Firing Activity Of Dopamine Neurons Research Articles

Mesolimbic Neural Response Dynamics Predict Future Individual Alcohol Drinking in Mice

BackgroundIndividual variability in response to rewarding stimuli is a striking but understudied phenomenon. The mesolimbic dopamine system is critical in encoding the reinforcing properties of both natural reward and alcohol; however, how innate or baseline differences in the response dynamics of this circuit define individual behavior and shape future vulnerability to alcohol remain unknown. MethodsUsing naturalistic behavioral assays, a voluntary alcohol drinking paradigm, in vivo fiber photometry, in vivo electrophysiology, and chemogenetics, we investigated how differences in mesolimbic neural circuit activity contribute to the individual variability seen in reward processing and, by proxy, alcohol drinking. ResultsWe first characterized heterogeneous behavioral and neural responses to natural reward and defined how these baseline responses predicted future individual alcohol-drinking phenotypes in male mice. We then determined spontaneous ventral tegmental area dopamine neuron firing profiles associated with responses to natural reward that predicted alcohol drinking. Using a dual chemogenetic approach, we mimicked specific mesolimbic dopamine neuron firing activity before or during voluntary alcohol drinking to link unique neurophysiological profiles to individual phenotype. We show that hyperdopaminergic individuals exhibit a lower neuronal response to both natural reward and alcohol that predicts lower levels of alcohol consumption in the future. ConclusionsThese findings reveal unique, circuit-specific neural signatures that predict future individual vulnerability or resistance to alcohol and expand the current knowledge base on how some individuals are able to titrate their alcohol consumption whereas others go on to engage in unhealthy alcohol-drinking behaviors.

Long-term methamphetamine self-administration increases mesolimbic mitochondrial oxygen consumption and decreases striatal glutathione

Neurotoxic regimens of methamphetamine (METH) are known to increase reactive oxygen species (ROS), affect redox homeostasis, and lead to damage in dopamine neurons. Functional changes induced by long-term METH self-administration on mitochondrial respiratory metabolism and redox homeostasis are less known. To fill this gap, we implanted a jugular catheter into adult male mice and trained them to nose poke for METH infusions. After several weeks of METH exposure, we collected samples of the ventral striatum (vST) and the ventral midbrain (vMB). We used HPLC to determine the levels of the ROS scavenger glutathione in its reduced (GSH) and oxidized forms. Then, we used high-resolution respirometry to determine the oxygen consumption rate (OCR) of mitochondrial complexes. Finally, using in vivo electrophysiology, we assessed changes in dopamine neuron firing activity in the VTA. METH self-administration produced a decrease of the GSH pool in vST, correlating with lifetime METH intake. We observed increased mitochondrial respiration across the two mesolimbic regions. METH self-administration decreases firing rate and burst activity but increases the number of spontaneously active dopamine neurons per track. We conclude that METH self-administration progressively decreased the antioxidant pool in sites of higher dopamine release and produced an increase in mitochondrial metabolism in the mesolimbic areas, probably derived from the increased number of dopamine neurons actively firing. However, dopamine neuron firing activity is decreased by METH self-administration, reflecting a new basal level of dopamine neurotransmission.

Female mice are resilient to age-related decline of substantia nigra dopamine neuron firing parameters

Degeneration of substantia nigra pars compacta dopamine neurons is a central feature in the pathology of Parkinson’s disease, which is characterized by progressive loss of motor and cognitive functions. The largest risk factors for Parkinson’s disease are age and sex; most cases occur after age 60 and males have nearly twice the incidence as females. Preclinical work has scarcely considered the influence of these 2 factors to disease risk and presentation. Here, we observed a progressive decline in dopamine neuron firing activity in male C57BL/6 mice by 18 months of age, while dopamine neurons from females remained largely unaffected. This was accompanied by increased mRNA expression of PINK1 in both males and females, and PARK2 primarily in males, both of which have been linked to Parkinson’s. Since the declining cell properties were accompanied by only slight decreases in locomotion in both sexes, it is likely that these age-related impairments in males represent a vulnerability to further insults that could predispose the neurons to neurodegenerative processes such as in Parkinson’s.

Mechanism of Manganese Dysregulation of Dopamine Neuronal Activity

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.

Triple reuptake inhibition of serotonin, norepinephrine, and dopamine increases the tonic activation of α2-adrenoceptors in the rat hippocampus and dopamine levels in the nucleus accumbens

Clinical studies have shown the therapeutic efficacy of an increase in dopamine (DA) transmission in treatment of major depressive disorder (MDD). In the present study, we investigated whether blockade of DA transporters in addition to serotonin (5-HT) and norepinephrine (NE) produced additional adaptations of monoaminergic systems. In vivo electrophysiological recordings were carried out in male anesthetized rats. Vehicle, the 5-HT reuptake inhibitor escitalopram, the NE/DA reuptake blocker nomifensine and their combination (triple reuptake inhibition; TRI) were delivered for 2 or 14 days. Firing activity of NE, 5-HT and DA neurons was assessed. Tonic activation of 5-HT1A receptors and α1- and α2-adrenoceptors was determined in the hippocampus and extracellular DA levels in the nucleus accumbens (NAc). Unlike escitalopram, nomifensine and TRI administration increased the tonic activation of α2-adrenoceptors in the hippocampus despite decreasing NE neuronal firing activity after 2 and 14 days of administration. The firing activity of 5-HT neurons was increased after prolonged nomifensine and TRI regimens, while addition of nomifensine to escitalopram prevented the early 2-day suppression of firing by 5-HT reuptake inhibition. The tonic activation of 5-HT1A receptors was enhanced only with escitalopram. Whereas escitalopram and nomifensine decreased firing activity of DA neurons after a 2-day administration, their combination normalized it to baseline level after 14 days; this was accompanied by a robust increase in extracellular DA levels in the NAc. In summary, these results indicate that TRI increases NE and DA but not 5-HT transmission, suggesting a differential efficacy profile in MDD patients.

Neurotensin receptor 1 deletion decreases methamphetamine self-administration and the associated reduction in dopamine cell firing.

We previously reported that a non-selective pharmacological blockade of neurotensin receptors in the ventral tegmental area (VTA) decreases methamphetamine (METH) self-administration in mice. Here, we explored the consequences of genetic deletion of neurotensin receptor 1 (NtsR1) on METH self-administration and VTA dopamine neuron firing activity. We implanted mice with an indwelling jugular catheter and trained them to nose-poke for intravenous infusions of METH. Mice with NtsR1 deletion (KO) acquired self-administration similar to wildtype (WT) and heterozygous (HET) littermates. However, in NtsR1 KO and HET mice, METH intake and motivated METH seeking decreased when the response requirement was increased to a fixed ratio 3 and when mice were tested on a progressive ratio protocol. After completion of METH self-administration, single cell in vivo extracellular recordings of dopamine firing activity in the VTA were obtained in anesthetized mice. Non-bursting dopamine neurons from KO mice fired at slower rates than those from WT mice, supporting an excitatory role for NtsR1 on VTA dopamine neuronal activity. In WT mice, a history of METH self-administration decreased dopamine cell firing frequency compared with cells from drug-naïve controls. NtsR1 KO and HET mice did not exhibit this decline in dopamine cell firing activity after METH experience. We also observed an increase in population activity following METH self-administration that was strongest in the WT group. Our results suggest a role for NtsR1 in METH-seeking behavior and indicate that ablation of NtsR1 prevents the detrimental effects of prolonged METH self-administration on VTA dopamine cell firing frequency.

Blockade of nifedipine‐sensitive Ca2+ channels decreases manganese accumulation on the dopamine neurons

Manganese (Mn) is an essential trace element involved in many physiological processes. Mn is transported into the cells through a number of transporters. Overexposure to Mn leads to its accumulation in the basal ganglia where it induces circuit dysregulation and a Parkinson-like syndrome referred to as manganism. The mechanisms by which Mn regulates the intrinsic firing behaviors of dopamine neurons and how Mn overexposure dysregulates this activity are not well understood. In this study, we investigated Mn's modulation of the excitability, intrinsic firing activity, Ca2+ homeostasis, and voltage-gated Ca2 channel expression in mouse dopamine neurons. We found that Mn increases the spontaneous firing activity of dopamine neuron via a concentration-dependent mechanism (10–100mM). Analysis of action potential morphology revealed that Mn truncated the amplitude and narrowed the width of action potentials and reduced coefficients of variation of the interspike interval. Unexpectedly, we found neither removal of external Ca2+ (Ca2+-free), chelation of intracellular Ca2+, nor combined chelation of internal and external Ca2+ altered Mn-regulation of action potential in dopamine neurons. Therefore, we asked whether Mn alters Ca2+ currents via the voltage-gated Ca2+ channels in the dopamine neurons. We found that Mn suppressed the peak amplitude of Ca2+ channel-mediated currents, and blockade of Ca2+ channels prevented Mn-stimulation of firing rate, reduction of action potential amplitude in dopamine neurons, and reduced 54Mn uptake in the CaV1-2, CaV1-3 expressing cells (p< 0.05, n=8–10). Finally, in vivo magnetic resonance imaging (MEMRI) revealed nifidepine-blockade of Ca2+ channels decreased Mn accumulation in the midbrain region of C57BL mice (p<0.05, n=6–8). Our data suggest a potential mechanism by which Mn can induce defects in basal ganglia function, namely a marked increase the excitability of dopaminergic neurons. Mn increases the spontaneous firing activity of dopamine neurons. Blockade of L-type Ca2+ channels inhibited Mn-stimulation of spontaneous firing activity of dopamine neurons. Manganese enhanced magnetic resonance imaging (MEMRI) provides evidence of an in vivo calcium-dependent mechanism involved in midbrain Mn accumulation. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Age‐Related Dysregulation of Neuronal Activity in Single Dopaminergic Neurons

Aging is a known risk factor for neurodegenerative diseases, including Parkinson's disease (PD) and Alzheimer's disease. Dopamine neurotransmission has been implicated in the etiology of PD and age‐related decline of motor control, motivation, and cognitive functions. Few studies have pursued cellular and synaptic mechanisms to explain the decline in midbrain dopamine neurotransmission with age. Here, we used in vivo single‐cell electrophysiological recordings in anesthetized mice to characterize changes in dopamine neurotransmission related to age. We used mice of 4, 12, 24, 30 months of age to record midbrain dopamine neuronal firing activity. Our preliminary data indicates a steady decrease of dopamine neuron firing activity with age, particularly in 30 month‐old mice. In a parallel experiment, using ex vivo whole cell patch clamp electrophysiology, we assessed excitability and firing pattern in midbrain dopamine neurons. To evaluate excitability, spontaneous firing was measured and step current injections from 20pA up to 400pA were also applied to induce firing. Our results show an increase in firing rate frequency and a decrease in the number of spikes with higher current injections, starting with 18 months of age, possibly indicating increased sensitivity to depolarization block. We are currently studying synaptic transmission by assessing glutamate receptor‐mediated burst firing in dopamine neurons in young and old mice. These results will provide a comprehensive assessment of the effects of age on firing induced by both intrinsic conductances and external synaptic input.Support or Funding InformationR01 from NIA (R01 AG052606) and T32 training grant from NIA (T32 AG052363)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

HIV-1 Tat regulation of dopamine transmission and microglial reactivity is brain region specific.

The transactivator of transcription protein, HIV-1 Tat, is linked to neuroAIDS, where degeneration of dopamine neurons occurs. Using a mouse model expressing GFAP-driven Tat protein under doxycycline (Dox) regulation, we investigated microglial-neuronal interactions in the rostral substantia nigra pars compacta (SNc). Immunohistochemistry for microglia and tyrosine hydroxylase (TH) showed that the ratio of microglia to dopamine neurons is smaller in the SNc than in the ventral tegmental area (VTA) and that this difference is maintained following 7-day Dox exposure in wild type animals. Administration of Dox to wild types had no effect on microglial densities. In addressing the sensitivity of neurons to potentially adverse effects of HIV-1 Tat, we found that HIV-1 Tat exposure in vivo selectively decreased TH immunoreactivity in the SNc but not in the VTA, while levels of TH mRNA in the SNc remained unchanged. HIV-1 Tat induction in vivo did not alter the total number of neurons in these brain regions. Application of Tat (5 ng) into dopamine neurons with whole-cell patch pipette decreased spontaneous firing activity. Tat induction also produced a decline in microglial cell numbers, but no microglial activation. Thus, disappearance of dopaminergic phenotype is due to a loss of TH immunoreactivity rather than to neuronal death, which would have triggered microglial activation. We conclude that adverse effects of HIV-1 Tat produce a hypodopamine state by decreasing TH immunoreactivity and firing activity of dopamine neurons. Reduced microglial numbers after Tat exposure in vivo suggest impaired microglial functions and altered bidirectional interactions between dopamine neurons and microglia.

The sigma-1 receptor modulates methamphetamine dysregulation of dopamine neurotransmission

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.

Dopamine reward prediction error signal codes the temporal evaluation of a perceptual decision report

Learning to associate unambiguous sensory cues with rewarded choices is known to be mediated by dopamine (DA) neurons. However, little is known about how these neurons behave when choices rely on uncertain reward-predicting stimuli. To study this issue we reanalyzed DA recordings from monkeys engaged in the detection of weak tactile stimuli delivered at random times and formulated a reinforcement learning model based on belief states. Specifically, we investigated how the firing activity of DA neurons should behave if they were coding the error in the prediction of the total future reward when animals made decisions relying on uncertain sensory and temporal information. Our results show that the same signal that codes for reward prediction errors also codes the animal's certainty about the presence of the stimulus and the temporal expectation of sensory cues.

Differential expression of long-term potentiation among identified inhibitory inputs to dopamine neurons.

The in vivo firing pattern of ventral tegmental area (VTA) dopamine neurons is controlled by GABA afferents originating primarily from the nucleus accumbens (NAc), rostromedial tegmental nucleus (RMTg), and local GABA neurons within the VTA. Although different forms of plasticity have been observed from GABA inputs to VTA dopamine neurons, one dependent on cyclic GMP synthesis and the other on adenylyl cyclase activation, it is unknown whether plasticity is differentially expressed in each. Using an optogenetic strategy, we show that identified inhibitory postsynaptic currents (IPSCs) from local VTA GABA neurons and NAc afferents exhibit a cyclic GMP-dependent long-term potentiation (LTP) that is capable of inhibiting the firing activity of dopamine neurons. However, this form of LTP was not induced from RMTg afferents. Only an adenylyl cyclase-mediated increase in IPSCs was exhibited by all three inputs. Thus discrete plasticity mechanisms recruit overlapping but different subsets of GABA inputs to VTA dopamine neurons.NEW & NOTEWORTHY We describe a mapping of plasticity expression, mediated by different mechanisms, among three distinct GABA afferents to ventral tegmental area (VTA) dopamine neurons: the rostromedial tegmental nucleus, the nucleus accumbens, and the local GABA neurons within the VTA known to synapse on VTA dopamine neurons. This work is the first demonstration that discrete plasticity mechanisms recruit overlapping but different subsets of GABA inputs to VTA dopamine neurons.

Cocaine Exposure Enhances the Activity of Ventral Tegmental Area Dopamine Neurons via Calcium-Impermeable NMDARs.

We show that cocaine-evoked synaptic changes onto ventral tegmental area (VTA) dopamine (DA) neurons leads to long-lasting increases in their burst firing. This increase is due to impaired function of Ca2+-activated small-conductance calcium-dependent potassium (SK) channels; SK channels regulate firing of VTA DA neurons, but this regulation was absent after cocaine. Cocaine exposure drives the insertion of GluN3A-containing NMDARs onto VTA DA neurons. These receptors are Ca2+-impermeable, and thus SK channels are not efficiently activated by synaptic activity. In GluN3A knock-out mice, cocaine did not alter SK channel function or VTA DA neuron firing. This study directly links synaptic changes to increased intrinsic excitability of VTA DA neurons after cocaine, and explains how acute cocaine induces long-lasting remodeling of the mesolimbic DA system.

Methamphetamine Regulation of Firing Activity of Dopamine Neurons.

Methamphetamine (METH) competes with dopamine uptake, increases dopamine efflux via the dopamine transporter, and affects the excitability of dopamine neurons. Here, we identified an unexpected property of METH on dopamine neuron firing activity. METH transiently increased the spontaneous spike activity of dopamine neurons followed by a progressive reduction of the spontaneous spike activity. METH broadened the action potentials, increased coefficients of variation of the interspike interval, and decreased the amplitude of afterhyperpolarization, which are consistent with changes in the activity of Ca2+-activated potassium (BK) channels. We found that METH decreased the activity of BK channels by stimulating BK-α subunit trafficking. Thus, METH modulation of dopamine neurotransmission and resulting behavioral responses is, in part, due to METH regulation of BK channel activity.

Interaction Between Brain Histamine and Serotonin, Norepinephrine, and Dopamine Systems: In Vivo Microdialysis and Electrophysiology Study.

Brain monoamines (serotonin, norepinephrine, dopamine, and histamine) play an important role in emotions, cognition, and pathophysiology and treatment of mental disorders. The interactions between serotonin, norepinephrine, and dopamine were studied in numerous works; however, histamine system received less attention. The aim of this study was to investigate the interactions between histamine and other monoamines, using in vivo microdialysis and electrophysiology. It was found that the inverse agonist of histamine-3 receptors, thioperamide, increased the firing activity of dopamine neurons in the ventral tegmental area. Selective agonist of histamine-3 receptors, immepip, reversed thiperamide-induced stimulation of firing activity of dopamine neurons. The firing rates of serotonin and norpeinephrine neurons were not attenuated by immepip or thioperamide. Thioperamide robustly and significantly increased extracellular concentrations of serotonin, norepinephrine, and dopamine in the rat prefrontal cortex and slightly increased norepinephrine and dopamine levels in the tuberomammillary nucleus of the hypothalamus. It can be concluded that histamine stimulates serotonin, norepinephrine, and dopamine transmission in the brain. Modulation of firing of dopamine neurons is a key element in functional interactions between histamine and other monoamines. Antagonists of histamine-3 receptors, because of their potential ability to stimulate monoamine neurotransmission, might be beneficial in the treatment of mental disorders.

Electrophysiological characterization of dopamine neuronal activity in the ventral tegmental area across the light-dark cycle.

Direct evidence that dopamine (DA) neurotransmission varies during the 24 h of the day is lacking. Here, we have characterized the firing activity of DA neurons located in the ventral tegmental area (VTA) using single-unit extracellular recordings in anesthetized rats kept on a standard light-dark cycle. DA neuronal firing activity was measured under basal conditions and in response to intravenous administration of increasing doses of amphetamine (AMPH: 0.5, 1, 2, 5 mg/kg), apomorphine (APO: 25, 50, 100, 200 µg/kg) and melatonin (MLT: 0.1, 1, 10 mg/kg) at different time intervals of the light-dark cycle. DA firing activity peaked between 07:00 and 11:00 h (3.5 ± 0.3 Hz) and between 19:00 and 23:00 h (4.1 ± 0.7 Hz), with lowest activity occurring between 11:00 and 15:00 h (2.4 ± 0.2 Hz) and between 23:00 and 03:00 h (2.6 ± 0.2 Hz). The highest number of spontaneously active neurons was observed between 03:00 and 06:00 h (2.5 ± 0.3 neurons/track), whereas the lowest was between 19:00 and 23:00 h (1.5 ± 0.2 neurons/track). The inhibitory effect of AMPH on DA firing rate was similar in both phases. The inhibitory effect of low dose of APO (25 μg/kg, dose selective for D2 autoreceptor) was more potent in the dark phase, whereas APO effects at higher doses were similar in both phases. Finally, MLT administration (1 mg/kg) produced a moderate inhibition of DA cell firing in both phases. These experiments demonstrate the existence of an intradiurnal rhythmic pattern of VTA DA neuronal firing activity and a higher pharmacological response of D2 autoreceptors in the dark phase.

PPARα Regulates Cholinergic-Driven Activity of Midbrain Dopamine Neurons via a Novel Mechanism Involving α7 Nicotinic Acetylcholine Receptors

Ventral tegmental area dopamine neurons control reward-driven learning, and their dysregulation can lead to psychiatric disorders. Tonic and phasic activity of these dopaminergic neurons depends on cholinergic tone and activation of nicotinic acetylcholine receptors (nAChRs), particularly those containing the β2 subunit (β2*-nAChRs). Nuclear peroxisome proliferator-activated receptors type-α (PPARα) tonically regulate β2*-nAChRs and thereby control dopamine neuron firing activity. However, it is unknown how and when PPARα endogenous ligands are synthesized by dopamine cells. Using ex vivo and in vivo electrophysiological techniques combined with biochemical and behavioral analysis, we show that activation of α7-nAChRs increases in the rat VTA both the tyrosine phosphorylation of the β2 subunit of nAChRs and the levels of two PPARα endogenous ligands in a Ca(2+)-dependent manner. Accordingly, in vivo production of endogenous PPARα ligands, triggered by α7-nAChR activation, blocks in rats nicotine-induced increased firing activity of dopamine neurons and displays antidepressant-like properties. These data demonstrate that endogenous PPARα ligands are effectors of α7-nAChRs and that their neuromodulatory properties depend on phosphorylation of β2*-nAChRs on VTA dopamine cells. This reveals an autoinhibitory mechanism aimed at reducing dopamine cell overexcitation engaged during hypercholinergic drive. Our results unveil important physiological functions of nAChR/PPARα signaling in dopamine neurons and how behavioral output can change after modifications of this signaling pathway. Overall, the present study suggests PPARα as new therapeutic targets for disorders associated with unbalanced dopamine-acetylcholine systems.

Electrophysiological impact of trazodone on the dopamine and norepinephrine systems in the rat brain

Previous study has documented the long-term effects of the antidepressant trazodone on the serotonin (5-HT) system. The present work examined the impact of sustained trazodone on ventral tegmental area (VTA) dopamine (DA) and locus ceruleus (LC) norepinephrine (NE) neurons firing activity, and characterized its effects at 5-HT2C, 5-HT2A receptors and α1- and α2-adrenoceptors. Electrophysiological recordings were carried out in anesthetized rats. Subcutaneously implanted minipumps delivered vehicle or trazodone (10mg/kg/day) for 2 or 14days. Administration of trazodone for 2 and 14days did not alter the firing activity of DA neurons. Systemic injection of trazodone, however, reversed the inhibitory effect of the 5-HT2C receptor agonist Ro 60,0175 on the DA neuronal firing, suggesting an antagonistic action of trazodone at this receptor. Administration of trazodone for 2days significantly enhanced the NE neurons firing. Despite a return of the NE neurons firing rate to the baseline following 14-day trazodone, the percentage of neurons discharging in burst was increased by this regimen. Administration of trazodone for 14days enhanced the tonic activation of postsynaptic α2-adrenoceptors, as indicated by the disinhibitory effect of the α2-adrenoceptor antagonist idazoxan on hippocampus pyramidal neurons firing. The inhibitory effect of acute trazodone on dorsal raphe (DR) 5-HT neurons firing was shown to be through the 5-HT1A receptor. Systemic injection of trazodone reversed the inhibitory action of 5-HT2A agonist DOI on the NE neurons firing rate, indicating its antagonistic action at 5-HT2A receptors. The enhancement in α2-adrenergic transmission by trazodone, and its 5-HT2A and 5-HT2C receptor antagonism may contribute to its therapeutic action in major depression.

An enhancement of the firing activity of dopamine neurons as a common denominator of antidepressant treatments?

We read with great interest the article by West & Weiss (2011), reporting that long-term administration of antidepressant medications and repeated electroconvulsive shocks increase the firing rate of dopamine (DA) neurons in the ventral tegmental area (VTA), and to a lesser extent the percentage of spikes occurring in bursts. At first glance, these findings appear remarkably striking and seem to provide a unifying link for the antidepressant response. A closer examination of the methodology reveals, however, significant factors that may have prematurely led to such a conclusion. A first look at the data reveals that the mean firing rate of the VTA DA neurons in their two control groups are approximately half of those reported over the past decades (2.0–2.5 Hz vs. 3.5–5 Hz) by our group (Chenu et al. 2009; Chernoloz et al. 2009; Dremencov et al. 2009; El Mansari et al. 2008; Ghanbari et al. 2009; Guiard et al. 2011; Katz et al. 2010) and by several other groups (Floresco et al. 2001; Franberg et al. 2009; Gill et al. 2011; Lodge & Grace, 2011; Melis et al. 2009; Moore et al. 2001; Tan et al. 2009; Valenti & Grace, 2010). In fact, we did not find any peer-reviewed article …

Acute in vivo nicotine administration enhances synchrony among dopamine neurons

Altered functional interactions among midbrain dopamine (DA) neurons contribute to the reinforcing properties of environmental stimuli and addictive drugs. To examine correlations among DA neurons, acute nicotine was administrated to rats via an intraperitoneal catheter and unit activity was measured using multi-tetrode in vivo recordings. Nicotine administration enhanced the correlated activity of simultaneously recorded DA neurons from the ventral tegmental area (VTA). The strength of the correlations between DA neuron pairs, as measured by cross covariance among two spike trains, showed dynamic changes over time. Nicotine produced a gradual rise in firing rate and burst activity that reached a stable plateau approximately 20 min after the intraperitoneal nicotine infusion. Shortly after that time the cross correlations measured using 5-ms bins increased significantly above baseline. In addition, nicotine increased the firing rates of DA neurons in the posterior VTA more than in the anterior VTA. Unlike nicotine, eticlopride administration also boosted DA neuron firing activity but did not enhance synchronization, indicating that the cross correlations induced by nicotine were not due to a non-specific increase in firing rate. The overall results show that nicotine induces nearly synchronous firing by a subset of DA neurons, and those changes in correlative firing will enhance the DA signal that contributes to nicotine-induced behavioral reinforcement.