Firing Rate Of Dopaminergic Neurons Research Articles

FGF2 activity regulates operant alcohol self-administration and mesolimbic dopamine transmission

Fibroblast growth factor 2 (FGF2) is involved in the development and maintenance of the brain dopamine system. We previously showed that alcohol exposure alters the expression of FGF2 and its receptor, FGF receptor 1 (FGFR1) in mesolimbic and nigrostriatal brain regions, and that FGF2 is a positive regulator of alcohol drinking. Here, we determined the effects of FGF2 and of FGFR1 inhibition on alcohol consumption, seeking and relapse, using a rat operant self-administration paradigm. In addition, we characterized the effects of FGF2-FGFR1 activation and inhibition on mesolimbic and nigrostriatal dopamine neuron activation using in vivo electrophysiology. We found that recombinant FGF2 (rFGF2) increased the firing rate and burst firing activity of dopaminergic neurons in the mesolimbic and nigrostriatal systems and led to increased operant alcohol self-administration. In contrast, the FGFR1 inhibitor PD173074 suppressed the firing rate of these dopaminergic neurons, and reduced operant alcohol self-administration. Alcohol seeking behavior was not affected by PD173074, but this FGFR1 inhibitor reduced post-abstinence relapse to alcohol consumption, albeit only in male rats. The latter was paralleled by the increased potency and efficacy of PD173074 in inhibiting dopamine neuron firing. Together, our findings suggest that targeting the FGF2-FGFR1 pathway can reduce alcohol consumption, possibly via altering mesolimbic and nigrostriatal neuronal activity.

Arecoline Induces an Excitatory Response in Ventral Tegmental Area Dopaminergic Neurons in Anesthetized Rats.

Arecoline is the principle psychoactive alkaloid in areca nuts. Areca nuts are chewable seeds of Areca catechu L., which are epidemic plants that grow in tropical and subtropical countries and cause dependency after long-term use. However, the mechanisms underlying such dependency remain largely unclear, and therefore, no effective interventions for its cessation have been developed. The present study aimed to examine the effects of arecoline on neurons of the ventral tegmental area (VTA). After rats were anesthetized and craniotomized, electrophysiological electrodes were lowered into the VTA to obtain extracellular recordings. The mean firing rate of dopaminergic and GABAergic neurons were then calculated and analyzed before and after arecoline treatment. The burst characteristics of the dopaminergic neurons were also analyzed. The results showed that arecoline evoked a significant enhancement of the firing rate of dopaminergic neurons, but not GABAergic neurons. Moreover, arecoline evoked remarkable burst firings in the dopaminergic neurons, including an increase in the burst rate, elongation in the burst duration, and an enhancement in the number of spikes per burst. Collectively, the findings revealed that arecoline significantly excited VTA dopaminergic neurons, which may be a mechanism underlying areca nut dependency and a potential target for areca nut cessation therapy.

Distinct Firing Activities of the Hypothalamic Arcuate Nucleus Neurons to Appetite Hormones.

The hypothalamic arcuate nucleus (Arc) is a central unit that controls the appetite through the integration of metabolic, hormonal, and neuronal afferent inputs. Agouti-related protein (AgRP), proopiomelanocortin (POMC), and dopaminergic neurons in the Arc differentially regulate feeding behaviors in response to hunger, satiety, and appetite, respectively. At the time of writing, the anatomical and electrophysiological characterization of these three neurons has not yet been intensively explored. Here, we interrogated the overall characterization of AgRP, POMC, and dopaminergic neurons using genetic mouse models, immunohistochemistry, and whole-cell patch recordings. We identified the distinct geographical location and intrinsic properties of each neuron in the Arc with the transgenic lines labelled with cell-specific reporter proteins. Moreover, AgRP, POMC, and dopaminergic neurons had different firing activities to ghrelin and leptin treatments. Ghrelin led to the increased firing rate of dopaminergic and AgRP neurons, and the decreased firing rate of POMC. In sharp contrast, leptin resulted in the decreased firing rate of AgRP neurons and the increased firing rate of POMC neurons, while it did not change the firing rate of dopaminergic neurons in Arc. These findings demonstrate the anatomical and physiological uniqueness of three hypothalamic Arc neurons to appetite control.

Orexin-B exerts excitatory effects on nigral dopaminergic neurons and alleviates motor disorders in MPTP parkinsonian mice

The study aimed to investigate the effects of orexin-B in Parkinson’s disease. The present study showed that orexin-B exerted marked excitatory effects via orexin-2 receptor on the nigral dopaminergic neurons in MPTP parkinsonian mice, while blocking orexin-2 receptor decreased the firing rate of dopaminergic neurons significantly. Furthermore, intracerebroventricular application of orexin-B relieved the degeneration of dopaminergic neurons, increased the general spontaneous activity and alleviated motor coordination in MPTP parkinsonian mice. The present study suggests that orexin-B could exert protective effects on dopaminergic neurons and improve motor disorders in parkinsonian mice. Such protective effects of orexin-B on Parkinson’s disease may be partially attributed to the excitatory effects on the nigral dopaminergic neurons.

Dopamine-dependent early synaptic and motor dysfunctions induced by α-synuclein in the nigrostriatal circuit

Misfolding and aggregation of α-synuclein are specific features of Parkinson’s disease and other neurodegenerative diseases defined as synucleinopathies. Parkinson’s disease progression has been correlated with the formation and extracellular release of α-synuclein aggregates, as well as with their spread from neuron to neuron. Therapeutic interventions in the initial stages of Parkinson’s disease require a clear understanding of the mechanisms by which α-synuclein disrupts the physiological synaptic and plastic activity of the basal ganglia. For this reason, we identified two early time points to clarify how the intrastriatal injection of α-synuclein-preformed fibrils in rodents via retrograde transmission induces time-dependent electrophysiological and behavioural alterations. We found that intrastriatal α-synuclein-preformed fibrils perturb the firing rate of dopaminergic neurons in the substantia nigra pars compacta, while the discharge of putative GABAergic cells of the substantia nigra pars reticulata is unchanged. The α-synuclein-induced dysregulation of nigrostriatal function also impairs, in a time-dependent manner, the two main forms of striatal synaptic plasticity, long-term potentiation and long-term depression. We also observed an increased glutamatergic transmission measured as an augmented frequency of spontaneous excitatory synaptic currents. These changes in neuronal function in the substantia nigra pars compacta and striatum were observed before overt neuronal death occurred. In an additional set of experiments, we were able to rescue α-synuclein-induced alterations of motor function, striatal synaptic plasticity and increased spontaneous excitatory synaptic currents by subchronic treatment with l-DOPA, a precursor of dopamine widely used in the therapy of Parkinson’s disease, clearly demonstrating that a dysfunctional dopamine system plays a critical role in the early phases of the disease.

The Rostromedial Tegmental Nucleus: Anatomical Studies and Roles in Sleep and Substance Addictions in Rats and Mice.

The rostromedial tegmental nucleus (RMTg), a brake of the dopamine system, is specifically activated by aversive stimuli, such as foot shock. It is principally composed of gamma-aminobutyric acid neurons. However, there is no exact location of the RMTg on the brain stereotaxic atlas. The RMTg can be defined by c-Fos staining elicited by psychostimulants, the position of retrograde-labeled neurons stained by injections into the ventral tegmental area (VTA), the terminal field formed by axons from the lateral habenula, and some molecular markers identified as specifically expressed in the RMTg such as FoxP1. The RMTg receives a broad range of inputs and produces diverse outputs, which indicates that the RMTg has multiple functions. First, the RMTg plays an essential role for non-rapid eye movement sleep. Additionally, the RMTg serves a vital role in response to addiction. Opiates increase the firing rates of dopaminergic neurons in the VTA by acting on μ-opioid receptors on RMTg neurons and their terminals inside the VTA. In this review, we summarize the recent research advances on the anatomical location of the RMTg in rats and mice, its projections, and its regulation of sleep–wake behavior and addiction.

The Impact of Appetite-Regulating Neuropeptide Leptin on Alcohol Use, Alcohol Craving and Addictive Behavior: A Systematic Review of Preclinical and Clinical Data.

The appetite regulating hormone leptin, which is mainly secreted from adipose tissue, is an important regulator of food intake and modulator of reward-driven behavior. Leptin exerts its biological actions via binding to the leptin receptor, which is expressed in the hypothalamus, but also in the hippocampus, the amygdala and the substantia nigra. In the ventral tegmental area (VTA), leptin attenuates the firing rate of dopaminergic neurons that project to the Nucleus accumbens (NAc), which serves as relay to other brain areas of the "addiction network", such as the prefrontal cortex. This suggests that leptin plays a role in the processing of rewards in the context of substance use disorders such as alcohol use disorder, especially through attenuation of dopaminergic activity in the mesolimbic reward system. This supports the plausibility of leptin's potential effects in alcohol use disorder. We searched MEDLINE from 1990 to February 2020. All abstracts were screened for relevance and we only included publications reporting original data with a full text available in English language. Studies that did not report leptin-data, reviews or case reports/series were not included. We identified a total of N=293 studies of whom a total of N=55 preclinical and clinical studies met the specified criteria. N=40 studies investigated the effects of alcohol on leptin plasma levels, N=9 studies investigated the effects of leptin on alcohol craving and N=6 studies investigated the effects of leptin on relapse and alcohol consumption. In this review of preclinical and clinical data, we assess the role of leptin in alcohol use and the development and maintenance of an alcohol use disorder, alcohol craving and relapse. Integrating the existing preclinical and clinical data on leptin may reveal new and innovative targets for the treatment of substance use disorders in the future.

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.

The impact of electrophysiology of central dopaminergic neurons and the depression-state induced by chronic neuropathic pain

To explore the underlying electrophysiological mechanism of depression induced by chronic pain in dopaminergic neurons in midbrain ventral tegmental area (VTA) of rats. Twenty-four healthy adult rats were divided into two groups randomly(n=12):12 rats formed the sham group by exposing the spared nerve, and another 12 rats were served as the spared nerve injury (SNI)group by branchedness sciatic nerve injury surgery. The mechanical allodynia test were detected on the day of 3, 7, 14, 28, 42 and 56 after surgery, and the depressive-like behaviors such as open-field test, sucrose preference and forcedswim test were detected at the same time. Then we used the Multichannel Acquisition Processor (MAP) system to record the firing activity of neurons in VTA in both Sham rats and SNI rats. ①Comparing to sham rats, the paw withdrawalmechanical threshold of SNI rats was decreased significantly (P< 0.01);② According to depression-related behavioral test, SNI rats showed significant difference in open field text, sucrose preference, focus swim text comparing with Sham rats (P< 0.01);③ The firing rate and burst activity of dopaminergic neuronsin midbrain VTA are increased in depression rats compare to sham rats(P<0.05). Chronic pain could induce depression, and the increase of spontaneous firing rate of dopaminergic neurons in midbrain VTA might be contribute to the depression induced by the chronic neuropathic pain.

Locus of onset and subpopulation specificity of in vivo ethanol effect in the reciprocal ventral tegmental area–nucleus accumbens circuit

Elevated levels of dopamine in the nucleus accumbens (nAc) as a consequence of increased activation of dopaminergic neurons in the VTA are associated with the reinforcing properties of ethanol consumption, but whether the initiation of drug-response is connected to a direct activation of dopaminergic cell bodies in the VTA region or involves GABAergic neurons in VTA and/or the nAc is unclear. To this end, neuronal firing rate was recorded simultaneously in the VTA and nAc of awake and freely-moving C57BL6/J mice receiving an intraperitoneal (i.p.) injection of ethanol (0.75, 2.0, or 3.5g/kg) or saline. Recorded units were classified based on electrophysiological properties and the pharmacological response to the dopamine D2 receptor agonist quinpirole into putative dopaminergic (DA) neurons and fast-spiking or slow-spiking putative GABAergic neurons. Our data show that ethanol acutely decreases the firing frequency of GABAergic units in both the VTA and nAc in a dose-dependent manner, and enhances the firing rate of DA neurons. In order to define the onset of ethanol-induced rate changes normalized population vectors describing the collective firing rate of classes of neurons over time were generated and compared with saline-treatment. Population vectors of DA neurons in the VTA and GABAergic units in the nAc showed a significant deviation from the saline condition within 40s following ethanol-administration (2.0g/kg), while inhibition of GABAergic units in the VTA had a slower onset. In conclusion, the data presented here suggests that EtOH exerts a direct effect on DA firing frequency, but that decreased firing frequency of inhibitory neurons in VTA and nAc contributes to the dopamine-elevating properties of ethanol.

Differential Effects of Cocaine on Dopamine Neuron Firing in Awake and Anesthetized Rats

Cocaine (benzoylmethylecgonine), a natural alkaloid, is a powerful psychostimulant and a highly addictive drug. Unfortunately, the relationships between its behavioral and electrophysiological effects are not clear. We investigated the effects of cocaine on the firing of midbrain dopaminergic (DA) neurons, both in anesthetized and awake rats, using pre-implanted multielectrode arrays and a recently developed telemetric recording system. In anesthetized animals, cocaine (10 mg/kg, intraperitoneally) produced a general decrease of the firing rate and bursting of DA neurons, sometimes preceded by a transient increase in both parameters, as previously reported by others. In awake rats, however, injection of cocaine led to a very different pattern of changes in firing. A decrease in firing rate and bursting was observed in only 14% of DA neurons. Most of the other DA neurons underwent increases in firing rate and bursting: these changes were correlated with locomotor activity in 52% of the neurons, but were uncorrelated in 29% of them. Drug concentration measurements indicated that the observed differences between the two conditions did not have a pharmacokinetic origin. Taken together, our results demonstrate that cocaine injection differentially affects the electrical activity of DA neurons in awake and anesthetized states. The observed increases in neuronal activity may in part reflect the cocaine-induced synaptic potentiation found ex vivo in these neurons. Our observations also show that electrophysiological recordings in awake animals can uncover drug effects, which are masked by general anesthesia.

Partial agonists for α4β2 nicotinic receptors stimulate dopaminergic neuron firing with relatively enhanced maximal effects

Partial agonists selective for α4β2 nicotinic ACh receptors have been developed for smoking cessation as they induce weak activation of native α4β2* receptors and inhibit effect of nicotine. However, it is unclear whether at brain functions there is an existence of receptor reserve that allows weak receptor activation to induce maximum physiological effects. We assessed the extent of α4β2 partial agonist-induced increase of firing rate in dopaminergic neurons and evaluated the influence of receptor reserve. The relative maximal effects and potencies of six nicotinic agonists were assessed on recombinant human α4β2 and α7 receptors expressed in mammalian cell lines by measuring calcium influx. Agonist-induced increase of the spontaneous firing rate of dopaminergic neurons was recorded using microelectrodes in the ventral tegmental area of rat brain slices. All α4β2 partial and full agonists increased the firing rate concentration-dependently. Their sensitivity to subtype-selective antagonists showed predominant activation of native α4β2* receptors. However, partial agonists with relative maximal effects as low as 33% on α4β2 receptors maximally increased the firing rate and induced additional depolarization block of firing, demonstrating that partial activation of receptors caused the maximum increase in firing rate in the presence of a receptor reserve. Partial α4β2 agonists induced relatively enhanced effects on the firing rate of dopaminergic neurons, and the effect was mainly attributed to the existence of native α4β2* receptor reserve. The results have implications in the understanding of physiological effects and therapeutic efficacies of α4β2 partial agonists.

Functional Interaction between Trace Amine-Associated Receptor 1 and Dopamine D2 Receptor

The ability of dopamine receptors to interact with other receptor subtypes may provide mechanisms for modulating dopamine-related functions and behaviors. In particular, there is evidence suggesting that the trace amine-associated receptor 1 (TAAR1) affects the dopaminergic system by regulating the firing rate of dopaminergic neurons or by altering dopamine D2 receptor (D2R) responsiveness to ligands. TAAR1 is a Gα(s) protein-coupled receptor that is activated by biogenic amines, "trace amines," such as β-phenylethylamine (β-PEA) and tyramine that are normally found at low concentrations in the mammalian brain. In the present study, we investigated the biochemical mechanism of interaction between TAAR1 and D2R and the role this interaction plays in D2R-related signaling and behaviors. Using a bioluminescence resonance energy transfer biosensor for cAMP, we demonstrated that the D2R antagonists haloperidol, raclopride, and amisulpride were able to enhance selectively a TAAR1-mediated β-PEA increase of cAMP. Moreover, TAAR1 and D2R were able to form heterodimers when coexpressed in human embryonic kidney 293 cells, and this direct interaction was disrupted in the presence of haloperidol. In addition, in mice lacking TAAR1, haloperidol-induced striatal c-Fos expression and catalepsy were significantly reduced. Taken together, these data suggest that TAAR1 and D2R have functional and physical interactions that could be critical for the modulation of the dopaminergic system by TAAR1 in vivo.

Direct effect of nicotine on mesolimbic dopamine release in rat nucleus accumbens shell

Nicotine stimulates dopamine (DA) cell firing via a local action at somatodendritic sites in the ventral tegmental area (VTA), increasing DA release in the nucleus accumbens (NAcc). Additionally, nicotine may also modulate DA release via a direct effect in the NAcc. This study examined the contribution of the latter mechanism on NAcc DA release by applying nicotine systemically, as well as locally in the VTA and NAcc shell region in rats. Furthermore, the effect of i.v. nicotine on cell firing rate of dopaminergic neurons in the VTA was measured. Systemic administration of nicotine (0.32 mg/kg s.c.) increased extracellular DA levels in the NAcc to ∼1.5 fold of baseline, while DA levels in the VTA remained unaffected. A similar DA increase was observed after local NAcc infusion of nicotine (1 μM and 10 μM). However, 10–1000-fold higher nicotine concentrations were required in the VTA to produce a comparable 150% increase in extracellular DA levels in the ipsilateral NAcc. Additionally, electrophysiological experiments showed that the dopaminergic firing rate in the VTA showed a trend towards an increase after a nicotine dose of 0.1 mg/kg i.v. Taken together these data indicate that the effects of nicotine on DA release at the level of the NAcc might be more important for the rewarding effects than originally proposed.

Mirtazapine Relieves Limb Paralysis of Unknown Etiology: A Three-Year Case Follow-Up

Back to table of contents Previous article Next article LettersFull AccessMirtazapine Relieves Limb Paralysis of Unknown Etiology: A Three-Year Case Follow-UpChien-Han Lai, M.D., M.Sc.Chien-Han LaiSearch for more papers by this author, M.D., M.Sc.Published Online:1 Oct 2011https://doi.org/10.1176/jnp.23.4.jnpe18AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor: “Mrs. M” is a housewife who has had bilateral limb paralysis (LP) of her legs for the last 3.3 years; she had no significant brain or lumbar spine findings in MRI of brain or lumbar-spine, biochemistry examination, and substance or toxicity screenings by many departments of internal and surgical medicine. She was transferred to our clinic because there were no pathologic results of medical examinations. No significant psychosocial stressors, depression (Hamilton Rating Scale for Depression [Ham-D]), or anxiety symptoms (Hamilton Rating Scale for Anxiety (Ham-A) were noted, except bilateral LP of legs, with decreased muscle power (MP: score 2), mild anorexia, low back pain (visual analog scale (VAS) score: 5), and insomnia. No other neurologic signs were found except bilateral LP of legs. Mirtazapine (30 mg/day) was used for the above complaints with unknown etiology, and Mrs. M had relief of LP with less pain feelings (VAS: 3), increased mp, better sleep, and appetite within 2 weeks. LP improved progressively in the following 1 month, with MP returning to normal (score: 5), pain relief (VAS: 1), and ability to walk without assistance. She continued mirtazapine use during the last 3 years; however, she complained that LP and pain would relapse with cessation of mirtazapine (MP: 3 and VAS: 4 if she discontinued mirtazapine use for longer than 1 month). She was still under continuous therapy with mirtazapine (30 mg/day) with good control of LP and pain up to the present (MP: 5; VAS: 1). There has been no significant psychopathology of depression (Ham-D: 0–1) or anxiety (Ham-A: 0–2) during these 3 years.DiscussionMirtazapine could enhance firing rates of dopaminergic neurons and adrenergic neurons in frontocortical and corticolimbic areas, such as frontal cortex, striatum, nucleus accumbens, and hippocampus.1 Dopaminergic-enhancing agents, such as L-dopa, has been reported to facilitate motor recovery in hemiplegic stroke patients.2 The precursor of norepinephrine or aromatic amino acid decarboxylase inhibitor could elevate norepinephrine level in cerebral cortex and hippocampus of sensorimotor cortex-ablated rats. The increase in norepinephrine level was correlated with motor-function recovery.3 Serotonin could give a significant number of stroke patients better outcomes of motor function after fluoxetine treatment, above and beyond the depression-treating effects.4Dept. of Psychiatry Buddhist Tzu-Chi General Hospital Taipei Branch Taipei, Taiwan Institute of Brain Science National Yang Ming University Taipei City, Taiwane-mail: [email protected]com.tw.Support: Buddhist Tzu-Chi General Hospital, Taipei Branch hospital project TCRD-TPE-97-02.1. Millan MJ , Gobert A , Rivet JM , et al.: Mirtazapine enhances frontocortical dopaminergic and corticolimbic adrenergic, but not serotonergic, transmission by blockade of alpha2-adrenergic and serotonin2C receptors: a comparison with citalopram. Eur J Neurosci 2000; 12:1079–1095Crossref, Medline, Google Scholar2. Scheidtmann K , Fries W , Muller F , et al.: Effect of levodopa in combination with physiotherapy on functional motor recovery after stroke: a prospective, randomised, double-blind study. Lancet 2001; 358:787–790Crossref, Medline, Google Scholar3. Kikuchi K , Nishino K , Ohyu H : Increasing CNS norepinephrine levels by the precursor L-dopa facilitates beam-walking recovery after sensorimotor cortex ablation in rats. Brain Res 2000; 860:130–135Crossref, Medline, Google Scholar4. Dam M , Tonin P , De Boni A , et al.: Effects of fluoxetine and maprotiline on functional recovery in poststroke hemiplegic patients undergoing rehabilitation therapy. Stroke 1996; 27:1211–1214Crossref, Medline, Google Scholar FiguresReferencesCited byDetailsCited ByNone Volume 23Issue 4 Fall 2011Pages E18-E18 Metrics Support: Buddhist Tzu-Chi General Hospital, Taipei Branch hospital project TCRD-TPE-97-02.PDF download History Published online 1 October 2011 Published in print 1 October 2011

The parabrachial nucleus is a critical link in the transmission of short latency nociceptive information to midbrain dopaminergic neurons

Many dopaminergic neurons exhibit a short-latency response to noxious stimuli, the source of which is unknown. Here we report that the nociceptive-recipient parabrachial nucleus appears to be a critical link in the transmission of pain related information to dopaminergic neurons. Injections of retrograde tracer into the substantia nigra pars compacta of the rat labelled neurons in both the lateral and medial parts of the parabrachial nucleus, and intra-parabrachial injections of anterograde tracers revealed robust projections to the pars compacta and ventral tegmental area. Axonal boutons were seen in close association with tyrosine hydroxylase-positive (presumed dopaminergic) and negative elements in these regions. Simultaneous extracellular recordings were made from parabrachial and dopaminergic neurons in the anaesthetized rat, during the application of noxious footshock. Parabrachial neurons exhibited a short-latency, short duration excitation to footshock while dopaminergic neurons exhibited a short-latency inhibition. Response latencies of dopaminergic neurons were reliably longer than those of parabrachial neurons. Intra-parabrachial injections of the local anasethetic lidocaine or the GABAA receptor antagonist muscimol reduced tonic parabrachial activity and the amplitude (and in the case of lidocaine, duration) of the phasic response to footshock. Suppression of parabrachial activity with lidocaine reduced the baseline firing rate of dopaminergic neurons, while both lidocaine and muscimol reduced the amplitude of the phasic inhibitory response to footshock, in the case of lidocaine sometimes abolishing it altogether. Considered together, these results suggest that the parabrachial nucleus is an important source of short-latency nociceptive input to the dopaminergic neurons.

A Basal Ganglia Pathway Drives Selective Auditory Responses in Songbird Dopaminergic Neurons via Disinhibition

Dopaminergic neurons in mammals respond to rewards and reward-predicting cues, and are thought to play an important role in learning actions or sensory cues that lead to reward. The anatomical sources of input that drive or modulate such responses are not well understood; these ultimately define the range of behavior to which dopaminergic neurons contribute. Primary rewards are not the immediate objective of all goal-directed behavior. For example, a goal of vocal learning is to imitate vocal-communication signals. Here, we demonstrate activation of dopaminergic neurons in songbirds driven by a basal ganglia region required for vocal learning, area X. Dopaminergic neurons in anesthetized zebra finches respond more strongly to the bird's own song (BOS) than to other sounds, and area X is critical for these responses. Direct pharmacological modulation of area X output, in the absence of auditory stimulation, is sufficient to bidirectionally modulate the firing rate of dopaminergic neurons. The only known pathway from song control regions to dopaminergic neurons involves a projection from area X to the ventral pallidum (VP), which in turn projects to dopaminergic regions. We show that VP neurons are spontaneously active and inhibited preferentially by BOS, suggesting that area X disinhibits dopaminergic neurons by inhibiting VP. Supporting this model, auditory-response latencies are shorter in area X than VP, and shorter in VP than dopaminergic neurons. Thus, dopaminergic neurons can be disinhibited selectively by complex sensory stimuli via input from the basal ganglia. The functional pathway we identify may allow dopaminergic neurons to contribute to vocal learning.

Phosphodiesterase 10A inhibition modulates the sensitivity of the mesolimbic dopaminergic system to d‐amphetamine: involvement of the D1‐regulated feedback control of midbrain dopamine neurons

Phosphodiesterase (PDE) 10A is highly expressed in medium spiny neurons of the striatum, at the confluence of the corticostriatal glutamatergic and the midbrain dopaminergic pathways, both believed to be involved in the physiopathology of schizophrenia. There is a growing body of evidence suggesting that targeting PDE10A may be beneficial for the treatment of positive symptoms in schizophrenia. The aim of the present study was to investigate how PDE10A inhibition modulates mesolimbic dopaminergic neurotransmission. We found that the selective PDE10A inhibitor, MP-10, blocked D-amphetamine-induced hyperactivity as well as D-amphetamine-induced dopamine efflux in the nucleus accumbens in a dose-dependent manner. We further investigated the mechanism by which PDE10A inhibition affects dopaminergic neurotransmission. We report that MP-10 potentiated the effect of a high but not a low dose of D-amphetamine on the mean firing rate of dopaminergic neurons recorded from the ventral tegmental area. Similarly, the effect of a high, but not a low dose of D-amphetamine, was completely reversed by the selective D(1) antagonist, SCH23390. These data suggest that the D(1)-regulated feedback control of midbrain dopamine neurons is a critical pathway involved in the modulation of the response of mesolimbic dopamine neurons to D-amphetamine by PDE10A inhibition.

Trace amine‐associated receptor 1 (TAAR1) modulates dopaminergic activity

The recent identification of the trace amine associated receptor 1 (TAAR1) provides an opportunity to dissociate the effects of trace amines on the dopamine transporter from receptor‐mediated effects. In order to separate both effects on a physiological level, a Taar1‐deficient mouse line was generated.Taar1‐deficient mice displayed increased sensitivity to amphetamine as revealed by enhanced amphetamine‐triggered increases in locomotor activity and augmented striatal release of dopamine as compared to wild‐type animals. Under baseline conditions, locomotion as well as extracellular striatal dopamine levels were similar between Taar1 knock‐out and wild‐type mice. Electrophysiological recordings revealed an elevated spontaneous firing rate of dopaminergic neurons in the ventral tegmental area of Taar1 knock‐out mice. The endogenous TAAR1 agonist p‐tyramine specifically decreased the spike frequency of these neurons in wild‐type but not in Taar1 knock‐out mice, consistent with the prominent expression of Taar1 in the ventral tegmental area.Taken together, the data reveal TAAR1 as regulator of dopaminergic neurotransmission.

Trace Amine-Associated Receptor 1 Modulates Dopaminergic Activity

The recent identification of the trace amine-associated receptor (TAAR)1 provides an opportunity to dissociate the effects of trace amines on the dopamine transporter from receptor-mediated effects. To separate both effects on a physiological level, a Taar1 knockout mouse line was generated. Taar1 knockout mice display increased sensitivity to amphetamine as revealed by enhanced amphetamine-triggered increases in locomotor activity and augmented striatal release of dopamine compared with wild-type animals. Under baseline conditions, locomotion and extracellular striatal dopamine levels were similar between Taar1 knockout and wild-type mice. Electrophysiological recordings revealed an elevated spontaneous firing rate of dopaminergic neurons in the ventral tegmental area of Taar1 knock-out mice. The endogenous TAAR1 agonist p-tyramine specifically decreased the spike frequency of these neurons in wild-type but not in Taar1 knockout mice, consistent with the prominent expression of Taar1 in the ventral tegmental area. Taken together, the data reveal TAAR1 as regulator of dopaminergic neurotransmission.