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Dopamine signaling in dorsal versus ventral striatum: The dynamic role of cholinergic interneurons
Mesostriatal dopaminergic neurons and striatal cholinergic interneurons participate in signaling the motivational signifcance of environmental stimuli and regulate striatal plasticity. Dopamine (DA) and acetylcholine (ACh) have potent interactions within the striatum at multiple levels that include presynaptic regulation of neurotransmitter release and postsynaptic effects in target cells (including ACh neurons). These interactions may be highly variable given the dynamic changes in the fring activities of parent DA and ACh neurons. Here, we consider how striatal ACh released from cholinergic interneurons acting at both nicotinic and muscarinic ACh receptors powerfully modulates DA transmission. This ACh-DA interaction varies in a manner that depends on the frequency of presynaptic activation, and will thus strongly infuence how DA synapses convey discrete changes in DA neuron activity that are known to signal events of motivational salience. Furthermore, this ACh modulation of DA transmission within striatum occurs via different profles of nicotinic and muscarinic receptors in caudate- putamen compared to nucleus accumbens, which may ultimately enable region-specifc targeting of striatal function. © 2011 Threlfell and Cragg.
Dopamine signaling in dorsal versus ventral striatum: the dynamic role of cholinergic interneurons.
Mesostriatal dopaminergic neurons and striatal cholinergic interneurons participate in signaling the motivational significance of environmental stimuli and regulate striatal plasticity. Dopamine (DA) and acetylcholine (ACh) have potent interactions within the striatum at multiple levels that include presynaptic regulation of neurotransmitter release and postsynaptic effects in target cells (including ACh neurons). These interactions may be highly variable given the dynamic changes in the firing activities of parent DA and ACh neurons. Here, we consider how striatal ACh released from cholinergic interneurons acting at both nicotinic and muscarinic ACh receptors powerfully modulates DA transmission. This ACh-DA interaction varies in a manner that depends on the frequency of presynaptic activation, and will thus strongly influence how DA synapses convey discrete changes in DA neuron activity that are known to signal events of motivational salience. Furthermore, this ACh modulation of DA transmission within striatum occurs via different profiles of nicotinic and muscarinic receptors in caudate-putamen compared to nucleus accumbens, which may ultimately enable region-specific targeting of striatal function.
Nitric oxide donors enhance the frequency dependence of dopamine release in nucleus accumbens
Dopamine (DA) neurotransmission in the nucleus accumbens (NAc) is critically involved in normal as well as maladaptive motivated behaviors including drug addiction. Whether the striatal neuromodulator nitric oxide (NO) influences DA release in NAc is unknown. We investigated whether exogenous NO modulates DA transmission in NAc core and how this interaction varies depending on the frequency of presynaptic activation. We detected DA with cyclic voltammetry at carbon-fiber microelectrodes in mouse NAc in slices following stimuli spanning a full range of DA neuron firing frequencies (1-100 Hz). NO donors 3-morpholinosydnonimine hydrochloride (SIN-1) or z-1-N-(3-ammoniopropyl)- N-(n-propyl)aminodiazen-1-ium-1,2-diolate (PAPA/NONOate) enhanced DA release with increasing stimulus frequency. This NO-mediated enhancement of frequency sensitivity of DA release was not prevented by inhibition of soluble guanylyl cyclase (sGC), DA transporters, or large conductance Ca 2+ -activated K channels, and did not require glutamatergic or GABAergic input. However, experiments to identify whether frequency-dependent NO effects were mediated via changes in powerful acetylcholine-DA interactions revealed multiple components to NO modulation of DA release. In the presence of a nicotinic receptor antagonist (dihydro-Β-erythroidine), NO donors increased DA release in a frequency-independent manner. These data suggest that NO in the NAc can modulate DA release through multiple GC-independent neuronal mechanisms whose net outcome varies depending on the activity in DA neurons and accumbal cholinergic interneurons. In the presence of accumbal acetylcholine, NO promotes the sensitivity of DA release to presynaptic activation, but with reduced acetylcholine input, NO will promote DA release in an activity-independent manner through a direct action on dopaminergic terminals. © 2011 American College of Neuropsychopharmacology. All rights reserved.
Dopamine release in the basal ganglia
Dopamine (DA) is a key transmitter in the basal ganglia, yet DA transmission does not conform to several aspects of the classic synaptic doctrine. Axonal DA release occurs through vesicular exocytosis and is action potential- and Ca 2+ -dependent. However, in addition to axonal release, DA neurons in midbrain exhibit somatodendritic release by an incompletely understood, but apparently exocytotic, mechanism. Even in striatum, axonal release sites are controversial, with evidence for DA varicosities that lack postsynaptic specialization, and largely extrasynaptic DA receptors and transporters. Moreover, DA release is often assumed to reflect a global response to a population of activities in midbrain DA neurons, whether tonic or phasic, with precise timing and specificity of action governed by other basal ganglia circuits. This view has been reinforced by anatomical evidence showing dense axonal DA arbors throughout striatum, and a lattice network formed by DA axons and glutamatergic input from cortex and thalamus. Nonetheless, localized DA transients are seen in vivo using voltammetric methods with high spatial and temporal resolution. Mechanistic studies using similar methods in vitro have revealed local regulation of DA release by other transmitters and modulators, as well as by proteins known to be disrupted in Parkinson's disease and other movement disorders. Notably, the actions of most other striatal transmitters on DA release also do not conform to the synaptic doctrine, with the absence of direct synaptic contacts for glutamate, GABA, and acetylcholine (ACh) on striatal DA axons. Overall, the findings reviewed here indicate that DA signaling in the basal ganglia is sculpted by cooperation between the timing and pattern of DA input and those of local regulatory factors.This article is part of a Special Issue entitled: Function and Dysfunction of the Basal Ganglia. © 2011 IBRO.
Heterogeneity of electrically evoked dopamine release and reuptake in substantia nigra, ventral tegmental area, and striatum.
Somatodendritic dopamine (DA) released in substantia nigra pars compacta (SNc) and the ventral tegmental area (VTA) may mediate extrasynaptic neuronal signaling. The concentration of extracellular DA ([DA]o) attained during somatodendritic activation will be governed by the density of release sites and properties of DA uptake. We evaluated these factors in SNc, VTA, and dorsal striatum with carbon-fiber microelectrodes and fast-scan cyclic voltammetry to monitor [DA]o during local electrical stimulation (10 Hz, 5 s) in guinea pig brain slices. Stimulated DA efflux was site specific, with significantly higher [DA]o in caudal (0.48 +/- 0.03 microM, mean +/- SE) than rostral SNc (0.16 +/- 0.01 microM), averaged over their mediolateral extents, and higher [DA]o in VTA (0.74 +/- 0.07 microM) than in medial (0.43 +/- 0.04 microM) or lateral SNc (0.29 +/- 0.05 microM), averaged rostrocaudally. Throughout SNc, evoked [DA]o correlated positively (r = 0.91) with the density of tyrosine-hydroxylase-immunoreactive cells. Modulation of evoked [DA]o by uptake was also site specific. The selective DA uptake inhibitor GBR 12909 significantly increased evoked [DA]o in caudal SNc (to 185 +/- 27%) and striatum (408 +/- 24%), but had no effect in rostral SNc or VTA. Conversely, the norepinephrine (NE) uptake inhibitor desipramine did not alter stimulated [DA]o in caudal SNc or striatum, but caused significant enhancement in rostral SNc (196 +/- 17%) and VTA (126 +/- 12%). Paroxetine, a selective 5-hydroxytryptamine uptake inhibitor had little effect in any region tested. Site-specific sensitivity to desipramine mandated evaluation of dopamine-beta-hydroxylase immunoreactivity (D beta H-ir) in midbrain. The density of filaments positive for D beta H-ir was greater in rostral SNc and VTA than in caudal SNc, suggesting DA clearance via the NE transporter in these regions. Importantly, D beta H-ir was most dense in sections rostral to SNc where no catecholamine signal was detected and no enhancement was observed with desipramine, indicating a lack of NE contribution to evoked release in any region examined. Taken together, these data confirmed that evoked somatodendritic [DA]o depends on DA cell density and on local uptake properties. Uptake was less efficient in SNc and VTA than in striatum. Moreover, enhancement of stimulated [DA]o by GBR 12909 demonstrated that evoked release from dendrites is not via reversal of the DA transporter. Lastly, the heterogeneous patterns of DA uptake within SNc and VTA were consistent with the pattern of degeneration in Parkinson's disease; less vulnerable DA cells, e.g., those in VTA, have less DA uptake than the more vulnerable cells of caudal SNc.
α-Synuclein and dopamine at the crossroads of Parkinson's disease.
α-Synuclein is central to the Lewy body neuropathology of Parkinson's disease (PD), a devastating neurodegenerative disorder characterized by numerous motor and non-motor manifestations. The cardinal motor symptoms are linked to death of dopaminergic neurons in the nigrostriatal pathway. Here we ask why these neurons are preferentially susceptible to neurodegeneration in PD and how α-synuclein is involved. To address these questions we bring together recent findings from genome-wide association studies, which reveal the involvement of α-synuclein gene variants in sporadic PD, with recent studies highlighting important roles for α-synuclein in synaptic transmission and dopaminergic neuron physiology. These latest advances add to our understanding of PD etiology and provide a central link between the genetic findings and neurodegeneration observed in sporadic PD.
Non-linear relationship between 5-HT transporter gene expression and frequency sensitivity of 5-HT signals.
Much evidence suggests that variation in expression of the 5-hydroxytryptamine (5-HT) transporter (5-HTT) is linked to risk of psychiatric illness, but the neurobiological basis of this association is uncertain. In this study, we investigated the impact of variation in 5-HTT expression on subsecond fluctuations in extracellular 5-HT concentrations ([5-HT](o) ). Stimulus-evoked [5-HT](o) was detected using fast-scan cyclic voltammetry at carbon-fibre microelectrodes in the substantia nigra in brain slices from 5-HTT knockout (KO) and 5-HTT over-expressing (OE) mice. Compared with wild-type (WT) controls, evoked [5-HT](o) was greater in KO and less in OE mice. In WT controls, evoked [5-HT](o) was frequency-sensitive; however, in both KO and OE mice, evoked [5-HT](o) showed a striking loss of frequency sensitivity. The latter was observed in WT mice after application of a 5-HTT blocker. These data show that while variation in 5-HTT expression modified the peak magnitude of [5-HT](o) evoked by any given stimulus in a gene dose dependent manner, there was a non-linear relationship between 5-HTT expression and frequency sensitivity. Overall, the findings suggest that variation in 5-HTT expression has a marked effect on frequency sensitivity which is a fundamental property of normal 5-HT transmission.
Constitutive histamine H2 receptor activity regulates serotonin release in the substantia nigra.
The substantia nigra pars reticulata (SNr) forms a principal output from the basal ganglia. It also receives significant histamine (HA) input from the tuberomammillary nucleus whose functions in SNr remain poorly understood. One identified role is the regulation of serotonin (5-HT) neurotransmission via the HA-H(3) receptor. Here we have explored regulation by another HA receptor expressed in SNr, the H(2)-receptor (H(2)R), by monitoring electrically evoked 5-HT release with fast-scan cyclic voltammetry at carbon-fiber microelectrodes in SNr in rat brain slices. Selective H(2)R antagonists (inverse agonists) ranitidine and tiotidine enhanced 5-HT release while the agonist amthamine suppressed release. The 'neutral' competitive antagonist burimamide alone was without effect but prevented ranitidine actions indicating that inverse agonist effects result from constitutive H(2)R activity independent of HA tone. H(2)R control of 5-HT release was most apparent (from inverse agonist effects) at lower frequencies of depolarization (< or = 20 Hz), and prevailed in the presence of antagonists of GABA, glutamate or H(3)-HA receptors. These data reveal that H(2)Rs in SNr are constitutively active and inhibit 5-HT release through H(2)Rs on 5-HT axons. These data may have therapeutic implications for Parkinson's disease, when SNr HA levels increase, and for neuropsychiatric disorders in which 5-HT is pivotal.
Synaptic release of dopamine in the subthalamic nucleus.
The direct modulation of subthalamic nucleus (STN) neurons by dopamine (DA) neurons of the substantia nigra (SN) is controversial owing to the thick caliber and low density of DA axons in the STN. The abnormal activity of the STN in Parkinson's disease (PD), which is central to the appearance of symptoms, is therefore thought to result from the loss of DA in the striatum. We carried out three experiments in rats to explore the function of DA in the STN: (i) light and electron microscopic analysis of tyrosine hydroxylase (TH)-, dopamine beta-hydroxylase (DbetaH)- and DA-immunoreactive structures to determine whether DA axons form synapses; (ii) fast-scan cyclic voltammetry (FCV) to determine whether DA axons release DA; and (iii) patch clamp recording to determine whether DA, at a concentration similar to that detected by FCV, can modulate activity and synaptic transmission/integration. TH- and DA-immunoreactive axons mostly formed symmetric synapses. Because DbetaH-immunoreactive axons were rare and formed asymmetric synapses, they comprised the minority of TH-immunoreactive synapses. Voltammetry demonstrated that DA release was sufficient for the activation of receptors and abolished by blockade of voltage-dependent Na+ channels or removal of extracellular Ca2+. The lifetime and concentration of extracellular DA was increased by blockade of the DA transporter. Dopamine application depolarized STN neurons, increased their frequency of activity and reduced the impact of gamma-aminobutyric acid (GABA)-ergic inputs. These findings suggest that SN DA neurons directly modulate the activity of STN neurons and their loss may contribute to the abnormal activity of STN neurons in PD.
Nitric oxide donors enhance the frequency dependence of dopamine release in nucleus accumbens.
Dopamine (DA) neurotransmission in the nucleus accumbens (NAc) is critically involved in normal as well as maladaptive motivated behaviors including drug addiction. Whether the striatal neuromodulator nitric oxide (NO) influences DA release in NAc is unknown. We investigated whether exogenous NO modulates DA transmission in NAc core and how this interaction varies depending on the frequency of presynaptic activation. We detected DA with cyclic voltammetry at carbon-fiber microelectrodes in mouse NAc in slices following stimuli spanning a full range of DA neuron firing frequencies (1-100 Hz). NO donors 3-morpholinosydnonimine hydrochloride (SIN-1) or z-1-[N-(3-ammoniopropyl)-N-(n-propyl)amino]diazen-1-ium-1,2-diolate (PAPA/NONOate) enhanced DA release with increasing stimulus frequency. This NO-mediated enhancement of frequency sensitivity of DA release was not prevented by inhibition of soluble guanylyl cyclase (sGC), DA transporters, or large conductance Ca(2+)-activated K(+) channels, and did not require glutamatergic or GABAergic input. However, experiments to identify whether frequency-dependent NO effects were mediated via changes in powerful acetylcholine-DA interactions revealed multiple components to NO modulation of DA release. In the presence of a nicotinic receptor antagonist (dihydro-β-erythroidine), NO donors increased DA release in a frequency-independent manner. These data suggest that NO in the NAc can modulate DA release through multiple GC-independent neuronal mechanisms whose net outcome varies depending on the activity in DA neurons and accumbal cholinergic interneurons. In the presence of accumbal acetylcholine, NO promotes the sensitivity of DA release to presynaptic activation, but with reduced acetylcholine input, NO will promote DA release in an activity-independent manner through a direct action on dopaminergic terminals.
Dopamine spillover after quantal release: rethinking dopamine transmission in the nigrostriatal pathway.
The predominance of dopamine (DA) receptors at extrasynaptic vs. synaptic sites implies that DA signaling is by diffusion-based volume transmission. In this review, we compare characteristics that regulate extracellular DA behavior in substantia nigra pars compacta (SNc) and striatum, including regional differences in structure (a 40% greater extracellular volume fraction in SNc vs. striatum) and in dynamic DA uptake (a 200-fold greater DA uptake rate in striatum vs. SNc). Furthermore, we test the assumption of diffusion-based volume transmission for SNc and striatum by modeling dynamic DA behavior after quantal release using region-specific parameters for diffusion and uptake at 37 degrees C. Our model shows that DA uptake does not affect peak DA concentration within 1 mum of a release site in either SNc or striatum because of the slow kinetics of DATs vs. diffusion. Rather, diffusion and dilution are the dominant factors governing DA concentration after quantal release. In SNc, limited DAT efficacy is reflected in a lack of influence of uptake on either amplitude or time course of DA transients after quantal release up to 10 mum from a release site. In striatum, the lack of effect of the DAT within 1 mum of a release site means that perisynaptic DATs do not "gate" synaptic spillover. This contrasts with the conventional view of DA synapses, in which DATs efficiently recycle DA by re-uptake into the releasing axon terminal. However, the model also shows that a primary effect of striatal uptake is to curtail DA lifetime after release. In both SNc and striatum, effective DA radius after quantal release is ~2 mum for activation of low-affinity DA receptors and 7-8 mum for high-affinity receptors; the corresponding spheres of influence would encompass tens to thousands of synapses. Thus, the primary mode of intercellular communication by DA, regardless of region, is volume transmission.
Alpha6-containing nicotinic acetylcholine receptors dominate the nicotine control of dopamine neurotransmission in nucleus accumbens.
Modulation of striatal dopamine (DA) neurotransmission plays a fundamental role in the reinforcing and ultimately addictive effects of nicotine. Nicotine, by desensitizing beta2 subunit-containing (beta2*) nicotinic acetylcholine receptors (nAChRs) on striatal DA axons, significantly enhances how DA is released by reward-related burst activity compared to nonreward-related tonic activity. This action provides a synaptic mechanism for nicotine to facilitate the DA-dependent reinforcement. The subfamily of beta2*-nAChRs responsible for these potent synaptic effects could offer a molecular target for therapeutic strategies in nicotine addiction. We explored the role of alpha6beta2*-nAChRs in the nucleus accumbens (NAc) and caudate-putamen (CPu) by observing action potential-dependent DA release from synapses in real-time using fast-scan cyclic voltammetry at carbon-fiber microelectrodes in mouse striatal slices. The alpha6-specific antagonist alpha-conotoxin-MII suppressed DA release evoked by single and low-frequency action potentials and concurrently enhanced release by high-frequency bursts in a manner similar to the beta2*-selective antagonist dihydro-beta-erythroidine (DHbetaE) in NAc, but less so in CPu. The greater role for alpha6*-nAChRs in NAc was not due to any confounding regional difference in ACh tone since elevated ACh levels (after the acetylcholinesterase inhibitor ambenonium) had similar outcomes in NAc and CPu. Rather, there appear to be underlying differences in nAChR subtype function in NAc and CPu. In summary, we reveal that alpha6beta2*-nAChRs dominate the effects of nicotine on DA release in NAc, whereas in CPu their role is minor alongside other beta2*-nAChRs (eg alpha4*), These data offer new insights to suggest striatal alpha6*-nAChRs as a molecular target for a therapeutic strategy for nicotine addiction.
Nicotine amplifies reward-related dopamine signals in striatum.
Reward-seeking behaviors depend critically on dopamine signaling--dopamine neurons encode reward-related information by switching from tonic to phasic (burst-like) activity. Using guinea pig brain slices, we show that nicotine, like cocaine and amphetamine, acts directly in striatum where it enhances dopamine release during phasic but not tonic activity. This amplification provides a mechanism for nicotine facilitation of reward-related dopamine signals, including responses to other primary reinforcers that govern nicotine dependence in smokers.
DAncing past the DAT at a DA synapse.
Spillover of dopamine (DA) from a release site into the extrasynaptic space is widely acknowledged. Indeed, spillover is necessary for signalling by DA because its receptors are predominantly extrasynaptic. Dopamine transporters (DATs) are often considered to participate in this process by 'gating' spillover. This article reviews the competition between DATs and diffusion in sculpting extracellular DA transients after quantal release, using a model based on data from the literature. Its conclusions challenge the view that DATs limit synaptic DA concentration and gate initial spillover from a release site; this is the work of diffusion. Rather, the greatest influence of DATs, or of their inhibition, is on the sphere of influence and lifetime of DA beyond a release site and, thus, on net extracellular concentration.
Presynaptic nicotinic receptors: a dynamic and diverse cholinergic filter of striatal dopamine neurotransmission.
The effects of nicotine on dopamine transmission from mesostriatal dopamine neurons are central to its reinforcing properties. Only recently however, has the influence of presynaptic nicotinic receptors (nAChRs) on dopaminergic axon terminals within striatum begun to be understood. Here, rather than simply enhancing (or inhibiting) dopamine release, nAChRs perform the role of a presynaptic filter, whose influence on dopamine release probability depends on presynaptic activity in dopaminergic as well as cholinergic neurons. Both mesostriatal dopaminergic neurons and striatal cholinergic interneurons play key roles in motivational and sensorimotor processing by the basal ganglia. Moreover, it appears that the striatal influence of dopamine and ACh cannot be fully appreciated without an understanding of their reciprocal interactions. We will review the powerful filtering by nAChRs of striatal dopamine release and discuss its dependence on activity in dopaminergic and cholinergic neurons. We will also review how nicotine, acting via nAChR desensitization, promotes the sensitivity of dopamine synapses to activity. This filtering action might provide a mechanism through which nicotine promotes how burst activity in dopamine neurons facilitates goal-directed behaviour and reinforcement processing. More generally, it indicates that we should not restrict our view of presynaptic nAChRs to simply enhancing neurotransmitter release. We will also summarize current understanding of the forms and functions of the diverse nAChRs purported to exist on dopaminergic axons. A greater understanding of nAChR form and function is imperative to guide the design of ligands with subtype-selective efficacy for improved therapeutic interventions in nicotine addiction as well as Parkinson's disease.
Meaningful silences: how dopamine listens to the ACh pause.
Mesostriatal dopaminergic neurons (DANs) and striatal cholinergic neurons (tonically active neurons, TANs) participate in signalling the behavioural or reward-related significance of stimuli in the environment. An antagonistic balance between dopamine (DA) and ACh is well known to regulate postsynaptic signal integration in the striatum. Recent findings have revealed additional presynaptic ACh-DA interactions of previously unappreciated sophistication. Striatal ACh acts presynaptically to polarize powerfully how opposing DAN activities are transduced into DA release. Furthermore, characteristic reward-related activities of TANs and DANs are temporally coincident but differently variant with reward probability. Reward-related DA signals could therefore be governed by the concomitant activity in TANs. This article discusses the dynamic implications for DA signalling when these phenomena act in concert. TAN pauses might powerfully enhance the contrast, or salience, of DA signals offered by reward-related bursts, and even by reward omission-related pauses, in DANs. Through such mechanisms, TAN-DAN interactions would be functionally cooperative.