Secreted Phospholipases A2 of Snake Venoms: Effects on the Peripheral Neuromuscular System with Comments on the Role of Phospholipases A2 in Disorders of the CNS and Their Uses in Industry

Neuro- and myotoxicological signs and symptoms are significant clinical features of envenoming snakebites in many parts of the world. The toxins primarily responsible for the neuro and myotoxicity fall into one of two categories—those that bind to and block the post-synaptic acetylcholine receptors (AChR) at the neuromuscular junction and neurotoxic phospholipases A₂ (PLAs) that bind to and hydrolyse membrane phospholipids of the motor nerve terminal (and, in most cases, the plasma membrane of skeletal muscle) to cause degeneration of the nerve terminal and skeletal muscle. This review provides an introduction to the biochemical properties of secreted sPLA₂s in the venoms of many dangerous snakes and a detailed discussion of their role in the initiation of the neurologically important consequences of snakebite. The rationale behind the experimental studies on the pharmacology and toxicology of the venoms and isolated PLAs in the venoms is discussed, with particular reference to the way these studies allow one to understand the biological basis of the clinical syndrome. The review also introduces the involvement of PLAs in inflammatory and degenerative disorders of the central nervous system (CNS) and their commercial use in the food industry. It concludes with an introduction to the problems associated with the use of antivenoms in the treatment of neuro-myotoxic snakebite and the search for alternative treatments.     

Inhibition of Snake Venoms and Phospholipases A2 by Extracts from Native and Genetically Modified Eclipta alba: Isolation of Active Coumestans

Abstract: We genetically modified Eclipta alba using Agrobacterium rhizogenes LBA 9402, with the aim of producing secondary metabolites with pharmacological properties against phospholipase A₂ and the myotoxic activities of snake venom. Extracts from in natura aerial parts and roots, both native and genetically modified (in vitro), were prepared and analysed by high‐performance liquid chromatography. In natura materials showed the coumestan wedelolactone at higher concentration in the aerial parts, while demethylwedelolactone appeared at higher concentration in roots. Among the modified roots, clone 19 showed higher concentrations of these coumestans. Our results show that the in natura extracts of plants collected from Botucatu and Ribeirão Preto were efficient in inhibiting snake venom phospholipase A₂ activity. Regarding in vitro material, the best effect against Crotalus durissus terrificus venom was that of clone 19. Clone 19 and isolated coumestans (wedelolactone and demethylwedelolactone) inhibited the myotoxic activity induced by basic phospholipases A₂ isolated from the venoms of Crotalus durissus terrificus (CB) and Bothrops jararacussu (BthTX‐I and II). The search for antivenom is justified by the need of finding active principles that are more efficient in neutralizing snake venoms and also as an attempt to complement serum therapy.     

In Vitro Antiplasmodial Activity of Phospholipases A2 and a Phospholipase Homologue Isolated from the Venom of the Snake Bothrops asper

The antimicrobial and antiparasite activity of phospholipase A₂ (PLA₂) from snakes and bees has been extensively explored. We studied the antiplasmodial effect of the whole venom of the snake Bothrops asper and of two fractions purified by ion-exchange chromatography: one containing catalytically-active phospholipases A₂ (PLA₂) (fraction V) and another containing a PLA₂ homologue devoid of enzymatic activity (fraction VI). The antiplasmodial effect was assessed on in vitro cultures of Plasmodium falciparum. The whole venom of B. asper, as well as its fractions V and VI, were active against the parasite at 0.13 ± 0.01 µg/mL, 1.42 ± 0.56 µg/mL and 22.89 ± 1.22 µg/mL, respectively. Differences in the cytotoxic activity on peripheral blood mononuclear cells between the whole venom and fractions V and VI were observed, fraction V showing higher toxicity than total venom and fraction VI. Regarding toxicity in mice, the whole venom showed the highest lethal effect in comparison to fractions V and VI. These results suggest that B. asper PLA₂ and its homologue have antiplasmodial potential.     

Molecular Characterization of Lys49 and Asp49 Phospholipases A2 from Snake Venom and Their Antiviral Activities against Dengue virus

We report the detailed molecular characterization of two PLA₂s, Lys49 and Asp49 isolated from Bothrops leucurus venom, and examined their effects against Dengue virus (DENV). The Bl-PLA₂s, named BlK-PLA₂ and BlD-PLA₂, are composed of 121 and 122 amino acids determined by automated sequencing of the native proteins and peptides produced by digestion with trypsin. They contain fourteen cysteines with pIs of 9.05 and 8.18 for BlK- and BlD-PLA₂s, and show a high degree of sequence similarity to homologous snake venom PLA₂s, but may display different biological effects. Molecular masses of 13,689.220 (Lys49) and 13,978.386 (Asp49) were determined by mass spectrometry. DENV causes a prevalent arboviral disease in humans, and no clinically approved antiviral therapy is currently available to treat DENV infections. The maximum non-toxic concentration of the proteins to LLC-MK2 cells determined by MTT assay was 40 µg/mL for Bl-PLA₂s (pool) and 20 µg/mL for each isoform. Antiviral effects of Bl-PLA₂s were assessed by quantitative Real-Time PCR. Bl-PLA₂s were able to reduce DENV-1, DENV-2, and DENV-3 serotypes in LLC-MK2 cells infection. Our data provide further insight into the structural properties and their antiviral activity against DENV, opening up possibilities for biotechnological applications of these Bl-PLA₂s as tools of research.     

砒石对哮喘小鼠胞质型磷脂酶A2基因表达及白三烯C4的影响

目的:探讨胞质型磷脂酶A2(cPLA2)mRNA表达、白三烯C4(TLC4)在哮喘发病中的作用及其相互关系,以及砒石对哮喘的治疗作用。方法:建立小鼠卵蛋白哮喘模型,砒石灌胃给药,用逆转录聚合酶链反应方法检测肺组织中cPLA2mRNA表达;ELISA方法检测支气管肺泡灌洗液(BALF)中LTC4含量;微量滴定法测定BALF中PLA2活性。应用新航YP200型压力换能器及Medlab生物信号采集系统检测小鼠肺功能Pmax和T呼T总。结果:哮喘小鼠肺组织cPLA2基因表达水平、BALF中PLA2活性、LTC4水平均较对照组显著升高。0.625、1.25、2.50及5.00mg·kg-1剂量的砒石可下调哮喘小鼠cPLA2mRNA表达,抑制哮喘小鼠BALF中PLA2活性和降低LTC4水平,改善哮喘小鼠肺功能。结论:支气管肺组织中cPLA2基因表达上调、PLA2活性和LTC4水平增高在卵蛋白(OVA)致敏小鼠哮喘发病中起着重要作用。砒石可显著抑制哮喘小鼠肺组织中cPLA2基因的表达,降低哮喘小鼠PLA2活性和降低LTC4水平,改善哮喘小鼠肺功能,具有抗哮喘活性。     

Neuropharmacology: Effects on Rat Brain K1- and K2-Opioid Receptors after Chronic Treatment with Non-peptide K-Agonists

Injection of K-agonist dynorphins and non-peptide K-agonists into the hippocampus induces a reduction in blood pressure. It has been postulated that K-opioid agonists and K-receptors are important in one mechanism of antihypertension and might have clinical potential for the treatment of hypertension. We have investigated whether chronic treatment with U-50488H and U-62066E, two non-peptide K-agonists, effects brain K₁- or K₂-receptor numbers or affinities in areas that might correlate with changes in blood pressure. K₁- and K₂-Opioid receptor affinities and densities were determined in cortex, hippocampus, hypothalamus, midbrain and pons after 14 days subcutaneous infusion of two non-peptide K-agonists, U-50488H and U-62066E, 9.6 mg kg day^?1, by means of osmotic minipumps, to spontaneously hypertensive rats (SHR) and to Wistar-Kyoto (WKY) rats. This infusion significantly reduced blood pressure. Brains were removed within 48 h of the end of drug infusion and K-receptor binding studies were performed on homogenates from each brain area using [³H]U-69593 to assay K₁-receptors and [³H]bremazocine to assay K₂-receptors. U-62066E treatment seemed to cause a slight decrease in the number of [³H]bremazocine binding sites (K₂-receptors) from 98.2 ± 9 to 74.9 ± 8 fmol (mg protein)^?1 in the hippocampus when compared with SHR controls. A small decrease in K₂-receptor density in the pons of WKY rats was also observed after U-50488H treatment (control, 51.2±5; U-50488H-treated, 24.3±9 fmol (mg protein)^?1). Although SHR blood pressure values were consistently reduced by treatment with K-agonists, there was little if any significant change in apparent numbers of K₁- or K₂-receptors or their affinities in any of the brain regions examined. These data indicate that although chronic treatment with K-agonists reduces blood pressure in SHR, the treatment does not elicit major changes in brain K-receptors either in SHR or in WKY rats. The potential use of K-agonists for treating hypertension might not cause receptor changes in the brain and might, therefore, result in fewer side effects or negligible rebound hypertension.     

Brain Functional Effects of Psychopharmacological Treatment in Major Depression: A Focus on Neural Circuitry of Affective Processing

In the last two decades, neuroimaging research has reached a much deeper understanding of the neurobiological underpinnings of major depression (MD) and has converged on functional alterations in limbic and prefrontal neural networks, which are mainly linked to altered emotional processing observed in MD patients. To date, a considerable number of studies have sought to investigate how these neural networks change with pharmacological antidepressant treatment. In the current review, we therefore discuss results from a) pharmacological functional magnetic resonance imaging (fMRI) studies investigating the effects of selective serotonin or noradrenalin reuptake inhibitors on neural activation patterns in relation to emotional processing in healthy individuals, b) treatment studies in patients with unipolar depression assessing changes in neural activation patterns before and after antidepressant pharmacotherapy, and c) predictive neural biomarkers of clinical response in depression. Comparing results from pharmacological fMRI studies in healthy individuals and treatment studies in depressed patients nicely showed parallel findings, mainly for a reduction of limbic activation in response to negative stimuli. A thorough investigation of the empirical findings highlights the importance of the specific paradigm employed in every study which may account for some of the discrepant findings reported in treatment studies in depressed patients.     

A Pharmacokinetic-pharmacodynamic Linking Model for the α2-Adrenergic Antagonism of Idazoxan on Clonidine-induced Mydriasis in the Rat

The relationship between concentration and inhibitory effect of the α₂-adrenoceptor antagonist idazoxan on clonidine-induced mydriasis has been studied in the rat using pharmacokinetic-pharmacodynamic simultaneous modelling. Fifteen minutes after the anaesthesia of rats with sodium pentobarbitone (55 mg kg-1, i.p.), and 5 min after the administration of clonidine (0·3 mg kg^?1, i.v.) to rats pretreated with idazoxan (3 mg kg^?1, i.v., and 3 and 10 mg kg^?1, orally) at different time intervals, pupil diameters were assessed. The pharmacokinetics of idazoxan were adequately described by a monoexponential equation. Using a pharmacokinetic-pharmacodynamic linking model, the concentration-effect relationships of idazoxan were derived, and were quantified by the inhibitory simple E_max model. At the effect compartment, the estimated apparent IC50 was 153·6 ng mL^?1. Values of clearance, volume of distribution and elimination half-life were 71·2 mL kg^?1 min^?1, 3134 mL kg^?1 and 30-5 min, respectively. These results could contribute to better characterization of the pharmacodynamic and toxicological profiles of idazoxan in experimental models in which a different pharmacokinetic behaviour of the drug is presumed.     

Agonist and Antagonist Effects of Aripiprazole on D2-Like Receptors Controlling Rat Brain Dopamine Synthesis Depend on the Dopaminergic Tone

Background:

The atypical antipsychotic drug aripiprazole binds with high affinity to a number of G protein coupled receptors, including dopamine D₂ receptors, where its degree of efficacy as a partial agonist remains controversial.

Methods:

We examined the properties of aripiprazole at D₂-like autoreceptors by monitoring the changes of dopamine synthesis in adult rat brain striatal minces incubated ex vivo. The effects of the dopaminergic tone on the properties of aripiprazole were assayed by comparing a basal condition (2mM K⁺, low dopaminergic tone) and a stimulated condition (15mM K⁺, where dopamine release mimics a relatively higher dopaminergic tone). We also used 2 reference compounds: quinpirole showed a clear agonistic activity and preclamol (S-(-)-PPP) showed partial agonism under both basal and stimulated conditions.

Results:

Aripiprazole under the basal condition acted as an agonist at D₂-like autoreceptors and fully activated them at about 10nM, inhibiting dopamine synthesis similarly to quinpirole. Higher concentrations of aripiprazole had effects not restricted to D₂-like autoreceptor activation. Under the stimulated (15mM K⁺) condition, nanomolar concentrations of aripiprazole failed to decrease dopamine synthesis but could totally block the effect of quinpirole.

Conclusions:

Under high dopaminergic tone, aripiprazole acts as a D₂-like autoreceptor antagonist rather than as an agonist. These data show that, ex vivo, alteration of dopaminergic tone by depolarization affects the actions of aripiprazole on D₂-like autoreceptors. Such unusual effects were not seen with the typical partial agonist preclamol and are consistent with the hypothesis that aripiprazole is a functionally selective D₂R ligand.     

The in vitro Effects of Galactose and its Derivatives on Rat Brain Mg2+‐ATPase Activity

Abstract: Galactosaemia is an inborn error of metabolism characterized by irreversible damage to neural tissue. To evaluate whether galactose metabolic disorders, (e.g. classical galactosaemia, galactokinase deficiency galactosaemia), is implicated for alterations of brain Mg²⁺‐ATPase activity, various concentrations (1–16 mM) of galactose, galactose‐1‐phosphate, galactitol, glucose‐1‐phosphate or glucose were preincubated with whole brain homogenates of suckling rats at 37 ° for 1 hr. Mg²⁺‐ATPase activities were determined according to Bowler & Tirri's (1974). Galactose‐1‐phosphate or glucose‐1‐phosphate excessively activated the brain Mg²⁺‐ATPase in a concentration‐dependent way. Additionally, galactitol, galactose or glucose stimulated the enzyme up to 35–45% (P<0.001) at concentrations >4 mM. A mixture of galactose‐1‐phosphate (2 mM), glactitol (2 mM) and galactose (4 mM), concentrations commonly found in blood and brain of untreated patients with classical galactosaemia, resulted in a 500% enzyme activation (P<0.001) as compared to control. Moreover, a mixture of galactitol (2 mM) and galactose (1 mM), concentrations measured in patients with galactokinase deficiency, caused an enzyme stimulation (35%, P<0.001). These findings suggest: a) The great Mg²⁺‐ATPase activation by galactose‐1‐phosphate or glucose‐1‐phosphate may be due to the epimer of galactose and the presence of phosphorus. b) The brain Mg²⁺‐ATPase stimulation by galactose and its derivatives could be toxic by modulating the Mg²⁺ concentration, the ATP availability, the activity of other ATP‐ and Mg²⁺‐dependent enzymes as well as the rates of protein synthesis and cell growth.     

Exploratory and Socio-Sexual Behaviour in the Male Laboratory Rat: A Methodological Approach for the Investigation of Drug Action

Abstract: There is an increasing demand for appropriate methods for analysing the pharmacological and toxicological action of chemical agents on behavioural patterns. The present study describes a non-instrumental approach to the study of exploratory and socio-sexual behaviours in the laboratory male rat. The behaviours were differentiated in terms of latency of onset, incidence, frequency and duration. Castrated and intact males were tested under three defined test situations. One test was focused on exploratory behaviour and two tests in which the male encountered an oestrous female or a castrated male were set up to study social and sexual behaviours. A multivariate statistical method was used to analyse differences in the behavioural profiles observed in the different tests. The data show that simultaneous recording of several spontaneous behaviours may be a useful technique for investigating how a compound influences behavioural processes.     

补阳还五汤及其有效成分对脑中风细胞膜流动性的影响

本文采用先进的自旋标记电子顺磁共振方法研究了补阳还五汤及有效成分黄芪甲苷、阿魏酸、川芎嗪、芦丁、绿原酸、紫檀烷苷、毛蕊异黄酮、芒柄花素、毛蕊异黄酮苷、芍药苷、丹皮酚和桷皮素体外给药对颈总动脉结扎和释放造成缺血－再灌损伤的大鼠脑细胞流动性的影响。该损伤大鼠用作脑中风模型，结果表明损伤大鼠脑细胞流动性较正常大鼠降低约8％，而补阳还五汤及其有效成分对正常细胞无影响但可使损伤大鼠脑细胞膜流动性增大，不同程度地恢复到接近于正常细胞膜流动性水平。本实验表明：细胞膜流动性是一个敏感而重要的生物学指标，反映细胞的活性状态，可用这一新的技术方法来研究补阳还五汤及其组方配伍的分子机理。     

Biochemical Effects of Baclofen (β-Parachlorophenyl-GABA) on the Dopamine and the Noradrenaline in the Rat Brain

Abstract Baclofen (fi-parachlorophenyl-GABA) caused an increase in the concentration of dopamine in the rat brain with a maximum of about 170 % of the control value after 1 hr and after doses of 50 mg/kg or more intraperitoneally. The α-methyltyrosine-induced disappearance of dopamine was inhibited to about the same extent in the corpus striatum and in the limbic system by baclofen. The accumulation of DOPA following decarboxylase inhibition was stimulated more in the corpus striatum than in the limbic system by baclofen, thus accounting for the fact that the concentration of dopamine was elevated about three times as much in the corpus striatum as in the limbic system. Amphetamine almost completely inhibited the rise in dopamine produced by baclofen. Baclofen did not cause any consistent changes in the concentration, the synthesis and the utilization of noradrenaline. These effects of baclofen are similar to those described following gammahydroxybutyric acid or axotomy. Hence, baclofen might also interrupt the nerve impulse flow in central dopamine neurones, perhaps by stimulating a central GABA mechanism.     

Age,Sex, and Reproductive Hormone Effects on Brain Serotonin-1A and Serotonin-2A Receptor Binding in a Healthy Population

There is a need for rigorous positron emission tomography (PET) and endocrine methods to address inconsistencies in the literature regarding age, sex, and reproductive hormone effects on central serotonin (5HT) 1A and 2A receptor binding potential (BP). Healthy subjects (n=71), aged 20–80 years, underwent 5HT1A and 2A receptor imaging using consecutive 90-min PET acquisitions with [¹¹C]WAY100635 and [¹⁸F]altanserin. Logan graphical analysis was used to derive BP using atrophy-corrected distribution volume (V_T) in prefrontal, mesiotemporal, occipital cortices, and raphe nucleus (5HT1A only). We used multivariate linear regression modeling to examine BP relationships with age, age², sex, and hormone concentrations, with post hoc regional significance set at p<0.008. There were small postsynaptic 5HT1A receptor BP increases with age and estradiol concentration in women (p=0.004–0.005) and a tendency for small 5HT1A receptor BP declines with age and free androgen index in men (p=0.05–0.06). Raphe 5HT1A receptor BP decreased 4.5% per decade of age (p=0.05), primarily in men. There was a trend for 15% receptor reductions in prefrontal cortical regions in women relative to men (post hoc p=0.03–0.10). The significant decline in 5HT2A receptor BP relative to age (8% per decade; p<0.001) was not related to sex or hormone concentrations. In conclusion, endocrine standardization minimized confounding introduced by endogenous hormonal fluctuations and reproductive stage and permitted us to detect small effects of sex, age, and endogenous sex steroid exposures upon 5HT1A binding. Reduced prefrontal cortical 5HT1A receptor BP in women vs men, but increased 5HT1A receptor BP with aging in women, may partially explain the increased susceptibility to affective disorders in women during their reproductive years that is mitigated in later life. 5HT1A receptor decreases with age in men might contribute to the known increased risk for suicide in men over age 75 years. Low hormone concentrations in adults <50 years of age may be associated with more extreme 5HT1A receptor BP values, but remains to be studied further. The 5HT2A receptor declines with age were not related to sex or hormone concentrations in this sample. Additional study in clinical populations is needed to further examine the affective role of sex–hormone–serotonin receptor relationships.     

Effects of DRD2 and CYP2D6 genotypes on delta EEG power response to aripiprazole in healthy male volunteers: a preliminary study

The aim of the present study was to evaluate the effects of polymorphisms in dopamine D2 receptor (DRD2) and cytochrome P450 (CYP) 2D6 genes on delta EEG power response to aripiprazole in healthy male volunteers. Seventeen volunteers were recruited according to the DRD2 Taq1A genotype, and separated into the following groups: homozygous wild-type (A2/A2, n = 7), heterozygous (A2/A1, n = 5) and homozygous variant-type (A1/A1, n = 5) groups. After enrollment in this study, they were genotyped for CYP2D6. The volunteers received single 10 mg oral doses of aripiprazole, in accordance with an open-label parallel group study design. Plasma levels of aripiprazole and its metabolite were determined and EEGs were obtained simultaneously. The pharmacodynamic parameter was absolute delta power in the Cz channel. The changes of delta power were not different according to DRD2 Taq1A genotypes. As to the CYP2D6 allele, the subjects had the following CYP2D6 genotypes: *10/*10 (n = 4), *1/*10 (n = 5), *1/*5 (n = 2), *1/*1 (n = 3), *2/*41 (n = 1), *2/*2 (n = 1), *2N/*10 (n = 1). Subjects exhibiting the *1/*5 and *1/*10 genotypes showed a trend toward high area under the plasma aripiprazole concentration-time curve (AUC), which was linearly related to area under the EEG response-time curve (AUEC). Our results demonstrate a need for further evaluation of the CYP2D6 genotypic effect on the pharmacodynamics of aripiprazole.     

Differential Effect of Orexin-1 and CRF-1 Antagonism on Stress Circuits: a fMRI Study in the Rat with the Pharmacological Stressor Yohimbine

Translational approaches to study the neural substrates of stress and assess the mechanistic efficacy of novel anti-anxiety agents necessitate the use of stressors with a similar degree of saliency across species. The alpha-2 adrenoreceptor antagonist yohimbine represents an attractive experimental tool owing to its well-documented stress-inducing properties in humans and laboratory species. We investigated the neural substrates engaged by yohimbine in the rat brain by using functional magnetic resonance imaging and mapped their modulation by neurotransmitter systems involved in stress responses. Yohimbine elicited a composite pattern of brain activation, highlighting the recruitment of cortico-striato-thalamic regions and extra-hypothalamic stress neurocircuits. This effect was strongly attenuated by the α-2-adrenoceptor agonist medetomidine and by the dopamine (DA) D₁ receptor antagonist {"type":"entrez-protein","attrs":{"text":"SCH23390","term_id":"1052733334","term_text":"SCH23390"}}SCH23390, thus revealing a primary contribution of both norepinephrine and DA on the neurofunctional cascade elicited by the drug. Pretreatment with the corticotrophin-releasing factor type-1 receptor (CRF1R) antagonist CP154,526 produced a region-dependent inhibition of yohimbine-induced activation in the amygdala, striatum, and cingulate cortex, while the orexin type-1 receptor (OX1R) antagonists GSK1059865 robustly inhibited the response in fronto-hippocampal regions as well as in several key components of the extended amygdala. CP154,526 and GSK1059865 did not prevent yohimbine-induced plasma corticosterone release, a finding that corroborates a central origin of the effects mapped. Our findings provide novel insight into the brain substrates and neurochemical mediators engaged by the stress-inducing agent yohimbine. The differential pattern of inhibition produced by CRF1R and OX1R antagonists suggests that these two neuropeptide systems can modulate the functional response to stress via distinct central neural pathways.     

Effects of a Single Lyric Analysis Intervention on Withdrawal and Craving With Inpatients on a Detoxification Unit: A Cluster-Randomized Effectiveness Study

Background: For patients hospitalized on inpatient detoxification units, reducing negative symptoms such as withdrawal and craving is a key treatment area. Although lyric analysis is a commonly utilized music therapy intervention for clients in substance abuse rehabilitation, there is a lack of randomized controlled music therapy studies systematically investigating how lyric analysis interventions can affect patients on a detoxification unit. Objective: The purpose of this cluster-randomized effectiveness study was to measure the effects of single-session group lyric analysis interventions on withdrawal and craving with patients on a detoxification unit. A secondary purpose of this study was to determine if relationships existed between treatment effects and participants’ familiarity with the song. Methods: Participants (N = 144) were cluster-randomized to experimental (posttest only) or wait-list control (pretest only) conditions to provide treatment to all participants in an inclusive single-session design. Results: Although participants in the experimental condition had lower withdrawal and craving means than participants in the control condition, these differences were not significant. Familiarity of the song in the lyric analysis was not related to withdrawal or craving. Conclusion: Group-based lyric analysis interventions may be effective for temporarily relieving withdrawal and craving in patients on a detoxification unit. Familiarity of the song did not affect results. Implications for clinical practice, suggestions for future research, and limitations are provided.     

Effects of HIV and Methamphetamine on Brain and Behavior: Evidence from Human Studies and Animal Models

Methamphetamine (Meth) use is frequent among HIV-infected persons. Combined HIV and Meth insults may exacerbate neural injury in vulnerable neuroanatomic structures or circuitries in the brain, leading to increased behavioral disturbance and cognitive impairment. While acute and chronic effects of Meth in humans and animal models have been studied for decades, the neurobehavioral effects of Meth in the context of HIV infection are much less explored. In-depth understanding of the scope of neurobehavioral phenotypes and mechanisms in HIV/Meth intersection is needed. The present report summarizes published research findings, as well as unpublished data, in humans and animal models with regard to neurobehavioral disturbance, neuroimaging, and neuropathology, and in vitro experimental systems, with an emphasis on findings emerging from the National Institute on Drug Abuse (NIDA) funded Translational Methamphetamine AIDS Research Center (TMARC). Results from human studies and animal (primarily HIV-1 gp120 transgenic mouse) models thus far suggest that combined HIV and Meth insults increase the likelihood of neural injury in the brain. The neurobehavioral effects include cognitive impairment and increased tendencies toward impaired behavioral inhibition and social cognition. These impairments are relevant to behaviors that affect personal and social risks, e.g. worse medication adherence, riskier behaviors, and greater likelihood of HIV transmission. The underlying mechanisms may include electrochemical changes in neuronal circuitries, injury to white matter microstructures, synaptodendritic damage, and selective neuronal loss. Utilization of research methodologies that are valid across species is instrumental in generating new knowledge with clinical translational value.