ABSTRACT
Manganese exposure produces Parkinson's-like neurologic symptoms, suggesting a selective dysregulation of dopamine transmission. It is unknown, however, how manganese accumulates in dopaminergic brain regions or how it regulates the activity of dopamine neurons. Our in vivo studies in male C57BLJ mice suggest that manganese accumulates in dopamine neurons of the VTA and substantia nigra via nifedipine-sensitive Ca2+ channels. Manganese produces a Ca2+ channel-mediated current, which increases neurotransmitter release and rhythmic firing activity of dopamine neurons. These increases are prevented by blockade of Ca2+ channels and depend on downstream recruitment of Ca2+-activated potassium channels to the plasma membrane. These findings demonstrate the mechanism of manganese-induced dysfunction of dopamine neurons, and reveal a potential therapeutic target to attenuate manganese-induced impairment of dopamine transmission.SIGNIFICANCE STATEMENT Manganese is a trace element critical to many physiological processes. Overexposure to manganese is an environmental risk factor for neurologic disorders, such as a Parkinson's disease-like syndrome known as manganism. We found that manganese concentration-dependently increased the excitability of dopamine neurons, decreased the amplitude of action potentials, and narrowed action potential width. Blockade of Ca2+ channels prevented these effects as well as manganese accumulation in the mouse midbrain in vivo Our data provide a potential mechanism for manganese regulation of dopaminergic neurons.
Subject(s)
Dopaminergic Neurons/drug effects , Dopaminergic Neurons/metabolism , Manganese/metabolism , Manganese/toxicity , Action Potentials/drug effects , Action Potentials/physiology , Animals , Cells, Cultured , Dose-Response Relationship, Drug , HEK293 Cells , Humans , Male , Mice , Mice, Inbred C57BL , Organ Culture TechniquesABSTRACT
Methamphetamine (METH) abuse is a major public health issue around the world, yet there are currently no effective pharmacotherapies for the treatment of METH addiction. METH is a potent psychostimulant that increases extracellular dopamine levels by targeting the dopamine transporter (DAT) and alters neuronal activity in the reward centers of the brain. One promising therapeutic target for the treatment of METH addiction is the sigma-1 receptor (σ1R). The σ1R is an endoplasmic reticulum-localized chaperone protein that is activated by cellular stress, and, unique to this chaperone, its function can also be induced or inhibited by different ligands. Upon activation of this unique "chaperone receptor", the σ1R regulates a variety of cellular functions and possesses neuroprotective activity in the brain. Interestingly, a variety of σ1R ligands modulate dopamine neurotransmission and reduce the behavioral effects of METH in animal models of addictive behavior, suggesting that the σ1R may be a viable therapeutic target for the treatment of METH addiction. In this review, we provide background on METH and the σ1R as well as a literature review regarding the role of σ1Rs in modulating both dopamine neurotransmission and the effects of METH. We aim to highlight the complexities of σ1R pharmacology and function as well as the therapeutic potential of the σ1R as a target for the treatment of METH addiction.
Subject(s)
Amphetamine-Related Disorders/drug therapy , Dopamine/metabolism , Methamphetamine , Neuroprotective Agents/therapeutic use , Receptors, sigma/metabolism , Amphetamine-Related Disorders/metabolism , Animals , Behavior, Addictive/drug therapy , Humans , Ligands , Methamphetamine/toxicity , Molecular Targeted Therapy , Synaptic Transmission/drug effects , Sigma-1 ReceptorABSTRACT
Dopamine neurotransmission is highly dysregulated by the psychostimulant methamphetamine, a substrate for the dopamine transporter (DAT). Through interactions with DAT, methamphetamine increases extracellular dopamine levels in the brain, leading to its rewarding and addictive properties. Methamphetamine also interacts with the sigma-1 receptor (σ1R), an inter-organelle signaling modulator. Using complementary strategies, we identified a novel mechanism for σ1R regulation of dopamine neurotransmission in response to methamphetamine. We found that σ1R activation prevents methamphetamine-induced, DAT-mediated increases in firing activity of dopamine neurons. In vitro and in vivo amperometric measurements revealed that σ1R activation decreases methamphetamine-stimulated dopamine efflux without affecting basal dopamine neurotransmission. Consistent with these findings, σ1R activation decreases methamphetamine-induced locomotion, motivated behavior, and enhancement of brain reward function. Notably, we revealed that the σ1R interacts with DAT at or near the plasma membrane and decreases methamphetamine-induced Ca2+ signaling, providing potential mechanisms. Broadly, these data provide evidence for σ1R regulation of dopamine neurotransmission and support the σ1R as a putative target for the treatment of methamphetamine addiction.
