- Differential housing and novelty response: Protection and risk from locomotor sensitization. [Journal Article]
- PBPharmacol Biochem Behav 2017 Jan 17
- CONCLUSIONS: Differential housing changes novelty and amphetamine locomotor response. Novelty response is altered into adulthood and provides evidence that enrichment can be used to reduce drug vulnerability.
- Simultaneous transplantation of fetal ventral mesencephalic tissue and encapsulated genetically modified cells releasing GDNF in a hemi-parkinsonian rat model of Parkinson's disease. [Journal Article]
- CTCell Transplant 2017 Jan 20
- Transplantation of fetal ventral mesencephalic (VM) neurons for Parkinson's disease (PD) is limited by poor survival and suboptimal integration of grafted tissue into the host brain. In a 6-OHDA rat ...
Transplantation of fetal ventral mesencephalic (VM) neurons for Parkinson's disease (PD) is limited by poor survival and suboptimal integration of grafted tissue into the host brain. In a 6-OHDA rat model of PD we investigated the feasibility of simultaneous transplantation of rat fetal VM tissue and polymer-encapsulated C2C12 myoblasts genetically modified to produce glial cell line-derived neurotrophic factor or mocktransfected myoblasts on graft function. Amphetamine-induced rotations were assessed prior and 2, 4, 6 and 9 weeks post-transplantation. We found that rats grafted with VM transplants and GDNF-capsules showed a significant functional recovery already 4 weeks after implantation. In contrast, rats from the VM transplant and mock-capsule group did not improve at any time point analyzed. Moreover, we detected a significantly higher number of tyrosine hydroxylase-immunoreactive (TH-ir) cells per graft (2 fold), a tendency for a larger graft volume and an overall higher TH-ir fiber outgrowth into the host brain (1.7 fold) in the group with VM transplants and GDNF-capsules as compared to the VM transplant and mock-capsule group. Most prominent was the TH-ir fiber outgrowth towards the capsule (9 fold). Grafting of GDNF pre-treated VM transplants in combination with the implantation of GDNF-capsules resulted in a tendency for a higher TH-ir fiber outgrowth into the host brain (1.7 fold) as compared to the group transplanted with untreated VM transplants and GDNF-capsules. No differences between groups were observed for the number of surviving TH-ir neurons or graft volume. In conclusion, our findings demonstrate that simultaneous transplantation of fetal VM tissue and encapsulated GDNF-releasing cells is feasible and support the graft survival and function. Pre-treatment of donor tissue with GDNF may offer a way to further improve cell transplantation approaches for PD.
- The N-terminus specifies the switch between transport modes of the human serotonin transporter. [Journal Article]
- JBJ Biol Chem 2017 Jan 19
- The serotonin transporter (SERT) and other monoamine transporters operate in either a forward transport mode, where the transporter undergoes a full transport cycle, or an exchange mode, where the tr...
The serotonin transporter (SERT) and other monoamine transporters operate in either a forward transport mode, where the transporter undergoes a full transport cycle, or an exchange mode, where the transporter seesaws through half-cycles. Amphetamines trigger the exchange-mode leading to substrate efflux. This efflux was proposed to rely on the N-terminus, which was suggested to adopt different conformations in the inward-, outward-facing and amphetamine-bound states. This prediction was verified by tryptic digestion of SERT-expressing membranes: in the absence of Na+, the N-terminus was rapidly digested. Amphetamine conferred protection against cleavage suggesting a relay between the conformational states of the hydrophobic core and the N-terminus. We searched for a candidate segment, which supported the conformational switch, by serial truncation removing 22 (ΔN22), 32 (ΔN32) or 42 (ΔN42) N-terminal residues. This did not affect surface expression, inhibitor binding and substrate influx. However, amphetamine-induced efflux by SERT-ΔN32 or SERT-ΔN42 (but not by SERT-ΔN22) was markedly diminished. We examined the individual steps in the transport cycle by recording transporter-associated currents: The recovery rate of capacitive peak - but not of steady-state - currents was significantly lower for SERT-ΔN32 than that of wild-type SERT and SERT-ΔN22. Thus, the exchange mode of SERT-ΔN32 was selectively impaired. Our observations show that the N-terminus affords the switch between transport modes. The findings are consistent with a model, where the N-terminus acts as a lever to support amphetamine-induced efflux by SERT.
- Analgesia and Sedation Requirements in Mechanically Ventilated Trauma Patients With Acute, Preinjury Use of Cocaine and/or Amphetamines. [Journal Article]
- A&AAnesth Analg 2017 Jan 16
- CONCLUSIONS: For trauma patients presenting with acute, preinjury use of cocaine and/or amphetamines, analgesic and sedative requirements are variables and may not be greater than those patients presenting with a stimulant-negative UDS to achieve desirable pain control and depth of sedation, although this observation should be interpreted cautiously in light of the wide CI observed in the propensity score--adjusted model. Although unexpected, these findings indicate that empirically increasing analgesic and sedative doses based on positive UDS results for these stimulants may not be necessary.
- Memory disrupting effects of nonmuscle myosin II inhibition depend on the class of abused drug and brain region. [Journal Article]
- LMLearn Mem 2017; 24(2):70-75
- Depolymerizing actin in the amygdala through nonmuscle myosin II inhibition (NMIIi) produces a selective, lasting, and retrieval-independent disruption of the storage of methamphetamine-associated me...
Depolymerizing actin in the amygdala through nonmuscle myosin II inhibition (NMIIi) produces a selective, lasting, and retrieval-independent disruption of the storage of methamphetamine-associated memories. Here we report a similar disruption of memories associated with amphetamine, but not cocaine or morphine, by NMIIi. Reconsolidation appeared to be disrupted with cocaine. Unlike in the amygdala, methamphetamine-associated memory storage was not disrupted by NMIIi in the hippocampus, nucleus accumbens, or orbitofrontal cortex. NMIIi in the hippocampus did appear to disrupt reconsolidation. Identification of the unique mechanisms responsible for NMII-mediated, amygdala-dependent disruption of memory storage associated with the amphetamine class may enable induction of retrieval-independent vulnerability to other pathological memories.
- Dampened amphetamine-stimulated behavior and altered dopamine transporter function in the absence of brain GDNF. [Journal Article]
- JNJ Neurosci 2017 Jan 17
- Midbrain dopamine neuron dysfunction contributes to various psychiatric and neurological diseases including drug addiction and Parkinson's disease. Because of its well-established dopaminotrophic eff...
Midbrain dopamine neuron dysfunction contributes to various psychiatric and neurological diseases including drug addiction and Parkinson's disease. Because of its well-established dopaminotrophic effects, the therapeutic potential of glial cell line-derived neurotrophic factor (GDNF) has been extensively studied in various disorders with disturbed dopamine homeostasis. The outcomes from pre-clinical and clinical studies vary, however, highlighting a need for a better understanding of the physiological role of GDNF on striatal dopaminergic function. Still, the current lack of appropriate animal models has limited this understanding. Thus, our lab has generated novel mouse models to study conditional Gdnf deletion in the central nervous system (CNS) during embryonic development and reduction of striatal GDNF levels in adult mice via AAV-Cre delivery. We found that both of these mice have reduced amphetamine-induced locomotor response and striatal dopamine efflux. Embryonic GDNF deletion in the central nervous system did not affect striatal dopamine levels or dopamine release, but dopamine reuptake was increased due to increased levels of both total and synaptic membrane--associated dopamine transporters. Collectively, these results suggest that endogenous GDNF plays an important role in regulating the function of dopamine transporters in the striatum.
- Effects of amphetamine and methylphenidate on attentional performance and impulsivity in the mouse 5-Choice Serial Reaction Time Task. [Journal Article]
- JPJ Psychopharmacol 2017 Jan 01; :269881116684339
- CONCLUSIONS: The use of variable stimulus duration, along with the division into high- and LA, and high-and LI subgroups, may improve the sensitivity of the 5-CSRTT when investigating drug effects on attention and impulsivity.
- Impact of Orexin-A Treatment on Food Intake, Energy Metabolism and Body Weight in Mice. [Journal Article]
- PlosPLoS One 2017; 12(1):e0169908
- Orexin-A and -B are hypothalamic neuropeptides of 33 and 28-amino acids, which regulate many homeostatic systems including sleep/wakefulness states, energy balance, energy homeostasis, reward seeking...
Orexin-A and -B are hypothalamic neuropeptides of 33 and 28-amino acids, which regulate many homeostatic systems including sleep/wakefulness states, energy balance, energy homeostasis, reward seeking and drug addiction. Orexin-A treatment was also shown to reduce tumor development in xenografted nude mice and is thus a potential treatment for carcinogenesis. The aim of this work was to explore in healthy mice the consequences on energy expenditure components of an orexin-A treatment at a dose previously shown to be efficient to reduce tumor development. Physiological approaches were used to evaluate the effect of orexin-A on food intake pattern, energy metabolism body weight and body adiposity. Modulation of the expression of brain neuropeptides and receptors including NPY, POMC, AgRP, cocaine- and amphetamine related transcript (CART), corticotropin-releasing hormone (CRH) and prepro-orexin (HCRT), and Y2 and Y5 neuropeptide Y, MC4 (melanocortin), OX1 and OX2 orexin receptors (Y2R, Y5R, MC4R, OX1R and OX2R, respectively) was also explored. Our results show that orexin-A treatment does not significantly affect the components of energy expenditure, and glucose metabolism but reduces intraperitoneal fat deposit, adiposity and the expression of several brain neuropeptide receptors suggesting that peripheral orexin-A was able to reach the central nervous system. These findings establish that orexin-A treatment which is known for its activity as an inducer of tumor cell death, do have minor parallel consequence on energy homeostasis control.
- The role of illicit drug use in sudden death in the young. [Journal Article]
- CYCardiol Young 2017; 27(S1):S75-S79
- The recreational use of illicit drugs remains an enormous and growing problem throughout the United States of America and around the world. Cocaine is most frequently thought of when considering the ...
The recreational use of illicit drugs remains an enormous and growing problem throughout the United States of America and around the world. Cocaine is most frequently thought of when considering the cardiovascular toxicity of illicit drugs. The association of cocaine use with sudden death due to myocardial ischaemia and infarction is well recognised, and this risk appears to be amplified by concomitant cigarette smoking and alcohol consumption. Like cocaine, amphetamine and its derivatives lead to indirect stimulation of the autonomic nervous system through the release of norepinephrine, dopamine, and serotonin in nerve terminals of the central and autonomic nervous systems. However, amphetamine lacks the ion channel-blocking properties of cocaine. Also similar to cocaine, coronary artery spasm may be induced in individuals with or without atherosclerotic disease and may lead to myocardial infarction. With the movement across the United States of America to legalise marijuana, or cannabis, for medicinal and recreational purposes, it is important to consider its potential deleterious effects. Marijuana has long been thought to have very few adverse effects with the exception of long-term dependence. There are, however, scattered reports of acute adverse events up to and including sudden death. These appear to be due to myocardial infarction. In conclusion, the incidence of sudden death associated with the use of these drugs varies from rare in the case of marijuana use to not infrequent with some drugs such as cocaine. It is important for care providers to recognise the potential for drug abuse when caring for a sudden cardiac arrest survivor.
New Search Next
- Prenatal Psychostimulant and Antidepressant Exposure and Risk of Hypertensive Disorders of Pregnancy. [Journal Article]
- JCJ Clin Psychiatry 2016; 77(11):1538-1545
- CONCLUSIONS: These data indicate that psychostimulant and SNRI exposure following the 20th week of gestation conveys considerable risk for the emergence of HDP. Overall, the findings suggest that heightened vascular reactivity to noradrenergic, rather than serotonergic, stimulation may be pivotal to HDP risk among women with psychiatric illness.