Comparative Neuropharmacology and Pharmacokinetics of Methamphetamine and Its Thiophene Analog Methiopropamine in Rodents.

Methiopropamine is a novel psychoactive substance (NPS) that is associated with several cases of clinical toxicity, yet little information is available regarding its neuropharmacological properties. Here, we employed in vitro and in vivo methods to compare the pharmacokinetics and neurobiological effects of methiopropamine and its structural analog methamphetamine. Methiopropamine was rapidly distributed to the blood and brain after injection in C57BL/6 mice, with a pharmacokinetic profile similar to that of methamphetamine. Methiopropamine induced psychomotor activity, but higher doses were needed (Emax 12.5 mg/kg; i.p.) compared to methamphetamine (Emax 3.75 mg/kg; i.p.). A steep increase in locomotor activity was seen after a modest increase in the methiopropamine dose from 10 to 12.5 mg/kg, suggesting that a small increase in dosage may engender unexpectedly strong effects and heighten the risk of unintended overdose in NPS users. In vitro studies revealed that methiopropamine mediates its effects through inhibition of norepinephrine and dopamine uptake into presynaptic nerve terminals (IC50 = 0.47 and 0.74 µM, respectively), while the plasmalemmal serotonin uptake and vesicular uptake are affected only at high concentrations (IC50 > 25 µM). In summary, methiopropamine closely resembles methamphetamine with regard to its pharmacokinetics, pharmacodynamic effects and mechanism of action, with a potency that is approximately five times lower than that of methamphetamine.

Human Brain Neuropharmacology: A Platform for Translational Neuroscience.

Central nervous system (CNS) drug development has been plagued by a failure to translate effective therapies from the lab to the clinic. There are many potential reasons for this, including poor understanding of brain pharmacokinetic (PK) and pharmacodynamic (PD) factors, preclinical study flaws, clinical trial design issues, the complexity and variability of human brain diseases, as well as species differences. To address some of these problems, we have developed a platform for CNS drug discovery comprising: drug screening of primary adult human brain cells; human brain tissue microarray analysis of drug targets; and high-content phenotypic screening methods. In this opinion, I summarise the theoretical basis and the practical development and use of this platform in CNS drug discovery.

Rats can learn a temporal task in a single session.

Fixed interval, peak interval, and temporal bisection procedures have been used to assess cognitive functions and address questions such as how animals perceive, represent, and reproduce time intervals. They have also been extensively used to test the effects of drugs on behavior, and to describe the neural correlates of interval timing. However, those procedures usually require several weeks of training for behavior to stabilize. Here, we investigated a variation of the Differential Reinforcement of Response Duration (DRRD) task with a target time of 1.2 s. We compared three types of training protocols and reported a procedure in which performance by the end of the very first session nearly matches the performance of long-term training. We also showed that the initial distribution of the responses is uni-modal and, as training evolves (and rats improve their performance), a second peak emerges and progressively shifts toward longer times. This one-day training protocol can be used to investigate temporal learning and may be especially useful to electrophysiological and neuropharmacological studies.

Cell-Specific Neuropharmacology.

Neuronal communication involves a multitude of neurotransmitters and an outstanding diversity of receptors and ion channels. Linking the activity of cell surface receptors and ion channels in defined neural circuits to brain states and behaviors has been a key challenge in neuroscience, since cell targeting is not possible with traditional neuropharmacology. We review here recent technologies that enable the effect of drugs to be restricted to specific cell types, thereby allowing acute manipulation of the brain's own proteins with circuit specificity. We highlight the importance of developing cell-specific neuropharmacology strategies for decoding the nervous system with molecular and circuit precision, and for developing future therapeutics with reduced side effects.

Wireless optofluidic brain probes for chronic neuropharmacology and photostimulation.

Both in vivo neuropharmacology and optogenetic stimulation can be used to decode neural circuitry, and can provide therapeutic strategies for brain disorders. However, current neuronal interfaces hinder long-term studies in awake and freely behaving animals, as they are limited in their ability to provide simultaneous and prolonged delivery of multiple drugs, are often bulky and lack multifunctionality, and employ custom control systems with insufficiently versatile selectivity for output mode, animal selection and target brain circuits. Here, we describe smartphone-controlled, minimally invasive, soft optofluidic probes with replaceable plug-like drug cartridges for chronic in vivo pharmacology and optogenetics with selective manipulation of brain circuits. We demonstrate the use of the probes for the control of the locomotor activity of mice for over four weeks via programmable wireless drug delivery and photostimulation. Owing to their ability to deliver both drugs and photopharmacology into the brain repeatedly over long time periods, the probes may contribute to uncovering the basis of neuropsychiatric diseases.

High frequency, real-time neurochemical and neuropharmacological measurements in situ in the living body.

The beautiful and complex brain machinery is perfectly synchronized, and our bodies have evolved to protect it against a myriad of potential threats. Shielded physically by the skull and chemically by the blood brain barrier, the brain processes internal and external information so that we can efficiently relate to the world that surrounds us while simultaneously and unconsciously controlling our vital functions. When coupled with the brittle nature of its internal chemical and electric signals, the brain's "armor" render accessing it a challenging and delicate endeavor that has historically limited our understanding of its structural and neurochemical intricacies. In this review, we briefly summarize the advancements made over the past 10 years to decode the brain's neurochemistry and neuropharmacology in situ, at the site of interest in the brain, with special focus on what we consider game-changing emerging technologies (eg, genetically encoded indicators and electrochemical aptamer-based sensors) and the challenges these must overcome before chronic, in situ chemosensing measurements become routine.

[Pharmacotherapy of chronic neuropathic pain]. / Pharmakologische Therapie chronischer neuropathischer Schmerzen.

Chronic neuropathic pain has a prevalence of 6.9-10% in the general population. The current recommendations for treatment are presented based on a literature search. Neuropathic pain requires the use of co-analgesic, antidepressant, anticonvulsant drugs and topical agents because non-opioid analgesic drugs are usually ineffective. The use of meta-analyses tricyclic antidepressants, selective serotonin-norephinephrine reuptake inhibitors, and calcium channel anticonvulsants are recommended as the drugs of first choice. Under certain conditions chronic neuropathic pain can be treated with opioids. Topical therapeutics are only used to treat peripheral neuropathic pain. At present the use of drugs is independent of the etiology of the pain. Comorbidities, concomitant medication, potential side effects and patients' age have to be considered in treatment planning.

High-throughput brain activity mapping and machine learning as a foundation for systems neuropharmacology.

Technologies for mapping the spatial and temporal patterns of neural activity have advanced our understanding of brain function in both health and disease. An important application of these technologies is the discovery of next-generation neurotherapeutics for neurological and psychiatric disorders. Here, we describe an in vivo drug screening strategy that combines high-throughput technology to generate large-scale brain activity maps (BAMs) with machine learning for predictive analysis. This platform enables evaluation of compounds' mechanisms of action and potential therapeutic uses based on information-rich BAMs derived from drug-treated zebrafish larvae. From a screen of clinically used drugs, we found intrinsically coherent drug clusters that are associated with known therapeutic categories. Using BAM-based clusters as a functional classifier, we identify anti-seizure-like drug leads from non-clinical compounds and validate their therapeutic effects in the pentylenetetrazole zebrafish seizure model. Collectively, this study provides a framework to advance the field of systems neuropharmacology.

Utilizing resources of neuropsychopharmacology to address the opioid overdose crisis.

BACKGROUND: North America is facing a severe public health crisis in the form of excessive numbers of deaths due to overdose from self-administration of opioids by individuals who are dependent on these substances. AIMS: There are many factors that must be addressed in order to gain control over this tragedy. Of particular relevance to neuropsychopharmacology is the fact that the problem is due in part to misuse of pharmaceuticals and especially the illicit production of the powerful synthetic opioids, fentanyl, and carfentanil. METHOD: The development and adoption of appropriate pharmacotherapies are of critical importance. We discuss specific options to deal effectively with both withdrawal from opioid dependence and substitution of clinically approved drugs in place of illicit substances. CONCLUSION: Hopefully, this crisis will reinvigorate both basic and clinical neuropsychopharmacological research leading to the develop new and more effective options for dealing with the many and varied elements of the current opioid crisis as described in the present commentary.

Neuropharmacology of attention.

Early philosophers and psychologists defined and began to describe attention. Beginning in the 1950's, numerous models of attention were developed. This corresponded with an increased understanding of pharmacological approaches to manipulate neurotransmitter systems. The present review focuses on the knowledge that has been gained about these neurotransmitter systems with respect to attentional processing, with emphasis on the functions mediated within the medial prefrontal cortex. Additionally, the use of pharmacotherapies to treat psychiatric conditions characterized by attentional dysfunction are discussed. Future directions include developing a more comprehensive understanding of the neural mechanisms underlying attentional processing and novel pharmacotherapeutic targets for conditions characterized by aberrant attentional processing.

Toxins as tools: Fingerprinting neuronal pharmacology.

Toxins have been used as tools for decades to study the structure and function of neuronal ion channels and receptors. The biological origin of these toxins varies from single cell organisms, including bacteria and algae, to complex multicellular organisms, including a wide variety of plants and venomous animals. Toxins are a structurally and functionally diverse group of compounds that often modulate neuronal function by interacting with an ion channel or receptor. Many of these toxins display high affinity and exquisite selectivity, making them valuable tools to probe the structure and function of neuronal ion channels and receptors. This review article provides an overview of the experimental techniques used to assess the effects that toxins have on neuronal function, as well as discussion on toxins that have been used as tools, with a focus on toxins that target voltage-gated and ligand-gated ion channels.

Three-dimensional patterning in biomedicine: Importance and applications in neuropharmacology.

Nature manufactures biological systems in three dimensions with precisely controlled spatiotemporal profiles on hierarchical length and time scales. In this article, we review 3D patterning of biological systems on synthetic platforms for neuropharmacological applications. We briefly describe 3D versus 2D chemical and topographical patterning methods and their limitations. Subsequently, an overview of introducing a third dimension in neuropharmacological research with delineation of chemical and topographical roles is presented. Finally, toward the end of this article, an explanation of how 3D patterning has played a pivotal role in relevant fields of neuropharmacology to understand neurophysiology during development, normal health, and disease conditions is described. The future prospects of organs-on-a--like devices to mimic patterned blood-brain barrier in the context of neurotherapeutic discovery and development for the prioritization of lead candidates, membrane potential, and toxicity testing are also described. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1369-1382, 2018.

Neuroimmune Pharmacology, 2nd Edition - A Perspective.

It has been almost nine years since the 1st edition of Neuroimmune Pharmacology was published on May 23rd, 2008. The 2nd edition of Neuroimmune Pharmacology by Ikezu and Gendelman (Editors) with Przedborski, Masliah and Cosentino (Associate Editors) manages to fulfill two separate missions: to provide comprehensive, but highly topical access to a rapidly evolving field and to serve as a standalone reference for scientists and clinicians in need of guidance regarding questions pertinent to neuroimmune pharmacology. Doing a PubMed search on the terms neuroimmune and pharmacology yields 1090 publications, with a first publication by Dougherty and Dafny, published in the Journal of Neuroscience Research in 1988, entitled "Neuroimmune intercommunication, central opioids, and the immune response to bacterial endotoxin." Since 2000, there have been 979 publications using these search terms, with 137 published since the beginning of 2016. The obvious conclusion to be drawn is that this is a burgeoning field that represents the cusp between our understanding of relationships between the immune and nervous systems and how we might treat disease with pharmacologic approaches when normal homeostatic mechanisms go awry.

Hypothesizing That Neuropharmacological and Neuroimaging Studies of Glutaminergic-Dopaminergic Optimization Complex (KB220Z) Are Associated With "Dopamine Homeostasis" in Reward Deficiency Syndrome (RDS).

BACKGROUND: There is need for better treatments of addictive behaviors, both substance and non-substance related, termed Reward Deficiency Syndrome (RDS). While the FDA has approved pharmaceuticals under the umbrella term Medication Assisted Treatment (MAT), these drugs are not optimal. OBJECTIVES: It is our contention that these drugs work well in the short-term by blocking dopamine function leading to psychological extinction. However, use of buprenorphine/Naloxone over a long period of time results in unwanted addiction liability, reduced emotional affect, and mood changes including suicidal ideation. METHODS: We are thus proposing a paradigm shift in addiction treatment, with the long-term goal of achieving "Dopamine Homeostasis." While this may be a laudable goal, it is very difficult to achieve. Nevertheless, this commentary briefly reviews past history of developing and subsequently, utilizing a glutaminergic-dopaminergic optimization complex [Kb220Z] shown to be beneficial in at least 20 human clinical trials and in a number of published and unpublished studies. RESULTS: It is our opinion that, while additional required studies could confirm these findings to date, the cited studies are indicative of achieving enhanced resting state functional connectivity, connectivity volume, and possibly, neuroplasticity. Conclusions/Importance: We are proposing a Reward Deficiency Solution System (RDSS) that includes: Genetic Addiction Risk Score (GARS); Comprehensive Analysis of Reported Drugs (CARD); and a glutaminergic-dopaminergic optimization complex (Kb220Z). Continued investigation of this novel strategy may lead to a better-targeted approach in the long-term, causing dopamine regulation by balancing the glutaminergic-dopaminergic pathways. This may potentially change the landscape of treating all addictions leading us to the promised land.