- Involvement of BDNF/TrkB signaling in the effect of diphenyl diselenide on motor function in a Parkinson's disease rat model. [Journal Article]
- EJEur J Pharmacol 2016 Nov 30
- Parkinson's disease is a progressive neurodegenerative disorder characterized by degeneration of nigrostriatal dopaminergic neurons. Diphenyl diselenide [(PhSe)2] is a compound with pharmacological p...
Parkinson's disease is a progressive neurodegenerative disorder characterized by degeneration of nigrostriatal dopaminergic neurons. Diphenyl diselenide [(PhSe)2] is a compound with pharmacological proprieties, such as antidepressant and neuroprotective. Therefore, this study investigated whether (PhSe)2 reverses motor impairment and neurochemical alterations in a model of Parkinson's disease induced by 6-hydroxydopamine (6-OHDA) in rats. For this, male Wistar rats received 20μg/3μl of 6-OHDA or vehicle into the right striatum. Three weeks later, animals were subjected to rotational behavioral test induced by D-amphetamine and randomly divided into four groups: Sham; (PhSe)2; 6-OHDA and 6-OHDA+(PhSe)2. The rats received (PhSe)2 (1mg/kg/day; i.g.) or vehicle (canola oil) during 30 days. After treatment, behavioral tests were performed in order to evaluate the motor function and the ipsilateral striatal tissue was collected for immunoblotting assay. (PhSe)2 treatment restored the normal motor behavior of 6-OHDA-infused rats in the cylinder, stepping and bridge tests, but not in the rotarod test. The 6-OHDA infusion and/or (PhSe)2 treatment did not alter the muscle strength and spontaneous locomotion in the forelimb support and open-field tests, respectively. Additionally, striatal brain-derived neurotrophic factor (BDNF), proBDNF and tyrosine hydroxylase (TH) levels of 6-OHDA-lesioned rats were decreased, while the tropomyosin-related kinase B (TrkB) levels were increased. (PhSe)2 treatment restored striatal proBDNF, TrkB and TH levels. Thus, (PhSe)2 treatment reversed some motor impairment and TH levels in a 6-OHDA model of Parkinson's disease in rats, demonstrating a potential neurorestorative role. Additionally, the BDNF/TrkB signaling recovery can be involved in its neurorestorative effect.
- Predicting the Abuse Liability of Entactogen-Class, New and Emerging Psychoactive Substances via Preclinical Models of Drug Self-administration. [Journal Article]
- CTCurr Top Behav Neurosci 2016 Dec 02
- Animal models of drug self-administration are currently the gold standard for making predictions regarding the relative likelihood that a recreational drug substance will lead to continued use and ad...
Animal models of drug self-administration are currently the gold standard for making predictions regarding the relative likelihood that a recreational drug substance will lead to continued use and addiction. Such models have been found to have high predictive accuracy and discriminative validity for a number of drug classes including ethanol, nicotine, opioids, and psychostimulants such as cocaine and methamphetamine. Members of the entactogen class of psychostimulants (drugs that produce an "open mind state" including feelings of interpersonal closeness, intimacy and empathy) have been less frequently studied in self-administration models. The prototypical entactogen 3,4-methylenedioxymethamphetamine (MDMA; "Ecstasy") supports self-administration but not with the same consistency nor with the same efficacy as structurally related drugs amphetamine or methamphetamine. Consistent with these observations, MDMA use is more episodic in the majority of those who use it frequently. Nevertheless, substantial numbers of MDMA users will meet the criteria for substance dependence at some point in their use history. This review examines the currently available evidence from rodent self-administration studies of MDMA and two of the new and emerging psychoactive substances (NPS) that produce entactogen type neuropharmacological responses - mephedrone (4-methylmethcathinone; 4MMC; "meow meow") and methylone (3,4-methylenedioxymethcathinone). Overall, the current evidence predicts that these NPS entactogens have enhanced abuse liability compared with MDMA.
- Cocaine- and amphetamine-regulated transcript peptide and calcium binding proteins immunoreactivity in the superficial layers of the superior colliculus in the guinea pig: Implications for visual sensory processing. [Journal Article]
- JCJ Chem Neuroanat 2016 Nov 28
- The purpose of this study was to investigate the distribution and colocalization of cocaine- and amphetamine-regulated transcript peptide (CART) and three calcium-binding proteins (calbindin, calreti...
The purpose of this study was to investigate the distribution and colocalization of cocaine- and amphetamine-regulated transcript peptide (CART) and three calcium-binding proteins (calbindin, calretinin and parvalbumin) in the superficial layers of the superior colliculus (SCs) in the guinea pig. The CART immunoreactivity was observed exclusively in the solitary fibers and neuropil, which formed various CART-ir tiers, that corresponded partially or entirely to anatomically defined layers of the SCs. The CART-ir structures exhibited a characteristic morphology with bundles of densely intermingled neuronal fibers and terminals. This pattern of CART immunoreactivity in the visually driven SCs strongly indicates that CART peptide as a putative neurotransmitter may play an important role in processing of visual information. Double-labeling immunofluorescence showed that CART did not colocalize with either calcium binding proteins (CaBPs). Immunolabeling for CaBPs revealed the presence of different neuronal populations, which were concentrated in variously pronounced tiers. Contrary to CART, the CaBPs immunoreactivity in perikarya was relatively high and CaBPs containing neurons displayed a variety of sizes and somatodendritic morphologies. Generally, CaBPs patterns in the SCs of the guinea pig differ, to some extent, from those of other rodents. These results prove the importance of studying the neurochemical cytoarchitecture of diverse mammals.
- Methamphetamine-related psychosis: an opportunity for assertive intervention and prevention. [Editorial]
- AAddiction 2016 Dec 01
- RasGRP1 promotes amphetamine-induced motor behavior through a Rhes interaction network ("Rhesactome") in the striatum. [Journal Article]
- SSSci Signal 2016 Nov 15; 9(454):ra111
- The striatum of the brain coordinates motor function. Dopamine-related drugs may be therapeutic to patients with striatal neurodegeneration, such as Huntington's disease (HD) and Parkinson's disease ...
The striatum of the brain coordinates motor function. Dopamine-related drugs may be therapeutic to patients with striatal neurodegeneration, such as Huntington's disease (HD) and Parkinson's disease (PD), but these drugs have unwanted side effects. In addition to stimulating the release of norepinephrine, amphetamines, which are used for narcolepsy and attention-deficit/hyperactivity disorder (ADHD), trigger dopamine release in the striatum. The guanosine triphosphatase Ras homolog enriched in the striatum (Rhes) inhibits dopaminergic signaling in the striatum, is implicated in HD and L-dopa-induced dyskinesia, and has a role in striatal motor control. We found that the guanine nucleotide exchange factor RasGRP1 inhibited Rhes-mediated control of striatal motor activity in mice. RasGRP1 stabilized Rhes, increasing its synaptic accumulation in the striatum. Whereas partially Rhes-deficient (Rhes(+/-)) mice had an enhanced locomotor response to amphetamine, this phenotype was attenuated by coincident depletion of RasGRP1. By proteomic analysis of striatal lysates from Rhes-heterozygous mice with wild-type or partial or complete knockout of Rasgrp1, we identified a diverse set of Rhes-interacting proteins, the "Rhesactome," and determined that RasGRP1 affected the composition of the amphetamine-induced Rhesactome, which included PDE2A (phosphodiesterase 2A; a protein associated with major depressive disorder), LRRC7 (leucine-rich repeat-containing 7; a protein associated with bipolar disorder and ADHD), and DLG2 (discs large homolog 2; a protein associated with chronic pain). Thus, this Rhes network provides insight into striatal effects of amphetamine and may aid the development of strategies to treat various neurological and psychological disorders associated with the striatal dysfunction.
- Effect of pseudoephedrine in sport: a systematic review. [Journal Article]
- BOBMJ Open Sport Exerc Med 2015; 1(1):e000066
- CONCLUSIONS: Owing to the limitations of the published studies in this field, we were unable to make any firm conclusions with respect to the overall effect of pseudoephedrine and its ergogenic effect. It is evident that there is a correlation between the dose administered and its ergogenic effects, but it is also evident that the side effects of using above the therapeutic dose outweigh the possible benefits of using pseudoephedrine in sport. Further research with larger sample sizes is required to determine the relationship between doses (≥180 mg) and concentrations in urine that cause an ergogenic effect.
- Evaluating a switch from meconium to umbilical cord tissue for newborn drug testing: A retrospective study at an academic medical center. [Journal Article]
- CBClin Biochem 2016 Nov 24
- CONCLUSIONS: Umbilical cord tissue toxicology testing yielded a similar detection rate compared to meconium testing. The use of umbilical cord tissue avoids detection of medications given to the neonate prior to meconium collection.
- Combined in vitro and in silico approaches to the assessment of stimulant properties of novel psychoactive substances - The case of the benzofuran 5-MAPB. [Journal Article]
- PNProg Neuropsychopharmacol Biol Psychiatry 2016 Nov 24
- Novel psychoactive substances (NPS) are increasingly prevalent world-wide although their pharmacological characteristics are largely unknown; those with stimulant properties, due to interactions with...
Novel psychoactive substances (NPS) are increasingly prevalent world-wide although their pharmacological characteristics are largely unknown; those with stimulant properties, due to interactions with the dopamine transporter (DAT), have addictive potential which their users may not realise. We evaluated the binding of 1-(1-benzofuran-5-yl)-N-methylpropan-2-amine (5-MAPB) to rat striatal DAT by means of quantitative autoradiography with [(125)I]RTI-121, and the effects of 5-MAPB on electrically-evoked dopamine efflux by fast-cyclic voltammetry in rat brain slices. 5-MAPB displaced [(125)I]RTI-121 in a concentration-dependent manner, with significant effects at 10 and 30μM. The voltammetry data suggest that 5-MAPB reduces the rate of dopamine reuptake; while the peak dopamine efflux was not increased, the area under the curve was augmented. 5-MAPB can also cause reverse dopamine transport consistent with stimulant properties, more similar to amphetamine than cocaine. Molecular modelling and docking studies compared the binding site of DAT in complex with 5-MAPB to dopamine, amphetamine, 5-APB, MDMA, cocaine and RTI-121. This structural comparison reveals a binding mode for 5-MAPB found in the primary binding (S1) site, central to transmembrane domains 1, 3, 6 and 8, which overlaps with the binding modes of dopamine, cocaine and its analogues. Atomistic molecular dynamics simulations further show that, when in complex with 5-MAPB, DAT can exhibit conformational transitions that spontaneously isomerize the transporter into inward-facing state, similarly to that observed in dopamine-bound DAT. These novel insights, offered by the combination of computational methods of biophysics with neurobiological procedures, provide structural context for NPS at DAT and relate them with their functional properties at DAT as the molecular target of stimulants.
- Methylphenidate modulates dorsal raphe neuronal activity: Behavioral and neuronal recordings from adolescent rats. [Journal Article]
- BRBrain Res Bull 2016 Nov 23; 128:48-57
- Methylphenidate (MPD) is a widely prescribed psychostimulants used for the treatment of attention deficit hyperactive disorder (ADHD). Unlike the psychostimulants cocaine and amphetamine, MPD does no...
Methylphenidate (MPD) is a widely prescribed psychostimulants used for the treatment of attention deficit hyperactive disorder (ADHD). Unlike the psychostimulants cocaine and amphetamine, MPD does not exhibit direct actions on the serotonin transporter, however there is evidence suggesting that the therapeutic effects of MPD may be mediated in part by alterations in serotonin transmission. This study aimed to investigate the role of the dorsal raphe (DR) nucleus, one of the major sources of serotonergic innervation in the mammalian brain, in the response to MPD exposure. Freely behaving adolescent rats previously implanted bilaterally with permanent electrodes were used. An open field assay and a wireless neuronal recording system were used to concomitantly record behavioral and DR electrophysiological activity following acute and chronic MPD exposure. Four groups were used: one control (saline) and three experimental groups treated with 0.6, 2.5, and 10.0mg/kg MPD respectively. Animals received daily MPD or saline injections on experimental days 1-6, followed by 3 washout days and MPD rechallenge dose on experimental day (ED)10. The same chronic dose of MPD resulted in either behavioral sensitization or tolerance, and we found that neuronal activity recorded from the DR neuronal units of rats expressing behavioral sensitization to chronic MPD exposure responded significantly differently to MPD rechallenge on ED10 compared to the DR unit activity recorded from animals that expressed behavioral tolerance. This correlation between behavioral response and DR neuronal activity following chronic MPD exposure provides evidence that the DR is involved in the acute effects as well as the chronic effects of MPD in adolescent rats.
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- Gestational exposure to perfluorooctanoic acid (PFOA): alterations in motor related behaviors. [Journal Article]
- NNeurotoxicology 2016 Nov 22
- Perfluoroalkyl and polyfluoroalkyl substances are used in commercial applications and developmental exposure has been implicated in alterations in neurobehavioral functioning. While associations betw...
Perfluoroalkyl and polyfluoroalkyl substances are used in commercial applications and developmental exposure has been implicated in alterations in neurobehavioral functioning. While associations between developmental perfluorooctanoic acid (PFOA) exposure and human outcomes have been inconsistent, studies in experimental animals suggest alterations in motor related behaviors. To examine a dose-response pattern of neurobehavioral effects following gestational exposure to PFOA, pregnant CD-1 mice received PFOA (0, 0.1, 0.3, 1.0mg/kg/day) via oral gavage from gestational day 1-17 and the male offspring examined. Motor activity assessments on postnatal day (PND)18, 19, and 20 indicated a shift in the developmental pattern with an elevated activity level observed in the 1.0mg/kg/day dose group on PND18. In the adult, no alterations were observed in body weights, activity levels, diurnal pattern of running wheel activity, startle response, or pre-pulse startle inhibition. In response to a subcutaneous injection of saline or nicotine (80μg/kg), all animals displayed a transient increase in activity likely associated with handling with no differences observed across dose groups. Inhibition of motor activity over 18days of 400μg/kg nicotine injection was not significantly different across dose groups. Hyperactivity induced by 2mg/kg (+)-methamphetamine hydrochloride intraperitoneal injection was significantly lower in the 1.0mg/kg/day PFOA dose group as compared to controls. Taken together, these data suggest that the effects on motor-related behaviors with gestational PFOA exposure do not mimic those reported for acute postnatal exposure. Changes were not observed at dose level under 1.0mg/kg/day PFOA. Further examination of pathways associated with methamphetamine-induced activity is warranted.