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Cocaine increases dopaminergic neuron and motor activity via midbrain ?1 adrenergic signaling.

ABSTRACT: Cocaine reinforcement is mediated by increased extracellular dopamine levels in the forebrain. This neurochemical effect was thought to require inhibition of dopamine reuptake, but cocaine is still reinforcing even in the absence of the dopamine transporter. Here, we demonstrate that the rapid elevation in dopamine levels and motor activity elicited by cocaine involves ?1 receptor activation within the ventral midbrain. Activation of ?1 receptors increases dopaminergic neuron burst firing by decreasing the calcium-activated potassium channel current (SK), as well as elevates dopaminergic neuron pacemaker firing through modulation of both SK and the hyperpolarization-activated cation currents (Ih). Furthermore, we found that cocaine increases both the pacemaker and burst-firing frequency of rat ventral-midbrain dopaminergic neurons through an ?1 adrenergic receptor-dependent mechanism within the ventral tegmental area and substantia nigra pars compacta. These results demonstrate the mechanism underlying the critical role of ?1 adrenergic receptors in the regulation of dopamine neurotransmission and behavior by cocaine.

SUBMITTER: Goertz RB

PROVIDER: S-EPMC4367457 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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Cocaine increases dopaminergic neuron and motor activity via midbrain α1 adrenergic signaling.

Goertz Richard Brandon RB Wanat Matthew J MJ Gomez Jorge A JA Brown Zeliene J ZJ Phillips Paul E M PE Paladini Carlos A CA

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20150313 5

Cocaine reinforcement is mediated by increased extracellular dopamine levels in the forebrain. This neurochemical effect was thought to require inhibition of dopamine reuptake, but cocaine is still reinforcing even in the absence of the dopamine transporter. Here, we demonstrate that the rapid elevation in dopamine levels and motor activity elicited by cocaine involves α1 receptor activation within the ventral midbrain. Activation of α1 receptors increases dopaminergic neuron burst firing by dec ...[more]

PMID: 25374094

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Project description:Dopamine neurotransmission has been found to play a role in addictive behavior and is altered in psychiatric disorders. Dopaminergic (DA) neurons display two functionally distinct modes of electrophysiological activity: low- and high-frequency firing. A puzzling feature of the DA neuron is the following combination of its responses: N-methyl-D-aspartate receptor (NMDAR) activation evokes high-frequency firing, whereas other tonic excitatory stimuli (?-amino-3-hydroxyl-5-methyl-4-isoxazolepropionate receptor (AMPAR) activation or applied depolarization) block firing instead. We suggest a new computational model that reproduces this combination of responses and explains recent experimental data. Namely, somatic NMDAR stimulation evokes high-frequency firing and is more effective than distal dendritic stimulation. We further reduce the model to a single compartment and analyze the mechanism of the distinct high-frequency response to NMDAR activation vs. other stimuli. Standard nullcline analysis shows that the mechanism is based on a decrease in the amplitude of calcium oscillations. The analysis confirms that the nonlinear voltage dependence provided by the magnesium block of the NMDAR determine its capacity to elevate the firing frequency. We further predict that the moderate slope of the voltage dependence plays the central role in the frequency elevation. Additionally, we suggest a repolarizing current that sustains calcium-independent firing or firing in the absence of calcium-dependent repolarizing currents. We predict that the ether-a-go-go current (ERG), which has been observed in the DA neuron, is the best fit for this critical role. We show that a calcium-dependent and a calcium-independent oscillatory mechanisms form a structure of interlocked negative feedback loops in the DA neuron. The structure connects research of DA neuron firing with circadian biology and determines common minimal models for investigation of robustness of oscillations, which is critical for normal function of both systems.

Dataset Information

Cocaine increases dopaminergic neuron and motor activity via midbrain ?1 adrenergic signaling.

Publications

Cocaine increases dopaminergic neuron and motor activity via midbrain α1 adrenergic signaling.

Similar Datasets

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