D-amphetamine maintenance therapy reduces cocaine use in female rats

Currently, there are no approved medications to treat cocaine addiction. In this context, d-amphetamine maintenance therapy is a promising pharmacological strategy to reduce cocaine use. In both male rats and human cocaine users, d-amphetamine treatment reduces cocaine taking and seeking. However, this has not been examined systematically in female animals, even though cocaine addiction afflicts both women and men, and the sexes can differ in their response to cocaine. Here, we determined how d-amphetamine maintenance therapy during cocaine self-administration influences cocaine use in female rats. In experiment 1, two groups of female rats received 14 intermittent access (IntA) cocaine self-administration sessions. One group received concomitant d-amphetamine maintenance treatment (COC + A rats; 5 mg/kg/day, via minipump), the other group did not (COC rats) After discontinuing d-amphetamine treatment, we measured responding for cocaine under a progressive ratio schedule, responding under extinction and cocaine-primed reinstatement of drug seeking. In experiment 2, we assessed the effects of d-amphetamine maintenance on these measures in already cocaine-experienced rats. To this end, rats first received 14 IntA cocaine self-administration sessions without d-amphetamine. They then received 14 more sessions now either with (COC/COC + A rats) or without (COC/COC rats) concomitant d-amphetamine treatment. In both experiments, d-amphetamine-treated rats showed reduced motivation to take and seek cocaine, responding less for cocaine both under progressive ratio and extinction conditions. In contrast, d-amphetamine treatment did not influence cocaine-primed reinstatement of cocaine seeking. Thus, d-amphetamine treatment reduces both the development and expression of addiction-relevant patterns of cocaine use in female animals.

Amphetamine use and psychiatric admissions: a 10-year perspective

Objective: We aimed to (i) describe the 10-year trend in admissions associated with amphetamine use, (ii) describe the distinguishing characteristics of people with an amphetamine-related diagnosis (ARD) and (iii) examine predictors of repeated admissions among people with an ARD. Method: We conducted a retrospective cohort study. We (i) counted the number of admissions with an ARD and evaluated any trends, and using univariate and multivariate tests, (ii) compared those who had an ARD with those who did not and (iii) compared those with an ARD who had one, two to four, and five or more admissions. Results: Admissions associated with amphetamine use increased between 2009 and 2015. Those with an ARD had significant differences in demographics, diagnosis and pattern of service use relative to those without an ARD. Amongst those with an ARD, a higher number of admissions was positively associated with a schizophrenia diagnosis but inversely associated with a transient psychotic disorder diagnosis. Conclusions: The increase in admissions associated with amphetamine use indicates that people with an ARD posed major demands on inpatient services. Targeting amphetamine treatment to those with psychotic disorders, both schizophrenia and transient psychotic disorders, may reduce hospital-related costs and re-admissions.

A New Old Tale: Dopamine Transporter implications in an animal model of Attention-Deficit Hyperactivity Disorder

Attention deficit/Hyperactivity disorder (ADHD) is one of the most diagnosed psychiatric disorders nowadays. The core symptoms of the condition include hyperactivity, impulsiveness and inattention. The main pharmacological treatment consists of psychostimulant drugs affecting Dopamine Transporter (DAT) function. We have previously shown that genetically modified mice lacking p35 protein (p35KO), which have reduced Cdk5 activity, present key hallmarks resembling those described in animal models useful for studying ADHD. The p35KO mouse displays spontaneous hyperactivity and shows a calming effect of methylphenidate or amphetamine treatment. Interestingly, dopaminergic neurotransmission is altered in these mice as they have an increased Dopamine (DA) content together with a low DA turnover. This led us to hypothesize that the lack of Cdk5 activity affects DAT expression and/or function in this animal model. In this study, we performed biochemical assays, cell-based approaches, quantitative fluorescence analysis and functional studies that allowed us to demonstrate that p35KO mice exhibit decreased DA uptake and reduced cell surface DAT expression levels in the striatum (STR). These findings are supported by in vitro observations in which the inhibition of Cdk5 activity in N2a cells induced a significant increase in constitutive DAT endocytosis with a concomitant increase in DAT localization to recycling endosomes. Taken together, these data provide strong evidence regarding the role of Cdk5 activity in DAT trafficking and function, thus contributing to the knowledge of DA neurotransmission physiology and also providing therapeutic options for the treatment of DA pathologies such as ADHD.

Prolonged Peripheral Immunosuppressive Responses as Consequences of Random Amphetamine Treatment, Amphetamine Withdrawal and Subsequent Amphetamine Challenges in Rats

Drug-induced immunosuppression may underline increased hypothalamic–pituitary–adrenal axis response to stress observed following chronic psychostimulant treatment. However, the consequences of random amphetamine (AMPH) treatment, withdrawal and AMPH challenge after withdrawal on the peripheral immunity and systemic corticosterone response are unknown. In this study, the total blood and spleen leukocyte, lymphocyte, T, B, NK, TCD4+/TCD8+ cell numbers and ratio, pro-inflammatory interferon gamma (IFN-γ), and anti-inflammatory interleukin-4 (IL-4) production, and plasma corticosterone concentration in Wistar rats were investigated after: chronic, random AMPH/SAL treatment alone (20 injections in 60 days, 1 mg/kg b.w., i.p.), AMPH/SAL withdrawal (for 20 consecutive days after random AMPH/SAL exposure) or AMPH/SAL challenge after withdrawal (single injection after the AMPH/SAL withdrawal phase). The results showed blood and spleen leukopenia, lymphopenia, lower blood production of IFN-ɤ, and increased plasma corticosterone concentration after the AMPH treatment, which were more pronounced in the AMPH after withdrawal group. In contrast, an increased number of blood NK cells and production of IL-4 after chronic, random AMPH treatment alone, were found. Blood AMPH-induced leukopenia and lymphopenia were due to decreased total number of T, B lymphocytes and, at least in part, of granulocytes and monocytes. Moreover, decreases in the number of blood TCD4+ and TCD8+ lymphocytes both in the AMPH chronic alone and withdrawal phases, were found.The major findings of this study are that AMPH treatment after the long-term withdrawal from previous random AMPH exposure, accelerates the drug-induced immunosuppressive and systemic corticosterone responses, suggesting prolonged immunosuppressive effects and an increase in incidence of infectious diseases. Graphical Abstract Prolonged peripheral immunosuppressive responses as consequences of random amphetamine…The results indicate that the chronic and random AMPH exposure alone and the acute (single injection) challenge of the drug after the withdrawal phase induced long-term immunosuppressive effects, which were similar to those occurring during the stress response, and sensitized the peripheral immunosuppressive and corticosterone responses of the rat to the disinhibitory effects of this stressor.