Can exposure to lisdexamfetamine dimesylate from juvenile period to peripubertal compromise male reproductive parameters in adult rats?

Lisdexamfetamine (LDX) is a d-amphetamine prodrug used to treat attention deficit and hyperactivity disorder, a common neurodevelopmental disorder in children and adolescents. Due to its action mediated by elevated levels of catecholamines, mainly dopamine and noradrenaline, which influence hormonal regulation and directly affect the gonads, this drug may potentially disrupt reproductive performance. This study evaluated the effects of exposure to LDX from the juvenile to peripubertal period (critical stages of development) on systemic and reproductive toxicity parameters in male rats. Male Wistar rats (23 days old) were treated with 0; 5.2; 8.6 or 12.1 mg/kg/day of LDX from post-natal day (PND) 23 to 53, by gavage. LDX treatment led to reduced daily food and water consumption, as well as a decrease in social behaviors. The day of preputial separation remained unaltered, although the treated animals exhibited reduced weight. At PND 54, the treated animals presented signs of systemic toxicity, evidenced by a reduction in body weight gain, increase in the relative weight of the liver, spleen, and seminal gland, reduction in erythrocyte and leukocyte counts, reduced total protein levels, and disruptions in oxidative parameters. In adulthood, there was an increase in immobile sperm, reduced sperm count, morphometric changes in the testis, and altered oxidative parameters, without compromising male sexual behavior and fertility. These findings showed that LDX-treatment during the juvenile and peripubertal periods induced immediate systemic toxicity and adversely influenced reproductive function in adult life, indicating that caution is necessary when prescribing this drug during the peripubertal phase.

The GLP-1 receptor agonist liraglutide reverses mania-like alterations and memory deficits induced by D-amphetamine and augments lithium effects in mice: Relevance for bipolar disorder.

Metabolic and psychiatric disorders present a bidirectional relationship. GLP-1 system, known for its insulinotropic effects, has also been associated with numerous regulatory effects in cognitive and emotional processing. GLP-1 receptors (GLP-1R) agonists present neuroprotective and antidepressant/anxiolytic properties. However, the effects of GLP-1R agonism in bipolar disorder (BD) mania and the related cognitive disturbances remains unknown. Here, we investigated the effects of the GLP-1R agonist liraglutide (LIRA) at monotherapy or combined with lithium (Li) against D-amphetamine (AMPH)-induced mania-like symptoms, brain oxidative and BDNF alterations in mice. Swiss mice received AMPH 2 mg/kg or saline for 14 days. Between days 8-14, they received LIRA 120 or 240 µg/kg, Li 47.5 mg/kg or the combination Li + LIRA, on both doses. After behavioral evaluation the brain areas prefrontal cortex (PFC), hippocampus and amygdala were collected. AMPH induced hyperlocomotion, risk-taking behavior and multiple cognitive deficits which resemble mania. LIRA reversed AMPH-induced hyperlocomotion, working and recognition memory impairments, while Li + LIRA240 rescued all behavioral changes induced by AMPH. LIRA reversed AMPH-induced hippocampal oxidative and neurotrophic changes. Li + LIRA240 augmented Li antioxidant effects and greatly reversed AMPH-induced BDNF changes in PFC and hippocampus. LIRA rescued the weight gain induced by Li in the course of mania model. Therefore, LIRA can reverse some mania-like behavioral alterations and combined with Li augmented the mood stabilizing and neuroprotective properties of Li. This study points to LIRA as a promising adjunctive tool for BD treatment and provides the first rationale for the design of clinical trials investigating its possible antimanic effect.

d-Amphetamine and methylmercury exposure during adolescence alters sensitivity to monoamine uptake inhibitors in adult mice.

Gestational exposure to methylmercury (MeHg), an environmental neurotoxicant, and adolescent administration of d-amphetamine (d-AMP) disrupt dopamine neurotransmission and alter voluntary behavior in adult rodents. We determined the impact of adolescent exposure to MeHg and d-AMP on monoamine neurotransmission in mice by assessing sensitivity to acute d-AMP, desipramine, and clomipramine, drugs that target dopamine, norepinephrine, and serotonin reuptake, respectively. Male C57Bl/6n mice were given 0 (control) or 3 ppm MeHg via drinking water from postnatal day 21 to 60 (murine adolescence). Within each group, mice were given once-daily injections of d-AMP or saline (i.p.) from postnatal day 28 to 42. This exposure regimen produced four treatment groups (n = 10-12/group): control, d-AMP, MeHg, and d-AMP + MeHg. As adults, the mice lever pressed under fixed-ratio schedules of reinforcement (FR 1, 5, 15, 30, 60, and 120). Acute i.p. injections of d-AMP (.3-1.7 mg/kg), desipramine (5.6-30 mg/kg), and clomipramine (5.6-30 mg/kg) were administered in adulthood after a stable behavioral baseline was established. Adolescent MeHg exposure increased saturation rate and minimum response time, an effect that was mitigated by chronic administration of d-AMP in adolescence. In unexposed mice, the three monoamine reuptake inhibitors had separable behavioral effects. Adolescent d-AMP increased sensitivity to acute d-AMP, desipramine, and clomipramine. Adolescent MeHg exposure alone did not alter drug sensitivity. Combined adolescent d-AMP + MeHg exposure enhanced sensitivity to acute d-AMP's and desipramine's effects on minimum response time. Adolescence is a vulnerable developmental period during which exposure to chemicals can have lasting effects on monoamine function and behavior.

The "induced hyperactivity" test for the de-risking of potential off-target activity of antihypertensive drugs.

INTRODUCTION: Compound X is a new proprietary antihypertensive agent that induces its pharmacodynamic effect at an approximate plasma Cmax.u of 0.6nmol/L (rat hypertension model). However, Compound X also shows potent off-target activity at PDE-10a (IC50~12nmol/L). Since PDE-10a is expressed predominantly in brain (striatum) and inhibition/knockout of PDE-10a have been reported to result in anti-psychotic effects, we have established the "induced hyperactivity" test for CNS de-risking of Compound X. METHODS: Male Wistar rats treated orally with vehicle or Compound X (single dose; 1-3-10mg/kg) were assessed for exploratory locomotor activity following induction of hyperactivity by d-amphetamine (2mg/kg) or the NMDA antagonist MK-801 (0.2mg/kg). The assay was validated with anti-psychotic drugs (haloperidol, clozapine). RESULTS: Induced hyperactivity was not antagonized by Compound X at doses relevant for its primary pharmacodynamic activity (0.1-0.3mg/kg, rat). Although sufficient plasma concentrations were reached with Compound X (Cmax.u up to ~8nmol/L at 10mg/kg) to show its PDE-10a activity, its low brain penetration (~10%) likely precluded any meaningful PDE-10a inhibition. In comparison, other blood pressure lowering agents such as prazosin (alpha-1 adrenoceptor antagonist) and isradipine (L-Type Ca(2+) channel blocker), but not the NO-donor ISDN, tended to attenuate induced hyperactivity in rats at high doses. CONCLUSION: The relevance of a potent in-vitro off-target hit (PDE-10a inhibition) by Compound X was attenuated by a robust in-vivo assay (rat induced hyperactivity test), hence lowering the potential liability profile of Compound X. Finally, this piece of investigative safety pharmacology work enabled early de-risking of Compound X based on its primary pharmacodynamic activity in a relevant rat model.

Role of P2X7 Receptor in an Animal Model of Mania Induced by D-Amphetamine.

The objective of this study was to explore the association between the P2X7 purinergic receptor (P2X7R) and neuroinflammation using a preclinical model of acute bipolar mania. We analyzed the modulatory effects of P2X7R agonist (3'-O-(4-benzoyl)benzoyl-adenosine 5'-triphosphate, BzATP) and antagonists (brilliant blue, BBG and 3-[[5-(2,3 dichlorophenyl)-1H-tetrazol-1-yl]methyl]pyridine hydrochloride, A438079) on assessments related to behavior (locomotor activity), neuroinflammation (interleukin-1 beta, IL-1ß; tumor necrosis factor alpha, TNF-α; and interleukin- 6, IL-6), oxidative stress (thiobarbituric acid reactive substances, TBARS) and neuroplasticity (brain-derived neurotrophic factor, BDNF) markers in a pharmacological model of mania induced by acute and chronic treatment with D-amphetamine (AMPH) (2 mg/kg) in mice. An apparent lack of responsiveness to AMPH was observed in terms of the locomotor activity in animals with blocked P2X7R or with genetic deletion of P2X7R in knockout (P2X7R(-/-)) mice. Likewise, P2X7R participated in the AMPH-induced increase of the proinflammatory and excitotoxic environment, as demonstrated by the reversal of IL-1ß, TNF-α, and TBARS levels caused by P2X7R blocking. Our results support the hypothesis that P2X7R plays a role in the neuroinflammation induced by AMPH in a preclinical model of mania, which could explain the altered behavior. The present data suggest that P2X7R may be a therapeutic target related to the neuroinflammation reported in bipolar disorder.

Neonatal propofol anesthesia modifies activity-dependent processes and induces transient hyperlocomotor response to d-amphetamine during adolescence in rats.

This study examined the influence of propofol anesthesia on the expression of activity-regulated molecules (BDNF and c-Fos) and synaptic plasticity markers (synaptophysin, GAP-43, drebrin) in the frontal cortex and thalamus of 7-day-old (P7) rats. Although these brain regions are the main targets of anesthetic action, they are contained in the cortico-striato-thalamo-cortical feedback loops, involved in naturally occurring and drug-induced psychoses. Therefore, functional integrity of these loops was examined in adolescent and adult rats through d-amphetamine-induced hyperactivity. Propofol treatment (25mg/kg) decreased exon-specific and total BDNF mRNA expression in the frontal cortex and thalamus, in a time-dependent manner. BDNF protein level was increased in the frontal cortex and decreased in the thalamus, which was accompanied by the change of phospho-TrkB expression. Similarly to BDNF, the expression of c-Fos was decreased in the frontal cortex while it was changed only at the protein level in the thalamus. Synaptic plasticity markers changed in a time- and region-specific manner, indicating increased synaptogenesis in the frontal cortex and synapse elimination in the thalamus in P7 rats after the propofol anesthesia exposure. These early molecular changes were followed by time-related, increased motor reaction to d-amphetamine in adolescent, but not in adult rats. Our study revealed that exposure of immature brain to propofol anesthesia during the critical phase of development provoked immediate changes in activity-dependent processes and synaptic adjustment, influencing brain capacity to integrate later developmental events and resulting in temporary altered response to acute psychotropic stimulation during adolescence.

Lithium modulates the production of peripheral and cerebral cytokines in an animal model of mania induced by dextroamphetamine.

OBJECTIVES: Several recent studies have suggested that the physiopathology of bipolar disorder (BD) is related to immune system alterations and inflammation. Lithium (Li) is a mood stabilizer that is considered the first-line treatment for this mood disorder. The goal of the present study was to investigate the effects of Li administration on behavior and cytokine levels [interleukin (IL)-1ß, IL-4, IL-6, IL-10, and tumor necrosis factor-alpha (TNF-α)] in the periphery and brains of rats subjected to an animal model of mania induced by amphetamine (d-AMPH). METHODS: Male Wistar rats were treated with d-AMPH or saline (Sal) for 14 days; on Day 8 of treatment, the rats were administered Li or Sal for the final seven days. Cytokine (IL-1ß, IL-4, IL-6, IL-10, and TNF-α) levels were evaluated in the cerebrospinal fluid (CSF), serum, frontal cortex, striatum, and hippocampus. RESULTS: The present study showed that d-AMPH induced hyperactivity in rats (p < 0.001), and Li treatment reversed this behavioral alteration (p < 0.001). In addition, d-AMPH increased the levels of IL-4, IL-6, IL-10, and TNF-α in the frontal cortex (p < 0.001), striatum (p < 0.001), and serum (p < 0.001), and treatment with Li reversed these cytokine alterations (p < 0.001). CONCLUSIONS: Li modulates peripheral and cerebral cytokine production in an animal model of mania induced by d-AMPH, suggesting that its action on the inflammatory system may contribute to its therapeutic efficacy.

Abuse liability assessment in preclinical drug development: predictivity of a translational approach for abuse liability testing using methylphenidate in four standardized preclinical study models.

OBJECTIVES: Preclinical abuse liability assessment of novel clinical CNS-active candidates involves several tests, addressing different aspects characteristic for abuse potential, which are considered predictive for substance abuse of these candidates, thus ensuring an appropriate translational approach. To demonstrate how such a strategy could work, a known drug of abuse, methylphenidate was evaluated in a full rodent test battery, comprising four test models, and in accordance with the requirements of the FDA, ICH and EMA guidelines. METHODS: Methylphenidate was tested orally at 2.5, 5 or 10mg/kg for its physical dependence potential in a repeated dose non-precipitated withdrawal test, for its drug profiling in a drug discrimination learning procedure (single escalating doses), and for its reinforcing properties in a conditioned place preference test (alternate dosing days) and an intravenous self-administration procedure (0.05 to 1mg/kg/IV infusion during 5 daily 1-h test sessions). The stimulant d-amphetamine served as positive control and was administered subcutaneously at 0.8mg/kg in the first three test models. In the intravenous self-administration procedure rats were habituated to intravenously self-administer d-amphetamine at 0.06mg/kg/IV infusion prior to methylphenidate substitution. RESULTS: Cessation of subchronic dosing up to 10mg/kg methylphenidate led to sustained or even exacerbated effects on locomotion and behavior, body temperature, body weight, food consumption, and alteration of the diurnal rhythm during withdrawal. Clear generalization to d-amphetamine was obtained in the drug discrimination test at 5 and 10mg/kg. Distinct reinforcing properties were present in the conditioned place preference test at 10mg/kg and in the intravenous self-administration study from 0.05mg/kg/IV infusion onwards. The maximum plasma exposure after oral administration of methylphenidate over the dose ranges tested in the present rat studies covered at least 1.9-fold to 18.9-fold the recommended human therapeutic exposure of 10ng/ml, a plasma level that is considered representative of the human efficacious methylphenidate dose. The ratio Cmax Hu/rat calculated from the intravenous self-administration data ranged from 14.9 to 576.5. Consequently the regulatory requirements, stating that preclinical drug abuse liability studies should include high doses that produce plasma levels that are multiples of the therapeutic dose were fulfilled (FDA, EMA, ICH). DISCUSSION: The presented preclinical models, implemented within a drug development environment, were considered highly predictive to assess the abuse potential of methylphenidate, and in accordance with the regulatory requirements of drug licensing authorities in terms of appropriate methods, dose selection and subsequent plasma exposure.

Preclinical pharmacokinetics, pharmacology and toxicology of lisdexamfetamine: a novel d-amphetamine pro-drug.

Lisdexamfetamine dimesylate (LDX) is a novel pro-drug of d-amphetamine that is currently used for the treatment of attention-deficit/hyperactivity disorder in children aged ≥ 6 years and adults. LDX is enzymatically cleaved to form d-amphetamine following contact with red blood cells, which reduces the rate of appearance and magnitude of d-amphetamine concentration in the blood and hence the brain when compared with immediate-release d-amphetamine at equimolar doses. Thus, the increase of striatal dopamine efflux and subsequent increase of locomotor activity following d-amphetamine is less prominent and slower to attain maximal effect following an equimolar dose of LDX. Furthermore, unlike d-amphetamine, the pharmacodynamic effects of LDX are independent of the route of administration underlining the requirement to be hydrolyzed by contact with red blood cells. It is conceivable that these pharmacokinetic and pharmacodynamic differences may impact the psychostimulant properties of LDX in the clinic. This article reviews the preclinical pharmacokinetics, pharmacology, and toxicology of LDX. This article is part of the Special Issue entitled 'CNS Stimulants'.

Combination effects of amphetamines under hyperthermia - the role played by oxidative stress.

Rise in body temperature is a life-threatening consequence of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) abuse. We evaluated the impact of hyperthermia on the cytotoxicity of combinations of MDMA and three other amphetamines, often co-ingested. For this, Hep G2 cells were exposed to MDMA, d-amphetamine, methamphetamine and 4-methylthioamphetamine, individually or combined, at 40.5 °C. The results were compared with normothermia data (37.0 °C). Mixture additivity expectations were calculated by independent action and concentration addition (CA) models. To delineate the mechanism(s) underlying the elicited effects, a range of stress endpoints was evaluated, including quantification of reactive oxygen/nitrogen species (ROS/RNS), lipid peroxidation, reduced/oxidized glutathione (GSH/GSSG), ATP and mitochondrial membrane potential (Δψm) changes. Our data show that, in hyperthermia, amphetamines acted additively and mixture effects were accurately predicted by CA. At 40.5 °C, even slight increases in the concentrations of each drug/mixture promoted significant rises in cytotoxicity, which quickly shifted from roughly undetectable to maximal mortality. Additionally, the increase of RNS/ROS production, decrease of GSH, ATP depletion and mitochondrial impairment were exacerbated under hyperthermia. Importantly, when equieffective cytotoxic concentrations of the mixture and individual amphetamines were compared for all tested stress endpoints, mixture effects did not deviate from those elicited by individual treatments, suggesting that these amphetamines have a similar mode of action, which is not altered in combination. Concluding, our data indicate that amphetamine mixtures produce deleterious effects, even when individual drugs are combined at negligible concentrations. These effects are strongly exacerbated in hyperthermia, emphasizing the potential increased risks of ecstasy intake, especially when hyperthermia occurs concurrently with polydrug abuse.

Effects of post-training heroin and d-amphetamine on consolidation of win-stay learning and fear conditioning.

It has been proposed that the reinforcing properties of drugs of abuse are due, in part, to their ability to enhance memory consolidation. To test this hypothesis, heroin (0.03-3 mg/kg, SC) and d-amphetamine (0.5-2 mg/kg, SC) were administered to male Sprague-Dawley rats immediately or 4 h after training on win-stay and fear conditioning tasks. On the win-stay, immediate post-training administration of lower doses of heroin and d-amphetamine enhanced acquisition, and probe tests further revealed that these drugs enhanced different aspects of learning. Higher doses had no effect or impaired performance, particularly when administered repeatedly. On fear conditioning, the memory-enhancing effects of immediate post-training administration of lower heroin and d-amphetamine doses were revealed only when a single tone-shock pairing procedure was employed. Therefore, under appropriate experimental conditions, mildly stimulatory doses of heroin and d-amphetamine enhanced the acquisition of tasks thought to involve different types of learning. These results support the hypothesis that one of the ways in which drugs of abuse such as opiates and psychomotor stimulants reinforce behavior is by enhancing memory consolidation processes.

Evaluation of acetylcholinesterase in an animal model of mania induced by D-amphetamine.

The present study aims to investigate the effects of mood stabilizers, lithium (Li) and valproate (VPA), on acetylcholinesterase (AChE) activity in the brains of rats subjected to an animal model of mania induced by D-amphetamine (D-AMPH). In the reversal treatment, Wistar rats were first given D-AMPH or saline (Sal) for 14 days. Between days 8 and 14, the rats were treated with Li, VPA, or Sal. In the prevention treatment, rats were pretreated with Li, VPA, or Sal. AChE activity was measured in the brain structures (prefrontal cortex, hippocampus, and striatum). Li, alone in reversion and prevention treatments, increased AChE activity in the brains of rats. VPA, alone in prevention treatment, increased AChE activity in all brain regions evaluated; in the reversion, only in the prefrontal. However, D-AMPH decreased activity of AChE in the striatum of rats in both the reversion and prevention treatments. VPA was able to revert and prevent this AChE activity alteration in the rat striatum. Our findings further support the notion that the mechanisms of mood stabilizers also involve changes in AChE activity, thus reinforcing the need for more studies to better characterize the role of acetylcholine in bipolar disorder.

Lithium and tamoxifen modulate cellular plasticity cascades in animal model of mania.

Lithium (Li) is the main mood stabilizer and acts on multiple biochemical targets, leading to neuronal plasticity. Several clinical studies have shown that tamoxifen (TMX) - a protein kinase C (PKC) inhibitor - has been effective in treating acute mania. The present study aims to evaluate the effects of TMX on biochemical targets of Li, such as glycogen synthase kinase-3ß (GSK-3ß), PKC, PKA, CREB, BDNF and NGF, in the brain of rats subjected to an animal model of mania induced by d-amphetamine (d-AMPH). Wistar rats were treated with d-AMPH (2mg/kg, once a day) or saline (Sal; NaCl 0.9%, w/v), Li (47.5 mg/kg, intraperitoneally (i.p.), twice a day) or TMX (1 mg/kg i.p., twice a day) or Sal in protocols of reversion and prevention treatment. Locomotor behavior was assessed using the open-field task, and protein levels were measured by immunoblot. Li and TMX reversed and prevented d-AMPH-induced hyperactivity. Western blot showed that d-AMPH significantly increased GSK-3 and PKC levels, and decreased pGSK-3, PKA, NGF, BDNF and CREB levels in the structures analyzed. Li and TMX were able to prevent and reverse these changes induced by d-AMPH in most structures evaluated. The present study demonstrated that the PKC inhibitor modulates the alterations in the behavior, neurotrophic and apoptosis pathway induced by d-AMPH, reinforcing the need for more studies of PKC as a possible target for treatment of bipolar disorder.

Effects of alpha-lipoic acid in an animal model of mania induced by D-amphetamine.

OBJECTIVES: Oxidative stress and neurotrophic factors are involved in the pathophysiology of bipolar disorder (BD). Alpha-lipoic acid (ALA) is a naturally occurring compound with strong antioxidant properties. The present study investigated ALA effects in an amphetamine-induced model of mania. METHODS: In the reversal protocol, adult mice were first given d-amphetamine (AMPH) 2 mg/kg, intraperitoneally (i.p.) or saline for 14 days. Between days 8 and 14, the animals received ALA 50 or 100 mg/kg orally, lithium (Li) 47.5 mg/kg i.p., or saline. In the prevention paradigm, mice were pretreated with ALA, Li, or saline prior to AMPH. Locomotor activity was assessed in the open-field task. Superoxide dismutase (SOD) activity, reduced glutathione (GSH), and thiobarbituric acid-reactive substance (TBARS) levels were evaluated in the prefrontal cortex (PFC), hippocampus (HC), and striatum (ST). Brain-derived neurotrophic factor (BDNF) levels were measured in the HC. RESULTS: ALA and Li prevented and reversed the AMPH-induced increase in locomotor activity. PREVENTION MODEL: ALA and Li co-administration with AMPH prevented the decrease in SOD activity induced by AMPH in the HC and ST, respectively; ALA and Li prevented GSH alteration in the HC and TBARS formation in all brain areas studied. REVERSAL MODEL: ALA reversed the decrease in SOD activity in the ST. TBARS formation was reversed by ALA and Li in all brain areas. Furthermore, ALA reversed AMPH-induced decreases in BDNF and GSH in the HC. CONCLUSIONS: Our findings showed that ALA, similarly to Li, is effective in reversing and preventing AMPH-induced behavioral and neurochemical alterations, providing a rationale for the design of clinical trials investigating ALA's possible antimanic effect.

Protein kinase C and oxidative stress in an animal model of mania.

The present study aims to investigate the effects of protein kinase C using the inhibitor Tamoxifen (TMX) on oxidative stress in a rat animal model of mania induced by d-amphetamine (d-AMPH). In the reversal model, d-AMPH or saline (Sal) were administered to rats for 14 days, and between days 8-14, rats were treated with TMX or Sal. In the prevention model, rats were pretreated with TMX or Sal, and between days 8-14, d-AMPH or Sal were administrated. In both experiments locomotor activity and risk-taking behavior were assessed by open-field test and oxidative stress was measured in prefrontal, amygdala, hippocampus and striatum. The results showed that TMX reversed and prevented d- AMPH-induced behavioral effects. In addition, the d-AMPH administration induced oxidative damage in both structures tested in two models. The TMX was able to reverse and prevent this impairment, however in a way dependent of cerebral area and technique evaluated. These findings reinforce the hypothesis that PKC play an important role in the pathophysiology of BD and the need for the study of inhibitors of PKC as a possible target for treatment the BD.

Opposing efficacy of group III mGlu receptor activators, LSP1-2111 and AMN082, in animal models of positive symptoms of schizophrenia.

RATIONALE: Several studies have suggested that modulation of the glutamatergic system via metabotropic glutamate receptors (mGlu) could be a new and efficient way to achieve antipsychotic-like activity. OBJECTIVES: Here, we decided to investigate the possible role of the group III mGlu receptor ligands, LSP1-2111, the group III mGlu receptor orthosteric agonist, preferentially stimulating mGlu4 receptors especially in low doses, and AMN082, the mGlu7 receptor positive modulator. We used MK-801- and amphetamine-induced hyperactivity tests, as well as DOI-induced head twitches in mice as models for positive symptoms of psychosis. The C57Bl/6J mGlu7 receptor knockout mice were used to confirm that AMN082-induced effect was receptor specific. A non-selective antagonist of the group II/III mGlu receptors, LY341495, was used to block LSP1-2111-induced effects. RESULTS: LSP1-2111 (1, 2, and 5 mg kg(-1)) dose dependently inhibited both MK-801- and amphetamine-induced hyperactivities. Moreover, the drug antagonized DOI-induced head twitches. The effects of the drug were antagonized by LY341495 administration (1.5 mg kg(-1), i.p.). In contrast, AMN082 (3 and 6 mg kg(-1)) had no effect on amphetamine-induced hyperactivity but induced an enhancement of MK-801-induced hyperactivity and DOI-induced head twitches in mice. In C57Bl/6J mGlu7 receptor knockout animals (KO), those effects of AMN082 were not observed. Moreover, mGlu7 KO animals were less sensitive for DOI-induced effect than their wild type littermates. CONCLUSIONS: Altogether, we propose that among group III mGlu receptors, mGlu4 receptor may be a promising target for the development of novel antipsychotic drugs.

Differences between dextroamphetamine and methamphetamine: behavioral changes and oxidative damage in brain of Wistar rats.

In this study methamphetamine (m-AMPH) and dextroamphetamine (d-AMPH) were compared to determine the potency of the two drugs on behavior and oxidative damage in brain of rats. Male adult Wistar rats were given single (acute administration) or repeated (chronic administration, 14 days) intraperitoneal injections of saline (0.9% NaCl), d-AMPH (2 mg/kg) or m-AMPH (0.25, 0.5, 1 or 2 mg/kg). Locomotor activity was evaluated in open-field apparatus 2 h after the last drug injection. Additionally, thiobarbituric acid reactive substances (TBARS) and protein carbonyl formation were measured in the prefrontal cortex, amygdala, hippocampus and striatum. In both experiments, d-AMPH and m-AMPH (all doses administered) increased the locomotor activity of animals, meantime, no significant difference between d-AMPH and m-AMPH was observed. d-AMPH and m-AMPH increased lipid and protein damage, but m-AMPH was more potent than d-AMPH, however, this effect varies depending on the brain region and the experimental protocol. The results of this study show that d-AMPH and m-AMPH have similar behavioral effects, which previous studies had already reported. On the other hand, this study demonstrated that the m-AMPH induces oxidative damage greater than d-AMPH, showing neurochemical differences previously unknown.

The neurotensin-1 receptor agonist PD149163 inhibits conditioned avoidance responding without producing catalepsy in rats.

Agonists for neurotensin (NT)-1 receptors have produced antipsychotic-like effects in many animals, including reversal of prepulse inhibition deficits and psychostimulant-induced increases in spontaneous activity. The present study sought to provide a basic assessment of the putative antipsychotic effects of PD149163 in rats using a two way conditioned avoidance response task, which is highly validated for screening antipsychotic drugs, and an inclined grid assessment, which is used to assess extrapyramidal side effect liability. PD149163 (0.0625-8.0 mg/kg) significantly suppressed conditioned avoidance responding (CAR) following administration of a 1.0 or 8.0 mg/kg dose. PD149163 failed to significantly increase catalepsy scores. The typical antipsychotic drug haloperidol (0.01-1.0 mg/kg) significantly suppressed CAR at a 0.1, 0.3, and 1.0 mg/kg dose, and a significant increase in catalepsy scores was found at the 1.0 mg/kg dose. The atypical antipsychotic drug clozapine (2.5-10.0 mg/kg) also produced a significant inhibition of CAR, which occurred following administration of a 10.0 mg/kg dose. Clozapine failed to significantly increase catalepsy scores. Finally, D-amphetamine (1.0 mg/kg), serving as a negative control, failed to suppress CAR or increase catalepsy scores. These data further suggest that PD149163 may have atypical antipsychotic-like properties.

Tamoxifen effects on respiratory chain complexes and creatine kinase activities in an animal model of mania.

The present study aimed to investigate the effects of tamoxifen (TMX) on locomotor behavior and on the activities of mitochondrial respiratory chain complexes and creatine kinase (CK) in the brain of rats subjected to an animal model of mania induced by d-amphetamine (D-AMPH)-reversion and prevention protocols. The D-AMPH administration increased locomotor activity in saline-treated rats under prevention and reversion treatment; furthermore, there was evident reduction in the locomotion in the D-amphetamine group treated with TMX. D-AMPH significantly decreased the activity of mitochondrial respiratory chain complexes in saline-treated rats in prefrontal cortex, hippocampus, striatum and amygdala in both prevention and reversion treatment. Depending on the cerebral area and evaluated complex, TMX was able to prevent and reverse this impairment. A decrease in CK activity was also verified in the brain of rats when D-AMPH was administrated in both experiments; the administration of TMX reversed but not prevented the decrease in CK activity induced by D-AMPH. The present study demonstrated that TMX reversed and prevented the alterations in behavioral and energy metabolism induced by D-AMPH (alterations were also observed in bipolar disorder), reinforcing the need for more studies about inhibitors of PKC as possible targets for new medications in the treatment of bipolar disorder.

The ugly side of amphetamines: short- and long-term toxicity of 3,4-methylenedioxymethamphetamine (MDMA, 'Ecstasy'), methamphetamine and D-amphetamine.

Amphetamine ('Speed'), methamphetamine ('Ice') and its congener 3,4-methylenedioxymethamphetamine (MDMA; 'Ecstasy') are illicit drugs abused worldwide for their euphoric and stimulant effects. Despite compelling evidence for chronic MDMA neurotoxicity in animal models, the physiological consequences of such toxicity in humans remain unclear. In addition, distinct differences in the metabolism and pharmacokinetics of MDMA between species and different strains of animals prevent the rationalisation of realistic human dose paradigms in animal studies. Here, we attempt to review amphetamine toxicity and in particular MDMA toxicity in the pathogenesis of exemplary human pathologies, independently of confounding environmental factors such as poly-drug use and drug purity.