Amphetamine Treatment Research Articles

Transcriptional profiling of SHR/NCrl prefrontal cortex shows hyperactivity-associated genes responsive to amphetamine challenge.

Several studies suggest a strong genetic component of attention-deficit/hyperactivity disorder (ADHD), a complex neurodevelopmental disorder characterized by inappropriate levels of hyperactivity, impulsivity and inattention. Determining specific genetic risk variants for each symptom dimension of ADHD may aid in the identification of the biological risk factors of the disorder. In this study, we explored the potential genetic underpinnings of the hyperactive phenotype of ADHD. To this end, we examined differentially expressed genes (DEGs) in the prefrontal cortex (PFC) of SHR/NCrl, an animal model of ADHD, compared with its genetic control, the Wistar Kyoto (WKY/NCrl) rat and the Wistar rat, strain used to represent the 'normal' heterogeneous population. Relative to WKY/NCrl and Wistar controls, SHR/NCrl showed hyperactivity in the open-field test. Treatment with the ADHD drug, amphetamine (AMPH) reduced hyperactivity in SHR/NCrl. Meanwhile, AMPH increased locomotor activity in WKY/NCrl and Wistar rats. Gene expression analysis found 21 common upregulated and 36 downregulated genes in the PFC of drug-naive SHR/NCrl when compared with WKY/NCrl and Wistar rats. Of these DEGs, expression levels of two genes, Atxn7 and Per2, which are involved in transcription and circadian rhythm, respectively, were downregulated following AMPH treatment in SHR/NCrl. Quantitative real-time-polymerase chain reaction analyses verified expression patterns of these genes in the PFC of drug-naïve and AMPH-treated SHR/NCrl. The present findings indicate genetic risk variants that may be associated with the hyperactive phenotype in ADHD. Further studies are warranted to establish the roles of Atxn7 and Per2 in mediating hyperactivity.

Effects of ketamine on the unconditioned and conditioned locomotor activity of preadolescent and adolescent rats: impact of age, sex, and drug dose.

Ketamine is used by preadolescent and adolescent humans for licit and illicit purposes. The goal of the present study was to determine the effects of acute and repeated ketamine treatment on the unconditioned behaviors and conditioned locomotor activity of preadolescent and adolescent rats. To assess unconditioned behaviors, female and male rats were injected with ketamine (5-40mg/kg), and distance traveled was measured on postnatal day (PD) 21-25 or PD 41-45. To assess conditioned activity, male and female rats were injected with saline or ketamine in either a novel test chamber or the home cage on PD 21-24 or PD 41-44. One day later, rats were injected with saline and conditioned activity was assessed. Ketamine produced a dose-dependent increase in the locomotor activity of preadolescent and adolescent rats. Preadolescent rats did not exhibit sex differences, but ketamine-induced locomotor activity was substantially stronger in adolescent females than males. Repeated ketamine treatment neither caused a day-dependent increase in locomotor activity nor produced conditioned activity in preadolescent or adolescent rats. The activity-enhancing effects of ketamine are consistent with the actions of an indirect dopamine agonist, while the inability of ketamine to induce conditioned activity is unlike what is observed after repeated cocaine or amphetamine treatment. This dichotomy could be due to ketamine's ability to both enhance DA neurotransmission and antagonize N-methyl-D-aspartate (NMDA) receptors. Additional research will be necessary to parse out the relative contributions of DA and NMDA system functioning when assessing the behavioral effects of ketamine during early ontogeny.

The amphetamine-associated context exerts a stronger motivational effect in low-anxiety rats than in high-anxiety rats

This study used the conditioned place preference test to explore the effects of subchronic amphetamine administration on drug-associated cues in rats with different emotional reactivity. We also examined the changes in markers of dopaminergic activity in brain regions in response to the amphetamine-paired context, after a withdrawal period preceded by subchronic amphetamine treatment. We used low-anxiety (LR) and high-anxiety (HR) rats, which are known to exhibit distinct levels of susceptibility to amphetamine. Compared to HR rats, LR rats spent significantly more time in the amphetamine-paired compartment after the withdrawal period preceded by subchronic amphetamine treatment. Compared to HR control rats, LR control rats showed higher expression of the D1 receptor in the nucleus accumbens core (NAC core) and basolateral amygdala and higher expression of the D2 receptor in the NAC core. After the amphetamine treatment and withdrawal period, the LR rats showed higher D1 receptor expression in the NAC core, an increased level of homovanilic acid (HVA) in the prefrontal cortex, the NAC and the central amygdala than HR rats, as well as lower D2 receptor expression in the NAC core and the amygdala than LR control rats.These results indicate that the differences in the activity of the dopaminergic mesolimbic system in the HR and LR rats are maintained and even enhanced after a multi-day break in the use of the drug, indicating the occurrence of sensitisation. These findings show that the innate reactivity of the limbic dopaminergic innervations, dependent on the level of emotional reactivity, may significantly and chronically modify the development and maintenance of sensitisation to amphetamine.

Dopamine transporter (DAT) genetic hypofunction in mice produces alterations consistent with ADHD but not schizophrenia or bipolar disorder

ADHD, schizophrenia and bipolar disorder are psychiatric diseases with a strong genetic component which share dopaminergic alterations. Dopamine transporter (DAT) genetics might be potentially implicated in all these disorders. However, in contrast to DAT absence, the effects of DAT hypofunction especially in developmental trajectories have been scarcely addressed. Thus, we comprehensively studied DAT hypofunctional mice (DAT+/-) from adolescence to adulthood to disentangle DAT-dependent alterations in the development of psychiatric-relevant phenotypes. From pre-adolescence onward, DAT+/- displayed a hyperactive phenotype, while responses to external stimuli and sensorimotor gating abilities were unaltered. General cognitive impairments in adolescent DAT+/- were partially ameliorated during adulthood in males but not in females. Despite this, attentional and impulsivity deficits were evident in DAT+/- adult males. At the molecular level, DAT+/- mice showed a reduced expression of Homer1a in the prefrontal cortex, while other brain regions as well as Arc and Homer1b expression were mostly unaffected. Amphetamine treatments reverted DAT+/- hyperactivity and rescued cognitive deficits. Moreover, amphetamine shifted DAT-dependent Homer1a altered expression from prefrontal cortex to striatal regions. These behavioral and molecular phenotypes indicate that a genetic-driven DAT hypofunction alters neurodevelopmental trajectories consistent with ADHD, but not with schizophrenia and bipolar disorders.

Amphetamine treatment affects the extra‐hypothalamic vasopressinergic system in a sex‐ and nucleus‐dependent manner

The lateral septum (LS), a brain structure implicated in addictive behaviours, regulates the activation of dopaminergic neurones in the ventral tegmental area. Vasopressinergic projections from the extended amygdala to the LS, which are sexually dimorphic, could be responsible for the vulnerability to addiction in a sex-dependent manner. The present study aimed to investigate the modulatory effects of amphetamine (AMPH) on the expression of vasopressin (AVP) in the vasopressinergic extra-hypothalamic system in sensitised male and female rats. Adult male and female Sprague-Dawley rats underwent an AMPH-locomotor sensitisation protocol. Acute AMPH increased AVP mRNA expression in the medial amygdala (MeA), whereas AMPH-induced sensitisation increased AVP mRNA expression in the bed nucleus of the stria terminalis (BNST) only in females. Interestingly, the increase in AVP expression in BNST was higher in oestrus females compared to dioestrus females and acute AMPH resulted in a decrease in AVP levels in the LS, only in males. Thus, there are complex and region-specific interactions between AMPH and the extra-hypothalamic vasopressinergic system in the brain, underlying possible alterations in different behaviours caused by acute and chronic AMPH exposure.

Participation of ghrelin signalling in the reciprocal regulation of hypothalamic NPY/POMC-mediated appetite control in amphetamine-treated rats

Hypothalamic neuropeptide Y (NPY) and proopiomelanocortin (POMC) have been documented to participate in amphetamine (AMPH)-induced appetite suppression. This study investigated whether ghrelin signalling is associated with changes in NPY/POMC-mediated appetite control. Rats were given AMPH daily for four days, and changes in food intake, body weight, plasma ghrelin, hypothalamic NPY, melanocortin 3 receptor (MC3R), ghrelin O-acyltransferase (GOAT), acyl ghrelin (AG) and ghrelin receptor (GHSR1a) were examined and compared. Food intake, body weight and NPY expression decreased, while MC3R expression increased and expressed reciprocally to NPY expression during AMPH treatment. Plasma ghrelin and hypothalamic AG/GOAT/GHSR1a expression decreased on Day 1 and Day 2, which was associated with the positive energy metabolism, and returned to normal levels on Day 3 and Day 4, which was associated with the negative energy metabolism; this expression pattern was similar to that of NPY. Infusion with a GHSR1a antagonist or an NPY antisense into the brain enhanced the decrease in NPY and AG/GOAT/GHSR1a expression and the increase in MC3R expression compared to the AMPH-treated group. Peripheral ghrelin and the central ghrelin system participated in the regulation in AMPH-induced appetite control. These results shed light on the involvement of ghrelin signalling in reciprocal regulation of NPY/POMC-mediated appetite control and may prove useful for the development of anti-obesity drugs.

Effects of amphetamine and methylphenidate on attentional performance and impulsivity in the mouse 5-Choice Serial Reaction Time Task.

Few studies have investigated the effects of conventional attention deficit-hyperactivity disorder (ADHD) medication in the mouse 5-choice serial reaction time task (5-CSRTT), and rat studies have yielded inconsistent results. We aimed to examine the effects of acute methylphenidate (MPH) and amphetamine (AMPH) treatment in the mouse 5-CSRTT. Trained male C57Bl/6J mice were tested in a variable stimulus duration schedule. Effects of AMPH (0.25, 0.5, and 1 mg/kg) and MPH (0.5, 1.0, and 2.0 mg/kg) on discriminative accuracy, omissions, and premature responses were assessed. Saline treatment data determined high- and low-attentive (LA), and high- and low-impulsive (LI) subgroups according to the upper and lower 30th percentiles, respectively. In the LA subgroup accuracy was improved by 0.5 mg/kg AMPH and 2 mg/kg MPH, while no effect was found in the high-attentive (HA) subgroup. Premature responses were increased by 1 mg/kg AMPH and 0.5 mg/kg MPH for all animals, and by 1 mg/kg AMPH for the LI subgroup. The use of variable stimulus duration, along with the division into high- and LA, and high-and LI subgroups, may improve the sensitivity of the 5-CSRTT when investigating drug effects on attention and impulsivity.

P.4.b.016 - A multiple ascending dose study with evidence for target engagement of BNC210; a negative allosteric modulator of alpha7 nAChR in development for anxiety

The relationship between stress response and positive affective states is thought to be bidirectional: whilst stress can lead to a blunted hedonic response, positive affect reduces the negative effects of stress. We have previously shown that persistently high positive affectivity as measured by 50-kHz ultrasonic vocalizations (USVs) is protective against chronic variable stress (CVS). The present study examined the effect of CVS on 50-kHz USVs elicited by amphetamine administration, simultaneously considering the stable inter-individual differences in positive affectivity. Forty juvenile male Wistar rats were categorised as of high (HC) or low (LC) positive affectivity based on their 50-kHz USV response to imitation of rough-and-tumble play (‘tickling’). As adults, the rats were subjected to four weeks of CVS, after which D-amphetamine was administered in five daily doses followed by a challenge dose (all 1 mg/kg IP) nine days later. CVS reduced sucrose preference in LC-rats only. After CVS, amphetamine-elicited 50-kHz USVs were significantly reduced in LC-rats, the effect of stress in HC-rats being smaller and less consistent. In previously stressed and amphetamine-treated LC-rats, locomotor response to amphetamine was attenuated. In stressed LC-rats, DOPAC levels and dopamine turnover were increased in striatum after amphetamine treatment, and dopamine D1 receptor levels were upregulated in nucleus accumbens. LC-rats had lower isoleucine levels in frontal cortex. These results show that stress-related changes in response to amphetamine are dependent on inter-individual differences in positive affectivity both at neurochemical and behavioural levels, and further support the notion of higher vulnerability of animals with low positive affect.

Opposite effects of acute and chronic amphetamine on Nurr1 and NF-κB p65 in the rat ventral tegmental area

Dopamine neurons are overstimulated by drugs of abuse and suffer molecular alterations that lead to addiction behavior. Nurr1 is a transcription factor crucial for dopamine neurons survival and dopamine production, activating the transcription of key genes like tyrosine hydroxylase (TH). Interestingly, nuclear factor-kappa B (NF-κB) has emerged as a new Nurr1 partner in response to inflammatory stimulus. In this study we evaluated the effects of single and repeated amphetamine administration in the expression of Nurr1 and the NF-κB p65 subunit in the rat ventral tegmental area (VTA). We found that acute amphetamine treatment increased Nurr1, p65 and TH protein levels in the VTA. On the other hand, chronic amphetamine treatment decreased Nurr1 and p65 protein levels, but TH was unchanged. Mammalian reporter assays in cell lines showed that p65 represses Nurr1 transcriptional activity in an artificial promoter driven by Nurr1 response elements and in the native rat TH promoter. These results indicate that Nurr1 and NF-κB p65 factors are involved in the adaptive response of dopamine neurons to psychostimulants and that both transcription factors could be regulating Nurr1-dependent transactivation in the VTA.

Effects of 21-day d-amphetamine and risperidone treatment on cocaine vs food choice and extended-access cocaine intake in male rhesus monkeys

BackgroundClinical trial data suggest amphetamine treatment is most efficacious in moderate to high frequency cocaine users. However, preclinical studies have examined amphetamine treatment effects under relatively limited cocaine access conditions with low to moderate cocaine intakes. This study determined d-amphetamine treatment effects on cocaine self-administration in rhesus monkeys under cocaine access conditions allowing for high daily cocaine intake. For comparison and as a negative control, treatment effects with the antipsychotic risperidone were also examined. MethodsContinuous 21-day treatments with ramping doses of d-amphetamine (days 1–7: 0.032mg/kg/h; days 8–21: 0.1mg/kg/h, i.v.) or risperidone (days 1–7: 0.001mg/kg/h; days 8–14: 0.0032mg/kg/h; days 15–21: 0.0056mg/kg/h, i.v.) were administered to rhesus monkeys (n=4) with daily access to two types of cocaine self-administration sessions: (1) a 2-h ‘choice’ session with concurrent availability of 1-g food pellets and intravenous cocaine injections (0–0.1mg/kg per injection) and (2) a 20-h ‘extended-access’ session with 0.1mg/kg per injection cocaine availability. ResultsTotal daily cocaine intake increased >6-fold during extended cocaine access. d-Amphetamine significantly decreased total cocaine intake, but not cocaine vs food choice. In contrast, risperidone did not significantly alter either total cocaine intake or cocaine vs. food choice. ConclusionsThese results confirm and extend previous results supporting treatment effectiveness for monoamine releasers, but not dopamine antagonists, to reduce cocaine self-administration. Moreover, these results suggest amphetamine treatment efficacy to decrease preclinical cocaine vs. food choice may depend upon cocaine access conditions.

Regrowth of Serotonin Axons in the Adult Mouse Brain Following Injury

It is widely believed that damaged axons in the adult mammalian brain have little capacity to regrow, thereby impeding functional recovery after injury. Studies using fixed tissue have suggested that serotonin neurons might be a notable exception, but remain inconclusive. We have employed invivo two-photon microscopy to produce time-lapse images of serotonin axons in the neocortex of the adult mouse. Serotonin axons undergo massive retrograde degeneration following amphetamine treatment and subsequent slow recovery of axonal density, which is dominated by new growth with little contribution from local sprouting. A stab injury that transects serotonin axons running in the neocortex is followed by local regression of cut serotonin axons and followed by regrowth from cut ends into and across the stab rift zone. Regrowing serotonin axons do not follow the pathways left by degenerated axons. The regrown axons release serotonin and their regrowth is correlated with recovery in behavioral tests.

Role of oxidative stress in disrupting the function of negative glucocorticoid response element in daily amphetamine-treated rats

Amphetamine (AMPH)-induced appetite suppression is associated with changes in hypothalamic reactive oxygen species (ROS), antioxidants, neuropeptides, and plasma glucocorticoid. This study explored whether ROS and glucocorticoid response element (GRE), which is the promoter site of corticotropin-releasing hormone (CRH) gene, participated in neuropeptides-mediated appetite control. Rats were treated daily with AMPH for four days, and changes in food intake, plasma glucocorticoid and expression levels of hypothalamic neuropeptide Y (NPY), proopiomelanocortin (POMC), superoxide dismutase (SOD), CRH, and glucocorticoid receptor (GR) were examined and compared. Results showed that food intake decreased and NPY gene down-regulated, while POMC, SOD, and CRH gene up-regulated during AMPH treatment. GR and GRE-DNA bindings were disrupted on Day 1 and Day 2 when glucocorticoid levels were still high. Pretreatment with GR inhibitor or ROS scavenger modulated mRNA levels in NPY, POMC, SOD and CRH in AMPH-treated rats. We suggest that disruptions of negative GRE (nGRE) on Day 1 and Day 2 are associated with an increase in oxidative stress during the regulation of NPY/POMC-mediated appetite control in AMPH-treated rats. These results advance the understanding of molecular mechanism in regulating AMPH-mediated appetite suppression.

Mesocortical Dopamine Phenotypes in Mice Lacking the Sonic Hedgehog Receptor Cdon

Motivated behaviors and many psychopathologies typically involve changes in dopamine release from the projections of the ventral tegmental area (VTA) and/or the substantia nigra pars compacta (SNc). The morphogen Sonic Hedgehog (Shh) specifies fates of midbrain dopamine neurons, but VTA-specific effects of Shh signaling are also being uncovered. In this study, we assessed the role of the Shh receptor Cdon in the development of VTA and SNc dopamine neurons. We find that Cdon is expressed in the proliferating progenitor zone of the embryonic ventral midbrain and that the number of proliferating cells in this region is increased in mouse Cdon−/− embryos. Consistent with a role of Shh in the regulation of neuronal proliferation in this region, we find that the number of tyrosine hydroxylase (TH)-positive neurons is increased in the VTA of Cdon−/− mice at birth and that this effect endures into adulthood. In contrast, the number of TH-positive neurons in the SNc is not altered in Cdon−/− mice at either age. Moreover, adult Cdon−/− mice have a greater number of medial prefrontal cortex (mPFC) dopamine presynaptic sites, and increased baseline concentrations of dopamine and dopamine metabolites selectively in this region. Finally, consistent with increased dopamine function in the mPFC, we find that adult Cdon−/− mice fail to exhibit behavioral plasticity upon repeated amphetamine treatment. Based on these data, we suggest that Cdon plays an important role encoding the diversity of dopamine neurons in the midbrain, influencing both the development of the mesocortical dopamine pathway and behavioral outputs that involve this neural circuitry.

Vitamin D3: A Role in Dopamine Circuit Regulation, Diet-Induced Obesity, and Drug Consumption.

The influence of micronutrients on dopamine systems is not well defined. Using mice, we show a potential role for reduced dietary vitamin D3 (cholecalciferol) in promoting diet-induced obesity (DIO), food intake, and drug consumption while on a high fat diet. To complement these deficiency studies, treatments with exogenous fully active vitamin D3 (calcitriol, 10 µg/kg, i.p.) were performed. Nondeficient mice that were made leptin resistant with a high fat diet displayed reduced food intake and body weight after an acute treatment with exogenous calcitriol. Dopamine neurons in the midbrain and their target neurons in the striatum were found to express vitamin D3 receptor protein. Acute calcitriol treatment led to transcriptional changes of dopamine-related genes in these regions in naive mice, enhanced amphetamine-induced dopamine release in both naive mice and rats, and increased locomotor activity after acute amphetamine treatment (2.5 mg/kg, i.p.). Alternatively, mice that were chronically fed either the reduced D3 high fat or chow diets displayed less activity after acute amphetamine treatment compared with their respective controls. Finally, high fat deficient mice that were trained to orally consume liquid amphetamine (90 mg/L) displayed increased consumption, while nondeficient mice treated with calcitriol showed reduced consumption. Our findings suggest that reduced dietary D3 may be a contributing environmental factor enhancing DIO as well as drug intake while eating a high fat diet. Moreover, these data demonstrate that dopamine circuits are modulated by D3 signaling, and may serve as direct or indirect targets for exogenous calcitriol.

Neural Correlates of Symptom Improvement Following Stimulant Treatment in Adults with Attention-Deficit/Hyperactivity Disorder.

The purposes of this study were to examine the impact of 3 weeks of amphetamine administration on intrinsic connectome-wide connectivity patterns in adults with attention-deficit/hyperactivity disorder (ADHD) and explore the association between stimulant-induced symptom improvement and functional connectivity alteration. Participants included 19 adults (age 20-55 years) diagnosed with ADHD using the Diagnostic and Statistical Manual of Mental Disorders, 4th ed., Text Revision (DSM-IV-TR) criteria per the Adult Clinician Diagnostic Scale taking part in amphetamine trials. For each patient, two 6-minute resting-state functional magnetic resonance imaging (R-fMRI) scans were acquired at baseline and after treatment. A fully data-driven multivariate analytic approach (i.e., multivariate distance matrix regression [MDMR]) was applied to R-fMRI data to characterize the distributed pharmacological effects in the entire functional connectome. Clinical efficacy was assessed using ADHD rating scale with adult prompts and the Adult Self-Report Scale v1.1 Symptom Checklist. We linked stimulant-induced functional connectivity changes to symptom amelioration using Spearman's correlation. Three weeks of administration of a stimulant significantly reduced ADHD symptoms. MDMR-based analyses on R-fMRI data highlighted the left dorsolateral prefrontal cortex (DLPFC, a key cognitive control region) and the medial prefrontal cortex (MPFC, the anterior core of default network) whose distributed patterns of functional connectivity across the entire brain were altered by psychostimulants. Follow-up intrinsic functional connectivity revealed that stimulants specifically decreased the positive functional connectivity between DLPFC-insula, DLPFC-anterior cingulate cortex, and MPFC-insula. Importantly, these functional connectivity changes are associated with symptom improvement. These results suggested that ADHD is associated with increased functional integration or decreased functional segregation between core regions of cognitive control, default, and salience networks. The apparent normalization of intrinsic functional interaction in these circuits (i.e., increased functional segregation) may underlie the clinical benefits produced by 3 weeks of amphetamine treatment.

Chronic variable stress prevents amphetamine-elicited 50-kHz calls in rats with low positive affectivity

The relationship between stress response and positive affective states is thought to be bidirectional: whilst stress can lead to a blunted hedonic response, positive affect reduces the negative effects of stress. We have previously shown that persistently high positive affectivity as measured by 50-kHz ultrasonic vocalizations (USVs) is protective against chronic variable stress (CVS). The present study examined the effect of CVS on 50-kHz USVs elicited by amphetamine administration, simultaneously considering the stable inter-individual differences in positive affectivity. Forty juvenile male Wistar rats were categorised as of high (HC) or low (LC) positive affectivity based on their 50-kHz USV response to imitation of rough-and-tumble play (‘tickling’). As adults, the rats were subjected to four weeks of CVS, after which D-amphetamine was administered in five daily doses followed by a challenge dose (all 1mg/kg IP) nine days later. CVS reduced sucrose preference in LC-rats only. After CVS, amphetamine-elicited 50-kHz USVs were significantly reduced in LC-rats, the effect of stress in HC-rats being smaller and less consistent. In previously stressed and amphetamine-treated LC-rats, locomotor response to amphetamine was attenuated. In stressed LC-rats, DOPAC levels and dopamine turnover were increased in striatum after amphetamine treatment, and dopamine D1 receptor levels were upregulated in nucleus accumbens. LC-rats had lower isoleucine levels in frontal cortex. These results show that stress-related changes in response to amphetamine are dependent on inter-individual differences in positive affectivity both at neurochemical and behavioural levels, and further support the notion of higher vulnerability of animals with low positive affect.

Midkine Is a Novel Regulator of Amphetamine-Induced Striatal Gliosis and Cognitive Impairment: Evidence for a Stimulus-Dependent Regulation of Neuroinflammation by Midkine.

Midkine (MK) is a cytokine that modulates amphetamine-induced striatal astrogliosis, suggesting a possible role of MK in neuroinflammation induced by amphetamine. To test this hypothesis, we studied astrogliosis and microglial response induced by amphetamine (10 mg/kg i.p. four times, every 2 h) in different brain areas of MK−/− mice and wild type (WT) mice. We found that amphetamine-induced microgliosis and astrocytosis are enhanced in the striatum of MK−/− mice in a region-specific manner. Surprisingly, LPS-induced astrogliosis in the striatum was blocked in MK−/− mice. Since striatal neuroinflammation induced by amphetamine-type stimulants correlates with the cognitive deficits induced by these drugs, we also tested the long-term effects of periadolescent amphetamine treatment (3 mg/kg i.p. daily for 10 days) in a memory task in MK−/− and WT mice. Significant deficits in the Y-maze test were only observed in amphetamine-pretreated MK−/− mice. The data demonstrate for the first time that MK is a novel modulator of neuroinflammation depending on the inflammatory stimulus and the brain area considered. The data indicate that MK limits amphetamine-induced striatal neuroinflammation. In addition, our data demonstrate that periadolescent amphetamine treatment in mice results in transient disruption of learning and memory processes in absence of endogenous MK.

Influence of amphetamine, γ-aminobutyric acid, and fosmidomycin on metabolic, transcriptional variations and determination of their biological activities in turnip (Brassica rapa ssp. rapa)

The impact of amphetamine (AMP), γ-aminobutyric acid (GABA), and fosmidomycin (FOS) on the contents of glucosinolates (GSLs), polyphenols, carotenoids, chlorophyll, anthocyanin, malondialdehyde, hydrogen peroxide, antioxidant, antimicrobial activities, and gene regulation of phytochemicals biosynthesis was studied in turnip plants. The AMP and GABA treatments were significantly increased the amount of GSLs. FOS-treated plants were obviously decreased the level of GSLs. Total phenolic, flavonoid contents, antioxidant, and antimicrobial activities were substantially increased in FOS-, GABA-, and AMP-treated plants. Lutein was higher in control compared to treated plants. The chlorophyll content considerably decreased, while anthocyanin, malondialdehyde, and hydrogen peroxide levels significantly increased with under GABA treatment. Furthermore, AMP-, GABA-, and FOS-treated plants were showed significant induction of expression of genes related to the secondary metabolites. These results demonstrated that the AMP and GABA significantly increased the contents of health-promoting compounds and enhanced biological activities in turnip plants.

A novel neuropeptide regulator of behavioral sensitization to cocaine

Aims: We have previously demonstrated in male rats that repeated exposure to amphetamine (AMPH) from earlyto midadolescence [postnatal day (P) 27 to 45] persistently alters the function of dopamine D1 receptors in the medial prefrontal cortex (mPFC). Here, we determined if this functional change was associated with altered D1 expression in the mPFC and nucleus accumbens (NAc), whether the timing of drug exposure (earlyvs. late-adolescence) influenced drug-induced plasticity, and whether adolescent AMPH exposure altered anxietyand depression-like behavior. Methods: Male and female Sprague-Dawley rats (n=78) were treatedwith salineor3mg/kgAMPH(i.p.) everyotherday (10 injections total) during early (P27 to 45) or late adolescence (P37 to 55). Sucrose preference (SP) tests were then performed after 1, 7, and 21 days of withdrawal. For each test, the consumption of water and 1% sucrose was measured for 48h. Before the last SP test, anxietylike behavior was assessed by measuring activity in an open-field arena and an elevated plus maze (EPM). Rats were sacrificed after finishing the last SP test, the mPFC and NAc were collected, and D1 protein levels were measured using Western blot analysis. Results: AMPH exposure induced a decrease of SP during the first test. In the EPM, early, but not late, AMPH treatment increased time spent in open arms. Lastly, we found decreased D1 levels in the mPFC following early AMPH exposure. Conclusions: Our preliminary findings suggest that adolescent AMPH exposure induces lasting changes in mPFC D1 expression, which may play a role in the anhedonia and “risk taking” behavior we observed. Importantly, these drug-induced changes are more robust following earlycompared to late-adolescent exposure, suggesting a heightened vulnerability to AMPH in early adolescence. Financial support: This study is supported byNIH (DA 029815).

Amphetamine exposure during adolescence alters anxiety- and depression-like behaviors and prefrontal cortex dopamine receptor expression in adulthood

Aims: We have previously demonstrated in male rats that repeated exposure to amphetamine (AMPH) from earlyto midadolescence [postnatal day (P) 27 to 45] persistently alters the function of dopamine D1 receptors in the medial prefrontal cortex (mPFC). Here, we determined if this functional change was associated with altered D1 expression in the mPFC and nucleus accumbens (NAc), whether the timing of drug exposure (earlyvs. late-adolescence) influenced drug-induced plasticity, and whether adolescent AMPH exposure altered anxietyand depression-like behavior. Methods: Male and female Sprague-Dawley rats (n=78) were treatedwith salineor3mg/kgAMPH(i.p.) everyotherday (10 injections total) during early (P27 to 45) or late adolescence (P37 to 55). Sucrose preference (SP) tests were then performed after 1, 7, and 21 days of withdrawal. For each test, the consumption of water and 1% sucrose was measured for 48h. Before the last SP test, anxietylike behavior was assessed by measuring activity in an open-field arena and an elevated plus maze (EPM). Rats were sacrificed after finishing the last SP test, the mPFC and NAc were collected, and D1 protein levels were measured using Western blot analysis. Results: AMPH exposure induced a decrease of SP during the first test. In the EPM, early, but not late, AMPH treatment increased time spent in open arms. Lastly, we found decreased D1 levels in the mPFC following early AMPH exposure. Conclusions: Our preliminary findings suggest that adolescent AMPH exposure induces lasting changes in mPFC D1 expression, which may play a role in the anhedonia and “risk taking” behavior we observed. Importantly, these drug-induced changes are more robust following earlycompared to late-adolescent exposure, suggesting a heightened vulnerability to AMPH in early adolescence. Financial support: This study is supported byNIH (DA 029815).