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Background: Hypothalamic neuropeptide Y (NPY) and two immediate early genes, c-fos and c-jun, have been found to be involved in regulating the appetite-suppressing effect of amphetamine (AMPH). The present study investigated whether cerebral catecholamine (CA) might regulate NPY and POMC expression and whether NPY Y1 receptor (Y1R) participated in activator protein-1 (AP-1)-mediated feeding., Methods: Rats were given AMPH daily for 4 days. Changes in the expression of NPY, Y1R, c-Fos, c-Jun, and AP-1 were assessed and compared., Results: Decreased CA could modulate NPY and melanocortin receptor 4 (MC4R) expressions. NPY and food intake decreased the most on Day 2, but Y1R, c-Fos, and c-Jun increased by approximately 350%, 280%, and 300%, respectively, on Day 2. Similarly, AP-1/DNA binding activity was increased by about 180% on Day 2. The expression patterns in Y1R, c-Fos, c-Jun, and AP-1/DNA binding were opposite to those in NPY during AMPH treatment. Y1R knockdown was found to modulate the opposite regulation between NPY and AP-1, revealing an involvement of Y1R in regulating NPY/AP-1-mediated feeding., Conclusions: These results point to a molecular mechanism of CA/NPY/Y1R/AP-1 signaling in the control of AMPH-mediated anorexia and may advance the medical research of anorectic and anti-obesity drugs.

Repeated exposure to psychostimulant drugs is associated with long-lasting changes in cognition, particularly in behavioral tasks that are sensitive to prefrontal cortex function. Adolescents may be especially vulnerable to these drug-induced cognitive changes because of the widespread adaptations in brain anatomy and function that are characteristic of normal development during this period. Here, we used a differential reinforcement of low rates of responding task in rats to determine if amphetamine (AMPH) exposure during adolescence would alter behavioral inhibition in adulthood. Between postnatal days (PND) 27 and 45, rats received every other day injections of saline or AMPH (3 mg/kg). At PND 125, rats were trained progressively through a series of four reinforcement schedules (DRL 5, 10, 15, and 30 s) that required them to withhold responding for the appropriate amount of time before a lever press was reinforced. Relative to controls, AMPH-treated rats displayed transient deficits in behavioral inhibition (i.e., decreases in efficiency ratio) that were only evident at DRL 5. In addition, they had increased responding during nonreinforced periods, which suggested increased perseveration and propensity to attribute incentive salience to reward-paired cues. Following challenge injections with AMPH (.25-1 mg/kg, i.p.), which were given 10 min before the start of DRL 30 test sessions, both groups exhibited dose-dependent decreases in efficiency. These results suggest that AMPH-induced alterations in incentive-motivation and perseveration are more robust and longer-lasting than its effects on impulse control., (© 2012 Wiley Periodicals, Inc.)

Rationale: Adult rats often produce 50-kHz ultrasonic vocalizations (USVs), particularly the frequency-modulated varieties, in appetitive situations. These calls are thought by some to reflect positive affective states and the reinforcing value of drugs such as amphetamine and cocaine., Objective: The objective of this study was to determine whether the number of unconditioned 50-kHz USVs elicited by amphetamine predicts the development and/or magnitude of drug-conditioned motivation., Methods: In three experiments, we recorded USVs before and after injections of 1 mg/kg amphetamine (i.v. or i.p.) administered once per session. Rats were categorized as "high callers" or "low callers" according to individual differences in the number of 50-kHz USVs elicited by their first amphetamine injection. We examined the conditioned appetitive behavior and conditioned place preference (CPP) that emerged in high and low callers after repeated pairings of amphetamine with specific contexts. We also examined whether amphetamine-induced calling was affected by treatment within an unfamiliar (test chamber) versus familiar (home cage) context., Results: Within an unfamiliar environment, the high callers consistently produced more amphetamine-induced 50-kHz USVs than the low callers. Compared to the low callers, high callers showed significantly greater amphetamine CPP as well as enhanced conditioned 50-kHz USVs and locomotor activity during anticipation of amphetamine. Individual differences were stable when amphetamine was administered in test chambers, but when it was administered in home cages, low callers showed an increase in 50-kHz calling that matched the high callers., Conclusions: These findings suggest that individual differences in drug-induced USVs can reveal environment-sensitive traits involved in drug-related appetitive motivation.

In a recent positron emission tomography (PET) study, we demonstrated the ability to measure amphetamine-induced dopamine (DA) release in the human cortex with the relatively high affinity dopamine D2/3 radioligand [(11)C]FLB 457. Herein we report on reproducibility and reliability of [(11)C]FLB 457 binding potential relative to non-displaceable uptake (BP(ND)) following an acute amphetamine challenge. Ten healthy human subjects were studied twice with [(11)C]FLB 457 following an acute amphetamine (oral, 0.5 mg kg(-1) dose) challenge on two-separate days approximately one week apart. D2/3 receptor binding parameters were estimated using a two-tissue compartment kinetic analysis in the cortical regions of interest and cerebellum (reference region). The test-retest variability and intraclass correlation coefficient were assessed for distribution volume (V(T)), binding potential relative to plasma concentration (BP(P)), and BP(ND) of [(11)C]FLB 457. The test-retest variability of [(11)C]FLB 457 V(T), BP(P) and BP(ND) were ≤ 17%, 22% and 11% respectively. These results, which are consistent with the published test-retest variability for this ligand measured under baseline conditions demonstrate that the post-amphetamine [(11)C]FLB 457 BP(ND) is reproducible. These data further support the use [(11)C]FLB 457 and amphetamine to characterize cortical dopamine transmission in neuropsychiatric disorders.

Amphetamine use by truck drivers for occupational purposes is widely known. The production and consumption of amphetamines was banned by the Brazilian National Health Surveillance Agency (ANVISA) in October 2011. This study analyzes persistent amphetamine use by truck drivers since the ban was implemented. A convenience sample of 427 truck drivers was taken along highways in São Paulo State in 2012. Participants were asked to answer a structured questionnaire and provide a urine sample to screen for recent amphetamine consumption through toxicological analysis. Among the interviewed drivers, 7% had used some illicit drug recently and 2.7% had used amphetamines. Amphetamines are still consumed by truck drivers despite the risks and the recent ban. The authorities should thus monitor the possession and use of amphetamines by drivers in order to effectively enforce the ban.

Glutamate acts as a neurotransmitter within the Central Nervous System (CNS) and modifies immune cell activity. In lymphocytes, NMDA glutamate receptors regulate intracellular calcium, the production of reactive oxygen species and cytokine synthesis. MK-801, a NMDA receptor open-channel blocker, inhibits calcium entry into mast cells, thereby preventing mast cell degranulation. Several lines of evidence have shown the involvement of NMDA glutamate receptors in amphetamine (AMPH)-induced effects. AMPH treatment has been reported to modify allergic lung inflammation. This study evaluated the effects of MK-801 (0.25mg/kg) and AMPH (2.0mg/kg), given alone or in combination, on allergic lung inflammation in mice and the possible involvement of NMDA receptors in this process. In OVA-sensitized and challenged mice, AMPH and MK-801 given alone decreased cellular migration into the lung, reduced IL-13 and IL10 levels in BAL supernatant, reduced ICAM-1 and L-selectin expression in granulocytes in the BAL and decreased mast cell degranulation. AMPH treatment also decreased IL-5 levels. When both drugs were administered, treatment with MK-801 reversed the decrease in the number of eosinophils and neutrophils induced by AMPH in the BAL of OVA-sensitized and challenged mice as well as the effects on the expression of L-selectin and ICAM-1 in granulocytes, the IL-10, IL-5 and IL-13 levels in BAL supernatants and increased mast cell degranulation. At the same time, treatment with MK-801, AMPH or with MK-801+AMPH increased corticosterone serum levels in allergic mice. These results are discussed in light of possible indirect effects of AMPH and MK-801 via endocrine outflow from the CNS (i.e., HPA-axis activity) to the periphery and/or as a consequence of the direct action of these drugs on immune cell activity, with emphasis given to mast cell participation in the allergic lung response of mice., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Rationale: Amphetamine has a significant potential for abuse and addiction. Among prolonged abusers, amphetamine withdrawal-induced depressive symptoms are common; however, their pathophysiological mechanism is not fully understood. Previously, we found that repeated treatment with amphetamine for 2 weeks induced oxidative stress in rat brain., Objectives: The purpose of the current study is to analyze whether abstinence from repeated amphetamine treatment in rats induces depressive-like behaviors and if oxidative damage in the brain continues during abstinence., Methods: Rats were given repeated treatment with amphetamine once daily at 1, 2, or 4 mg/kg for 14 days. From 10 to 14 days after final amphetamine treatment, behavioral changes were monitored using open field test, novel object recognition test, and forced swim test. Oxidative damage in the medial frontal cortex and hippocampus was analyzed by immunohistochemistry., Results: We found that drug abstinence after repeated amphetamine stimulation decreased locomotor activity and exploratory behavior in the open field test, increased immobility in the forced swim test, and had no significant effect on the recognition index in the novel object recognition test. We also found that amphetamine abstinence increased levels of 4-hydroxynonenal-protein adducts and 8-hydroxyguanosine in rat medial frontal cortex and in CA3 and dentate gyrus regions of the hippocampus., Conclusions: These results suggest that amphetamine abstinence displays depressive-like behaviors in rats and induces oxidative damage to lipids and RNA in rat brain. Our findings indicate that the process of oxidative stress may play a role in pathophysiological changes during drug abstinence from repeated amphetamine stimulation.

Kv10.1 (Eag1), member of the Kv10 family of voltage-gated potassium channels, is preferentially expressed in adult brain. The aim of the present study was to unravel the functional role of Kv10.1 in the brain by generating knockout mice, where the voltage sensor and pore region of Kv10.1 were removed to render non-functional proteins through deletion of exon 7 of the KCNH1 gene using the '3 Lox P strategy'. Kv10.1-deficient mice show no obvious alterations during embryogenesis and develop normally to adulthood; cortex, hippocampus and cerebellum appear anatomically normal. Other tests, including general health screen, sensorimotor functioning and gating, anxiety, social behaviour, learning and memory did not show any functional aberrations in Kv10.1 null mice. Kv10.1 null mice display mild hyperactivity and longer-lasting haloperidol-induced catalepsy, but there was no difference between genotypes in amphetamine sensitization and withdrawal, reactivity to apomorphine and haloperidol in the prepulse inhibition tests or to antidepressants in the haloperidol-induced catalepsy. Furthermore, electrical properties of Kv10.1 in cerebellar Purkinje cells did not show any difference between genotypes. Bearing in mind that Kv10.1 is overexpressed in over 70% of all human tumours and that its inhibition leads to a reduced tumour cell proliferation, the fact that deletion of Kv10.1 does not show a marked phenotype is a prerequisite for utilizing Kv10.1 blocking and/or reduction techniques, such as siRNA, to treat cancer.

Rationale: The head-twitch response (HTR) is a rapid side-to-side rotational head movement that occurs in rats and mice after administration of serotonergic hallucinogens and other 5-HT2A agonists. The HTR is widely used as a behavioral assay for 5-HT2A activation and to probe for interactions between the 5-HT2A receptor and other transmitter systems., Objective: High-speed video recordings were used to analyze the head movement that occurs during head twitches in C57BL/6J mice. Experiments were also conducted in C57BL/6J mice to determine whether a head-mounted magnet and a magnetometer coil could be used to detect the HTR induced by serotonergic hallucinations based on the dynamics of the response., Results: Head movement during the HTR was highly rhythmic and occurred within a specific frequency range (mean head movement frequency of 90.3 Hz). Head twitches produced wave-like oscillations of magnetometer coil voltage that matched the frequency of head movement during the response. The magnetometer coil detected the HTR induced by the serotonergic hallucinogens 2,5-dimethoxy-4-iodoamphetamine (DOI; 0.25, 0.5, and 1.0 mg/kg, i.p.) and lysergic acid diethylamide (LSD; 0.05, 0.1, 0.2, and 0.4 mg/kg, i.p.) with extremely high sensitivity and specificity. Magnetometer coil recordings demonstrated that the non-hallucinogenic compounds (+)-amphetamine (2.5 and 5.0 mg/kg, i.p.) and lisuride (0.8, 1.6, and 3.2 mg/kg, i.p.) did not induce the HTR., Conclusions: These studies confirm that a magnetometer coil can be used to detect the HTR induced by hallucinogens. The use of magnetometer-based HTR detection provides a high-throughput, semi-automated assay for this behavior, and offers several advantages over traditional assessment methods.

Rationale: Accumulating evidence supports the involvement of the ventral striatum (VS) in spatial information processing. The multiple cortical glutamatergic and mesolimbic dopaminergic (DAergic) afferences on the same neurons in the ventral striatum provide the neuroanatomical substrate for glutamate and dopamine functional interaction. However, there is little evidence in the literature on how this interaction affects the ability to encode spatial information., Objective: First, we evaluated the effect of intra-VS bilateral infusion of different doses of amphetamine (0.3, 0.75, and 1.5 μg/side) on the ability to detect spatial novelty in mice. Next, we examined the impact produced on the same abilities by intra-VS infusion of ineffective doses of amphetamine (0.3 μg/side) in association with N-methyl-D-aspartate (NMDA) (3.125 ng/side) or α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) (0.25 ng/side) receptor antagonist., Results: The results show that infusion of amphetamine impairs detection of spatial novelty, affecting also exploratory activity and marginally the detection of nonspatial novelty. In contrast, an association of subthreshold doses of amphetamine with NMDA or AMPA receptor antagonists exerted a selective effect on reactivity to a spatial change., Conclusions: These findings demonstrate that enhanced DAergic activity in the VS enhances glutamate receptor antagonist-induced impairment in learning and memory.

Drug addicts have severe disruptions in many physiological and behavioral rhythms, such as the sleep/wake cycle. Interestingly, amphetamine, a psychostimulant, is able to alter many circadian patterns, which are independent of the master biological clock located in the suprachiasmatic nucleus. To increase our understanding of the circadian regulation of amphetamine on clock gene expression, rats received subcutaneous injections of d-amphetamine and the clock gene mRNA levels were analyzed using real-time PCR to obtain a daily profile. In the striatum, acute injection of d-amphetamine did not alter Period (Per)1, Per2 and Reverse erythroblastosis virus α (Rev-erbα) expressions. Chronic administration shifted the phase of Per1 and Per2 expressions from a nocturnal to diurnal pattern and advance shifted the peak of Rev-erbα in d-amphetamine-treated animals. In contrast, the rhythm of Brain and muscle Arnt-like protein-1 (Bmal1) was shifted from a diurnal to a nocturnal pattern by both acute and chronic treatments. These results demonstrated that chronic d-amphetamine treatment altered the expression of clock genes in the striatum. This might further influence the expression of related gene within the striatum and lead to behavioral and physiological changes which are associated to drug addiction., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Studies in rodents have shown that psychostimulant drugs such as cocaine and amphetamine cause endorphin release in the brain reward system. There is also evidence for the involvement of the opioid system in human psychostimulant dependence. The acute effects of an i.v. psychostimulant drug on the brain opioid system, however, have not yet been investigated in humans. We hypothesized that an i.v. dose of amphetamine as compared to placebo would cause an opioid release in the human brain reward system, measurable as a reduction of the binding potential of the μ-opioid receptor radioligand [(11)C]carfentanil. Ten healthy young men were examined using positron emission tomography (PET) and [(11)C]carfentanil in three sessions: at baseline; after placebo; after an i.v. amphetamine dose of 0.3 mg/kg bodyweight. The order of amphetamine and placebo was double-blinded and randomized. PET examinations were performed with a Siemens high resolution research tomograph. Data were analysed with the simplified reference tissue model, applying manually drawn regions of interest for every subject. Using repeated measures analysis of variance, we found no significant differences in [(11)C]carfentanil binding potential between amphetamine and placebo conditions in any of the investigated brain regions. In contrast to data from rodent studies and a recent study of oral amphetamine administration in humans, an i.v. dose of amphetamine does not cause any acute opioid release in healthy human subjects. The postulated role of the opioid system in mediating the effects of amphetamine needs to be further investigated in animal models of the disease as well as in patient populations.

Rationale: The Drug Effects Questionnaire (DEQ) is widely used in studies of acute subjective response (SR) to a variety of substances, but the format of the DEQ varies widely across studies, and details of its psychometric properties are lacking. Thus, the field would benefit from demonstrating the reliability and validity of the DEQ for use across multiple substances., Objective: The current study evaluated the psychometric properties of several variations of DEQ items, which assessed the extent to which participants (1) feel any substance effect(s), (2) feel high, (3) like the effects, (4) dislike the effects, and (5) want more of the substance using 100-mm visual analog scales., Methods: DEQ data from three placebo-controlled studies were analyzed to examine SR to amphetamine, nicotine, and alcohol. We evaluated the internal structure of the DEQ for use with each substance as well as relationships between scale items, measures of similar constructs, and substance-related behaviors., Results: Results provided preliminary psychometric support for items assessing each DEQ construct (feel, high, dislike, like, and more)., Conclusions: Based on the study results, we identify several common limitations of extant variants of the DEQ and recommend an improved version of the measure. The simplicity and brevity of the DEQ combined with its promising psychometric properties support its use in future SR research across a variety of substances.

Background: In recent years, amphetamine-type stimulants (ATS) have increased dramatically in East-south Asia, especially in China. Most ATS users suffered from psychosis comorbidity, and depression is the main syndrome in ATS users., Methodology: A cross-sectional study of depressive symptoms and associated factors among ATS users was conducted in compulsory and voluntary drug detoxification and rehabilitation centers of Beijing and Guangdong Province from March, 2010 to August, 2010. Total 402 eligible participants were recruited and investigated by trained interviewers using a structured questionnaire, the depression was measured by the short 13-item Beck Depression Inventory (BDI-13). Multiple logistic regression was used to determine the impact of associated risk factors of depressive symptoms (%≥8). PRINCIPLE FINDING: The mean score of BDI-13 is 8.11, and 169 participants (42.04%) have depressive symptoms, including 106 (26.37%) with moderate and 63 (15.67%) with severe depressive symptoms. Higher dose of ATS use, history of ATS relapse were associated with moderate and severe depressive symptoms, the adjusted odds ratios (OR) was 2.62, (95% CI: 1.45-4.74) and 2.01 (95% CI: 1.18-3.42) respectively. The cessation of 12 months or more had less risk of depressive symptoms than the current users, the OR was 0.46 (95% CI: 0.24-0.91), and the ATS users reporting nicotine dependence and alcohol drinking had significantly more risk of depressive symptoms for 3.11 (1.83-5.28) and 2.22 (1.35-3.65) times than those without these behaviors., Conclusions: Depressive symptoms co-occurred frequently among ATS users in China. The efforts that facilitate drug users' attempts to stop using ATS use and relapse, quit cigarette smoking and stop alcohol drinking during the ATS treatment and management process should be supported as they may contribute to improving the mental health among this population.

Rationale: Depletion of brain serotonin (5-HT) results in impulsive behaviour as measured by increased premature responding in the five-choice serial reaction time (5-CSRT) test. Acute selective blockade of 5-HT2C receptors also increases this form of impulsive action, whereas 5-HT2C receptor stimulation reduces premature responding., Objectives: These experiments determined the impact of genetic disruption of 5-HT2C receptor function on impulsive responding in the 5-CSRT test., Methods: Food-restricted 5-HT2C receptor null mutant and wild-type (WT) mice were trained on the 5-CSRT test in which subjects detect and correctly respond to brief light stimuli for food reinforcement. Impulsivity is measured as premature responses that occur prior to stimulus presentation., Results: Both lines of mice quickly learned this task, but there were no genotype differences in premature responding or any other aspect of performance. A series of drug challenges were then given. The 5-HT2C receptor agonist Ro60-0175 (0.6 mg/kg) reduced premature responding in WT mice but not mutant mice. The 5-HT2C receptor antagonist SB242084 increased premature responding in WT mice only. Cocaine increased premature responding at 7.5 mg/kg but not at a higher dose that disrupted overall responding; these effects were observed in both lines of mice. Amphetamine (0.25 and 0.5 mg/kg) did not affect premature responding, but disrupted other aspects of performance in both genotypes., Conclusions: Genetic deletion of 5-HT2C receptor function does not induce an impulsive state or exacerbate that state induced by psychomotor stimulants but does prevent the acute effects of 5-HT2C receptor stimulation or blockade on impulsive action.

Amphetamine is a major drug of abuse in Sweden and in the other Nordic countries. The demographics of amphetamine abusers in Sweden and the concentrations of this stimulant in blood are reported for 10 years of forensic blood samples (2001-2010). Using a forensic toxicology database (TOXBASE), we studied 1183 amphetamine-related deaths, 20,452 users of illicit drugs, and 47,366 people arrested for driving under the influence of drugs (DUID). Most amphetamine abusers were male (82%-87%), and their average age was 33 to 39 years with males being 2 to 3 years older than females (P < 0.001). Mean (median) concentrations of amphetamine in blood were 1.25 (0.40) mg/L in autopsy cases, 0.61 (0.40) mg/L in users of illicit drugs, and 0.76 (0.58) mg/L in DUID suspects. Median concentration in DUID suspects was significantly higher than in the other forensic materials (P < 0.001). Women also had higher median concentrations of amphetamine in blood than male abusers of this central stimulant (P < 0.001). The major coingested drugs were benzodiazepines (41%), cannabis (26%), opiates (21%), and alcohol (18%) in autopsy cases. Polydrug use was less common in DUID suspects and users of illicit drugs, although benzodiazepines (13%), tetrahydrocannabinol (12%), and opiates (5%) were often identified along with amphetamine. Because median concentration of amphetamine was higher in living subjects (DUID suspects) compared with amphetamine-related deaths, this points toward toxicity of coingested drugs or adverse drug-drug interaction as being responsible for death.

Previous investigations of the default-mode network (DMN) in persons with attention-deficit/hyperactivity disorder (ADHD) have shown reduced functional connectivity between the anterior and posterior aspects. This finding was originally demonstrated in adults with ADHD, then in youth with ADHD, and has been tentatively linked to ultra low frequency oscillations within the DMN. The current study evaluates the specificity of DMN abnormalities to neuronal oscillations in the ultra low frequency range, and examines the regional specificity of these DMN aberrations in medicated and unmedicated adults with, and those without ADHD. An individually matched sample of adults with and without ADHD completed 6-minute sessions of resting-state magnetoencephalography (MEG). Participants with ADHD were known responders to stimulant medications and completed two sessions (predrug/postdrug). MEG data were coregistered to the participant's MRI, corrected for head motion, fitted to a regional-level source model, and subjected to spectral analyses to extract neuronal population activity in regions of the DMN. The unmedicated adults with ADHD exhibited broadband deficits in medial prefrontal cortices (MPFC), but not other DMN regions compared to adults without ADHD. Unmedicated patients also showed abnormal cross-frequency coupling in the gamma range between the MPFC and posterior cingulate areas, and disturbed balance within the DMN as activity in posterior regions was stronger than frontal regions at beta and lower frequencies, which dissipated at higher γ-frequencies. Administration of pharmacotherapy significantly increased prefrontal alpha activity (8-14 Hz) in adults with ADHD, and decreased the cross-frequency gamma coupling. These results indicate that neurophysiological aberrations in the DMN of patients with ADHD are not limited to ultra slow oscillations, and that they may be primarily attributable to abnormal broadband activity in the MPFC., (Copyright © 2011 Wiley Periodicals, Inc.)

Drugs of abuse induce neuroplasticity in the natural reward pathway, specifically the nucleus accumbens (NAc), thereby causing development and expression of addictive behavior. Recent evidence suggests that natural rewards may cause similar changes in the NAc, suggesting that drugs may activate mechanisms of plasticity shared with natural rewards, and allowing for unique interplay between natural and drug rewards. In this study, we demonstrate that sexual experience in male rats when followed by short or prolonged periods of loss of sex reward causes enhanced amphetamine reward, indicated by sensitized conditioned place preference for low-dose (0.5 mg/kg) amphetamine. Moreover, the onset, but not the longer-term expression, of enhanced amphetamine reward was correlated with a transient increase in dendritic spines in the NAc. Next, a critical role for the transcription factor ΔFosB in sex experience-induced enhanced amphetamine reward and associated increases in dendritic spines on NAc neurons was established using viral vector gene transfer of the dominant-negative binding partner ΔJunD. Moreover, it was demonstrated that sexual experience-induced enhanced drug reward, ΔFosB, and spinogenesis are dependent on mating-induced dopamine D1 receptor activation in the NAc. Pharmacological blockade of D1 receptor, but not D2 receptor, in the NAc during sexual behavior attenuated ΔFosB induction and prevented increased spinogenesis and sensitized amphetamine reward. Together, these findings demonstrate that drugs of abuse and natural reward behaviors act on common molecular and cellular mechanisms of plasticity that control vulnerability to drug addiction, and that this increased vulnerability is mediated by ΔFosB and its downstream transcriptional targets.

Repeated administration of the indirect dopamine receptor agonist amphetamine (AMPH) produces robust locomotor sensitization and additional behavioral abnormalities. Accumulating evidence suggests that the developmental timing of drug exposure can critically influence this effect. The present study compared the consequences of withdrawal from repeated AMPH exposure in adolescence and adulthood on information processing and locomotor sensitization in C57BL/6 mice. Animals were injected daily with AMPH (1 or 2.5 mg/kg) or vehicle on 7 consecutive days starting either from postnatal day 35 to 42, or from postnatal day 70 to 77, following which they were given a 4 week withdrawal period before behavioral and pharmacological testing commenced. We found that withdrawal from the higher dose of AMPH (2.5 mg/kg/day) given either in adolescence or adulthood similarly disrupted selective associative learning as measured by the latent inhibition paradigm. None of the AMPH withdrawal groups displayed alterations in sensorimotor gating in the form of prepulse inhibition. Withdrawal from adult AMPH exposure at both doses induced marked locomotor sensitization, whereas adolescent pre-treatment with the higher (2.5 mg/kg/day) but not lower (1 mg/kg/day) dose of AMPH potentiated the locomotor-enhancing effects of acute AMPH re-challenge. Our study suggests that withdrawal from repeated AMPH exposure in adolescence and adulthood has similar consequences on selective associative learning, but the two manipulations differ with respect to their efficacy to induce long-term locomotor sensitization to the drug. The latter finding supports the hypothesis that the precise developmental timing determines, at least in part, the impact on long-term dopamine-associated sensitization processes., (Copyright © 2012 Elsevier B.V. and ECNP. All rights reserved.)

It was already found that Ang II AT₁ receptors are involved in the neuroadaptative changes induced by a single exposure to amphetamine, and such changes are related to the development of behavioral and neurochemical sensitization. The induction of the immediately early gene c-fos has been used to define brain activated areas by amphetamine. Our aim was to evaluate the participation of AT₁ receptors in the neuronal activation induced by amphetamine sensitization. The study examined the c-fos expression in mesocorticolimbic areas induced by amphetamine challenge (0.5 mg/kg i.p) in animals pretreated with candesartan, a selective AT₁ receptor blocker (3 mg/kg p.o × 5 days), and amphetamine (5 mg/kg i.p) 3 weeks before the challenge. Increased c-fos immunoreactivity was found in response to the amphetamine challenge in the dorsomedial caudate-putamen and nucleus accumbens, and both responses were blunted by the AT₁ receptor blocker pretreatment. In the infralimbic prefrontal cortex, increased c-fos immunoreactivity was found in response to amphetamine and saline challenge, and both were prevented by the AT₁ receptor blocker. No differences were found neither in ventral tegmental area nor prelimbic cortex between groups. Our results indicate an important role for brain Ang II in the behavioral and neuronal sensitization induced by amphetamine.

This article analyzes appropriate public policies for enhancement use of two most important stimulant drugs: Ritalin (methylphenidate) and Adderall (mixed amphetamine salts). The author argues that appropriate regulation of cognition enhancement drugs cannot be a result of a general discussion on cognitive enhancements as such, but has to be made on a case-by-case basis. Starting from the recently proposed taxation approach to cognition enhancement drugs, the author analyzes available, moderately permissive models of regulation. After a thorough analysis of relevant characteristics of methylphenidate and amphetamine, the author concludes that a moderately liberal permissive regulation of enhancement use by healthy adults might be appropriate for extended release forms of methylphenidate. However, due to their danger profile, amphetamine and instant release forms of methylphenidate should not be made readily available to healthy adults and would need to be prohibited.

This article examines rates of nonmedical use and diversion of extended-release amphetamine and extended-release oral methylphenidate in the United States. Prescription dispensing data were sourced from retail pharmacies. Nonmedical use data were collected from the Researched Abuse, Diversion and Addiction-Related Surveillance (RADARS) System Drug Diversion Program and Poison Center Program. Drug diversion trends nearly overlapped for extended-release amphetamine and extended-release oral methylphenidate. Calls to poison centers were generally similar; however, calls regarding extended-release amphetamine trended slightly lower than those for extended-release oral methylphenidate. Data suggest similar diversion and poison center call rates for extended-release amphetamine and extended-release oral methylphenidate.

Background: Numerous studies have indicated that serotonin (5-HT)1B receptor ligands affect the behavioral effects of psychostimulants (cocaine, amphetamine), including the reinforcing activities of these drugs., Methods: To substantiate a role for those receptors in incentive motivation for amphetamine, we used the extinction/reinstatement model to examine the effects of the 5-HT1B receptor ligands on the reinstatement of extinguished amphetamine-seeking behavior. Rats trained to self-administer amphetamine (0.06 mg/kg/infusion) subsequently underwent the extinction procedure. These rats were then tested for the amphetamine-primed or amphetamine-associated cue-induced reinstatement of extinguished amphetamine-seeking behavior., Results: The 5-HT1B receptor antagonist SB 216641 (5-7.5 mg/kg) attenuated the amphetamine (1.5 mg/kg)- and the amphetamine-associated cue combined with the threshold dose of amphetamine (0.5 mg/kg)-induced reinstatement of amphetamine-seeking behavior. The 5-HT1B receptor agonist CP 94253 (1.25-5 mg/kg) also inhibited the amphetamine-seeking behavior induced by amphetamine (1.5 mg/kg) but not by the cue combined with the threshold dose of amphetamine. The inhibitory effect of CP94253 on amphetamine-seeking behavior remained unaffected by the 5-HT1B receptor antagonist., Conclusion: Our results indicate that tonic activation of 5-HT1B receptors is involved in amphetamine- and cue-induced reinstatement of amphetamine-seeking behavior and that the inhibitory effects of 5-HT1B receptor antagonists on these phenomena are directly related to the motivational aspects of amphetamine abuse. The inhibitory effect of CP 94253 on amphetamine-seeking behavior seems to be unrelated to 5-HT1B receptor activation and may result from a general reduction of motivation.

We previously generated a knock-in mouse line with a cocaine-insensitive dopamine transporter (DAT-CI mice). These mice lost several behavioral responses to cocaine, but retained their response to amphetamine. DAT-CI mice are hyperdopaminergic due to reduced DAT function, and may thus be a good model for studying attention deficit hyperactivity disorder (ADHD). These mice had been behaviorally characterized while they were on a mixed genetic background. However as the colony was propagated over time, the mixed genetics were shifted toward a pure C57Bl/6J background--via a common breeding scheme known as "backcrossing." Several phenotypes appeared to have changed during this time frame. In this study, we investigated whether backcrossing altered the hyperlocomotive phenotype and behavioral responses to amphetamine, a drug used to treat ADHD. C57-congenic DAT-CI mice had high spontaneous locomotor activity that could be suppressed by low doses of amphetamine. Furthermore, their locomotion was not stimulated by very high doses of amphetamine (20mg/kg). After the reversion to a mixed genetic background by breeding with the 129 strain, the C57:129 hybrid DAT-CI mice displayed reduced basal locomotor activity compared to the C57-congenic mutant mice, and regained locomotor stimulation by high-dose amphetamine. The calming effect of amphetamine at low doses was retained in both strains. In summary, reduced DAT function in DAT-CI mice leads to a hyperdopaminergic state, and an ADHD-like phenotype in both strains. The data show that the genetic background of DAT-CI mice affects their locomotor phenotypes and their responses to amphetamine. Since the differences in genetic background between the strains of mice have a significant impact on the ADHD-like phenotype and the response to amphetamine, further study with these strains could identify the genetic underpinnings affecting the severity of ADHD-related symptoms and the treatment response., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Rationale: Frequency-modulated 50-kHz ultrasonic vocalizations (USVs) are emitted by adult rats in response to psychostimulants and non-pharmacological appetitive stimuli and thus have been proposed to model positive affect., Objective: The main aim was to determine whether rewarding doses of morphine increase 50-kHz call rate or alter the relative prevalence of the trill call subtype., Methods: In experiment 1, USVs were recorded from adult male Long-Evans rats after subchronic morphine (1 mg/kg subcutaneous (SC)) administration, acute challenge with morphine (1 and 3 mg/kg SC) or amphetamine (1 mg/kg IP, positive control), and in conjunction with locomotor activity tests with morphine (1 and 3 mg/kg SC). In experiments 2 and 3, the USV altering, rewarding, and locomotor effects of morphine were examined using a conditioned place preference (CPP) procedure., Results: In experiment 1, morphine (1 mg/kg) initially suppressed calling; rats became tolerant to this effect with repeated exposure. Tested subsequently in singly- and pair-tested rats, morphine markedly decreased USVs but significantly increased locomotor activity. In experiments 2 and 3, morphine produced a significant CPP without increasing either unconditioned or conditioned USV emission. Morphine did not detectably alter the relative prevalence of 50-kHz call subtypes., Conclusions: Although 50-kHz calls, and the trill call subtype in particular, have been proposed as an animal model of positive mood, not all euphoriant drugs acutely increase the rate of 50-kHz calling or consistently promote trill calls.

Differential rearing decreases psychostimulant-induced hyperactivity. In general, environmental enrichment decreases the locomotor response to low unit doses of psychostimuluants, whereas isolation increases the response. It is not clear whether the changes in locomotor activity are due to an enrichment-induced decrease or an isolation-induced increase. Therefore, the current experiments examined the ability of enrichment rearing, as compared with isolation and standard rearing, to attenuate amphetamine-induced hyperactivity following acute administration, repeated administration, and sensitization of a low (0.3 mg/kg) and moderate (1.0 mg/kg) dose of amphetamine. Rats were reared under enriched, isolated, or standard conditions. Enrichment slowed the acquisition of amphetamine-induced hyperactivity and attenuated the expression of amphetamine-induced sensitization, but only at the low unit dose. Enrichment did not protect against the expression of conditioned hyperactivity at either of the doses tested. The behavior of standard condition rats was generally closer to that of isolated condition rats than enriched condition rats, suggesting that the enrichment attenuates the response to amphetamine as opposed to isolation rearing increasing the response to amphetamine. These results suggest that the effects of enrichment are because of enrichment manipulation and not simply a contrast from the effects of isolation.

Asthma is an allergic lung disease can be modulated by drugs that modify the activity of central nervous system (CNS) such as amphetamine (AMPH). AMPH is a highly abused drug that exerts potent effects on behavior and immunity. In this study we investigated the mechanism involved in the effects of long-term AMPH treatment on the increased magnitude of allergic lung response. We evaluated mast cells degranulation, cytokines release, airways responsiveness and, expression of adhesion molecules. Male Wistar rats were treated with AMPH or vehicle (PBS) for 21 days and sensitized with ovalbumin (OVA) one week after the first injection of vehicle or AMPH. Fourteen days after the sensitization, the rats were challenged with an OVA aerosol, and 24h later their parameters were analyzed. In allergic rats, the treatment with AMPH exacerbated the lung cell recruitment due increased expression of ICAM-1, PECAM-1 and Mac-1 in granulocytes and macrophages recovered from bronchoalveolar lavage. Elevated levels of IL-4, but decreased levels of IL-10 were also found in samples of lung explants after AMPH treatment. Conversely, the ex-vivo tracheal hyper-responsiveness to methacholine (MCh) was reduced by AMPH treatment, whereas the force contraction of tracheal segments due to in vitro antigen challenge remained unaltered. Our findings suggest that lung inflammation and airway hyper-responsiveness due to OVA challenge are under the distinct control of AMPH during long-term treatment. Our data strongly indicate that AMPH positively modulates allergic lung inflammation via the increase of ICAM-1, PECAM-1, Mac-1 and IL-4. AMPH also abrogates the release of the anti-inflammatory cytokine IL-10., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Background: Cocaine dependence is a substantial public health problem, yet there are no clearly effective medication treatments. Amphetamine and topiramate have both shown promise for the treatment of cocaine dependence in preclinical and early-stage clinical studies., Methods: Eighty-one cocaine-dependent adults were randomized to receive a combination of extended-release mixed amphetamine salts (MAS-ER) and topiramate or placebo for 12 weeks under double-blind conditions. MAS-ER doses were titrated over 2 weeks to a maximum dose of 60 mg daily, and topiramate doses were titrated over 6 weeks to a maximum dose of 150 mg twice daily. All participants received a supportive behavioral intervention. The primary outcome was the proportion of individuals who achieved 3 consecutive weeks of abstinence as measured by urine toxicology confirmed self-report., Results: The overall proportion of participants who achieved 3 consecutive weeks of abstinence was larger in the extended-release mixed amphetamine salts and topiramate group (33.3%) than in placebo group (16.7%). There was a significant moderating effect of baseline total number of cocaine use days (Wald χ(2) = 3.75, df = 1, p = .05) on outcome, suggesting that the combination treatment was most effective for participants with a high baseline frequency of cocaine use., Conclusions: The results of this study supported our hypothesis that the combination of MAS-ER and topiramate would be superior to placebo in achieving 3 weeks of consecutive abstinence. These findings provide evidence that the combination of MAS-ER and topiramate is efficacious in promoting abstinence in cocaine-dependent individuals., (Copyright © 2012 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

The neuronal PAS domain protein 4 (Npas4) is a transcription factor that is almost exclusively expressed in the mammalian brain. As an activity-dependent transcription factor, Npas4 regulates the transcription of discrete genes and transcriptionally controls the experience-dependent learning and memory. In this study, we explored the impact of the psychostimulant amphetamine (AMPH) on Npas4 protein expression in the rat striatum. We found that acute systemic injection of AMPH had a minimal effect on protein levels of Npas4 in the caudate putamen (CPu) and nucleus accumbens (NAc), while AMPH readily increased protein products of the immediate early gene c-Fos in these regions. In contrast, repeated administration of AMPH (5mg/kg, once daily for 5 days) triggered a significant increase in Npas4 expression in the NAc, although repeated AMPH did not alter Npas4 in the CPu. These data demonstrate that Npas4 is an AMPH-sensitive transcription factor. It is inducible selectively in the NAc in response to repeated AMPH administration., (Published by Elsevier Ireland Ltd.)

Repeated intermittent exposure to amphetamine (AMPH) results in the development of persistent behavioral and neurological changes. When drug exposure is paired with a specific environment, contextual cues can control conditioned responses, context-specific sensitization, and alterations in dendritic morphology in the nucleus accumbens (NAc). Intact N-methyl-D-aspartate (NMDA) glutamate receptor signaling is thought to be required for associative learning. The acquisition of context-specific behavioral sensitization to AMPH and extinction of conditioned hyperactivity have been investigated in two genetically modified mouse strains: the serine racemase homozygous knockout (SR-/-) and glycine transporter 1 heterozygous mutant (GlyT1-/+). These strains have reciprocally altered NMDA receptor co-agonists, D-serine and glycine, levels that result in decreased (SR-/-) or increased (GlyT1-/+) NMDA receptor signaling. AMPH-induced changes in dendritic morphology in the NAc were also examined. SR-/- mice showed reduced expression of context-specific sensitization and conditioned hyperactivity. However, the conditioned hyperactivity in these mice is completely resistant to extinction. Extinction reversed AMPH-induced increased in NAc spine density in wild-type but not SR-/- mice. GlyT1 -/+ mice showed a more rapid acquisition of sensitization, but no alteration in the extinction of conditioned hyperactivity. The SR-/- data demonstrate that a genetic model of NMDA receptor hypofunction displays a reduced ability to extinguish conditioned responses to drug-associated stimuli. Findings also demonstrate that the morphological changes in the NAc encode conditioned responses that are sensitive to extinction and reduced NMDA receptor activity. NMDA receptor hypofunction may contribute to the comorbidity of substance abuse in schizophrenia.

Repeated exposure to amphetamine (AMPH) induces long-lasting behavioral changes, referred to as sensitization, that are accompanied by various neuroadaptations in the brain. To investigate the chemical changes that occur during behavioral sensitization, we applied a comparative proteomics approach to screen for neuropeptide changes in a rodent model of AMPH-induced sensitization. By measuring peptide profiles with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and comparing signal intensities using principal component analysis and variance statistics, subsets of peptides are found with significant differences in the dorsal striatum, nucleus accumbens, and medial prefrontal cortex of AMPH-sensitized male Sprague-Dawley rats. These biomarker peptides, identified in follow-up analyses using liquid chromatography and tandem mass spectrometry, suggest that behavioral sensitization to AMPH is associated with complex chemical adaptations that regulate energy/metabolism, neurotransmission, apoptosis, neuroprotection, and neuritogenesis, as well as cytoskeleton integrity and neuronal morphology. Our data contribute to a growing number of reports showing that in addition to the mesolimbic dopamine system, which is the best known signaling pathway involved with reinforcing the effect of psychostimulants, concomitant chemical changes in other pathways and in neuronal organization may play a part in the overall effect of chronic AMPH exposure on behavior., (© 2012 The Authors Journal of Neurochemistry © 2012 International Society for Neurochemistry.)

Recently, we reported that an initial decrease followed by recovery of food intake was observed during four days of amphetamine (AMPH) treatment and suggested that these changes in response were mediated by changes in neuropeptide Y (NPY) and proopiomelanocortin (POMC). Here we investigated if Y1 receptor (Y1R) and/or Y5 receptor (Y5R) might be involved in this regulation. Rats were treated daily with AMPH for four days. Changes in the expression levels of Y1R, Y5R, melanocortin receptor 3 (MC3R), and NPY were assessed and compared. Results showed that Y1R and MC3R increased, with a maximal increase of about 210% on Day 2 but with a restoration to the normal level on Day 4. In contrast, NPY decreased with a biggest reduction of about 45% on Day 2 and the pattern of expression during AMPH treatment was opposite to those of Y1R and MC3R, while the expression of Y5R was not changed. Central inhibitions of NPY formation or Y1R activity modulated the anorectic response of AMPH and the reciprocal regulation of NPY and MC3R, revealing a crucial role of Y1R in this action. It is suggested that Y1R participates in the reciprocal regulation of NPY- and MC3R-containing neurons in the hypothalamus during the anorectic effect of AMPH. These results may further the understanding of Y1R in the control of eating., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Rationale: Repeated exposure to psychostimulants alters behavioral responses to reward-related cues; however, the motivational underpinnings of this effect have not been fully characterized., Objectives: The following study was designed to examine how amphetamine sensitization affects performance in rats on a series of Pavlovian and operant tasks that distinguish between general-incentive and outcome-selective forms of conditioned responses., Methods: Adult male rats underwent Pavlovian and instrumental training for food pellet rewards. Following training, rats were sensitized to D-amphetamine (2 mg/kg for 7 days). Rats were subsequently tested on an outcome-selective Pavlovian-instrumental transfer (PIT) task, an outcome-reinstatement task, and an outcome devaluation task. Additionally, in a separate experiment, PIT was assessed in amphetamine-sensitized and control rats using a Pavlovian backward-conditioned stimulus., Results: Repeated amphetamine exposure sensitized locomotor activity to acute amphetamine challenge. Amphetamine altered responses to CS presentations by increasing conditioned approach. During tests of PIT, amphetamine-treated rats showed no outcome-selectivity in their responding, responding to a CS whether or not it shared a common outcome with the instrumental response. No effect of amphetamine sensitization was observed on tests of outcome-selective reinstatement by outcome delivery or action selection based on outcome value. Amphetamine-sensitized rats showed impaired outcome-selective PIT to a backward CS but were unaltered in conditioned approach., Conclusions: Amphetamine sensitization prevents outcome-selective responding during PIT, which is dissociable from amphetamine's effects on conditioned approach. These data suggest fundamental alterations in how stimuli motivate action in addiction.

Drug craving critically depends on the function of the interoceptive insular cortex, and may be triggered by contextual cues. However, the role of the insula in the long-term memory linking context with drug craving remains unknown. Such a memory trace probably resides in some neocortical region, much like other declarative memories. Studies in humans and rats suggest that the insula may include such a region. Rats chronically implanted with bilateral injection cannulae into the high-order rostral agranular insular cortex (RAIC) or the primary interoceptive posterior insula (pIC) were conditioned to prefer the initially aversive compartment of a 2-compartment place preference apparatus by repeatedly pairing it to amphetamine. We found a reversible but long-lasting loss (ca. 24 days) of amphetamine-conditioned place preference (CPP) and a decreased expression in the insula of zif268, a crucial protein in memory reconsolidation, when anisomycin (ANI) was microinjected into the RAIC immediately after the reactivation of the conditioned amphetamine/context memory. ANI infusion into the RAIC without reactivation did not change CPP, whereas ANI infusion into pIC plus caused a 15 days loss of CPP. We also found a 24 days loss of CPP when we reversibly inactivated pIC during extinction trials. We interpret these findings as evidence that the insular cortex, including the RAIC, is involved in a context/drug effect association. These results add a drug-related memory function to the insular cortex to the previously found role of the pIC in the perception of craving or malaise.

Background: China has experienced an epidemic of amphetamine-type stimulant (ATS) use in recent years. The present study explored the status and correlates of HIV and hepatitis C virus (HCV) infection among ATS users in China., Methods: A multicenter cross-sectional study of HIV and HCV status and associated behaviors among ATS users was conducted in 6 provinces from September 2009 to December 2010. Socioeconomic/behavioral risk factors were measured. Blood samples were collected to test for HIV and HCV antibodies., Results: Of the 1327 ATS users, the prevalence of HIV and exposure to HCV were 4.5% and 43.5%, respectively, with large geographic variations (0%-20.3% and 8.6%-67.1%, respectively). HIV infection was independently associated with living in Yunnan province [adjusted odds ratio = 15.8; 95% confidence interval (CI): 2.0 to 125.1), polydrug use (adjusted odds ratio = 2.6; 95% CI: 1.3 to 5.4), increased frequency of sexual behavior (adjusted odds ratio = 2.0; 95% CI: 1.1 to 4.1), history of sex with sexually transmitted infection-positive persons (adjusted odds ratio = 11.4; 95% CI: 1.3 to 98.9), and HCV infection (adjusted odds ratio = 2.8; 95% CI: 1.2 to 6.7). HCV was associated with study site, marital status, unemployment (adjusted odds ratio = 1.8; 95% CI: 1.3 to 2.4), a longer duration of ATS use, and history of injection use of ATS (adjusted odds ratio = 13.3; 95% CI: 1.5 to 116.1)., Conclusions: The prevalence of HIV was high among ATS users in Yunnan province but quite rare elsewhere, and the prevalence of exposure to HCV was high in 6 provinces. Risk factors emphasize the need for new prevention strategies toward this population at risk in China.

The influence of haloperidol intracutaneous injections on the development of spontaneous catalepsy phenomenon in SHR mice which received intraperitoneal injections of d,l-amphetamine (10 mg/kg) and haloperidol (5 mg/kg) alternately during 12 days, was studied ("neurochemical aggression"). It was demonstrated that alternating injections of d,l-amphetamine and haloperidol decrease the spontaneous catalepsy duration. Daily intracutaneous injections of haloperidol (0,25 mg/kg) prevented these changes but disrupted the spontaneous catalepsy phenomenon recovery by the 10-th day of measurements. A lower dosage (0,1 mg/kg) of haloperidol did not affect the results of the research. A conclusion was made that subchronic injections of haloperidol might have a protective effect in acute period of "neurochemical aggression" but slow down brain functioning recovery.

Acute amphetamine administration activates glycogen synthase kinase-3 (GSK3) by reducing its inhibitory serine-phosphorylation in mouse striatum and cerebral cortex. This results from Akt inactivation and is required for certain behavioral effects of amphetamine, such as increased locomotor activity. Here we tested if regulation of Akt and GSK3 was similarly affected by longer-term administration of amphetamine, as well as of methylphenidate, since each of these is administered chronically in patients with attention deficit hyperactivity disorder (ADHD). Akt is activated by post-translational phosphorylation on Thr308, and modulated by Ser473 phosphorylation, whereas phosphorylation on Ser21/9 inhibits the two GSK3 isoforms, GSK3α and GSK3β. After eight days of amphetamine or methylphenidate treatment, striatal Akt and GSK3 were dephosphorylated similar to reported changes after acute amphetamine treatment. Oppositely, in the cerebral cortex and hippocampus Akt and GSK3 phosphorylation increased after eight days of amphetamine or methylphenidate treatment. These opposite brain region changes in Akt and GSK3 phosphorylation matched opposite changes in the association of Akt with β-arrestin and GSK3, which after eight days of amphetamine treatment were increased in the striatum and decreased in the cerebral cortex. Thus, whereas the acute dephosphorylating effect of stimulants on Akt and GSK3 in the striatum was maintained, the response switched in the cerebral cortex after eight days of amphetamine or methylphenidate treatment to cause increased phosphorylation of Akt and GSK3. These results demonstrate that prolonged administration of stimulants causes brain region-selective differences in the regulation of Akt and GSK3., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Objective: We evaluated the hypothesis that later start of stimulant treatment of attention-deficit/hyperactivity disorder adversely affects academic progress in mathematics and language arts among 9- to 12-year-old children., Methods: We linked nationwide data from the Icelandic Medicines Registry and the Database of National Scholastic Examinations. The study population comprised 11,872 children born in 1994-1996 who took standardized tests in both fourth and seventh grade. We estimated the probability of academic decline (drop of ≥ 5.0 percentile points) according to drug exposure and timing of treatment start between examinations. To limit confounding by indication, we concentrated on children who started treatment either early or later, but at some point between fourth-grade and seventh-grade standardized tests., Results: In contrast with nonmedicated children, children starting stimulant treatment between their fourth- and seventh-grade tests were more likely to decline in test performance. The crude probability of academic decline was 72.9% in mathematics and 42.9% in language arts for children with a treatment start 25 to 36 months after the fourth-grade test. Compared with those starting treatment earlier (≤ 12 months after tests), the multivariable adjusted risk ratio (RR) for decline was 1.7 (95% confidence interval [CI]: 1.2-2.4) in mathematics and 1.1 (95% CI: 0.7-1.8) in language arts. The adjusted RR of mathematics decline with later treatment was higher among girls (RR, 2.7; 95% CI: 1.2-6.0) than boys (RR, 1.4; 95% CI: 0.9-2.0)., Conclusions: Later start of stimulant drug treatment of attention-deficit/hyperactivity disorder is associated with academic decline in mathematics.

Rationale: Addiction is a disease of learning and memory, as learning processes underlying acquisition, extinction, and reinstatement of drug-paired associations play central roles in addiction. Early developmental stress enhances risk for drug problems in adulthood. Environmental factors influencing learning and memory processes relevant to addiction remain incompletely characterized., Objectives: To determine effects of prenatal immune activation and developmental stress on conditioned place preference to amphetamine, and reversal learning., Methods: Pregnant Sprague-Dawley rats were injected with polyinosinic:polycytidylic acid (poly I:C) or vehicle on gestational day 14. Half of the male offspring received 2 h of restraint stress at post-natal day 35. Behavioral testing was performed in adulthood., Results: Restraint stress inhibited acquisition of place preference to low-dose amphetamine (0.5 mg/kg), while poly I:C treatment had no measurable effect on place preference acquisition. In contrast, drug-induced reinstatement of preference for drug-paired chamber was enhanced in offspring of poly I:C-treated dams [F(1,25)05.31, p00.03]. Performance on a Morris water maze reversal learning task was impaired in poly I:C offspring. Reversal learning performance was correlated with place preference reinstatement in non-stressed (r200.42, p00.0095), but not stressed rats (r2 00.04, p00.49)., Conclusions: Prenatal immune activation enhances drug induced reinstatement of conditioned place preference. These data demonstrate longstanding impact on behaviors with potential influence on risk for drug relapse as a consequence of prenatal immune activation. Further study is needed to determine clinical and epidemiological consequences of similar exposures in human populations.

Like illness-inducing agents (e.g., lithium chloride), drugs of abuse also suppress intake of a taste solution. To explore the nature of this drug-induced intake reduction, in the current study three aqueous stimuli with different initial values served as the conditioned stimuli (CSs) that were paired with a standard dose of amphetamine in a voluntary intake procedure and lick patterns were analyzed. Consistent with earlier studies, amphetamine significantly reduced intake of all three CSs (quinine, sodium chloride, and orange odor). In contrast to studies that analyze orofacial responses, we found that lick cluster size was significantly lowered by amphetamine, indicating that the psychoactive drug induced a conditioned reduction in taste palatability., (© 2012 American Psychological Association)

Rationale: Regulator of G-protein signaling 4 (RGS4) is a brain-enriched negative modulator of G-protein-coupled receptor signaling. Decreased availability of RGS4 in the frontal cortex and striatum has been described in animal models of schizophrenia and drug addiction. However, cellular and behavioral consequences of dysregulated RGS4-dependent receptor signaling in the brain remain poorly understood., Objective: This study aims to investigate whether RGS4, through inhibiting the function of mGluR5 receptors in the dorsal striatum (dSTR), regulates cellular and behavioral responses to acute amphetamine., Methods: After herpes simplex virus-RGS4 was infused into the dSTR, RGS4 overexpression as well as binding of recombinant RGS4 to mGluR5 was assessed. The effect of RGS4 overexpression on behavioral activity induced by the intrastriatal mGluR5 agonist, DHPG, or amphetamine was recorded. Activation of extracellular signal-regulated kinase (ERK) and Akt (protein kinase B) was measured in the dSTR tissue at the end of each behavioral experiment., Results: RGS4 overexpressed in the dSTR coimmunoprecipitated with mGluR5 receptors and suppressed both behavioral activity and phospho-ERK levels induced by DHPG. RGS4 overexpression or the mGluR5 antagonist, 3-((2-methyl-4-thiazolyl)ethynyl)pyridine (MTEP), attenuated amphetamine-induced phospho-ERK (but not phospho-Akt) levels. RGS4 suppressed amphetamine-induced vertical activity and augmented horizontal activity over 90 min. Similarly, MTEP augmented amphetamine-induced horizontal activity, but did not affect vertical activity., Conclusions: The present data demonstrate that RGS4 in the dSTR attenuates amphetamine-induced ERK signaling and decreases the behavioral efficacy of acute amphetamine likely by limiting mGluR5 function.

Chronic amphetamine injection increased spontaneous neuronal activity in sensomotor cortex and decreased spike activity in caudate nucleus. The neuronal ability to perform the conditioned reactions was greater in the cortex and smaller in the nucleus caudatus. By biochemical investigations it was showed the hyperactivity of dopaminergic system in the caudate nucleus compared to that in sensomotor cortex. During chronic amphetamine administration haloperidol caused effects similar to the ones caused by amphetamine on neuronal spike activity in sensomotor cortex and did not influence spike activity and neuronal conditioned reactions in the caudate nucleus. The short-term haloperidol action reduced the enzymes activity and particularly the biogenic amines level leading to the normalization of transmitter metabolism.

Drugs of abuse are known to reduce intake of a taste conditioned stimulus (conditional stimulus, CS), a behavioral response sometimes seen as paradoxical because the same drugs also serve as rewards in other behavioral procedures. In the present study we compared patterns of intake and palatability (assessed using microstructural analysis of licking) for a standard saccharin CS paired with the following: lithium chloride, morphine, amphetamine, or sucrose. We found that morphine and amphetamine, like lithium-induced illness, each suppressed CS intake and caused a reduction in saccharin palatability. Sucrose, a rewarding stimulus, did not reduce the palatability of the saccharin CS. We interpret these finds as evidence that drugs of abuse induce conditioned taste aversions., (© 2012 American Psychological Association)

Rationale: 3-((2-Methyl-1,3-thiazol-4-yl)ethynyl)pyridine hydrochloride (MTEP) is a metabotropic glutamate receptor 5 (mGluR5) antagonist that may alter drug sensitivity in differentially reared rats due to its involvement in the psychostimulant reward pathway and plasticity., Objectives: The purpose of this study was to assess the effects of MTEP on acute amphetamine-induced hyperactivity, conditioned hyperactivity, and sensitization., Methods: Rats were reared in an enriched (EC), isolated (IC), or standard (SC) condition after which rats were either administered MTEP (1.0 mg/kg, ip) or saline prior to an acute (0.5 or 1.0 mg/kg, sc) or repeated (0.3 mg/kg, sc) amphetamine exposure. Rats undergoing repeated amphetamine exposure were administered MTEP prior to conditioned hyperactivity and sensitization tests., Results: EC and SC rats administered with MTEP prior to acute amphetamine demonstrated attenuated amphetamine-induced locomotor activity compared to controls, while IC rats administered MTEP following repeated amphetamine exposure demonstrated attenuated amphetamine-induced locomotor activity. Interestingly, MTEP treatment only altered conditioned hyperactivity in EC rats, as MTEP pretreatment resulted in conditioned hyperactivity in EC rats while conditioned hyperactivity was not observed in EC rats pretreated with saline., Conclusions: Glutamatergic pathways are altered during differential rearing, which differentially alters the role of mGluR5 in EC, IC, and SC rats when administered psychostimulant acutely versus repeatedly. These findings suggest that differential rearing alters glutamatergic function, which reduces sensitivity to psychostimulants.

Background: Laboratory tasks that measure various facets of impulsivity derived from self-report questionnaires are important for elucidating the behavioral consequences of impulsivity in humans and for back-translating these facets to non-human species. Negative urgency, or mood-based rash action, is a self-report facet of impulsivity linked to problem substance use; however, a valid behavioral task is lacking., Methods: The current studies were designed to bridge self-report questionnaire and behavioral measures of negative urgency in humans and to determine if this could be back-translated to rats., Results: Humans scoring high in negative urgency showed greater behavioral responding and increased frustration following unexpected reward omission on a monetary-based task compared to subjects low in negative urgency. Rats also showed elevated responding for either sucrose pellets or intravenous amphetamine following unexpected reward omission., Conclusion: These results suggest that impulsive behavior engendered by unexpected reward omission may represent a valid behavioral model of negative urgency linked to substance abuse., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Individually, motor training, pharmacological interventions, and housing animals in an enriched environment (EE) following spinal cord injury (SCI) result in limited functional improvement but, when combined, may enhance motor function. Here, we tested amphetamine (AMPH)-enhanced skilled motor training following a unilateral C3-C4 contusion injury on the qualitative components of reaching and on skilled forelimb function, as assessed using single-pellet and staircase reaching tasks. Kinematic analysis evaluated the quality of the reach, and unskilled locomotor function was also tested. Animals receiving AMPH and skilled forelimb training performed better than operated control animals on qualitative reaching, but not on skilled reaching. Those that received the combination treatment and were housed in EE cages showed significantly less improvement in qualitative reaching and grasping. Kinematic analysis revealed a decrease in digit abduction during skilled reaching among all groups, with no differences among groups. Kinematics provided no evidence that improved function was related to improved quality of reach. There was no evidence of neuroprotection in the cervical spinal cord. The absence of evidence for kinematic improvement or neuroprotection suggested that AMPH-enhanced motor training is due primarily to supraspinal effects, an enhancement of attention during skilled motor training, or plasticity in supraspinal circuitry involved with motor control.

Several authors have shown that injections of the GABA(A) agonist muscimol into the medial shell region of the nucleus accumbens (AcbSh) result in large increases in food, but not water, intake. In previous studies we demonstrated that intra-AcbSh injections of either muscimol or of the indirect dopamine agonist amphetamine increase response output on a food-reinforced progressive ratio schedule. In the current experiment we extended these observations by examining the effects of muscimol and amphetamine injections on the performance of a water-reinforced progressive ratio task in mildly deprived animals. We found that muscimol did not affect the number of responses made in the water-reinforced task, even though a marked increase in responding was observed after amphetamine. Muscimol did, however, significantly increase food intake in the same animals. The results suggest that the enhancing effects of intra-AcbSh muscimol differ from those of amphetamine in that they are selective for food-reinforced behaviors., (Copyright © 2011. Published by Elsevier Inc.)

Numerous preclinical studies have demonstrated that noncontingent methamphetamine (METH) administration rapidly decreases both dopamine (DA) transporter (DAT) and vesicular monoamine-2 transporter (VMAT-2) function. Because of the importance of transporter function to the abuse and neurotoxic liabilities of METH, and previous research indicating that the effects of noncontingent METH treatment do not necessarily predict effects of contingent exposure, the present study examined the acute impact of METH self-administration on these transporters. Results revealed that five days of METH self-administration (4 h/session; 0.06 mg/infusion) decreased DAT and VMAT-2 activity, as assessed in synaptosomes and vesicles, respectively, prepared from striatal tissue 1 h after the final self-administration session. METH self-administration increased core body temperatures as well. Brain METH and amphetamine (AMPH) levels, assessed 1 h after the final self-administration session, were approximately twice greater in high-pressing rats compared to low-pressing rats despite similar changes in DAT function. In conclusion, the present manuscript is the first to describe transporter function and METH/AMPH levels after self-administration in rodents. These data provide a foundation to investigate complex questions including how the response of dopaminergic systems to METH self-administration contributes to contingent-related processes such as dependence., (Copyright © 2011 Wiley Periodicals, Inc.)

A number of data indicate that serotonin (5-HT) 5-HT(1B) receptor ligands affect the behavioral effects of psychostimulants. In the present study we examined effects of the selective 5-HT(1B) receptor antagonist N-[3-[3-(dimethylamino)ethoxy]-4-methoxyphenyl]-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]-4-carboxamide hydrochloride (SB 216641) and the agonist 5-propoxy-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-pyrrolo[3,2-b]pyridine hydrochloride (CP 94253) on amphetamine self-administration in rats. SB 216641 administered in doses of 2.5-7.5 mg/kg did not affect the self-administration of amphetamine injected in unit doses of 0.06 or 0.12 mg/kg/infusion. On the other hand, CP 94253 administered in doses of 2.5 or 5 mg/kg attenuated amphetamine self-administration, yet the effect of 2.5 mg/kg of the agonist was fairly weak and significant only in case of a higher unit dose of the psychostimulant. The inhibitory effect of CP 94253 administered in a dose of 5mg/kg on the self-administration of amphetamine injected in a unit dose of 0.06 mg/kg/infusion was significantly reduced by SB 216641 administrated in a dose of 7.5 mg/kg. These results indicate that tonic activation of 5-HT(1B) receptors is not involved in the self-administration of amphetamine, while pharmacological stimulation of these receptors attenuates this behavioral phenomenon., (Copyright © 2012 Elsevier B.V. All rights reserved.)

This report describes a behavioral test protocol for assessing anxiety in mice and rats in single or multiple sessions. The test is based on exposure of animals to an open-space elevated platform with suspended steep slopes attached on two opposite sides. In this test, all animals cross frequently onto and spend more time in the areas adjacent to slopes than in the areas adjacent to a void space. Balb/c mice (albinos) were shown consistently to be more anxious than CD-1 mice (albinos), c57/Bl6J and c57/Bl6N (pigmented) mice; they do not cross onto the slopes. When Balb/c mice are treated with amphetamine or diazepam, the number of crossings on the platform is significantly increased but only diazepam-treated mice do cross onto the slopes. In the presence of a protected space on the platform, the behavior of c57/Bl6J compares to that of Balb/c mice; they stop crossings onto the slopes and demonstrate avoidance response. Unlike the current existing tests, the present open-space anxiety test demonstrates reliable and consistent results with strong construct and discriminant validity. It provides unequivocal measures of fear-induced anxiety, which are not confounded with measures of fear-induced escape/avoidance responses, hyperactivity or impulsive responses.