found in Portugal. Moreover, the data found in this study outlook the possibility of using the voltammetric methods to investigate the potential harmful effects of interaction between drugs such as MDMA and methamphetamine and other substances often used together in ecstasy tablets. less...

Relatively few studies have addressed the psychometric properties of self-report measures of amphetamine use. This study examines the reliability and validity of the Risk Behavior Assessment's (RBA) lifetime and recent amphetamine-use questions. To evaluate validity, 4027 out-of-treatment primarily cocaine and heroin users provided urine samples that were compared to self-report data; to evaluate reliability, 218 completed the RBA at two time points, 48h apart. In the overall sample, self-reports demonstrated moderately high validity, with a 95% accuracy rate (kappa=.54). When analysis was restricted to recent amphetamine users validity was slightly lower (71.5% accuracy; kappa=.41). Test-retest data indicated good reliability for self-reports of ever having used amphetamine (kappa=.79), and amphetamine use in the past 30days (.75<r<.91). Out-of-treatment drug users provided accurate self-reports of amphetamine use. Reliable and valid measures are essential for describing and predicting trends in amphetamine use, evaluating the effectiveness of interventions, and developing policies and programs. less...

Recruitment and repetitive firing of spinal motoneurons depend on the activation of persistent inward calcium and sodium currents (PICs) that are in turn facilitated by serotonin and norepinephrine that arise primarily from the brainstem. Considering that in rats, motoneuron PICs are greatly facilitated by increasing the presynaptic release of norepinephrine with amphetamine, we sought similar evidence for the modulation of PICs in human motoneurons. Pairs of motor units were recorded during a gradually increasing and then decreasing voluntary contraction. The firing frequency (F) of the lower-threshold (control) motor unit was used as an estimate of the synaptic input to the higher-threshold (test) motor unit. Generally, PICs are initiated during the recruitment of a motoneuron and subsequently, provide a fixed depolarizing current that helps the synaptic input maintain firing until derecruitment. Thus, the amplitude of the PIC in the test motor unit was estimated from the difference in synaptic input (DeltaF) needed to maintain minimal firing once the PIC was fully activated (measured at the time of test unit derecruitment), compared to the larger synaptic input required to initiate firing prior to full PIC activation (measured at the time of test unit recruitment; DeltaF = Frecruit - Fderecruit). Moreover, the activation time of the PIC was estimated as the minimal contraction duration needed to produce a maximal PIC (DeltaF). In 5 subjects, oral administration of amphetamine, but not placebo, increased the DeltaF by 62% (from 3.7+/- 0.6 imp/s to 6.0 +/- 0.8 imp/s, p = 0.001) and decreased the time needed to activate a maximal DeltaF from approximately 2s to 0.5s. Both findings suggest that the endogenous facilitation of PICs from brainstem derived norepinephrine plays an important role in modulating human motoneuron excitability, readying motoneurons for rapid and sustained activity during periods of high arousal such as stress or fear. less...

We describe the development and validation of a method for the quantification of drugs of abuse, using gas chromatography-mass spectrometry (GC/MS), in human placenta. Concentration ranges covered were 5-500ng/g for amphetamine, methamphetamine, MDMA, methadone, cocaine, benzoylecgonine, cocaethylene, morphine, 11-nor-9-carboxy-delta-9-tetrahydrocannabinol, nicotine, and cotinine. Intra-assay and inter-assay imprecisions were less than 15.7% for lower quality control samples and less than 14.9% for medium and high quality control samples. Recovery range was 36.2-83.7%. Placenta samples were kept at -80 degrees C until analysis; analytes were stable after three freeze-thaw cycles (samples stored at -20 degrees C). This accurate and precise assay has sufficient sensitivity and specificity for the analysis of specimens collected from women who voluntarily terminated their pregnancy at 12th week of gestation. The method has proven to be robust and accurate for the quantification of the principal recreational drugs of abuse in this period of the prenatal life. This is the first report that highlights the presence of drugs of abuse during the first trimester of gestation. less...

Attention-deficit/hyperactivity disorder (ADHD) is a behavioral disorder characterized by atypical levels of inattention, hyperactivity, and impulsivity that impair daily living activities. Although commonly associated with children and adolescents, current literature and practice now demonstrate the impairment the disorder may impose on adults as well. Central nervous system (CNS) stimulant medications are the first-line therapy for ADHD. CNS stimulants include methylphenidate and amphetamine derivatives. Longer-acting formulations used once daily are often preferred to avoid medication administration during school or work as well as to avoid side effects associated with rapid fluctuations in serum concentrations associated with multiple daily dosing. Lisdexamfetamine, a new, novel amphetamine product, has been shown to provide efficacy upwards of 12 hours in children and adults with a side effect profile similar to those of other longer-acting amphetamine products. Owing to its unique prodrug composition and the need for oral administration to activate the medication, lisdexamfetamine may offer advantages in clinical situations where stimulant abuse is a concern. less...