Tegmental Area Dopamine Neurons Research Articles

A feature-specific prediction error model explains dopaminergic heterogeneity.

The hypothesis that midbrain dopamine (DA) neurons broadcast a reward prediction error (RPE) is among the great successes of computational neuroscience. However, recent results contradict a core aspect of this theory: specifically that the neurons convey a scalar, homogeneous signal. While the predominant family of extensions to the RPE model replicates the classic model in multiple parallel circuits, we argue that these models are ill suited to explain reports of heterogeneity in task variable encoding across DA neurons. Instead, we introduce a complementary 'feature-specific RPE' model, positing that individual ventral tegmental area DA neurons report RPEs for different aspects of an animal's moment-to-moment situation. Further, we show how our framework can be extended to explain patterns of heterogeneity in action responses reported among substantia nigra pars compacta DA neurons. This theory reconciles new observations of DA heterogeneity with classic ideas about RPE coding while also providing a new perspective of how the brain performs reinforcement learning in high-dimensional environments.

Win-Paired Cues Modulate the Effect of Dopamine Neuron Sensitization on Decision Making and Cocaine Self-administration: Divergent Effects Across Sex

BackgroundBoth psychostimulant use and engagement with probabilistic schedules of reward sensitize the mesocorticolimbic dopamine (DA) system. Such behaviors may act synergistically to explain the high comorbidity between stimulant use and gambling disorder. The salient audiovisual stimuli of modern electronic gambling may exacerbate the situation. MethodsTo probe these interactions, we sensitized ventral tegmental area DA neurons via chronic chemogenetic stimulation while rats (n = 134) learned a rat gambling task in the presence or absence of casino-like cues. The same rats then learned to self-administer cocaine. In a separate cohort (n = 25), we confirmed that our chemogenetic methods sensitized the locomotor response to cocaine and potentiated phasic excitability of ventral tegmental area DA neurons through in vivo electrophysiological recordings. ResultsIn the absence of cues, sensitization promoted risk taking in both sexes. When rewards were cued, sensitization expedited the development of a risk-preferring phenotype in males while attenuating cue-induced risk taking in females. ConclusionsWhile these results provide further confirmation that ventral tegmental area DA neurons critically modulate risky decision making, they also reveal stark sex differences in the decisional impact that dopaminergic signals exert when winning outcomes are cued. As previously observed, risky decision making on the cued rat gambling task increased as both males and females learned to self-administer cocaine. The combination of DA sensitization and win-paired cues while gambling led to significantly greater cocaine taking, but these rats did not show any increase in risky choice as a result. Therefore, cocaine and heavily cued gambles may partially substitute for each other once the DA system has been rendered labile through sensitization, thereby compounding addiction risk across modalities.

Songbird subthalamic neurons project to dopaminergic midbrain and exhibit singing-related activity.

Skill learning requires motor output to be evaluated against internal performance benchmarks. In songbirds, ventral tegmental area (VTA) dopamine neurons (DA) signal performance errors important for learning, but it remains unclear which brain regions project to VTA and how these inputs may contribute to DA error signaling. Here, we find that the songbird subthalamic nucleus (STN) projects to VTA and that STN microstimulation can excite VTA neurons. We also discover that STN receives inputs from motor cortical, auditory cortical, and ventral pallidal brain regions previously implicated in song evaluation. In the first neural recordings from songbird STN, we discover that the activity of most STN neurons is associated with body movements and not singing, but a small fraction of neurons exhibits precise song timing and performance error signals. Our results place the STN in a pathway important for song learning, but not song production, and expand the territories of songbird brain potentially associated with song learning.NEW & NOTEWORTHY Songbird subthalamic (STN) neurons exhibit singing-related signals and are interconnected with the motor cortical nucleus, auditory pallium, ventral pallidum, and ventral tegmental area, areas important for song generation and learning.

Repeated but Not Single Administration of Ketamine Prolongs Increases of the Firing Activity of Norepinephrine and Dopamine Neurons.

BackgroundClinical studies have shown that the rapid antidepressant effect of the glutamate N-methyl-D-aspartate receptor antagonist ketamine generally disappears within 1 week but can be maintained by repeated administration. Preclinical studies showed that a single ketamine injection immediately increases the firing and burst activity of norepinephrine (NE) neurons, but not that of serotonin (5-HT) neurons. It also enhances the population activity of dopamine (DA) neurons. In the present study, we investigated whether such alterations of monoamine neuronal firing are still present 1 day after a single injection, and whether they can be maintained by repeated injections.MethodsRats received a single ketamine injection or 6 over 2 weeks and the firing activity of dorsal raphe nucleus 5-HT, locus coeruleus NE, and ventral tegmental area DA neurons was assessed.ResultsOne day following a single injection of ketamine, there was no change in the firing activity of 5-HT, NE, or DA neurons. One day after repeated ketamine administration, however, there was a robust increase of the firing activity of NE neurons and an enhancement of burst and population activities of DA neurons, but still no change in firing parameters of 5-HT neurons. The increased activity of NE neurons was no longer present 3 days after the last injection, whereas that of DA neurons was still present. DA neurons were firing normally 7 days after repeated injections.ConclusionThese results imply that the enhanced activity of NE and DA neurons may play a significant role in the maintenance of the antidepressant action of ketamine.

Long-term administration of cariprazine increases locus coeruleus noradrenergic neurons activity and serotonin1A receptor neurotransmission in the hippocampus.

Cariprazine, the novel dopamine (DA) D3-preferring D3/D2 and serotonin (5-HT)1A receptor partial agonist, has activity as an adjunctive therapy in major depressive disorder (MDD). This study aims to investigate the effects of chronic cariprazine administration in combination with the selective serotonin reuptake inhibitor escitalopram on the activity of monoaminergic systems. Rats received cariprazine alone and in adjunct to escitalopram for 2 and 14 days and the firing activity of dorsal raphe nucleus 5-HT, locus coeruleus norepinephrine (NE) and ventral tegmental area DA neurons was assessed. 5-HT and NE neurotransmission in hippocampus pyramidal neurons was evaluated by assessing tonic activation of their 5-HT1A, and α1- and α2-adrenergic receptors, using their selective antagonists. Two and 14-day cariprazine regimens increased the firing rate of NE, but not 5-HT and DA neurons. Addition of cariprazine to escitalopram reversed the inhibitory effect of escitalopram on NE but not 5-HT and DA neurons. In the hippocampus, there was an increase in neurotransmission at 5-HT1A receptors in cariprazine-treated rats, but no change in overall NE transmission by either regimen. Cariprazine increased NE neuronal firing and reversed the escitalopram-induced inhibition of these neurons. Despite a lack of effect on 5-HT neuronal firing activity, there was an increase in tonic activation of hippocampus 5-HT1A receptors by cariprazine alone but not with the combination. These effects provide a possible rationale for the clinical efficacy of cariprazine as an adjunctive strategy in patients with MDD.

P-56LOCAL BLOCKADE OF THE MU OPIOID RECEPTOR REVEALS THE DUAL MOTOR EFFECT OF ETHANOL IN pVTA

Previous electrophysiological and behavioral data have revealed the existence of ethanol opposite effects (excitatory and inhibitory) on the posterior ventral tegmental area (pVTA) dopamine (DA) neurons activity. These activating and depressing effects of ethanol could be the result of two concurrent and opposing mechanisms, one increasing and the other reducing GABA release …

A Persistent Na<sup>+</sup> Current and Its Contribution to Burst-Like Firing in Ventral Tegmental Area Dopamine Neurons

The ventral tegmental area dopamine (DA VTA) neurons have the spontaneous tonic activity and an alteration of firing pattern from tonic to burst accelerates dopamine transmission more effectively in the mesoaccumbal dopaminergic system, leading to the reinforcing process of drugs of abuse such as alcohol and nicotine. In the present study, we examined whether a persistent Na+ current would contribute to burst firing in DA VTA neuronsusing nystatin-perforated recording. Tetrodotoxin (TTX) (1 μM) or riluzole (10 μM) hyperpolarized the membrane potential and stopped spontaneous firing of DA VTA neurons. In voltage-clamp analysis, a TTX and riluzole-sensitive and persistent Na+ current was activated at ?60 mV and reached maximal amplitude at ?40 mV. This persistent Na+ current was potentiated by a negative shift of the voltage of activation by eliminating Ca2+ from the extracellular solution. The Ca2+-free extracellular solution depolarized the membrane potential and increased the firing frequency of DA VTA neurons. When a continuous hyperpolarizing current was injected, the firing pattern of the DA VTA neurons transformed into burst-like firing; with average spike number of 4.9, average inter-spike interval of 221 ms, and an average plateau potential, on which the train of spikes generated, was 11 mV. The burst-like firing of DA VTA neurons was abolished by 10 μM riluzole. The concurrent blockade of both T-type Ca2+ current and small conductance Ca2+-activated K+(SK) currents by 100 μM nickel did not induce burst-like firing with or without continuous hyperpolarizing current injection in DA VTA neurons. In conclusion, increases in a persistent Na+ current that mediates a depolarizing driving force by removing extracellular Ca2+ contributes to burst-like firing in DA VTA neurons.

Nicotine Enhances the Excitability of Gaba Neurons in the Ventral Tegmental Area via Activation of Alpha 7 Nicotinic Receptors on Glutamate Terminals

Ventral tegmental area dopamine (DA) and GABA neurons express nicotinic acetylcholine receptor (nAChR) subtypes, whose net activation results in enhancement of DA release in the nucleus accumbens (NAc). This effect decreases after repeated nicotine (NIC) treatment via desensitization. We evaluated the effects of acute NIC on glutamate decarboxylase (GAD67)-positive GABA neurons in the VTA of green fluorescent protein (GFP) knockin (GAD-GFP) mice, and determined the expression of selected nAChR subunits in VTA GABA neurons. In vivo, tachylphylaxis accrued to repeated systemic, but not local administration of NIC. Microelectrophoretic application of NIC and the α7 nAChR partial agonist JN403 markedly enhanced the firing rate of VTA GABA neurons. This activation was suppressed by intraperitoneal administration of the α7 nAChR antagonist methyllycaconitine (MLA, 1 mg/kg), or the glutamate (GLU) NMDA receptor antagonist APV (1 mg/kg), but not by the non-selective non-competitive antagonist mecamylamine (MEC, 1 mg/kg). In patch clamp studies in the slice preparation, the α7 nAChR agonist choline (1-10 mM), in the presence of the muscarinic cholinergic antagonist atropine (50 μM), enhanced sEPSC and mini-EPSC frequency, but not amplitude, which was blocked by MLA (0.5 μM). JN403 (0.1-1 μM) enhanced evoked EPSCs, without affecting membrane currents of VTA GABA neurons. In patch clamp studies in dissociated VTA GABA neurons, choline+atropine failed to induce whole-cell current responses in most cells tested. Single cell RT-qPCR revealed that most GABA neurons did not express α7 nAChRs. Together, this indicates that NIC excites VTA GABA neurons via α7 nAChRs located on GLUergic terminals.

Mimicking synaptic effects of addictive drugs with selective dopamine neuron stimulation

The synaptic changes induced by initial drug exposure leave a trace on neural systems that can eventually manifest in compulsive drug-seeking behavior. A single injection of cocaine has been shown to induce a change in the AMPA receptor (AMPAR) subunit composition at glutamatergic synapses onto ventral tegmental area (VTA) dopamine (DA) neurons. This change is long-lasting (up to months following self-administration) and represents an important functional change at the synaptic level following cocaine use. We recently published findings that cocaine's action at the DA transporter (DAT) is necessary for the induction of AMPAR redistribution and that this can also be mimicked by selective DA neuron stimulation. The stimulation effect is dependent on D1 receptors within the VTA. Furthermore other addictive drugs, although they act through distinct mechanisms, also induce this synaptic change. Here we discuss literature that expands on these observations in an attempt to further clarify the synaptic changes following early drug use.

Aversive stimuli alter ventral tegmental area dopamine neuron activity via a common action in the ventral hippocampus.

Stress is a physiological, adaptive response to changes in the environment, but can also lead to pathological alterations, such as relapse in psychiatric disorders and drug abuse. Evidence demonstrates that the dopamine (DA) system plays a role in stress; however, the nature of the effects of sustained stressors on DA neuron physiology has not been adequately addressed. By using a combined electrophysiological, immunohistochemical and behavioral approach, we examined the response of ventral tegmental area DA neurons in rats to acute as well as repeated stressful events using noxious (footshock) and psychological (restraint) stress. We found that aversive stimuli induced a pronounced activation of the DA system both electrophysiologically (population activity; i.e., number of DA neurons firing spontaneously) and behaviorally (response to psychostimulants). Moreover, infusion of TTX into the ventral hippocampus (vHPC) reversed both behavioral and electrophysiological effects of stress, indicating that the hyperdopaminergic condition associated with stress is driven by hyperactivity within the vHPC. Therefore, the stress-induced activation of the DA system may underlie the propensity of stress to exacerbate psychotic disorders or predispose an individual to drug-seeking behavior. Furthermore, the vHPC represents a critical link between context-dependent DA sensitization, stress-induced potentiation of amphetamine responsivity, and the increase in DA associated with stressors.

Cocaine Seeking Habits Depend upon Dopamine-Dependent Serial Connectivity Linking the Ventral with the Dorsal Striatum

A neuroanatomical principle of striatal organization has been established through which ventral domains, including the nucleus accumbens, exert control over dorsal striatal processes mediated by so-called "spiraling," striato-nigro-striatal, circuitry. We have investigated the functional significance of this circuitry in the control over a cocaine-seeking habit by using an intrastriatal disconnection procedure that combined a selective, unilateral lesion of the nucleus accumbens core and infusion of a dopamine receptor antagonist into the contralateral dorsolateral striatum, thereby disrupting striato-midbrain-striatal serial connectivity bilaterally. We show that this disconnection selectively decreased drug-seeking behavior in rats extensively trained under a second-order schedule of cocaine reinforcement. These data thereby define the importance of interactions between ventral and dorsal domains of the striatum, mediated by dopaminergic transmission, in the neural mechanisms underlying the development and performance of cocaine-seeking habits that are a key characteristic of drug addiction.

The laterodorsal tegmentum is essential for burst firing of ventral tegmental area dopamine neurons.

In response to behaviorally salient stimuli, dopamine (DA) neurons fire in bursts. Burst firing induces a large transient increase in synaptic DA and is regarded as the functionally relevant mode of transmission that signals reward and modulates goal-directed behavior. DA neuron burst firing is dynamically regulated by afferent inputs, and it is not present in vitro because of severing of afferent processes. However, what afferents are requisite for burst firing in vivo is not known. Here, we show that tonic input from the laterodorsal tegmental nucleus (LDTg) is required for glutamate-elicited burst firing in ventral tegmental area DA neurons of anesthetized rats. Also, after LDTg inactivation, DA neurons fire as they do in vitro (i.e., as pacemakers); even direct glutamate application fails to cause them to burst fire under these conditions. These data show that the LDTg is critical to normal DA function, and thus, pathology within this region may lead to aberrant DA signaling.

Dissociation of rewarding and dopamine transporter-mediated properties of amphetamine.

The interaction of amphetamine (AMPH) with the dopamine (DA) transporter (DAT) is thought to be critically important for the DA-elevating actions of this drug. It is commonly believed that DA elevations are involved in the rewarding/reinforcing properties of AMPH and other drugs of abuse. Here, we found that DAT deletion did not eliminate the rewarding effects of AMPH as measured by conditioned place preference (CPP). In fact, mice in which the DAT gene has been deleted (DAT-KO mice) exhibited AMPH-induced CPP for many weeks after the time when extinction occurred in WT mice. Moreover, systemic AMPH still increased extracellular DA in the nucleus accumbens (NAc) of mice lacking the DAT, although local infusion of AMPH into the NAc did not have this effect. By using voltammetry in NAc slices, we found that AMPH did not decrease the rate of DA clearance. The rate of ventral tegmental area DA neuron firing was dramatically inhibited by AMPH in brain slices from WT mice, but there was no inhibition of firing in DAT-KO mice. AMPH-induced CPP was abolished by pretreatment with WAY-100635, a serotonin 5-HT(1A) receptor antagonist, in DAT-KO mice, but the drug did not change AMPH place preference in WT mice. Therefore, despite the absence of the DAT, AMPH displays rewarding effects and causes an increase in extracellular DA in the NAc of DAT-KO mice, acting indirectly in this case. The 5-HT system may be involved in the rewarding effects of AMPH in these mice.

The putative dopamine D3 receptor agonist 7-OH-DPAT: lack of mesolimbic selectivity.

7-Hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT), an agonist with relative selectivity for the dopamine D3 receptor, was examined in several electrophysiological assays to determine whether it exhibits preferential effects in the mesolimbic versus nigrostriatal dopamine systems. Extracellular single unit activities of substantia nigra pars compacta (A9) and ventral tegmental area (A10) dopamine neurons, and caudate-putamen and nucleus accumbens neurons, were recorded in male rats anesthetized with chloral hydrate. Intravenous (+/-)-7-OH-DPAT potently and completely inhibited the firing of both A9 and A10 dopamine neurons (ED50's: 3.5 +/- 0.7 micrograms/kg and 3.9 +/- 0.9 micrograms/kg, respectively). The active enantiomer, (+)-7-OH-DPAT, was 2 to 3 times more potent than the racemic drug (ED50's: 1.2 +/- 0.3 micrograms/kg and 1.7 +/- 0.4 micrograms/kg for A9 and A10 cells, respectively). There were no significant differences in potency for either form in inhibiting A9 and A10 dopamine neurons. In other studies, iontophoretically applied (+)-7-OH-DPAT caused current-dependent inhibitions of spontaneously active or glutamate-driven caudate-putamen and nucleus accumbens neurons (I50 values, 6.5 and 7.9 nA, respectively). Again, no difference in potency between cell populations was noted. Finally, in cell-attached patch-clamp recordings from freshly dissociated rat caudate-putamen neurons, an 85 pS K+ channel known to be activated by dopamine and the "D2-like" agonist quinpirole was also observed with (+/-)-7-OH-DPAT (0.2-1 microM) applied in the patch pipette.(ABSTRACT TRUNCATED AT 250 WORDS)