No description available.

Chronic exposure to psychostimulants such as amphetamine (AMPH) can induce long-term disruptions in cognition via actions on prefrontal cortex dopamine. Previous work has shown that two types of executive functions, set shifting and working memory (WM), are disrupted by AMPH sensitization and that these cognitive domains are impaired in schizophrenics and stimulant abusers. We assessed the effects of AMPH sensitization on behavioural flexibility using a cross-maze set shifting task and a WM task using the delayed spatial win-shift (SWSh) task in Long Evans (LE) and Sprague Dawley (SD) rats. Rats were exposed to an AMPH sensitization regimen (15 AMPH or saline injections: 1-5 mg/kg every 2nd day, increasing the dose by 1 mg every 3rd injections) following habituation on the mazes. In experiment 1, LE and SD rats were initially trained on a visual cue discrimination. During the set shift, rats were required to shift from the previously acquired visual-cue-based strategy to a response strategy (e.g.; always turn left, ignore the visual cue). For the reversal, rats were trained to reverse their turn direction. AMPH treatment did not impair learning of the initial cue discrimination in either strain. However, AMPH treated rats learned the response discrimination faster than controls during the set shift and AMPH treated LE rats were faster than controls to reach acquisition criterion during the response reversal. AMPH treatment neither impaired nor improved reversal learning in SD rats. In experiment 2, rats were tested on the SWSh task in which spatial information acquired during a training phase was used 30 minutes later during the testing phase in order to retrieve food pellets on the maze. In this task, AMPH treated rats were faster to re-attain criterion than control rats. Correlational analysis further revealed that AMPH sensitized rats that required more days to reach criterion before AMPH treatment (i.e. slow learners) tended to make more errors during re-acquisition of the memory task. Viewed collectively, these results suggest that chronic AMPH treatment can enhance behavioural flexibility and WM assessed in this manner. However, repeated AMPH exposure may have exacerbated pre-existing cognitive deficits in slow learning rats.

Stimulant medications such as D-amphetamine, mixed-salts (75% D- and25% L-) amphetamine; Adderall®, and methylphenidate are first-line treatmentsfor Attention-Deficit/Hyperactivity Disorder (ADHD). In vivo studies havepredominantly focused on these stimulants in the context of drug abuse, andtheir therapeutic mechanistic properties are only theoretical. Previously, in vivotechniques have been limited by poor temporal and spatial resolution, andcharacterizations of these medications in rodent models have not been possibleat low, clinically relevant levels. In order to address these issues, our laboratoryused in vivo high speed chronoamperometric microelectrodes to characterize theeffects of local applications of D-amphetamine, L-amphetamine, D,Lamphetamine,and Adderall® at low levels in the striatum and nucleusaccumbens of 3-6 month old, male Fischer 344 (F344) rats. Our results showedsignificant differences between the faster kinetics of dopamine (DA) releasesignals caused by D,L-amphetamine and the slower kinetics resulting from Damphetamine.These data support that resulting DA concentrations evoked by DandD,L-amphetamine are correlated with the amount of D-amphetamine in thedrug and only the time courses of the signals are affected by L-amphetamine.Additionally, locally applied D- and L-amphetamine caused DA release signalswith similar amplitudes or concentrations of evoked DA; however, the signalswere significantly faster for L-amphetamine. Adderall® caused significantlygreater DA release that lasted over a longer time course compared to DA releasecaused by D- or D,L-amphetamine. These data support the hypothesis thatamphetamine isomers, alone or in combination, interact differently with the DAtransporter (DAT) to subsequently cause reversal of transport of DA out ofpresynaptic membranes of DA neuronal projections. Finally, reversemicrodialysis studies were carried out to assess low levels of D-amphetamine,Adderall® (75% D-, 25% L-amphetamine), methylphenidate, and a new mixedsaltsamphetamine that we referred to as Reverse Adderall (75% L-, 25% Damphetamine)in the striatum of F344 rats. These data reveal a stimulantconcentration-response curve for DA with double plateaus that may be explainedby dual mechanisms of reverse transport of DA through the DAT. In addition,reverse microdialysis of methylphenidate caused DA overflow similar to theeffects of the other stimulants.

Chronic exposure to psychostimulants such as amphetamine (AMPH) can induce long-term disruptions in cognition via actions on prefrontal cortex dopamine. Previous work has shown that two types of executive functions, set shifting and working memory (WM), are disrupted by AMPH sensitization and that these cognitive domains are impaired in schizophrenics and stimulant abusers. We assessed the effects of AMPH sensitization on behavioural flexibility using a cross-maze set shifting task and a WM task using the delayed spatial win-shift (SWSh) task in Long Evans (LE) and Sprague Dawley (SD) rats. Rats were exposed to an AMPH sensitization regimen (15 AMPH or saline injections: 1-5 mg/kg every 2nd day, increasing the dose by 1 mg every 3rd injections) following habituation on the mazes. In experiment 1, LE and SD rats were initially trained on a visual cue discrimination. During the set shift, rats were required to shift from the previously acquired visual-cue-based strategy to a response strategy (e.g.; always turn left, ignore the visual cue). For the reversal, rats were trained to reverse their turn direction. AMPH treatment did not impair learning of the initial cue discrimination in either strain. However, AMPH treated rats learned the response discrimination faster than controls during the set shift and AMPH treated LE rats were faster than controls to reach acquisition criterion during the response reversal. AMPH treatment neither impaired nor improved reversal learning in SD rats. In experiment 2, rats were tested on the SWSh task in which spatial information acquired during a training phase was used 30 minutes later during the testing phase in order to retrieve food pellets on the maze. In this task, AMPH treated rats were faster to re-attain criterion than control rats. Correlational analysis further revealed that AMPH sensitized rats that required more days to reach criterion before AMPH treatment (i.e. slow learners) tended to make more errors during re-acquisition of the memory task. Viewed collectively, these results suggest that chronic AMPH treatment can enhance behavioural flexibility and WM assessed in this manner. However, repeated AMPH exposure may have exacerbated pre-existing cognitive deficits in slow learning rats.

There has been a significant increase in the use of amphetamine type stimulants (ATS) in Australia over the last decade, and according to the National Drug Strategy Household Survey (2004) results, amphetamine is the second most commonly reported illicit substance used by Australians after cannabis. It has been widely documented that illicit drug users, and in particular ATS users, experience high levels of psychiatric comorbidity and particularly high levels of depression. Depression is one of the leading diseases in the modern world and causes significant burden to those who suffer from it. The main aim of this study is to determine the levels of depression among a sample of regular amphetamine users and investigate the subjective experience of life quality among those with comorbid depression and those without. This study was a separate component of a randomised controlled trial for regular amphetamine users in Queensland and New South Wales (Baker, Lee, Claire, Lewin, Grant et al, 2003). Participants were required to be 18 years and over and regular users of amphetamines as defined by use of amphetamines on at least four occasions in the previous month. A total of 2 14 participants were recruited from a range of sources into the study. Levels of depression (measured by the BDI-11), quality of life (WHOQoL BREF), dependence status (SDS) and drug use patterns (OTI) were all examined. High levels of depression were found among the same with 84.6% of the sample reporting clinically significant depression with a large proportion of this group falling into the moderate to severe spectrum (7 1 %). Results identified several areas of major risk for poor quality of life for amphetamine users, including dependence, frequency of use and route of administration, and showed how these risks areas can be compounded by level of depression to create significantly decreased quality of life. No amphetamine withdrawal scales were administered in the assessment protocol for this study. It is possible that some of the reported symptoms of depression could be related in part to an amphetamine withdrawal syndrome. Further study of the natural history of withdrawal and the prevalence of related metal health symptoms is warranted. This sample was a treatment seeking, dependent group of amphetamine users. The results confirm the high rates of mental health comorbidity among regular amphetamine users and highlights the added burden of disease that this group suffers. The results have implications for treatment services, which need to manage both comorbidity and individual aspects that contribute to an improved quality of life. Further analyses examining treatment outcomes for this group would be useful.

Thesis--Auburn University, 2009. / Abstract. Vita. Includes bibliographical references.

It has been suggested that adult attention-deficit/hyperactivity disorder (ADHD) may reflect affective temperaments, which involve mild manic and/or depressive traits as part of one’s personality. Such innate traits are associated with poor attention. Stimulant medications, given for ADHD, can worsen manic symptoms, thereby worsening attentional symptoms paradoxically, by worsening the underlying mood condition that causes poor attention. This study examines the nature of response to stimulant medication in subjects with affective temperament (Cyclothymia, Hyperthymia, Dysthymia). A retrospective cohort study was conducted of 87 subjects from Tufts Medical Center Mood Disorders Program. Subjects were included if they had ever been prescribed stimulant medications. Prior diagnosis of adult ADHD, or not, also was assessed. This sample was assessed using TEMPS-A scale to measure affective temperaments, and the CGI-I scale to assess clinical change in mood/anxiety and attention/cognition. Data analysis was conducted using descriptive statistics and stratification. This study has several limitations. Researchers and subjects were not blinded; all subjects received stimulants, with no non-stimulant control group; and treatment response was assessed retrospectively. Nonetheless, no such data exist in the scientific literature previously, and thus this pilot data adds to our present knowledge. 61% of the sample had an affective temperament (using the strictest definition of 75% or more TEMPS items endorsed). Of these, the most common was cyclothymic (40%) followed by hyperthymic (24%). The main treatment results were that most patients (55%) had no effect on mood/anxiety, but a large number (43%) had worsening mood/anxiety symptoms. 37% had mild or moderate improvement in cognition. Stratified by ADHD diagnosis, stimulant effects were somewhat better with, than without, ADHD diagnosis, for cognition but not for mood/anxiety. In ADHD subjects, 49% had worsening mood and/or anxiety symptoms, while 44% had some improvement in cognition/attention. In non-ADHD subjects, 30% had worsening mood and/or anxiety symptoms, while 30% had some improvement in cognition/attention. In conclusion, we found that most people (61%) treated with amphetamine stimulants identified in a mood specialty clinic were diagnosable with affective temperaments, especially cyclothymia. Amphetamine stimulant worsened mood/anxiety symptoms in about one-half of subjects, and improved cognition symptoms only about one-third subjects. Prior ADHD diagnosis was associated with somewhat improved cognitive, but not mood/anxiety, outcomes. These results suggest that amphetamine stimulant treatment in an affectively ill population may have harmful mood/anxiety effects, and has only partly beneficial cognitive effects.

Chronic exposure to psychostimulants such as amphetamine (AMPH) can induce long-term disruptions in cognition via actions on prefrontal cortex dopamine. Previous work has shown that two types of executive functions, set shifting and working memory (WM), are disrupted by AMPH sensitization and that these cognitive domains are impaired in schizophrenics and stimulant abusers. We assessed the effects of AMPH sensitization on behavioural flexibility using a cross-maze set shifting task and a WM task using the delayed spatial win-shift (SWSh) task in Long Evans (LE) and Sprague Dawley (SD) rats. Rats were exposed to an AMPH sensitization regimen (15 AMPH or saline injections: 1-5 mg/kg every 2nd day, increasing the dose by 1 mg every 3rd injections) following habituation on the mazes. In experiment 1, LE and SD rats were initially trained on a visual cue discrimination. During the set shift, rats were required to shift from the previously acquired visual-cue-based strategy to a response strategy (e.g.; always turn left, ignore the visual cue). For the reversal, rats were trained to reverse their turn direction. AMPH treatment did not impair learning of the initial cue discrimination in either strain. However, AMPH treated rats learned the response discrimination faster than controls during the set shift and AMPH treated LE rats were faster than controls to reach acquisition criterion during the response reversal. AMPH treatment neither impaired nor improved reversal learning in SD rats. In experiment 2, rats were tested on the SWSh task in which spatial information acquired during a training phase was used 30 minutes later during the testing phase in order to retrieve food pellets on the maze. In this task, AMPH treated rats were faster to re-attain criterion than control rats. Correlational analysis further revealed that AMPH sensitized rats that required more days to reach criterion before AMPH treatment (i.e. slow learners) tended to make more errors during re-acquisition of the memory task. Viewed collectively, these results suggest that chronic AMPH treatment can enhance behavioural flexibility and WM assessed in this manner. However, repeated AMPH exposure may have exacerbated pre-existing cognitive deficits in slow learning rats. / Medicine, Faculty of / Graduate

No description available.

Cocaine use disorder is a serious public health issue for which no approved pharmacotherapies exist. The development of a pharmacotherapy for cocaine use disorder is a priority for the National Institute on Drug Abuse. Amphetamine maintenance has been shown to be effective to reduce cocaine use in double-blind placebo controlled clinical trials, but has not been approved due to concerns over safety and abuse liability. Development of new pharmacotherapies is facilitated by preclinical testing for effectiveness and identification of new targets for medication development. The first part of this dissertation develops a novel non-human primate cocaine self-administration choice procedure that is modeled after a human laboratory cocaine self-administration choice procedure to improve translational research and facilitate medication development. The second part of this dissertation is devoted to examining the mechanisms of amphetamine maintenance-induced decreases in cocaine use. In the novel non-human primate choice procedure, monkeys chose between injections of cocaine or food pellets (0, 1, 3 or 10) in a 9-choice discrete trials procedure. The reinforcers were available on concurrent independent progressive-ratio schedules. Monkeys chose between cocaine and food in a dose- and magnitude-dependent manner. Maintenance on 7 days of lisdexamfetamine and amphetamine decreased cocaine choices without decreasing food responding, providing evidence that this model may be able to predict drugs that will have clinical efficacy to decrease cocaine use. The next set of experiments examined the effects of amphetamine maintenance on the abuse-related behavioral (intracranial self-stimulation, ICSS) and neurochemical [nucleus accumbens dopamine (DA) and serotonin (5-HT)] effects of cocaine, methylenedioxypyrovalerone, and methamphetamine in rats. Amphetamine maintenance produced sustained increases in ICSS baseline responding and nucleus accumbens DA levels without affecting 5-HT levels. Amphetamine maintenance also attenuated the behavioral and neurochemical abuse-related effects of cocaine but not those of methamphetamine, and with MDPV, amphetamine maintenance decreased the abuse-related neurochemical effect of MDPV, but not the abuse-related behavioral effect. This suggests that amphetamine would likely be most effective against cocaine, least effective against methamphetamine and between the two for MDPV. These data suggest targets that selectively release DA will be the most effective against cocaine use disorder.