Disruption of mitochondrial complex I induces progressive parkinsonism.

Loss of functional mitochondrial complex I (MCI) in the dopaminergic neurons of the substantia nigra is a hallmark of Parkinson's disease. Yet, whether this change contributes to Parkinson's disease pathogenesis is unclear. Here we used intersectional genetics to disrupt the function of MCI in mouse dopaminergic neurons.

Author Correction: Dopamine metabolism by a monoamine oxidase mitochondrial shuttle activates the electron transport chain.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Dopamine metabolism by a monoamine oxidase mitochondrial shuttle activates the electron transport chain.

Monoamine oxidase (MAO) metabolizes cytosolic dopamine (DA), thereby limiting auto-oxidation, but is also thought to generate cytosolic hydrogen peroxide (HO). We show that MAO metabolism of DA does not increase cytosolic HO but leads to mitochondrial electron transport chain (ETC) activity. This is dependent upon MAO anchoring to the outer mitochondrial membrane and shuttling electrons through the intermembrane space to support the bioenergetic demands of phasic DA release.

The Synaptic Vesicle Glycoprotein 2: Structure, Function, and Disease Relevance.

The synaptic vesicle glycoprotein 2 (SV2) family is comprised of three paralogues: SV2A, SV2B, and SV2C. In vertebrates, SV2s are 12-transmembrane proteins present on every secretory vesicle, including synaptic vesicles, and are critical to neurotransmission. Structural and functional studies suggest that SV2 proteins may play several roles to promote proper vesicular function.

Selective D and D receptor antagonists oppositely modulate cocaine responses in mice via distinct postsynaptic mechanisms in nucleus accumbens.

The dopamine D receptor (DR) has emerged as a promising pharmacotherapeutic target for the treatment of several diseases including schizophrenia, Parkinson's disease, and substance use disorders. However, studies investigating the DR's precise role in dopamine neurotransmission or how it may be exploited to modulate responses to drugs of abuse have produced contrasting results, in part because most DR-targeted compounds often also interact with D receptors (DR). To resolve this issue, we set out to systematically characterize and compare the consequences of selective DR or DR antagonists on the behavioral-stimulant properties of cocaine in mice, and to identify putative neurobiological mechanisms underlying their behavior-modifying effects.

Bioinspired Honokiol Analogs and Their Evaluation for Activity on the Norepinephrine Transporter.

In traditional Asian medicinal systems, preparations of the root and stem bark of species are widely used to treat anxiety and other nervous disturbances. The biphenyl-type neolignans honokiol and magnolol are the main constituents of bark extracts. In the central nervous system, bark preparations that contain honokiol are thought to primarily interact with γ-aminobutyric acid A (GABA) receptors.

Early Ambulation in Patients With External Ventricular Drains: Results of a Quality Improvement Project.

Introduction: Prolonged immobility in patients in the intensive care unit (ICU) can lead to muscle wasting and weakness, longer hospital stays, increased number of days in restraints, and hospital-acquired infections. Increasing evidence demonstrates the safety and feasibility of early mobilization in the ICU. However, there is a lack of evidence in the safety and feasibility of mobilizing patients with external ventricular drains (EVDs).

Immunochemical analysis of the expression of SV2C in mouse, macaque and human brain.

The synaptic vesicle glycoprotein 2C (SV2C) is an undercharacterized protein with enriched expression in phylogenetically old brain regions. Its precise role within the brain is unclear, though various lines of evidence suggest that SV2C is involved in the function of synaptic vesicles through the regulation of vesicular trafficking, calcium-induced exocytosis, or synaptotagmin function. SV2C has been linked to multiple neurological disorders, including Parkinson's disease and psychiatric conditions.

Selective Enhancement of Dopamine Release in the Ventral Pallidum of Methamphetamine-Sensitized Mice.

Drugs of abuse induce sensitization, which is defined as enhanced response to additional drug following a period of withdrawal. Sensitization occurs in both humans and animal models of drug reinforcement and contributes substantially to the addictive nature of drugs of abuse, because it is thought to represent enhanced motivational wanting for drug. The ventral pallidum, a key member of the reward pathway, contributes to behaviors associated with reward, such as sensitization.

Alteration to Dopaminergic Synapses Following Exposure to Perfluorooctane Sulfonate (PFOS), in Vitro and in Vivo.

Our understanding of the contribution exposure to environmental toxicants has on neurological disease continues to evolve. Of these, Parkinson's disease (PD) has been shown to have a strong environmental component to its etiopathogenesis. However, work is still needed to identify and characterize environmental chemicals that could alter the expression and function of the nigrostriatal dopamine system.

Reduced vesicular monoamine transport disrupts serotonin signaling but does not cause serotonergic degeneration.

We previously demonstrated that mice with reduced expression of the vesicular monoamine transporter 2 (VMAT2 LO) undergo age-related degeneration of the catecholamine-producing neurons of the substantia nigra pars compacta and locus ceruleus and exhibit motor disturbances and depressive-like behavior. In this work, we investigated the effects of reduced vesicular transport on the function and viability of serotonin neurons in these mice. Adult (4-6 months of age), VMAT2 LO mice exhibit dramatically reduced (90%) serotonin release capacity, as measured by fast scan cyclic voltammetry.

Chronic Nicotine Exposure Attenuates Methamphetamine-Induced Dopaminergic Deficits.

Repeated methamphetamine (METH) administrations cause persistent dopaminergic deficits resembling aspects of Parkinson's disease. Many METH abusers smoke cigarettes and thus self-administer nicotine; yet few studies have investigated the effects of nicotine on METH-induced dopaminergic deficits. This interaction is of interest because preclinical studies demonstrate that nicotine can be neuroprotective, perhaps owing to effects involving α4β2 and α6β2 nicotinic acetylcholine receptors (nAChRs).

Increased Vesicular Monoamine Transporter 2 (VMAT2; Slc18a2) Protects against Methamphetamine Toxicity.

The psychostimulant methamphetamine (METH) is highly addictive and neurotoxic to dopamine terminals. METH toxicity has been suggested to be due to the release and accumulation of dopamine in the cytosol of these terminals. The vesicular monoamine transporter 2 (VMAT2; SLC18A2) is a critical mediator of dopamine handling.

Exposure to the polybrominated diphenyl ether mixture DE-71 damages the nigrostriatal dopamine system: role of dopamine handling in neurotoxicity.

In the last several decades polybrominated diphenyl ethers (PBDEs) have replaced the previously banned polychlorinated biphenyls (PCBs) in multiple flame retardant utilities. As epidemiological and laboratory studies have suggested PCBs as a risk factor for Parkinson's disease (PD), the similarities between PBDEs and PCBs suggest that PBDEs have the potential to be neurotoxic to the dopamine system. The purpose of this study was to evaluate the neurotoxic effects of the PBDE mixture, DE-71, on the nigrostriatal dopamine system and address the role of altered dopamine handling in mediating this neurotoxicity.

Methamphetamine self-administration acutely decreases monoaminergic transporter function.

Numerous preclinical studies have demonstrated that noncontingent methamphetamine (METH) administration rapidly decreases both dopamine (DA) transporter (DAT) and vesicular monoamine-2 transporter (VMAT-2) function. Because of the importance of transporter function to the abuse and neurotoxic liabilities of METH, and previous research indicating that the effects of noncontingent METH treatment do not necessarily predict effects of contingent exposure, the present study examined the acute impact of METH self-administration on these transporters. Results revealed that five days of METH self-administration (4 h/session; 0.

Methamphetamine self-administration causes persistent striatal dopaminergic alterations and mitigates the deficits caused by a subsequent methamphetamine exposure.

Preclinical studies have demonstrated that repeated methamphetamine (METH) injections (referred to herein as a "binge" treatment) cause persistent dopaminergic deficits. A few studies have also examined the persistent neurochemical impact of METH self-administration in rats, but with variable results. These latter studies are important because: 1) they have relevance to the study of METH abuse; and 2) the effects of noncontingent METH treatment do not necessarily predict effects of contingent exposure.

Methamphetamine treatment during development attenuates the dopaminergic deficits caused by subsequent high-dose methamphetamine administration.

Administration of high doses of methamphetamine (METH) causes persistent dopaminergic deficits in both nonhuman preclinical models and METH-dependent persons. Noteworthy, adolescent [i.e.