Armodafinil as a Potential Pharmacological Treatment for Attention Deficit Hyperactivity Disorder in Adults: A Review.

INTRODUCTION: Armodafinil is a psychostimulant that promotes alertness, and it has been shown to improve attention, memory, and fatigue in healthy adults and adults with neurodevelopmental conditions that share symptoms with Attention Deficit Hyperactivity Disorder (ADHD). It is generally well tolerated and safe, and most of the adverse events reported are considered not serious. However, the available evidence on the efficacy of armodafinil for the treatment of ADHD in adults is scarce. OBJECTIVE: The present review aims to perform a systematized search of the available evidence on the possible therapeutic benefit of armodafinil treatment in adult patients with ADHD. METHODS: A literature review using PubMed was conducted to compile and summarize the available clinical and scientific evidence on the possible use of armodafinil as a pharmacological treatment in adult patients with ADHD. RESULTS: From the 86 articles reviewed, the available evidence showed that both acute and chronic treatment with armodafinil can improve wakefulness, memory, impulse control, and executive functions in adults with sleep disorders and other conditions. In addition, evidence of improvement in cognitive functions and mood alterations in other neuropsychiatric conditions was shown. CONCLUSION: Armodafinil could be useful for the treatment of ADHD in adults, according to the review of the literature from both pre-clinical and clinical studies.

Dysfunction of the Neurovascular Unit by Psychostimulant Drugs.

'Drug abuse' has been recognized as one of the most pressing epidemics in contemporary society. Traditional research has primarily focused on understanding how drugs induce neurotoxicity or degeneration within the central nervous system (CNS) and influence systems related to reward, motivation, and cravings. However, recent investigations have increasingly shifted their attention toward the detrimental consequences of drug abuse on the blood-brain barrier (BBB). The BBB is a structural component situated in brain vessels, responsible for separating brain tissue from external substances to maintain brain homeostasis. The BBB's function is governed by cellular interactions involving various elements of the 'neurovascular unit (NVU),' such as neurons, endothelial cells, astrocytes, pericytes, and microglia. Disruption of the NVU is closely linked to serious neurodegeneration. This review provides a comprehensive overview of the harmful effects of psychostimulant drugs on the BBB, highlighting the mechanisms through which drugs can damage the NVU. Additionally, the review proposes novel therapeutic targets aimed at protecting the BBB. By understanding the intricate relationships between drug abuse, BBB integrity, and NVU function, researchers and clinicians may uncover new strategies to mitigate the damaging impact of drug abuse on brain health.

Interaction of Diamine Oxidase with Psychostimulant Drugs for ADHD Management.

Histamine intolerance occurs when there is an imbalance between histamine production and the capacity for histamine degradation. Diamine oxidase (DAO) is the main enzyme for the catabolism of ingested histamine degradation in the gastrointestinal tract and its deficiency has been linked to allergy-like symptoms. Psychostimulant drugs are commonly used to treat Attention Deficit Hyperactivity Disorder (ADHD), but their interaction with DAO is not well characterized. In this work, we evaluated the effects of psychostimulant drugs (methylphenidate and lisdexamfetamine) on in vitro DAO activity and in the human cell line of enterocytes (Caco-2), evaluating DAO expression (mRNA and protein) and DAO activity. Methylphenidate and lisdexamfetamine did not repress the in vitro DAO activity. In addition, in Caco-2 cells, lisdexamfetamine promoted a strong upregulation of DAO mRNA levels, whereas methylphenidate tended to induce DAO activity. To sum up, methylphenidate and lisdexamfetamine treatments do not reduce DAO activity. These findings could be useful for physicians prescribing these two drugs to ADHD patients affected by DAO deficiency.

Time course of plasticity-related alterations following the first exposure to amphetamine in juvenile rats.

In vulnerable consumers, the first drug exposure induces various neurobehavioral adaptations that may represent the starting point toward addiction. Elucidating the neuroplastic mechanisms underlying that first rewarding experience would contribute to understanding the transition from recreational to compulsive drug use. In a preclinical model with juvenile rats, we analyzed the time-dependent fluctuations in the expression of neuroplasticity-related genes like the brain-derived neurotrophic factor (BDNF), its tropomyosin receptor kinase B (TrkB), the cAMP response element-binding protein (CREB), the microRNA-132, the Rho GTPase-activating protein 32 (p250GAP), the corticotropin-releasing factor (CRF), and the neurotransmitters contents in the nucleus accumbens (NAc) and the dorsal striatum (DS) 45, 90, and 180 min after an amphetamine (AMPH) injection. As expected, AMPH altered the concentration of norepinephrine, dopamine, DOPAC, and serotonin in a region- and time-dependent manner. Regarding gene expression, AMPH at 45 min upregulated BDNF and primiR-132 expression in NAc and downregulated TrkB expression in DS. At 90 min, AMPH upregulated TrkB, CREB, p250GAP, and primiR-132 expression in NAc and BDNF, primiR-132, and CRF in DS. At 180 min, only BNDF in NAc continued to be upregulated by AMPH. Based on the levels of AMPH-induced hyperactivity, we classified the rats as low and high AMPH responders. High AMPH responders characterized by overexpressing BDNF, CREB, p250GAP, and CRF in NAc and by showing lower levels of dopamine and serotonin metabolites and turnovers in both regions. Our findings demonstrated that a single AMPH administration is enough to induce neuroplastic adaptations, especially in the NAc of prone rats.

Neurobiological Mechanisms Modulating Emotionality, Cognition and Reward-Related Behaviour in High-Fat Diet-Fed Rodents.

Affective and substance-use disorders are associated with overweight and obesity-related complications, which are often due to the overconsumption of palatable food. Both high-fat diets (HFDs) and psychostimulant drugs modulate the neuro-circuitry regulating emotional processing and metabolic functions. However, it is not known how they interact at the behavioural level, and whether they lead to overlapping changes in neurobiological endpoints. In this literature review, we describe the impact of HFDs on emotionality, cognition, and reward-related behaviour in rodents. We also outline the effects of HFD on brain metabolism and plasticity involving mitochondria. Moreover, the possible overlap of the neurobiological mechanisms produced by HFDs and psychostimulants is discussed. Our in-depth analysis of published results revealed that HFDs have a clear impact on behaviour and underlying brain processes, which are largely dependent on the developmental period. However, apart from the studies investigating maternal exposure to HFDs, most of the published results involve only male rodents. Future research should also examine the biological impact of HFDs in female rodents. Further knowledge about the molecular mechanisms linking stress and obesity is a crucial requirement of translational research and using rodent models can significantly advance the important search for risk-related biomarkers and the development of clinical intervention strategies.

Tactile Stimulation in Adult Rats Modulates Dopaminergic Molecular Parameters in the Nucleus accumbens Preventing Amphetamine Relapse.

Amphetamine (AMPH) is a psychostimulant drug frequently related to addiction, which is characterized by functional and molecular changes in the brain reward system, favoring relapse development, and pharmacotherapies have shown low effectiveness. Considering the beneficial influences of tactile stimulation (TS) in different diseases that affect the central nervous system (CNS), here we evaluated if TS applied in adult rats could prevent or minimize the AMPH-relapse behavior also accessing molecular neuroadaptations in the nucleus accumbens (NAc). Following AMPH conditioning in the conditioned place preference (CPP) paradigm, male rats were submitted to TS (15-min session, 3 times a day, for 8 days) during the drug abstinence period, which were re-exposed to the drug in the CPP paradigm for additional 3 days for relapse observation and molecular assessment. Our findings showed that besides AMPH relapse, TS prevented the dopamine transporter (DAT), dopamine 1 receptor (D1R), tyrosine hydroxylase (TH), mu opioid receptor (MOR) increase, and AMPH-induced delta FosB (ΔFosB). Based on these outcomes, we propose TS as a useful tool to treat psychostimulant addiction, which is subsequent to clinical studies; it could be included in detoxification programs together with pharmacotherapies and psychological treatments already conventionally established.

Time-dependent changes in striatal monoamine levels and gene expression following single and repeated amphetamine administration in rats.

As drug addiction may result from pathological usurpations of learning and memory's neural mechanisms, we focused on the amphetamine-induced time-dependent neurochemical changes associated with neural plasticity. We used juvenile rats as the risk for drug abuse is higher during adolescence. Experiment 1 served to define the appropriate amphetamine dose and the neurochemical effects of a single administration. In experiment 2, rats received seven amphetamine or saline injections in the open-field test throughout a twelve-day period. We measured the mRNA levels of the brain-derived neurotrophic factor (BDNF), its tropomyosin receptor kinase B (TrkB), the cAMP response element-binding protein (CREB), the microRNA-132, the Rho GTPase-activating protein 32 (p250GAP), the corticotropin-releasing factor (CRF), and monoamines and amino-acids contents in the nucleus accumbens and the dorsal striatum 45, 90, and 180 min after the last injection. We found that amphetamine changed gene expression only at certain time points and in a dose and region-dependent manner. Repeated but not single administrations upregulated accumbal and striatal BDNF (180 min) and striatal pri-miR-132 (90 min) expression, while downregulated accumbal CREB levels (90 min). As only some drug users develop addiction, we compared brain parameters between low and high amphetamine responders. Prone subjects characterized by having reduced striatal 5-HT metabolism, higher accumbal BDNF and TrkB expression, and lower levels of CREB in the dorsal striatum and p250GAP in both regions. Thus, individual differences in drug-induced changes in neurotransmission and gene expression in nigrostriatal and mesolimbic dopaminergic pathways may underlie the plasticity adaptations associated with behavioral sensitization to amphetamine.

[Transition of adolescents with attention deficit/hyperactivity disorder. Implications for treatment of adults]. / La transición del adolescente con trastorno por déficit de atención con hiperactividad. Implicaciones en el tratamiento en el adulto.

Attention deficit hyperactivity disorder (ADHD) is a chronic, complex and multifactorial neurodevelopmental disorder associated with high rates of concurrent psychiatric disorders, along with problems and complications on different areas of individual functioning. ADHD is not exclusively a childhood disorder, 40-60% persisting into adulthood with an estimated prevalence of 2.5-5%. Adolescence is a stage where great and continuous changes occur, associated with a lower adherence to treatment, a greater vulnerability to the emergence of academic problems, more risk-behaviors, the onset of substance use and higher rates of other comorbid disorders. The transition to adult services or units also occurs at this stage, requiring greater coordination between child/adolescent and adult services to ensure continuity of care in a phase of life in which the patient is particularly vulnerable. As in the case of children and adolescents, the recommended treatment for adults with ADHD is the multimodal and multidisciplinary approach, that combines medication with psychological or psychosocial strategies, such as psycho-education, cognitive behavioral therapy or coaching, adapted to the individual needs of each patient. Clinical guidelines recommend psycho-stimulant drugs as first-line treatments for adult patients with ADHD.

El trastorno por déficit de atención con hiperactividad (TDAH) es un trastorno del neurodesarrollo crónico, complejo y multifactorial asociado con elevadas tasas de concurrencia con otros trastornos psiquiátricos, junto con problemas y repercusiones en diferentes áreas del funcionamiento del individuo. El TDAH no es exclusivo de la edad infanto-juvenil, estimándose una persistencia del 40-60% en la edad adulta, de modo que entre 2.5 y 5% de adultos continúan presentando este trastorno. La adolescencia es una etapa en la que se producen grandes y continuos cambios y que se asocia con una menor adherencia al tratamiento, una mayor vulnerabilidad a la aparición de problemas académicos, más conductas de riesgo, el inicio en el consumo de sustancias y la aparición de otros trastornos comórbidos. Se produce también la transición a los servicios o unidades de adultos, siendo necesaria una mayor coordinación entre los servicios infanto-juveniles y de adultos para asegurar una continuidad de la intervención en una etapa d e la vida en la que el paciente es especialmente vulnerable. Como en el caso de los niños y adolescentes, el tratamiento recomendado en el adulto con TDAH es el abordaje multimodal y multidisciplinar, que combina la medicación con estrategias psicológicas o psicosociales, como la psicoeducación, la terapia cognitivo conductual o el coaching, adaptadas a las necesidades individuales de cada paciente. Los fármacos psicoestimulantes son considerados de primera elección en adultos por las guías clínicas.

Role of nitric oxide in psychostimulant-induced neurotoxicity.

In recent decades, consumption of psychostimulants has been significantly increased all over the world, while exact mechanisms of neurochemical effects of psychomotor stimulants remained unclear. It is assumed that the neuronal messenger nitric oxide (NO) may be involved in mechanisms of neurotoxicity evoked by psychomotor stimulants. However, possible participation of NO in various pathological states is supported mainly by indirect evidence because of its short half-life in tissues. Aim of this review is to describe the involvement of NO and the contribution of lipid peroxidation (LPO) and acetylcholine (ACH) release in neurotoxic effects of psychostimulant drugs. NO was directly determined in brain structures by electron paramagnetic resonance (EPR). Both NO generation and LPO products as well as release of ACH were increased in brain structures following four injections of amphetamine (AMPH). Pretreatment of rats with the non-selective inhibitor of NO-synthase (NOS) N-nitro-L-arginine or the neuronal NOS inhibitor 7-nitroindazole significantly reduced increase of NO generation as well as the rise of ACH release induced by AMPH. Both NOS inhibitors injected prior to AMPH had no effect on enhanced levels of LPO products. Administration of the noncompetitive NMDA receptor antagonist dizocilpine abolished increase of both NO content and concentration of LPO products induced by of the psychostimulant drug. Dizocilpine also eliminated the influence of AMPH on the ACH release. Moreover, the neurochemical and neurotoxic effects of the psychostimulant drug sydnocarb were compared with those of AMPH. Single injection of AMPH showed a more pronounced increase in NO and TBARS levels than after an equimolar concentration of sydnocarb. The findings demonstrate the crucial role of NO in the development of neurotoxicity elicited by psychostimulants and underline the key role of NOS in AMPH-induced neurotoxicity.

Multiple Orgasms in Men-What We Know So Far.

INTRODUCTION: There is much popular discussion on strategies to facilitate multiple orgasms in men (ie, 100,000+ hits in Google), yet the topic has not received an objective comprehensive review in the literature. AIM: To review the literature on male multiple orgasms. METHODS: We searched the literature for publications on "male multiple orgasms" and factors influencing male multiple orgasms in Google, PubMed, and PsychINFO. This yielded 15 relevant publications. MAIN OUTCOME MEASURES: A comprehensive overview on the topic of male multiple orgasms and factors that influence the propensity of men to experience multiple orgasms. RESULTS: Few men are multiorgasmic: <10% for those in their 20s, and <7% after the age of 30. The literature suggests 2 types of male multiple orgasms: "sporadic" multiorgasms, with interorgasmic intervals of several minutes, and "condensed" multiorgasms, with bursts of 2-4 orgasms within a few seconds to 2 minutes. Multiple orgasms appear physiologically similar to the single orgasm in mono-orgasmic men. However, in a single case study, a multiorgasmic man did not experience with his first orgasm the prolactin surge that usually occurs with orgasm in mono-orgasmic men. Various factors may facilitate multiple orgasms: (1) practicing to have an orgasm without ejaculation; (2) using psychostimulant drugs; (3) having multiple and/or novel sexual partners; or (4) using sex toys to enhance tactile stimulation. However, confirmatory physiological data on any of these factors are few. In some cases, the ability to experience multiple orgasms may increase after medical procedures that reduce ejaculation (eg, prostatectomy or castration), but what factor(s) influence this phenomenon is poorly investigated. CONCLUSION: Despite popular interest, the topic of male multiple orgasms has received surprisingly little scientific assessment. The role of ejaculation and physiological change during the refractory period in inhibiting multiple orgasms has barely been investigated.

Functional mechanisms of neurotransmitter transporters regulated by lipid-protein interactions of their terminal loops.

The physiological functions of neurotransmitter:sodium symporters (NSS) in reuptake of neurotransmitters from the synapse into the presynaptic nerve have been shown to be complemented by their involvement, together with non-plasma membrane neurotransmitter transporters, in the reverse transport of substrate (efflux) in response to psychostimulants. Recent experimental evidence implicates highly anionic phosphatidylinositol 4,5-biphosphate (PIP(2)) lipids in such functions of the serotonin (SERT) and dopamine (DAT) transporters. Thus, for both SERT and DAT, neurotransmitter efflux has been shown to be strongly regulated by the presence of PIP(2) lipids in the plasma membrane, and the electrostatic interaction of the N-terminal region of DAT with the negatively charged PIP(2) lipids. We examine the experimentally established phenotypes in a structural context obtained from computational modeling based on recent crystallographic data. The results are shown to set the stage for a mechanistic understanding of physiological actions of neurotransmitter transporters in the NSS family of membrane proteins. This article is part of a Special Issue entitled: Lipid-protein interactions.

Differential effects of cocaine on histone posttranslational modifications in identified populations of striatal neurons.

Drugs of abuse, such as cocaine, induce changes in gene expression and epigenetic marks including alterations in histone posttranslational modifications in striatal neurons. These changes are thought to participate in physiological memory mechanisms and to be critical for long-term behavioral alterations. However, the striatum is composed of multiple cell types, including two distinct populations of medium-sized spiny neurons, and little is known concerning the cell-type specificity of epigenetic modifications. To address this question we used bacterial artificial chromosome transgenic mice, which express EGFP fused to the N-terminus of the large subunit ribosomal protein L10a driven by the D1 or D2 dopamine receptor (D1R, D2R) promoter, respectively. Fluorescence in nucleoli was used to sort nuclei from D1R- or D2R-expressing neurons and to quantify by flow cytometry the cocaine-induced changes in histone acetylation and methylation specifically in these two types of nuclei. The two populations of medium-sized spiny neurons displayed different patterns of histone modifications 15 min or 24 h after a single injection of cocaine or 24 h after seven daily injections. In particular, acetylation of histone 3 on Lys 14 and of histone 4 on Lys 5 and 12, and methylation of histone 3 on Lys 9 exhibited distinct and persistent changes in the two cell types. Our data provide insights into the differential epigenetic responses to cocaine in D1R- and D2R-positive neurons and their potential regulation, which may participate in the persistent effects of cocaine in these neurons. The method described should have general utility for studying nuclear modifications in different types of neuronal or nonneuronal cell types.