Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation

Search Page

My NCBI Filters
Results by year

Table representation of search results timeline featuring number of search results per year.

Year Number of Results
2008 1
2009 2
2010 1
2011 2
2013 3
2014 4
2015 5
2016 6
2017 3
2018 4
2019 3
2020 4
2021 3
Text availability
Article attribute
Article type
Publication date

Search Results

30 results
Results by year
Filters applied: . Clear all
Page 1
. 2021 Jul 15.
doi: 10.1111/jnc.15473. Online ahead of print.

Regional and sex differences in spontaneous striatal dopamine transmission

Affiliations

Regional and sex differences in spontaneous striatal dopamine transmission

James N Brundage et al. J Neurochem. .

Abstract

Striatal dopamine release is key for learning and motivation and is composed of subregions including the dorsal striatum (DS), nucleus accumbens core, and the nucleus accumbens shell. Spontaneously occurring dopamine release was compared across these subregions. Dopamine release/uptake dynamics differ across striatal subregions, with dopamine transient release amplitude and release frequency greatest in male mice, and the largest signals observed in the DS. Surprisingly, female mice exhibited little regional differences in dopamine release for DS and nucleus accumbens core regions, but lower release in the nucleus accumbens shell. Blocking voltage-gated K+ channel (Kv channels) with 4-aminopyridine enhanced dopamine detection without affecting reuptake. The 4-aminopyridine effects were greatest in ventral regions of female mice, suggesting regional differences in Kv channel expression. The dopamine transporter blocker cocaine also enhanced detection across subregions in both sexes, with greater overall increased release in females than males. Thus, sex differences in dopamine transmission are apparent and likely include differences in the Kv channel and dopamine transporter function. The lack of regional differences in dopamine release observed in females indicates differential regulation of spontaneous and evoked dopamine release.

Keywords: Kv channels; accumbens; cocaine; dopamine; sex differences; striatum.

Supplementary info

Grant support
Proceed to details
. 2021 Jun 17.
doi: 10.1007/s10571-021-01120-4. Online ahead of print.

Methamphetamine Exposure During Development Causes Lasting Changes to Mesolimbic Dopamine Signaling in Mice

Affiliations

Methamphetamine Exposure During Development Causes Lasting Changes to Mesolimbic Dopamine Signaling in Mice

Daniel J Torres et al. Cell Mol Neurobiol. .

Abstract

Methamphetamine (MA) abuse remains a public health issue. Prenatal MA exposure (PME) poses a significant health problem, as we know very little about the drug's long-term physiological impact on the developing human brain. We investigated the long-term consequences of early MA exposure using a mouse model that targets the brain growth spurt, which occurs during human third-trimester. Adult mice previously subjected to acute MA during post-natal days 4-9 exhibited hyperactivity during the Open-Field Test, while exhibiting no motor coordination changes during the Rotarod Test. Neonatal MA exposure reduced basal dopamine (DA) uptake rates in adult nucleus accumbens slices compared with saline-injected controls. Although slices from neonatal MA-exposed mice showed no change in evoked DA signals in the presence of MA, they exhibited potentiated non-evoked DA release through DA efflux in response to MA. These data suggest that developmental MA exposure alters brain development to produce long-lasting physiological changes to the adult mesolimbic DA system, as well as altering responses to acute MA exposure in adulthood. This study provides new insights into an important, under-investigated area in drugs of abuse research.

Keywords: Development; Dopamine; Fast-scan cyclic voltammetry; Methamphetamine; Prenatal methamphetamine exposure.

Supplementary info

Grant support
Proceed to details
. 2021 Apr 13;15:631825.
doi: 10.3389/fnins.2021.631825. eCollection 2021.

Selenoprotein P Modulates Methamphetamine Enhancement of Vesicular Dopamine Release in Mouse Nucleus Accumbens Via Dopamine D2 Receptors

Affiliations
Free PMC article

Selenoprotein P Modulates Methamphetamine Enhancement of Vesicular Dopamine Release in Mouse Nucleus Accumbens Via Dopamine D2 Receptors

Daniel J Torres et al. Front Neurosci. .
Free PMC article

Abstract

Dopamine (DA) transmission plays a critical role in processing rewarding and pleasurable stimuli. Increased synaptic DA release in the nucleus accumbens (NAc) is a central component of the physiological effects of drugs of abuse. The essential trace element selenium mitigates methamphetamine-induced neurotoxicity. Selenium can also alter DA production and turnover. However, studies have not directly addressed the role of selenium in DA neurotransmission. Selenoprotein P (SELENOP1) requires selenium for synthesis and transports selenium to the brain, in addition to performing other functions. We investigated whether SELENOP1 directly impacts (1) DA signaling and (2) the dopaminergic response to methamphetamine. We used fast-scan cyclic voltammetry to investigate DA transmission and the response to methamphetamine in NAc slices from C57/BL6J SELENOP1 KO mice. Recordings from SELENOP1 KO mouse slices revealed reduced levels of evoked DA release and slower DA uptake rates. Methamphetamine caused a dramatic increase in vesicular DA release in SELENOP1 KO mice not observed in wild-type controls. This elevated response was attenuated by SELENOP1 application through a selenium-independent mechanism involving SELENOP1-apolipoprotein E receptor 2 (ApoER2) interaction to promote dopamine D2 receptor (D2R) function. In wild-type mice, increased vesicular DA release in response to methamphetamine was revealed by blocking D2R activation, indicating that the receptor suppresses the methamphetamine-induced vesicular increase. Our data provide evidence of a direct physiological role for SELENOP1 in the dopaminergic response to methamphetamine and suggest a signaling role for the protein in DA transmission.

Keywords: apolipoprotein E receptor 2; dopamine; fast-scan cyclic voltammetry; methamphetamine; selenoprotein P.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Proceed to details
. 2020 Dec 16;9(12):1285.
doi: 10.3390/antiox9121285.

Spontaneous Formation of Melanin from Dopamine in the Presence of Iron

Affiliations
Free PMC article

Spontaneous Formation of Melanin from Dopamine in the Presence of Iron

David M Hedges et al. Antioxidants (Basel). .
Free PMC article

Abstract

Parkinson's disease is associated with degeneration of neuromelanin (NM)-containing substantia nigra dopamine (DA) neurons and subsequent decreases in striatal DA transmission. Dopamine spontaneously forms a melanin through a process called melanogenesis. The present study examines conditions that promote/prevent DA melanogenesis. The kinetics, intermediates, and products of DA conversion to melanin in vitro, and DA melanogenesis under varying levels of Fe3+, pro-oxidants, and antioxidants were examined. The rate of melanogenesis for DA was substantially greater than related catecholamines norepinephrine and epinephrine and their precursor amino acids tyrosine and l-Dopa as measured by UV-IR spectrophotometry. Dopamine melanogenesis was concentration dependent on the pro-oxidant species and Fe3+. Melanogenesis was enhanced by the pro-oxidant hydrogen peroxide (EC50 = 500 μM) and decreased by the antioxidants ascorbate (IC50 = 10 μM) and glutathione (GSH; IC50 = 5 μM). Spectrophotometric results were corroborated by tuning a fast-scan cyclic voltammetry system to monitor DA melanogenesis. Evoked DA release in striatal brain slices resulted in NM formation that was prevented by GSH. These findings suggest that DA melanogenesis occurs spontaneously under physiologically-relevant conditions of oxidative stress and that NM may act as a marker of past exposure to oxidative stress.

Keywords: dopamine; iron; melanin; neuromelanin; oxidative stress.

Conflict of interest statement

The authors declare no competing financial interest.

Supplementary info

Grant support
Proceed to details
. 2020 Nov 15;179:108293.
doi: 10.1016/j.neuropharm.2020.108293. Epub 2020 Aug 29.

Corticotropin releasing factor, but not alcohol, modulates norepinephrine release in the rat central nucleus of the amygdala

Affiliations

Corticotropin releasing factor, but not alcohol, modulates norepinephrine release in the rat central nucleus of the amygdala

David M Hedges et al. Neuropharmacology. .

Abstract

Alcohol misuse and dependence is a widespread health problem. The central nucleus of the amygdala (CeA) plays important roles in both the anxiety associated with alcohol (ethanol) dependence and the increased alcohol intake that is observed during withdrawal in dependent animals. We and others have shown the essential involvement of the corticotropin releasing factor (CRF) system in alcohol's synaptic effects on the CeA and in the development of ethanol dependence. Another system that has been shown to be critically involved in the molecular underpinnings of alcohol dependence is the norepinephrine (NE) system originating in the locus coeruleus. Both the CRF and NE systems act in concert to facilitate a stress response: central amygdalar afferents release CRF in the locus coeruleus promoting widespread release of NE. In this study, we are the first to use fast-scan cyclic voltammetry to classify local electrically-evoked NE release in the CeA and to determine if acute alcohol and CRF modulate it. Evoked NE release is action potential dependent, is abolished after depletion of monoaminergic vesicles, differs pharmacologically from dopamine release, is insensitive to acute alcohol, and decreases in response to locally applied CRF. Taken together, these results indicate that NE release in the CeA is released canonically in a vesicular-dependent manner, and that while acute alcohol does not directly alter NE release, CRF decreases it. Our results suggest that CRF acts locally on NE terminals as negative feedback and potentially prevents hyperactivation of the CRF-norepinephrine stress pathway.

Keywords: Alcohol; Amygdala; CRF; Norepinephrine; Stress; Voltammetry.

Supplementary info

Publication types, MeSH terms, Substances, Grant support
Proceed to details
. 2020 May;237(5):1317-1330.
doi: 10.1007/s00213-020-05459-2. Epub 2020 Jan 21.

Methamphetamine increases dopamine release in the nucleus accumbens through calcium-dependent processes

Affiliations
Free PMC article

Methamphetamine increases dopamine release in the nucleus accumbens through calcium-dependent processes

Jordan T Yorgason et al. Psychopharmacology (Berl). 2020 May.
Free PMC article

Abstract

Rationale: Methamphetamine (METH) enhances exocytotic dopamine (DA) signals and induces DA transporter (DAT)-mediated efflux in brain striatal regions such as the nucleus accumbens (NAc). Blocking sigma receptors prevents METH-induced DA increases. Sigma receptor activation induces Ca2+ release from intracellular stores, which may be responsible for METH-induced DA increases.

Objectives: The role of intracellular and extracellular Ca2+ in METH-induced DA increases and associated behavior was tested.

Methods: METH-induced Ca2+ release was measured in hNPC-derived DA cells using ratiometric Ca2+ imaging. In mouse brain slices, fast-scan cyclic voltammetry was used to measure METH effects on two measures of dopamine: electrically stimulated and DAT-mediated efflux. Intracellular and extracellular Ca2+ was removed through pharmacological blockade of Ca2+ permeable channels (Cd2+ and IP3 sensitive channels), intracellular Ca2+ chelation (BAPTA-AM), or non-inclusion (zero Ca2+). Lastly, METH effects on dopamine-mediated locomotor behavior were tested in rats. Rats received intra-NAc injections of ACSF or 2-aminoethoxydiphenyl borate (2-APB; IP3 receptor blocker) and intraperitoneal METH (5 mg/kg) to test the role of intracellular Ca2+ release in DA-mediated behaviors.

Results: Reducing Ca2+ extracellular levels and Ca2+ release from intracellular stores prevented intracellular Ca2+ release. Intracellular Ca2+ chelation and blocking intracellular Ca2+ release reduced METH effects on voltammetric measures of dopamine. Blocking intracellular Ca2+ release via 2-APB resulted in increased METH-induced circling behavior.

Conclusions: METH induces NAc DA release through intracellular Ca2+ activity. Blocking intracellular Ca2+ release prevents METH effects on DA signals and related behavior.

Keywords: Accumbens; Calcium signaling; Dopamine; Dopamine transporter; Methamphetamine; Striatum; Voltammetry.

Supplementary info

MeSH terms, Substances, Grant support
Proceed to details
. Mar-Apr 2020;13(2):403-411.
doi: 10.1016/j.brs.2019.11.012. Epub 2019 Dec 4.

Mechanical stimulation of cervical vertebrae modulates the discharge activity of ventral tegmental area neurons and dopamine release in the nucleus accumbens

Affiliations
Free PMC article

Mechanical stimulation of cervical vertebrae modulates the discharge activity of ventral tegmental area neurons and dopamine release in the nucleus accumbens

Kyle B Bills et al. Brain Stimul. Mar-Apr 2020.
Free PMC article

Abstract

Background: Growing evidence suggests that mechanical stimulation modulates substrates in the supraspinal central nervous system (CNS) outside the canonical somatosensory circuits.

Objective/methods: We evaluate mechanical stimulation applied to the cervical spine at the C7-T1 level (termed "MStim") on neurons and neurotransmitter release in the mesolimbic dopamine (DA) system, an area implicated in reward and motivation, utilizing electrophysiological, pharmacological, neurochemical and immunohistochemical techniques in Wistar rats.

Results: Low frequency (45-80 Hz), but not higher frequency (115 Hz), MStim inhibited the firing rate of ventral tegmental area (VTA) GABA neurons (52.8% baseline; 450 s) while increasing the firing rate of VTA DA neurons (248% baseline; 500 s). Inactivation of the nucleus accumbens (NAc), or systemic or in situ antagonism of delta opioid receptors (DORs), blocked MStim inhibition of VTA GABA neuron firing rate. MStim enhanced both basal (178.4% peak increase at 60 min) and evoked DA release in NAc (135.0% peak increase at 40 min), which was blocked by antagonism of DORs or acetylcholine release in the NAc. MStim enhanced c-FOS expression in the NAc, but inhibited total expression in the VTA, and induced translocation of DORs to neuronal membranes in the NAc.

Conclusion: These findings demonstrate that MStim modulates neuron firing and DA release in the mesolimbic DA system through endogenous opioids and acetylcholine in the NAc. These findings demonstrate the need to explore more broadly the extra-somatosensory effects of peripheral mechanoreceptor activation and the specific role for mechanoreceptor-based therapies in the treatment of substance abuse.

Keywords: Accumbens; Dopamine; GABA; Mechanoreceptors; Opioid receptors; VTA.

Conflict of interest statement

Declaration of competing interest The authors declare no competing financial interests.

Supplementary info

Publication types, MeSH terms, Substances, Grant support
Proceed to details
. 2019 May 1;149:45-54.
doi: 10.1016/j.neuropharm.2019.01.021. Epub 2019 Jan 30.

Alpha6-containing nicotinic acetylcholine receptor is a highly sensitive target of alcohol

Affiliations
Free PMC article

Alpha6-containing nicotinic acetylcholine receptor is a highly sensitive target of alcohol

Fenfei Gao et al. Neuropharmacology. .
Free PMC article

Abstract

Alcohol use disorder (AUD) is a serious public health problem that results in tremendous social, legal and medical costs to society. Unlike other addictive drugs, there is no specific molecular target for ethanol (EtOH). Here, we report a novel molecular target that mediates EtOH effects at concentrations below those that cause legally-defined inebriation. Using patch-clamp recording of human α6*-nicotinic acetylcholine receptor (α6*-nAChR) function when heterologously expressed in SH-EP1 human epithelial cells, we found that 0.1-5 mM EtOH significantly enhances α6*-nAChR-mediated currents with effects that are dependent on both EtOH and nicotine concentrations. EtOH exposure increased both whole-cell current rising slope and decay constants. This EtOH modulation was selective for α6*-nAChRs since it did not affect α3β4-, α4β2-, or α7-nAChRs. In addition, 5 mM EtOH also increased the frequency and amplitude of dopaminergic neuron transients in mouse brain nucleus accumbens slices, that were blocked by the α6*-nAChR antagonist, α-conotoxin MII, suggesting a role for native α6*-nAChRs in low-dose EtOH effects. Collectively, our data suggest that α6*-nAChRs are sensitive targets mediating low-dose EtOH effects through a positive allosteric mechanism, which provides new insight into mechanisms involved in pharmacologically-relevant alcohol effects contributing to AUD.

Keywords: Alcohol; Alpha 6 subunit; Ethanol; Nicotinic acetylcholine receptor; Patch-clamp; SH-EP1 cells.

Conflict of interest statement

DISCLOSURES OF INTERSEST

Dr. Gao, FF reports no disclosures

D. Chen, DJ reports no disclosures

Mr. Xiaokuang Ma reports no disclosures

Dr. Sudweeks reports no disclosures

Dr. Yorgason JT reports no disclosures

Dr. Ming Gao reports no disclosures

Mr. Dharshaun Turner reports no disclosures

Dr. Eaton, JB reports no disclosures

Dr. McIntosh, JM reports no disclosures

Dr. Lukas RJ reports no disclosures

Dr. Whiteraker, P reports no disclosures

Dr. Chang, YC reports no disclosures

Dr. Steffensen SC reports no disclosures

Dr. Wu, J reports no disclosures

Supplementary info

Publication types, MeSH terms, Substances, Grant support
Proceed to details
. 2019 Apr 17;10(4):2033-2044.
doi: 10.1021/acschemneuro.8b00360. Epub 2018 Oct 16.

Chronic Social Isolation Stress during Peri-Adolescence Alters Presynaptic Dopamine Terminal Dynamics via Augmentation in Accumbal Dopamine Availability

Affiliations
Free PMC article

Chronic Social Isolation Stress during Peri-Adolescence Alters Presynaptic Dopamine Terminal Dynamics via Augmentation in Accumbal Dopamine Availability

Anushree N Karkhanis et al. ACS Chem Neurosci. .
Free PMC article

Abstract

Chronic peri-adolescent stress in humans increases risk to develop a substance use disorder during adulthood. Rats reared in social isolation during peri-adolescence (aSI; 1 rat/cage) period show greater ethanol and cocaine intake compared to group housed (aGH; 4 rats/cage) rats. In addition, aSI rats have a heightened dopamine response in the nucleus accumbens (NAc) to rewarding and aversive stimuli. Furthermore, single pulse electrical stimulation in slices containing NAc core elicits greater dopamine release in aSI rats. Here, we further investigated dopamine release kinetics and machinery following aSI. Dopamine release, across a wide range of stimulation intensities and frequencies, was significantly greater in aSI rats. Interestingly, subthreshold intensity stimulations also resulted in measurable dopamine release in accumbal slices from aSI but not aGH rats. Extracellular [Ca2+] manipulations revealed augmented calcium sensitivity of dopamine release in aSI rats. The readily releasable pools of dopamine, examined by bath application of Ro-04-1284/000, a vesicular monoamine transporter 2 (VMAT2) inhibitor, were depleted faster in aGH rats. Western blot analysis of release machinery proteins (VMAT2, Synaptogyrin-3, Syntaxin-1, and Munc13-3) showed no difference between the two groups. Tyrosine hydroxylase (TH) protein expression levels, however, were elevated in aSI rats. The greater dopamine release could potentially be explained by higher levels of TH, the rate-limiting step for dopamine synthesis. This augmented responsivity of the dopamine system and heightened dopamine availability post-aSI may lead to an increased risk of addiction vulnerability.

Keywords: D2/D3 autoreceptors; dopamine availability; dopamine kinetics; nucleus accumbens core; peri-adolescent stress; social isolation; tyrosine hydroxylase.

Supplementary info

Publication types, MeSH terms, Substances, Grant support
Proceed to details
. 2018 Nov;42(11):2186-2195.
doi: 10.1111/acer.13883. Epub 2018 Oct 3.

Glutamate Transmission to Ventral Tegmental Area GABA Neurons Is Altered by Acute and Chronic Ethanol

Affiliations
Free PMC article

Glutamate Transmission to Ventral Tegmental Area GABA Neurons Is Altered by Acute and Chronic Ethanol

Stephanie B Williams et al. Alcohol Clin Exp Res. 2018 Nov.
Free PMC article

Abstract

Background: Ventral tegmental area (VTA) GABA neurons have been heavily implicated in alcohol reinforcement and reward. In animals that self-administer alcohol, VTA GABA neurons exhibit increased excitability that may contribute to alcohol's rewarding effects. The present study investigated the effects of acute and chronic ethanol exposure on glutamate (GLU) synaptic transmission to VTA GABA neurons.

Methods: Whole-cell recordings of evoked, spontaneous, and miniature excitatory postsynaptic currents (eEPSCs, sEPSCs, and mEPSCs, respectively) were performed on identified GABA neurons in the VTA of GAD67-GFP+ transgenic mice. Three ethanol exposure paradigms were used: acute ethanol superfusion; a single ethanol injection; and chronic vapor exposure.

Results: Acute ethanol superfusion increased the frequency of EPSCs but inhibited mEPSC frequency and amplitude. During withdrawal from a single injection of ethanol, the frequency of sEPSCs was lower than saline controls. There was no difference in α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/N-methyl-d-aspartate (NMDA) ratio between neurons following withdrawal from a single exposure to ethanol. However, following withdrawal from chronic ethanol, sEPSCs and mEPSCs had a greater frequency than air controls. There was no difference in AMPA/NMDA ratio following chronic ethanol.

Conclusions: These results suggest that presynaptic mechanisms involving local circuit GLU neurons, and not GLU receptors, contribute to adaptations in VTA GABA neuron excitability that accrue to ethanol exposure, which may contribute to the rewarding properties of alcohol via their regulation of mesolimbic dopamine transmission.

Keywords: GABA; Ethanol; Glutamate; Ventral Tegmental Area.

Supplementary info

Publication types, MeSH terms, Substances, Grant support
Proceed to details
. 2018 Oct 10;38(41):8845-8859.
doi: 10.1523/JNEUROSCI.1116-18.2018. Epub 2018 Aug 27.

Granulocyte Colony Stimulating Factor Enhances Reward Learning through Potentiation of Mesolimbic Dopamine System Function

Affiliations
Free PMC article

Granulocyte Colony Stimulating Factor Enhances Reward Learning through Potentiation of Mesolimbic Dopamine System Function

Munir Gunes Kutlu et al. J Neurosci. .
Free PMC article

Abstract

Deficits in motivation and cognition are hallmark symptoms of multiple psychiatric diseases. These symptoms are disruptive to quality of life and often do not improve with available medications. In recent years there has been increased interest in the role of the immune system in neuropsychiatric illness, but to date no immune-related treatment strategies have come to fruition. The cytokine granulocyte-colony stimulating factor (G-CSF) is known to have trophic and neuroprotective properties in the brain, and we recently identified it as a modulator of neuronal and behavioral plasticity. By combining operant tasks that assess discrete aspects of motivated behavior and decision-making in male mice and rats with subsecond dopamine monitoring via fast-scan cyclic voltammetry, we defined the role of G-CSF in these processes as well as the neural mechanism by which it modulates dopamine function to exert these effects. G-CSF enhanced motivation for sucrose as well as cognitive flexibility as measured by reversal learning. These behavioral outcomes were driven by mesolimbic dopamine system plasticity, as systemically administered G-CSF increased evoked dopamine release in the nucleus accumbens independent of clearance mechanisms. Importantly, sustained increases in G-CSF were required for these effects as acute exposure did not enhance behavioral outcomes and decreased dopamine release. These effects seem to be a result of the ability of G-CSF to alter local inflammatory signaling cascades, particularly tumor necrosis factor α. Together, these data show G-CSF as a potent modulator of the mesolimbic dopamine circuit and its ability to appropriately attend to salient stimuli.SIGNIFICANCE STATEMENT Emerging evidence has highlighted the importance of the immune system in psychiatric diseases states. However, the effects of peripheral cytokines on motivation and cognitive function are largely unknown. Here, we report that granulocyte-colony stimulating factor (G-CSF), a pleiotropic cytokine with known trophic and neuroprotective properties in the brain, acts directly on dopaminergic circuits to enhance their function. These changes in dopaminergic dynamics enhance reward learning and motivation for natural stimuli. Together, these results suggest that targeting immune factors may provide a new avenue for therapeutic intervention in the multiple psychiatric disorders that are characterized by motivational and cognitive deficits.

Keywords: cytokine; dopamine; immune system; learning and memory; motivation; voltammetry.

Supplementary info

Publication types, MeSH terms, Substances, Grant support
Proceed to details
. 2018 May;43(6):1405-1414.
doi: 10.1038/npp.2017.291. Epub 2017 Nov 29.

Methamphetamine Induces Dopamine Release in the Nucleus Accumbens Through a Sigma Receptor-Mediated Pathway

Affiliations
Free PMC article

Methamphetamine Induces Dopamine Release in the Nucleus Accumbens Through a Sigma Receptor-Mediated Pathway

David M Hedges et al. Neuropsychopharmacology. 2018 May.
Free PMC article

Abstract

Methamphetamine (METH) is a drug with a high addictive potential that is widely abused across the world. Although it is known that METH dysregulates both dopamine transmission and dopamine reuptake, the specific mechanism of action remains obscure. One promising target of METH is the sigma receptor, a chaperone protein located on the membrane of the endoplasmic reticulum. Using fast-scan cyclic voltammetry, we show that METH-enhancement of evoked dopamine release and basal efflux is dependent on sigma receptor activation. METH-induced activation of sigma receptors results in oxidation of a cysteine residue on VMAT2, which decreases transporter function. Unilateral injections of the sigma receptor antagonist BD-1063 prior to METH administration increased dopamine-related ipsilateral circling behavior, indicating the involvement of sigma receptors. These findings suggest that interactions between METH and the sigma receptor lead to oxidative species (most likely superoxide) that in turn oxidize VMAT2. Altogether, these findings show that the sigma receptor has a key role in METH dysregulation of dopamine release and dopamine-related behaviors.

Supplementary info

Publication types, MeSH terms, Substances, Grant support
Proceed to details
. 2017 Feb 22;37(8):2086-2096.
doi: 10.1523/JNEUROSCI.3064-16.2017. Epub 2017 Jan 23.

Cholinergic Interneurons Underlie Spontaneous Dopamine Release in Nucleus Accumbens

Affiliations
Free PMC article

Cholinergic Interneurons Underlie Spontaneous Dopamine Release in Nucleus Accumbens

Jordan T Yorgason et al. J Neurosci. .
Free PMC article

Abstract

The release of dopamine from terminals in the NAc is regulated by a number of factors, including voltage-gated ion channels, D2-autoreceptors, and nAChRs. Cholinergic interneurons (CINs) drive dopamine release through activation of nAChRs on dopamine terminals. Using cyclic voltammetry in mouse brain slices, nAChR-dependent spontaneous dopamine transients and the mechanisms underlying the origin were examined in the NAc. Spontaneous events were infrequent (0.3 per minute), but the rate and amplitude were increased after blocking Kv channels with 4-aminopyridine. Although the firing frequency of CINs was increased by blocking glutamate reuptake with TBOA and the Sk blocker apamin, only 4-aminopyridine increased the frequency of dopamine transients. In contrast, inhibition of CIN firing with the μ/δ selective opioid [Met5]enkephalin (1 μm) decreased spontaneous dopamine transients. Cocaine increased the rate and amplitude of dopamine transients, suggesting that the activity of the dopamine transporter limits the detection of these events. In the presence of cocaine, the rate of spontaneous dopamine transients was further increased after blocking D2-autoreceptors. Blockade of muscarinic receptors had no effect on evoked dopamine release, suggesting that feedback inhibition of acetylcholine release was not involved. Thus, although spontaneous dopamine transients are reliant on nAChRs, the frequency was not strictly governed by the activity of CINs. The increase in frequency of spontaneous dopamine transients induced by cocaine was not due to an increase in cholinergic tone and is likely a product of an increase in detection resulting from decreased dopamine reuptake.SIGNIFICANCE STATEMENT The actions of dopamine in the NAc are thought to be responsible for endogenous reward and the reinforcing properties of drugs of abuse, such as psychostimulants. The present work examines the mechanisms underlying nAChR-induced spontaneous dopamine release. This study demonstrates that spontaneous dopamine release is (1) dependent of the activation of nicotinic receptors, (2) independent on the spontaneous activity of cholinergic interneurons, and (3) that cocaine increased the detection of dopamine transients by prolonging the presence and increasing the diffusion of dopamine in the extracellular space. The release of acetylcholine is therefore responsible for spontaneous dopamine transients, and cocaine augments dopamine tone without altering activity of cholinergic interneurons.

Keywords: D2; cocaine; nicotinic; opioid; striatum; voltametry.

Supplementary info

Publication types, MeSH terms, Substances, Grant support
Proceed to details
. 2017 Mar 1;117(3):1163-1170.
doi: 10.1152/jn.00694.2016. Epub 2016 Dec 28.

Presynaptic gain control by endogenous cotransmission of dopamine and GABA in the olfactory bulb

Affiliations
Free PMC article

Presynaptic gain control by endogenous cotransmission of dopamine and GABA in the olfactory bulb

Christopher E Vaaga et al. J Neurophysiol. .
Free PMC article

Abstract

In the olfactory bulb, lateral inhibition mediated by local juxtaglomerular interneurons has been proposed as a gain control mechanism, important for decorrelating odorant responses. Among juxtaglomerular interneurons, short axon cells are unique as dual-transmitter neurons that release dopamine and GABA. To examine their intraglomerular function, we expressed channelrhodopsin under control of the DAT-cre promoter and activated olfactory afferents within individual glomeruli. Optical stimulation of labeled cells triggered endogenous dopamine release as measured by cyclic voltammetry and GABA release as measured by whole cell GABAA receptor currents. Activation of short axon cells reduced the afferent presynaptic release probability via D2 and GABAB receptor activation, resulting in reduced spiking in both mitral and external tufted cells. Our results suggest that short axon cells influence glomerular activity not only by direct inhibition of external tufted cells but also by inhibition of afferent inputs to external tufted and mitral cells.NEW & NOTEWORTHY Sensory systems, including the olfactory system, encode information across a large dynamic range, making synaptic mechanisms of gain control critical to proper function. Here we demonstrate that a dual-transmitter interneuron in the olfactory bulb controls the gain of intraglomerular afferent input via two distinct mechanisms, presynaptic inhibition as well as inhibition of a principal neuron subtype, and thereby potently controls the synaptic gain of afferent inputs.

Keywords: GABA; dopamine; fast-scanning cyclic voltammetry; olfactory bulb; short axon cell.

Supplementary info

Publication types, MeSH terms, Substances, Grant support