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. 2024 Apr 17;14(1):50.
doi: 10.1186/s13578-024-01228-2.

Ivermectin increases striatal cholinergic activity to facilitate dopamine terminal function

Affiliations

Ivermectin increases striatal cholinergic activity to facilitate dopamine terminal function

Hillary A Wadsworth et al. Cell Biosci. .

Abstract

Ivermectin (IVM) is a commonly prescribed antiparasitic treatment with pharmacological effects on invertebrate glutamate ion channels resulting in paralysis and death of invertebrates. However, it can also act as a modulator of some vertebrate ion channels and has shown promise in facilitating L-DOPA treatment in preclinical models of Parkinson's disease. The pharmacological effects of IVM on dopamine terminal function were tested, focusing on the role of two of IVM's potential targets: purinergic P2X4 and nicotinic acetylcholine receptors. Ivermectin enhanced electrochemical detection of dorsal striatum dopamine release. Although striatal P2X4 receptors were observed, IVM effects on dopamine release were not blocked by P2X4 receptor inactivation. In contrast, IVM attenuated nicotine effects on dopamine release, and antagonizing nicotinic receptors prevented IVM effects on dopamine release. IVM also enhanced striatal cholinergic interneuron firing. L-DOPA enhances dopamine release by increasing vesicular content. L-DOPA and IVM co-application further enhanced release but resulted in a reduction in the ratio between high and low frequency stimulations, suggesting that IVM is enhancing release largely through changes in terminal excitability and not vesicular content. Thus, IVM is increasing striatal dopamine release through enhanced cholinergic activity on dopamine terminals.

Keywords: FSCV; Ivermectin; Parkinson’s; Purinergic P2X4 receptors; Receptors.

Conflict of interest statement

None of the authors have competing interests with the present studies.

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. 2024 May 1;15(9):1738-1754.
doi: 10.1021/acschemneuro.3c00478. Epub 2024 Apr 13.

Catharanthine Modulates Mesolimbic Dopamine Transmission and Nicotine Psychomotor Effects via Inhibition of α6-Nicotinic Receptors and Dopamine Transporters

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Catharanthine Modulates Mesolimbic Dopamine Transmission and Nicotine Psychomotor Effects via Inhibition of α6-Nicotinic Receptors and Dopamine Transporters

Benjamin M Williams et al. ACS Chem Neurosci. .

Abstract

Iboga alkaloids, also known as coronaridine congeners, have shown promise in the treatment of alcohol and opioid use disorders. The objective of this study was to evaluate the effects of catharanthine and 18-methoxycoronaridine (18-MC) on dopamine (DA) transmission and cholinergic interneurons in the mesolimbic DA system, nicotine-induced locomotor activity, and nicotine-taking behavior. Utilizing ex vivo fast-scan cyclic voltammetry (FSCV) in the nucleus accumbens core of male mice, we found that catharanthine or 18-MC differentially inhibited evoked DA release. Catharanthine inhibition of evoked DA release was significantly reduced by both α4 and α6 nicotinic acetylcholine receptors (nAChRs) antagonists. Additionally, catharanthine substantially increased DA release more than vehicle during high-frequency stimulation, although less potently than an α4 nAChR antagonist, which confirms previous work with nAChR antagonists. Interestingly, while catharanthine slowed DA reuptake measured via FSCV ex vivo, it also increased extracellular DA in striatal dialysate from anesthetized mice in vivo in a dose-dependent manner. Superfusion of catharanthine or 18-MC inhibited the firing rate of striatal cholinergic interneurons in a concentration dependent manner, which are known to potently modulate presynaptic DA release. Catharanthine or 18-MC suppressed acetylcholine currents in oocytes expressing recombinant rat α6/α3β2β3 or α6/α3β4 nAChRs. In behavioral experiments using male Sprague-Dawley rats, systemic administration of catharanthine or 18-MC blocked nicotine enhancement of locomotor activity. Importantly, catharanthine attenuated nicotine self-administration in a dose-dependent manner while having no effect on food reinforcement. Lastly, administration of catharanthine and nicotine together greatly increased head twitch responses, indicating a potential synergistic hallucinogenic effect. These findings demonstrate that catharanthine and 18-MC have similar, but not identical effects on striatal DA dynamics, striatal cholinergic interneuron activity and nicotine psychomotor effects.

Keywords: 18-methoxycoronaridine; Nicotine; addiction; catharanthine; dopamine; nicotinic acetylcholine receptors; nucleus accumbens core; self-administration; voltammetry.

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. 2023 Sep 15;24(18):14147.
doi: 10.3390/ijms241814147.

Whole-Body Vibration Prevents Neuronal, Neurochemical, and Behavioral Effects of Morphine Withdrawal in a Rat Model

Affiliations

Whole-Body Vibration Prevents Neuronal, Neurochemical, and Behavioral Effects of Morphine Withdrawal in a Rat Model

Gavin C Jones et al. Int J Mol Sci. .

Abstract

Peripheral mechanoreceptor-based treatments such as acupuncture and chiropractic manipulation have shown success in modulating the mesolimbic dopamine (DA) system originating in the ventral tegmental area (VTA) of the midbrain and projecting to the nucleus accumbens (NAc) of the striatum. We have previously shown that mechanoreceptor activation via whole-body vibration (WBV) ameliorates neuronal and behavioral effects of chronic ethanol exposure. In this study, we employ a similar paradigm to assess the efficacy of WBV as a preventative measure of neuronal and behavioral effects of morphine withdrawal in a Wistar rat model. We demonstrate that concurrent administration of WBV at 80 Hz with morphine over a 5-day period significantly reduced adaptations in VTA GABA neuronal activity and NAc DA release and modulated expression of δ-opioid receptors (DORs) on NAc cholinergic interneurons (CINs) during withdrawal. We also observed a reduction in behavior typically associated with opioid withdrawal. WBV represents a promising adjunct to current intervention for opioid use disorder (OUD) and should be examined translationally in humans.

Keywords: VTA; addiction; dopamine; mechanoreceptors; morphine; nucleus accumbens; opioid abuse; whole-body vibration.

Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

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. 2023 Oct:113:145-155.
doi: 10.1016/j.bbi.2023.07.007. Epub 2023 Jul 13.

Interleukin-10 enhances activity of ventral tegmental area dopamine neurons resulting in increased dopamine release

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Interleukin-10 enhances activity of ventral tegmental area dopamine neurons resulting in increased dopamine release

Joakim W Ronström et al. Brain Behav Immun. 2023 Oct.

Abstract

Dopamine transmission from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) regulates important aspects of motivation and is influenced by the neuroimmune system. The neuroimmune system is a complex network of leukocytes, microglia and astrocytes that detect and remove foreign threats like bacteria or viruses and communicate with each other to regulate non-immune (e.g neuronal) cell activity through cytokine signaling. Inflammation is a key regulator of motivational states, though the effects of specific cytokines on VTA circuitry and motivation are largely unknown. Therefore, electrophysiology, neurochemical, immunohistochemical and behavioral studies were performed to determine the effects of the anti-inflammatory cytokine interleukin-10 (IL-10) on mesolimbic activity, dopamine transmission and conditioned behavior. IL-10 enhanced VTA dopamine firing and NAc dopamine levels via decreased VTA GABA currents in dopamine neurons. The IL-10 receptor was localized on VTA dopamine and non-dopamine cells. The IL-10 effects on dopamine neurons required post-synaptic phosphoinositide 3-kinase activity, and IL-10 appeared to have little-to-no efficacy on presynaptic GABA terminals. Intracranial IL-10 enhanced NAc dopamine levels in vivo and produced conditioned place aversion. Together, these studies identify the IL-10R on VTA dopamine neurons as a potential regulator of motivational states.

Keywords: Accumbens; Conditioned Learning; Dopamine; GABA; Interleukin-10; VTA.

Conflict of interest statement

Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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. 2023 Jun;60(6):3113-3129.
doi: 10.1007/s12035-023-03263-5. Epub 2023 Feb 18.

Role of α6-Nicotinic Receptors in Alcohol-Induced GABAergic Synaptic Transmission and Plasticity to Cholinergic Interneurons in the Nucleus Accumbens

Affiliations

Role of α6-Nicotinic Receptors in Alcohol-Induced GABAergic Synaptic Transmission and Plasticity to Cholinergic Interneurons in the Nucleus Accumbens

Hillary A Wadsworth et al. Mol Neurobiol. 2023 Jun.

Abstract

The prevailing view is that enhancement of dopamine (DA) transmission in the mesolimbic system, consisting of DA neurons in the ventral tegmental area (VTA) that project to the nucleus accumbens (NAc), underlies the reward properties of ethanol (EtOH) and nicotine (NIC). We have shown previously that EtOH and NIC modulation of DA release in the NAc is mediated by α6-containing nicotinic acetylcholine receptors (α6*-nAChRs), that α6*-nAChRs mediate low-dose EtOH effects on VTA GABA neurons and EtOH preference, and that α6*-nAChRs may be a molecular target for low-dose EtOH. However, the most sensitive target for reward-relevant EtOH modulation of mesolimbic DA transmission and the involvement of α6*-nAChRs in the mesolimbic DA reward system remains to be elucidated. The aim of this study was to evaluate EtOH effects on GABAergic modulation of VTA GABA neurons and VTA GABAergic input to cholinergic interneurons (CINs) in the NAc. Low-dose EtOH enhanced GABAergic input to VTA GABA neurons that was blocked by knockdown of α6*-nAChRs. Knockdown was achieved either by α6-miRNA injected into the VTA of VGAT-Cre/GAD67-GFP mice or by superfusion of the α-conotoxin MII[H9A;L15A] (MII). Superfusion of MII blocked EtOH inhibition of mIPSCs in NAc CINs. Concomitantly, EtOH enhanced CIN firing rate, which was blocked by knockdown of α6*-nAChRs with α6-miRNA injected into the VTA of VGAT-Cre/GAD67-GFP mice. The firing rate of CINs was not enhanced by EtOH in EtOH-dependent mice, and low-frequency stimulation (LFS; 1 Hz, 240 pulses) caused inhibitory long-term depression at this synapse (VTA-NAc CIN-iLTD) which was blocked by knockdown of α6*-nAChR and MII. Ethanol inhibition of CIN-mediated evoked DA release in the NAc was blocked by MII. Taken together, these findings suggest that α6*-nAChRs in the VTA-NAc pathway are sensitive to low-dose EtOH and play a role in plasticity associated with chronic EtOH.

Keywords: Alcohol; Alpha6 nAChRs (α6*-nAChRs); Cholinergic interneurons (CINs); Nicotine (NIC); Nicotinic acetylcholine receptors (nAChRs).

Conflict of interest statement

Competing Interests The authors declare no competing interests.

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. 2023 Jan 18;24(3):1929.
doi: 10.3390/ijms24031929.

Opioid-Induced Reductions in Amygdala Lateral Paracapsular GABA Neuron Circuit Activity

Affiliations

Opioid-Induced Reductions in Amygdala Lateral Paracapsular GABA Neuron Circuit Activity

Joakim W Ronström et al. Int J Mol Sci. .

Abstract

Opioid use and withdrawal evokes behavioral adaptations such as drug seeking and anxiety, though the underlying neurocircuitry changes are unknown. The basolateral amygdala (BLA) regulates these behaviors through principal neuron activation. Excitatory BLA pyramidal neuron activity is controlled by feedforward inhibition provided, in part, by lateral paracapsular (LPC) GABAergic inhibitory neurons, residing along the BLA/external capsule border. LPC neurons express µ-opioid receptors (MORs) and are potential targets of opioids in the etiology of opioid-use disorders and anxiety-like behaviors. Here, we investigated the effects of opioid exposure on LPC neuron activity using immunohistochemical and electrophysiological approaches. We show that LPC neurons, and other nearby BLA GABA and non-GABA neurons, express MORs and δ-opioid receptors. Additionally, DAMGO, a selective MOR agonist, reduced GABA but not glutamate-mediated spontaneous postsynaptic currents in LPC neurons. Furthermore, in LPC neurons, abstinence from repeated morphine-exposure in vivo (10 mg/kg/day, 5 days, 2 days off) decrease the intrinsic membrane excitability, with a ~75% increase in afterhyperpolarization and ~40-50% enhanced adenylyl cyclase-dependent activity in LPC neurons. These data show that MORs in the BLA are a highly sensitive targets for opioid-induced inhibition and that repeated opioid exposure results in impaired LPC neuron excitability.

Keywords: GABA; basolateral amygdala; intercalated; morphine; opioid; paracapsular.

Conflict of interest statement

The authors declare no conflict of interest.

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. 2022 Oct 20;23(20):12630.
doi: 10.3390/ijms232012630.

Mechanical Stimulation Alters Chronic Ethanol-Induced Changes to VTA GABA Neurons, NAc DA Release and Measures of Withdrawal

Affiliations

Mechanical Stimulation Alters Chronic Ethanol-Induced Changes to VTA GABA Neurons, NAc DA Release and Measures of Withdrawal

Kyle B Bills et al. Int J Mol Sci. .

Abstract

Therapeutic activation of mechanoreceptors (MStim) in osteopathy, chiropractic and acupuncture has been in use for hundreds of years with a myriad of positive outcomes. It has been previously shown to modulate the firing rate of neurons in the ventral tegmental area (VTA) and dopamine (DA) release in the nucleus accumbens (NAc), an area of interest in alcohol-use disorder (AUD). In this study, we examined the effects of MStim on VTA GABA neuron firing rate, DA release in the NAc, and behavior during withdrawal from chronic EtOH exposure in a rat model. We demonstrate that concurrent administration of MStim and EtOH significantly reduced adaptations in VTA GABA neurons and DA release in response to a reinstatement dose of EtOH (2.5 g/kg). Behavioral indices of EtOH withdrawal (rearing, open-field crosses, tail stiffness, gait, and anxiety) were substantively ameliorated with concurrent application of MStim. Additionally, MStim significantly increased the overall frequency of ultrasonic vocalizations, suggesting an increased positive affective state.

Keywords: alcohol; dopamine; mechanoreceptors; physical medicine.

Conflict of interest statement

The authors (K.B.B., S.C.S., D.Z.O., G.C.J., J.N.B., E.K.B., C.A.S., J.T.Y., J.D.B. and H.Y.K) declare no conflict of interest.

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. 2022 Jul 12:16:944243.
doi: 10.3389/fncel.2022.944243. eCollection 2022.

Dopamine D2-Subtype Receptors Outside the Blood-Brain Barrier Mediate Enhancement of Mesolimbic Dopamine Release and Conditioned Place Preference by Intravenous Dopamine

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Dopamine D2-Subtype Receptors Outside the Blood-Brain Barrier Mediate Enhancement of Mesolimbic Dopamine Release and Conditioned Place Preference by Intravenous Dopamine

J Daniel Obray et al. Front Cell Neurosci. .

Abstract

Dopamine (DA) is a cell-signaling molecule that does not readily cross the blood-brain barrier. Despite this, peripherally administered DA enhances DA levels in the nucleus accumbens and alters DA-related behaviors. This study was designed to investigate whether DA subtype-2 receptors are involved in the enhancement of nucleus accumbens (NAc) DA levels elicited by intravenous DA administration. This was accomplished by using microdialysis in the NAc and extracellular single unit recordings of putative DA neurons in the ventral tegmental area (VTA). Additionally, the reinforcing properties of intravenous DA were investigated using a place conditioning paradigm and the effects of intravenous DA on ultrasonic vocalizations were assessed. Following administration of intravenous dopamine, the firing rate of putative DA neurons in the VTA displayed a biphasic response and DA levels in the nucleus accumbens were enhanced. Pretreatment with domperidone, a peripheral-only DA D2 receptor (D2R) antagonist, reduced intravenous DA mediated increases in VTA DA neuron activity and NAc DA levels. Pretreatment with phentolamine, a peripheral α-adrenergic receptor antagonist, did not alter the effects of IV DA on mesolimbic DA neurotransmission. These results provide evidence for peripheral D2R mediation of the effects of intravenous DA on mesolimbic DA signaling.

Keywords: domperidone; dopamine; dopamine 2 receptor; mesolimbic pathway; microdialysis; nucleus accumbens; ventral tegmental area.

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.

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. 2022 May 18;13(10):1534-1548.
doi: 10.1021/acschemneuro.2c00033. Epub 2022 Apr 28.

Effectiveness and Relationship between Biased and Unbiased Measures of Dopamine Release and Clearance

Affiliations

Effectiveness and Relationship between Biased and Unbiased Measures of Dopamine Release and Clearance

Anna C Everett et al. ACS Chem Neurosci. .

Abstract

Fast-scan cyclic voltammetry (FSCV) is an effective tool for measuring dopamine release and clearance throughout the brain, especially the striatum where dopamine terminals are abundant and signals are heavily regulated by release machinery and the dopamine transporter (DAT). Peak height measurement is perhaps the most common method for measuring dopamine release, but it is influenced by changes in clearance. Michaelis-Menten-based modeling has been a standard in measuring dopamine clearance, but it is problematic in that it requires experimenter fitted modeling subject to experimenter bias. This study presents the use of the first derivative (velocity) of evoked dopamine signals as an alternative approach for measuring and distinguishing dopamine release from clearance. Maximal upward velocity predicts reductions in dopamine peak height due to D2 and GABAB receptor stimulation and by alterations in calcium concentrations. The Michaelis-Menten maximal velocity (Vmax) measure, an approximation for DAT levels, predicts maximal downward velocity in slices and in vivo. Dopamine peak height and upward velocity were similar between wild-type and DAT knock-out (DATKO) mice. In contrast, downward velocity was lower and exponential decay (tau) was higher in DATKO mice, supporting the use of both measures for extreme changes in DAT activity. In slices, the competitive DAT inhibitors cocaine, PTT, and WF23 increased peak height and upward velocity differentially across increasing concentrations, with PTT and cocaine reducing these measures at high concentrations. Downward velocity and tau values decreased and increased respectively across concentrations, with greater potency and efficacy observed with WF23 and PTT. In vivo recordings demonstrated similar effects of WF23, PTT, and cocaine on measures of release and clearance. Tau was a more sensitive measure at low concentrations, supporting its use as a surrogate for the Michaelis-Menten measure of apparent affinity (Km). Together, these results inform on the use of these various measures for dopamine release and clearance.

Keywords: Michaelis−Menten; dopamine; dopamine transporter; fast-scan cyclic voltammetry; kinetics; striatum.

Conflict of interest statement

Conflicts of Interest: The authors declare no competing financial interest.

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. 2022 Apr 5;39(1):110633.
doi: 10.1016/j.celrep.2022.110633.

Diurnal rhythms in cholinergic modulation of rapid dopamine signals and associative learning in the striatum

Affiliations

Diurnal rhythms in cholinergic modulation of rapid dopamine signals and associative learning in the striatum

Taylor A Stowe et al. Cell Rep. .

Abstract

Dysregulation of biological rhythms plays a role in a wide range of psychiatric disorders. We report mechanistic insights into the rhythms of rapid dopamine signals and cholinergic interneurons (CINs) working in concert in the rodent striatum. These rhythms mediate diurnal variation in conditioned responses to reward-associated cues. We report that the dopamine signal-to-noise ratio varies according to the time of day and that phasic signals are magnified during the middle of the dark cycle in rats. We show that CINs provide the mechanism for diurnal variation in rapid dopamine signals by serving as a gain of function to the dopamine signal-to-noise ratio that adjusts across time of day. We also show that conditioned responses to reward-associated cues exhibit diurnal rhythms, with cue-directed behaviors observed exclusively midway through the dark cycle. We conclude that the rapid dopamine signaling rhythm is mediated by a diurnal rhythm in CIN activity, which influences learning and motivated behaviors across the time of day.

Keywords: CP: Neuroscience; Pavlovian; acetylcholine; circadian; diurnal; dopamine; interneurons; learning; motivation; nucleus accumbens; striatum.

Conflict of interest statement

Declaration of interests The authors declare no competing interests.

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. 2022 Mar;46(3):396-409.
doi: 10.1111/acer.14775. Epub 2022 Feb 1.

The peripheral dopamine 2 receptor antagonist domperidone attenuates ethanol enhancement of dopamine levels in the nucleus accumbens

Affiliations

The peripheral dopamine 2 receptor antagonist domperidone attenuates ethanol enhancement of dopamine levels in the nucleus accumbens

James Daniel Obray et al. Alcohol Clin Exp Res. 2022 Mar.

Abstract

Background: Dopamine neuron firing in the ventral tegmental area (VTA) and dopamine release in the nucleus accumbens have been implicated in reward learning. Ethanol is known to increase both dopamine neuron firing in the VTA and dopamine levels in the nucleus accumbens. Despite this, some discrepancies exist between the dose of ethanol required to enhance firing in vivo and ex vivo. In the present study we investigated the effects of peripheral dopamine 2 subtype receptor antagonism on ethanol's effects on dopamine neurotransmission.

Methods: Plasma catecholamine levels were assessed following ethanol administration across four different doses of EtOH. Microdialysis and voltammetry were used to assess the effects of domperidone pretreatment on ethanol-mediated increases in dopamine release in the nucleus accumbens. A place conditioning paradigm was used to assess conditioned preference for ethanol and whether domperidone pretreatment altered this preference. Open-field and loss-of-righting reflex paradigms were used to assess the effects of domperidone on ethanol-induced sedation. A rotarod apparatus was used to assess the effects of domperidone on ethanol-induced motor impairment.

Results: Domperidone attenuated ethanol's enhancement of mesolimbic dopamine release under non-physiological conditions at intermediate (1.0 and 2.0 g/kg) doses of ethanol. Domperidone also decreased EtOH-induced sedation at 2.0 g/kg. Domperidone did not alter ethanol conditioned place preference nor did it affect ethanol-induced motor impairment.

Conclusions: These results show that peripheral dopamine 2 receptors mediate some of the effects of ethanol on nonphysiological dopamine neurotransmission, although these effects are not related to the rewarding properties of ethanol.

Keywords: domperidone; dopamine; dopamine 2 receptor; ethanol; microdialysis.

Conflict of interest statement

CONFLICT OF INTEREST

The authors have no conflict of interest to disclose.

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. 2022 Jan;27(1):e13108.
doi: 10.1111/adb.13108. Epub 2021 Oct 29.

Modulation of dopamine release by ethanol is mediated by atypical GABAA receptors on cholinergic interneurons in the nucleus accumbens

Affiliations

Modulation of dopamine release by ethanol is mediated by atypical GABAA receptors on cholinergic interneurons in the nucleus accumbens

Jordan T Yorgason et al. Addict Biol. 2022 Jan.

Abstract

Previous studies indicate that moderate-to-high ethanol (EtOH) concentrations enhance dopamine (DA) neurotransmission in the mesolimbic DA system from the ventral tegmental area (VTA) and projecting to the nucleus accumbens core (NAc). However, voltammetry studies demonstrate that moderate-to-high EtOH concentrations decrease evoked DA release at NAc terminals. The involvement of γ-aminobutyric acid (GABA) receptors (GABAA Rs), glycine (GLY) receptors (GLYRs) and cholinergic interneurons (CINs) in mediating EtOH inhibition of evoked NAc DA release were examined. Fast scan cyclic voltammetry, electrophysiology, optogenetics and immunohistochemistry techniques were used to evaluate the effects of acute and chronic EtOH exposure on DA release and CIN activity in C57/BL6, CD-1, transgenic mice and δ-subunit knockout (KO) mice (δ-/-). Ethanol decreased DA release in mice with an IC50 of 80 mM ex vivo and 2.0 g/kg in vivo. GABA and GLY decreased evoked DA release at 1-10 mM. Typical GABAA R agonists inhibited DA release at high concentrations. Typical GABAA R antagonists had minimal effects on EtOH inhibition of evoked DA release. However, EtOH inhibition of DA release was blocked by the α4 β3 δ GABAA R antagonist Ro15-4513, the GLYR antagonist strychnine and by the GABA ρ1 (Rho-1) antagonist TPMPA (10 μM) and reduced significantly in GABAA R δ-/- mice. Rho-1 expression was observed in CINs. Ethanol inhibited GABAergic synaptic input to CINs from the VTA and enhanced firing rate, both of which were blocked by TPMPA. Results herein suggest that EtOH inhibition of DA release in the NAc is modulated by GLYRs and atypical GABAA Rs on CINs containing δ- and Rho-subunits.

Keywords: GABA; accumbens; alcohol; cholinergic; dopamine; nicotinic.

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. 2022 Mar;160(6):598-612.
doi: 10.1111/jnc.15473. Epub 2021 Aug 16.

Regional and sex differences in spontaneous striatal dopamine transmission

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Regional and sex differences in spontaneous striatal dopamine transmission

James N Brundage et al. J Neurochem. 2022 Mar.

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.

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CONFLICT OF INTEREST

The authors declare no competing financial interests.

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. 2022 Oct;42(7):2433-2438.
doi: 10.1007/s10571-021-01120-4. Epub 2021 Jun 17.

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. 2022 Oct.

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.

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Conflict of interest

None.

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. 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

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

Daniel J Torres et al. Front Neurosci. .

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