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Gastrin-releasing peptide receptors (GRPRs) are promising targets in oligometastatic prostate cancer. We have recently used 55 Co (T 1/2 =  17.5 h) as a label for next day PET imaging of GRPR expression obtaining high imaging contrast. The radionuclide-chelator combination can significantly influence the biodistribution of radiopeptides. Therefore, in this study, we hypothesized that the properties of 55 Co-labeled PEG 2 -RM26 can be improved by identifying the optimal macrocyclic chelator. All analogues (X-PEG 2 -RM26, X = NOTA,NODAGA,DOTA,DOTAGA) were successfully labeled with radiocobalt with high yields and demonstrated high stability. The radiopeptides bound specifically and with picomolar affinity to GRPR and their cellular processing was characterized by low internalization. The best binding capacity was found for DOTA-PEG 2 -RM26. Ex vivo biodistribution in PC-3 xenografted mice was characterized by rapid blood clearance via renal excretion. Tumor uptake was similar for all conjugates at 3 h pi, exceeding the uptake in all other organs. Higher kidney uptake and longer retention were associated with N-terminal negative charge (DOTAGA-containing conjugate). Tumor-to-organ ratios increased over time for all constructs, although significant chelator-dependent differences were observed. Concordant with affinity measurements, DOTA-analog had the best retention of activity in tumors, resulting in the highest tumor-to-blood ratio 24 h pi, which translated into high contrast PET/CT imaging (using 55 Co).

The human amygdala consists of subdivisions contributing to various functions. However, principles of structural organization at the cellular and molecular level are not well understood. Thus, we re-analyzed the cytoarchitecture of the amygdala and generated cytoarchitectonic probabilistic maps of ten subdivisions in stereotaxic space based on novel workflows and mapping tools. This parcellation was then used as a basis for analyzing the receptor expression for 15 receptor types. Receptor fingerprints, i.e., the characteristic balance between densities of all receptor types, were generated in each subdivision to comprehensively visualize differences and similarities in receptor architecture between the subdivisions. Fingerprints of the central and medial nuclei and the anterior amygdaloid area were highly similar. Fingerprints of the lateral, basolateral and basomedial nuclei were also similar to each other, while those of the remaining nuclei were distinct in shape. Similarities were further investigated by a hierarchical cluster analysis: a two-cluster solution subdivided the phylogenetically older part (central, medial nuclei, anterior amygdaloid area) from the remaining parts of the amygdala. A more fine-grained three-cluster solution replicated our previous parcellation including a laterobasal, superficial and centromedial group. Furthermore, it helped to better characterize the paralaminar nucleus with a molecular organization in-between the laterobasal and the superficial group. The multimodal cyto- and receptor-architectonic analysis of the human amygdala provides new insights into its microstructural organization, intersubject variability, localization in stereotaxic space and principles of receptor-based neurochemical differences.

Substance abuse among older adults has received little attention in the past, presumably because this population has traditionally accounted for only a small percentage of the drug abuse problem in the United States. The aging of the baby boomer generation (born 1946–1964), however, will soon swell the ranks of older adults and dramatically alter the demography of American society. Several observations suggest that this expansion will likely be accompanied by a precipitous increase in the abuse of drugs, including prescription medications and illicit substances, among older adults. While it is now evident that the brain changes continuously across life, how drugs of abuse interact with these age-related changes remains unclear. The dynamic nature of brain function, however, suggests that substance abuse during older age may augment the risks and require unique considerations for diagnosis and treatment. In addition to describing current and projected prevalence estimates of substance abuse among older adults, the present review discusses how aging affects brain systems involved in drug abuse, and explores the potential impact of drug abuse on the aging brain. Future directions for substance abuse research among older adults will also be considered.

Recently, two extrastriate visual areas on the posterior fusiform gyrus, areas FG1 and FG2, were identified based on cytoarchitectonical criteria (Caspers et al. in Brain Struct Funct 218:511–526, 2013a ). They are located within the object-related ventral visual stream at the transition between early and higher-order (category-specific) visual areas. FG2 has a topographical position which is best comparable to the face or visual word-form recognition area. However, the precise function of FG2 is presently unknown. Since transmitter receptors are key molecules of neurotransmission, we analysed the regional and laminar distribution of 15 different receptor binding sites by means of quantitative in vitro receptor autoradiography. Significant differences between receptor densities of both areas were found for NMDA, GABA B , M 3 , nicotinic α 4 /β 2 and 5-HT 1A receptors as well as for GABA A associated benzodiazepine binding sites. These results support the cytoarchitectonic segregation of FG1 and FG2 into two distinct cortical areas. In addition, principal component and hierarchical cluster analyses of the multireceptor data of both fusiform areas and 24 visual, auditory, somatosensory and multimodal association areas not only revealed the typical receptor architectonic characteristics of visual areas for FG1 and FG2, but also suggest their putative function as object recognition regions due to the similarity of their receptor fingerprints with those of areas of the ventral visual stream. Furthermore, FG1 and FG2 build a cluster with the multimodal association areas of the inferior parietal lobule. This underlines their hierarchically high position in the visual system of the human cerebral cortex.

Rationale In order to improve upon the pharmacological properties of the neuroactive steroid ganaxolone, it was used as the starting point in the design of novel neurosteroids that replace the 17β-acetyl side chain with an isoxazole bioisostere. Objectives UCI-50027 (3-[3α-hydroxy-3β-methyl-5α-androstan-17β-yl]-5-(hydroxymethyl)isoxazole) was designed as an orally active neuroactive steroid specifically targeted at the gamma-aminobutyric acid(A) receptor (GABA A R). Methods UCI-50027 was tested in vitro in Xenopus oocytes expressing human GABA A Rs and in vivo as an anticonvulsant, for ataxic effects and for anxiolytic activity. Results In vitro, UCI-50027 dose-dependently enhanced the activity of GABA at human α 1 β 2 γ 2L , α 2 β 1 γ 2L , and α 4 β 3 δ GABA A Rs. Consistent with its action as a positive allosteric modulator (PAM), it had no direct activity in the absence of GABA. UCI-50027 protected against acute pentylenetetrazol (PTZ)-induced convulsions with an ED 50 of 6 mg/kg p.o. In the rotarod (RR) paradigm in mice, the AD 50 (the ataxic dose where half of the animals fail the RR test) was found to be 38 mg/kg p.o., giving a therapeutic index (TI = RR AD 50 /PTZ ED 50 )∼6 versus 2.8 for ganaxolone. In the mouse-elevated plus maze (EPM) model for anxiety, UCI-50027 showed a minimum effective dose (MED) ≤0.3 mg/kg p.o. Thus, the TI (TI = RR AD 50 /EPM MED) for the compound as an anxiolytic is ≥127 versus 3.3 for ganaxolone. Conclusions UCI-50027 is an orally active neuroactive steroid with pharmacological activity consistent with a GABA A R PAM that has an improved separation between anticonvulsant/anxiolytic and rotarod effects, potent activity as an anticonvulsant and anxiolytic when compared to ganaxolone.

Pharmacological MRI (phMRI) methods map the hemodynamic response to drug challenge as a surrogate for changes in neuronal activity. However, the central effects of drugs can be complex and include activity at the primary site of action, downstream effects in other brain regions and direct effects on vasculature and neurovascular coupling. Univariate analysis, normally applied to phMRI data, does not discriminate between these effects, and can result in anatomically non-specific activation patterns. We analysed inter-subject correlations in the amplitude of the slow phMRI response to map functionally connected brain regions recruited in response to pharmacological challenge. Application of d-amphetamine and fluoxetine revealed well-defined functional structure underlying the widespread signal changes detected via standard methods. Correlated responses were found to delineate key neurotransmitter pathways selectively targeted by these drugs, corroborating a tight correspondence between the phMRI response and changes in neurotransmitter systems specific to the pharmacological action. In vivo mapping of correlated responses in this way greatly extends the range of information available from phMRI studies and provides a new window into the function of neurotransmitter systems in the active state. This approach may provide new important insights regarding the central systems underlying pharmacological action.

The olfactory bulbectomized (OB) rat, an animal model of chronic depression with comorbid anxiety, exhibits a profound dysregulation of the brain serotonergic signalling, a neurotransmission system involved in pain transmission and modulation. We here report an increased nociceptive response of OB rats in the tail flick test which is reverted after chronic, but not acute, administration of fluoxetine. Autoradiographic studies demonstrated down-regulation of 5-HT transporters ([ 3 H]citalopram binding) and decreased functionality of 5-HT 1A receptors (8-OH-DPAT-stimulated [ 35 S]GTPγS binding) in the dorsal horn of the lumbar spinal cord in OB rats. Acute administration of fluoxetine (5–40 mg/kg i.p.) did not modify tail flick latencies in OB rats. However, chronic fluoxetine (10 mg/kg/day s.c., 14 days; osmotic minipumps) progressively attenuated OB-associated thermal hyperalgesia, and a total normalization of the nociceptive response was achieved at the end of the treatment with the antidepressant. In these animals, autoradiographic studies revealed further down-regulation of 5-HT transporters and normalization in the functionality of 5-HT 1A receptors on the spinal cord. On the other hand, acute morphine (0.5–10 mg/kg s.c.) produced a similar analgesic effect in OB and sham and OB rats, and no changes were detected in the density ([ 3 H]DAMGO binding) and functionality (DAMGO-stimulated [ 35 S]GTPγS binding) of spinal μ-opioid receptors in OB rats before and after chronic fluoxetine. Our findings demonstrate the participation of the spinal serotonergic system in the increased thermal nociception exhibited by the OB rat and the antinociceptive effect of chronic fluoxetine in this animal model of depression.

The blood-brain barrier (BBB) blocks the passage of active molecules from the blood which makes drug delivery to the brain a challenging problem. Oral drug delivery using chemically modified drugs to enhance their transport properties or remove the blocking of drug transport across the BBB is explored as a common approach to address these problems, but with limited success. Local delivery of drugs directly to the brain interstitium using implants such as polymeric wafers, gels, and catheters has been recognized as a promising alternative particularly for the treatment of brain cancer (glioma) and neurodegenerative disorders. The aim of this study was to introduce a new solution by engineering a drug-releasing implant for local drug delivery in the brain, based on titanium (Ti) wires with titania nanotube (TNT) arrays on their surfaces. Drug loading and drug release characteristics of this system were explored using two drugs commonly used in oral brain therapy: dopamine (DOPA), a neurotransmitter agent; and doxorubicin (DOXO), an anticancer drug. Results showed that TNT/Ti wires could provide a considerable amount of drugs (>170 μg to 1000 μg) with desirable release kinetics and controllable release time (1 to several weeks) and proved their feasibility for use as drug-releasing implants for local drug delivery in the brain. In this report, a new drug-releasing platform in the form of nanoengineered Ti wires with TNT arrays is proposed as an alternative for local delivery of chemotherapeutics in the brain to bypass the BBB. To prove this concept, drug loading and release characteristics of two drugs important for brain therapy (the neurotransmitter DOPA and the anticancer drug DOXO) were explored. Titania nanotube arrays on the surface of Ti wires (TNT/Ti) were fabricated using a simple anodization process, followed by separate loading of two drugs (DOPA and DOXO) inside the nanotube structures. The loading and in vitro release characteristics of prepared TNT/Ti implants were examined using thermogravimetric analysis (TGA) UV-Vis spectroscopy. Scanning electron microscopy studies confirmed that well-ordered, vertically aligned, densely packed nanotube arrays with an average diameter of 170 nm and length 70 μm were formed on the surface of TNT/Ti wires. TGA results showed a total drug loading of 170 μg and 1200 μg inside the TNTs for DOPA and DOXO respectively. Two-phase drug release behavior was observed including a fast release (burst) for the first 6 hours and a prolonged slow release phase for 8 days, both with acceptable dosage and desirable release kinetics. The physical, structural, loading and release characteristics of prepared TNT/Ti implants showed several advantages in comparison with existing and clinically proved brain implants. Our results confirmed that TNT/Ti wires can be successfully employed as a suitable platform to release neurotransmitters such as DOPA and anticancer drugs such as DOXO. Hence, they are a feasible alternative as drug-releasing implants for local drug delivery in the brain to combat neurodegenerative disorders or brain tumors.

Sigma (σ) receptors have recently been identified as potential targets for the development of novel therapeutics aimed at mitigating the effects of methamphetamine. Particularly, σ receptors are believed to mitigate some of the neurotoxic effects of methamphetamine through modulation of dopamine, dopamine transporters and body temperature. Furthermore, recent evidence suggests that targeting σ receptors may prevent cognitive impairments produced by methamphetamine. In the present study, an optimized σ receptor antagonist, AZ66, was evaluated against methamphetamine-induced neurotoxicity and cognitive dysfunction. AZ66 was found to be highly selective for σ receptors compared to 64 other sites tested. Pretreatment of male, Swiss Webster mice with i.p. dosing of AZ66 significantly attenuated methamphetamine-induced striatal dopamine depletions, striatal dopamine transporter reductions and hyperthermia. Additionally, neurotoxic dosing with methamphetamine caused significant memory impairment in the object recognition test, which was attenuated when animals were pretreated with AZ66; similar trends were observed in the step-through passive avoidance test. Taken together, these results suggest that targeting σ receptors may provide neuroprotection against the neurotoxicity and cognitive impairments produced by methamphetamine.

Neurological injury, as a result of stroke and traumatic brain injury, causes significant morbidity and mortality. Despite the importance of these conditions, the basis of current treatment remains supportive. In recent years, our increasing understanding of the pathophysiological mechanisms of secondary injury, for example excitotoxity, has led to a search for specific agents that can intercept these pathological pathways and act as pharmaceutical neuroprotectants. While successful in the laboratory, these agents have yet to demonstrate efficacy in the clinical arena. The reasons for these failures are varied and incompletely understood, but significant factors include inconclusive pharmacokinetic data, particularly regarding blood brain barrier penetration, and the heterogenous nature of these pathologies in humans. Microdialysis is an established, commercially available, clinical and research tool that is used to sample brain extracellular fluid. It provides the technology to determine the cerebral penetration of drugs and it measures biological markers of brain tissue injury. It can therefore be used to determine the biochemical efficacy of therapeutic manoeuvres. In this review we address the practical application of this technology to the process of drug development.