Firing Pattern Of Dopaminergic Neurons Research Articles

Gabapentin regulates dopaminergic neuron firing and theta oscillation in the ventral tegmental area to reverse depression-like behavior in chronic neuropathic pain state.

PurposeVentral tegmental area (VTA) dopamine system plays an important role in depression and is also involved in pain experience. In this study, we investigated the VTA dopaminergic (DA) neuron firing and local field potential (LFP) in pain-related depression, and we try to explore the underlying relationship between pain and depression.Materials and methodsWe used neuropathic pain model [spare nerve injury (SNI)] to induce pain-related depression. The Dixon up–down method was used to test mechanical hypersensitivity. Behavioral changes like open field test, sucrose preference test, and forced swim test were used to test depression-like behaviors. Gabapentin (GBP) was used to explore the chronic analgesic treatment that could reverse pain-related depression. To investigate the in vivo variations of VTA DA neuron firing and LFP, multichannel acquisition processor system was used.ResultsWe used SNI to induce depression-like behaviors. Repeated GBP treatment reversed these behaviors after 14 days of injection. An in vivo electrophysiological analysis of the firing characteristics of VTA DA neurons and LFP revealed that SNI increased the firing rate of DA neurons, but not the burst firing activity. Surprisingly, chronic GBP reversed the firing rate of DA neurons and reduced the burst firing activity. Moreover, SNI increased the LFP power in delta and theta oscillation and decreased it in beta oscillation. Repeated administration of GBP significantly suppressed theta oscillation. Above all, chronic GBP altered these characteristics to reverse depression-like behaviors.ConclusionThe present study confirmed that the tonic firing activity of VTA DA neurons, but not the burst firing activity, was the key factor in peripheral neuropathy–induced depression. Chronic GBP regulated the firing pattern of DA neurons and decreased theta oscillation in VTA to treat pain-related depression. This variation tendency of electrophysiological characteristics of VTA DA neurons and theta oscillation in VTA might represent an attempt to cope with pain-related negative mood disorder.

Involvement of AMPA/Kainate Glutamate Receptor in the Extinction and Reinstatement of Morphine-Induced Conditioned Place Preference: A Behavioral and Molecular Study.

Glutamate receptors in mesolimbic areas such as the nucleus accumbens, ventral tegmental area, prefrontal cortex (PFC), and hippocampus (HIP) are a component of the mechanisms of drug-induced reward and can modulate the firing pattern of dopaminergic neurons in the reward system. In addition, several lines of study have indicated that cAMP response element-binding protein (CREB) and c-fos have important role in morphine-induced conditioned place preference (CPP) induced by drugs of abuse, such as morphine, cocaine, nicotine, and alcohol. Therefore, in the present study, we investigated the changes in phosphorylated CREB (p-CREB) and c-fos induction within the nucleus accumbens (NAc), HIP, and PFC after intracerebroventricular (ICV) administration of different doses of CNQX or vehicle during extinction period or reinstatement of morphine-induced CPP. In all groups, the CPP procedure was done; afterward, the conditioning scores were recorded by Ethovision software. After behavioral test recording, we dissected out the NAc, HIP, and PFC regions and measured the p-CREB/CREB ratio and c-fos level by Western blot analysis. Our results showed that administration of CNQX significantly shortened the extinction of morphine CPP. Besides, ICV microinjection of CNQX following extinction period decreased the reinstatement of morphine CPP in extinguished rats. In molecular section, in treatment group, all mentioned factors were dose-dependently decreased in comparison with vehicle group (DMSO) after ICV microinjection of different doses of CNQX but not in pre-extinction microinjection. These findings suggested that antagonism of AMPA receptor decreased p-CREB/CREB ratio and c-fos level in the PFC, NAc, and HIP. Modulation of the drug memory reconsolidation may be useful for faster extinction of drug-induced reward and attenuation of drug-seeking behavior.

Firing pattern modulation through SK channel current increase underlies neuronal survival in an organotypic slice model of Parkinson's disease.

Dopaminergic (DA) neurons in substantia nigra pars compacta (SNc) are vulnerable to excitotoxicity in Parkinson's disease (PD). Neurotoxic stimuli may alter the firing patterns of DA neurons. However, whether firing pattern change underlies neurotoxic stress-induced death of DA neurons remains unknown. In this study, we established long-term cultures of SNc organotypic slices and used this model to evaluate the neurotoxic effects on firing mode and DA neuronal viability following chronic treatment with neurotoxin 6-hydroxydopamine (6-OHDA). Using whole-cell patch clamp to explore the intrinsic membrane properties and firing mode, we showed that chronic exposure to 6-OHDA raised the resting membrane potential of SNc DA neurons and altered their firing pattern, causing it to switch from a regular rhythmic pacemaking firing to an irregular bursting. This firing pattern change correlated with increased death of SNc DA neurons. The 6-OHDA-induced firing pattern change correlated with an increase in the activity of the small conductance calcium-activated potassium channel (SK channel) and with an increase in both the level and activity of protein phosphatase 2A (PP2A). Activation of the SK channel by its agonist 1-EBIO attenuated 6-OHDA-induced firing irregularity and death, while the SK channel antagonist apamin exacerbated the toxic effects of 6-OHDA. Thus, SK channel current is a substantial element in sustaining the SNc DA neuronal rhythmic pacemaking and homeostasis and perturbing SK channel activity underlies 6-OHDA-induced neurotoxicity.

A small-conductance Ca2+-dependent K+ current regulates dopamine neuron activity: a combined approach of dynamic current clamping and intracellular imaging of calcium signals

To analyze the small-conductance calcium-dependent K current observed in dopaminergic neurons of the rat midbrain, we have developed a new dynamic current clamping method that incorporates recording of intracellular Ca levels. As reported earlier, blocking the small-conductance current with apamin shifted the firing modes of dopaminergic neurons and changed the firing rate and spike afterhyperpolarization. We modeled the kinetic properties of the current and assessed the model in a real-time computational system. Here, we show that the spike afterhyperpolarization is regulated by the small-conductance current, an effect that is observed in dopaminergic neurons. Thus, this current can effectively shape the autonomous firing patterns of dopaminergic neurons.

A Dynamic Role for GABA Receptors on the Firing Pattern of Midbrain Dopaminergic Neurons

Dopaminergic neurons are subject to a significant background GABAergic input in vivo. The presence of this GABAergic background might be expected to inhibit dopaminergic neuron firing. However, dopaminergic neurons are not all silent but instead fire in single-spiking and burst firing modes. Here we present evidence that phasic changes in the tonic activity of GABAergic afferents are a potential extrinsic mechanism that triggers bursts and pauses in dopaminergic neurons. We find that spontaneous single-spiking is more sensitive to activation of GABA receptors than phasic N-methyl-D-aspartate (NMDA)-mediated burst firing in rat slices (P15-P31). Because tonic activation of GABA(A) receptors has previously been shown to suppress burst firing in vivo, our results suggest that the activity patterns seen in vivo are the result of a balance between excitatory and inhibitory conductances that interact with the intrinsic pacemaking currents observed in slices. Using the dynamic clamp technique, we applied balanced, constant NMDA and GABA(A) receptor conductances into dopaminergic neurons in slices. Bursts could be produced by disinhibition (phasic removal of the GABA(A) receptor conductance), and these bursts had a higher frequency than bursts produced by the same NMDA receptor conductance alone. Phasic increases in the GABA(A) receptor conductance evoked pauses in firing. In contrast to NMDA receptor, application of constant AMPA and GABA(A) receptor conductances caused the cell to go into depolarization block. These results support a bidirectional mechanism by which GABAergic inputs, in balance with NMDA receptor-mediated excitatory inputs, control the firing pattern of dopaminergic neurons.

κ opioids selectively control dopaminergic neurons projecting to the prefrontal cortex

Dopaminergic afferents arising from the ventral tegmental area (VTA) are crucial elements in the neural circuits that mediate arousal, motivation, and reinforcement. Two major targets of these afferents are the medial prefrontal cortex (mPFC) and the nucleus accumbens (NAc). Whereas dopamine (DA) in the mPFC has been implicated in working memory and attentional processes, DA in the NAc is required for responding to reward predictive cues. These distinct functions suggest a role for independent firing patterns of dopaminergic neurons projecting to these brain regions. In fact, DA release in mPFC and NAc can be differentially modulated. However, to date, electrophysiological studies have largely overlooked heterogeneity among VTA neurons. Here, we provide direct evidence for differential neurotransmitter control of DA neural activity and corresponding DA release based on projection target. Kappa opioid receptor agonists inhibit VTA DA neurons that project to the mPFC but not those that project to the NAc. Moreover, DA levels in the mPFC, but not the NAc, are reduced after local infusion of kappa opioid receptor agonists into the VTA. These findings demonstrate that DA release in specific brain regions can be independently regulated by opioid targeting of a subpopulation of VTA DA neurons. Selective control of VTA DA neurons projecting to the mPFC has important implications for understanding addiction, attention disorders, and schizophrenia, all of which are associated with DA dysfunction in the mPFC.

Pallidal control of substantia nigra dopaminergic neuron firing pattern and its relation to extracellular neostriatal dopamine levels

The firing patterns of dopaminergic neurons in vivo are strongly modulated by afferent input. The principal GABAergic inputs to the dopaminergic neurons of the substantia nigra originate from neurons of the neostriatum, globus pallidus and substantia nigra pars reticulata. It has previously been shown that the firing pattern of nigral dopaminergic neurons can be manipulated by pharmacologically induced excitation or inhibition of the globus pallidus with relatively little effect on firing rate. We used this technique to explore the relation between the firing pattern of dopaminergic neurons and extracellular dopamine levels in the neostriatum in vivo. Specifically, we tested whether an increase in burst firing in dopaminergic neurons produced by increased pallidal activity led to increased extracellular dopamine levels in the neostriatum. Single unit extracellular recording combined with simultaneous microdialysis was used to measure the firing rates and patterns of dopaminergic neurons and extracellular striatal dopamine levels, respectively, during bicuculline-induced excitation of the globus pallidus. Pallidal excitation resulted in a marked increase in burst firing in dopaminergic neurons along with only a slight increase in firing rate, but produced a significant elevation (approximately 45%) in neostriatal dopamine levels. These data suggest that afferent-induced burst firing in dopaminergic neurons leads to an increase in extracellular dopamine levels in the neostriatum when compared with less bursty patterns with similar overall firing rates.

GABAergic Control of the Firing Pattern of Substantia Nigra Dopaminergic Neurons

Excitatory amino acid afferents originating in the frontal cortex, subthalamic nucleus, and pedunculopontine nucleus play an important role in the modulation of dopaminergic neuron firing pattern, although these inputs may not be the only ones important for the control of the firing pattern in vivo. The predominant inputs to dopamine neurons in the substantia nigra are GABAergic, the best characterized of which originate from the neostriatum and globus pallidus. Studies show that substantia nigra dopaminergic neurons also receive a significant input from the axon collaterals of substantia nigra pars reticulata projection neurons. Dopaminergic neurons have been shown to exhibit both GABAA and GABAB responses in vitro. In vivo extracellular recordings from dopaminergic neurons in urethane-anesthetized rats following direct stimulation of striatum, globus pallidus, or antidromic stimulation of substantia nigra pars reticulata projection neurons revealed that all three afferents produce inhibition of dopaminergic neurons. Data from experiments using minute local pressure application of GABAA and GABAB antagonists show that the inhibition arising from each of the principal GABAergic inputs is completely and reversibly blocked by the GABAA antagonist. Local application of GABAA and GABAB antagonists differentially affect the firing pattern of dopaminergic neurons. The pattern of activity of substantia nigra dopaminergic neurons was quantified by computing autocorrelograms, coefficients of variation, and the percentage of spikes fired in bursts. Local nigral application of the GABAA antagonist, bicuculline, through the recording pipette markedly increases the proportion of neurons that fire in the bursty mode, or shifts single dopaminergic neurons firing in the pacemaker or random modes to bursty firing when applied by local pressure injection. Conversely, local application of the GABA, antagonist, saclofen, through the recording pipette (or excitotoxic lesion of globus pallidus) decreases bursty firing and produces a modest increase in the proportion of neurons that fire in a pacemaker-like mode.