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Oestradiol influences on dopamine release from the nucleus accumbens shell: sex differences and the role of selective oestradiol receptor subtypes.

ABSTRACT: BACKGROUND AND PURPOSE:Females are more sensitive than males to both the acute and prolonged effects of psychomotor stimulants. In females, this is regulated by oestradiol, which enhances dopamine release in the dorsal striatum. In this study, we tested the acute effect of oestradiol on dopamine release in the nucleus accumbens (NAc) shell after cocaine administration and investigated which oestradiol receptors (ERs) contribute to sex differences in the response to cocaine. EXPERIMENTAL APPROACH:The ability of oestradiol benzoate (EB) to acutely modulate the effect of cocaine on phasic dopamine release in the NAc shell was measured by fast-scan cyclic voltammetry in anaesthetized male and female rats. The roles of ER subtypes, ER? and ER?, was determined with selective agonists. KEY RESULTS:EB acutely enhanced the effect of cocaine on stimulated dopamine release from the NAc shell in females but not in male rats only at levels of stimulation expected to optimally saturate dopamine transporters. Enhanced dopamine release after cocaine administration was also observed in females after selective activation of ER? but not ER?. EB attenuated the effect of cocaine on NAc shell dopamine reuptake in males but not in females. CONCLUSIONS AND IMPLICATIONS:Oestradiol acutely and rapidly regulates dopamine release in females and dopamine reuptake in males. In females, oestradiol rapidly enhances the effect of cocaine on dopamine release, likely via activation of ER?. The effect of oestradiol in males is not seen with selective receptor subtype activation, a topic deserving of further study. LINKED ARTICLES:This article is part of a themed section on The Importance of Sex Differences in Pharmacology Research. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.21/issuetoc.

SUBMITTER: Yoest KE

PROVIDER: S-EPMC6877897 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Oestradiol influences on dopamine release from the nucleus accumbens shell: sex differences and the role of selective oestradiol receptor subtypes.

Yoest Katie E KE Cummings Jennifer A JA Becker Jill B JB

British journal of pharmacology 20181218 21

<h4>Background and purpose</h4>Females are more sensitive than males to both the acute and prolonged effects of psychomotor stimulants. In females, this is regulated by oestradiol, which enhances dopamine release in the dorsal striatum. In this study, we tested the acute effect of oestradiol on dopamine release in the nucleus accumbens (NAc) shell after cocaine administration and investigated which oestradiol receptors (ERs) contribute to sex differences in the response to cocaine.<h4>Experiment ...[more]

PMID: 30381823

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Project description:The aim of this work was to determine the effect of nicotine desensitization on dopamine (DA) release in the dorsal striatum and shell of the nucleus accumbens (NAc) from brain slices. In vitro fast-scan cyclic voltammetry analysis was used to evaluate dopamine release in the dorsal striatum and the NAc shell of Sprague-Dawley rats after infusion of nicotine, a nicotinic acetylcholine receptor (nAChR) antagonist mecamylamine (Mec), and an α4β2 cholinergic receptor antagonist (DHβe). DA release related to nicotine desensitization in the striatum and NAc shell was compared. In both structures, tonic release was suppressed by inhibition of the nicotine receptor (via Mec) and the α4β2 receptor (via DHβe). Paired-pulse ratio (PPR) was facilitated in both structures after nicotine and Mec infusion, and this facilitation was suppressed by increasing the stimulation interval. After variable frequency stimulation (simulating phasic burst), nicotine infusion induced significant augmentation of DA release in the striatum that was not seen in the absence of nicotine. In contrast, nicotine reduced phasic DA release in NAc, although frequency augmentation was seen both with and without nicotine. Evaluation of DA release evoked by various trains (high-frequency stimulation (HFS) 100 Hz) of high-frequency stimulation revealed significant enhancement after a train of three or more pulses in the striatum and NAc. The concentration differences between tonic and phasic release related to nicotine desensitization were more pronounced in the NAc shell. Nicotine desensitization is associated with suppression of tonic release of DA in both the striatum and NAc shell that may occur via the α4β2 subtype of nAChR, whereas phasic frequency-dependent augmentation and HFS-related gating release is more pronounced in the striatum than in the NAc shell. Differences between phasic and tonic release associated with nicotine desensitization may underlie processing of reward signals in the NAc shell, and this may have major implications for addictive behavior.

Project description: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.

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Project description:BackgroundThe nucleus accumbens (NAc) is an important region in motivation and reward. Glutamatergic inputs from the infralimbic cortex (ILC) to the shell region of the NAc (NAcSh) have been implicated in driving the motivation to seek reward through repeated action-based behavior. While this has primarily been studied in males, observed sex differences in motivational circuitry and behavior suggest that females may be more sensitive to rewarding stimuli. These differences have been implicated for the observed vulnerability in women to substance use disorders.MethodsWe used an optogenetic self-stimulation task in addition to ex vivo electrophysiological recordings of NAcSh neurons in mouse brain slices to investigate potential sex differences in ILC-NAcSh circuitry in reward-seeking behavior. Glutamatergic neurons in the ILC were infected with an AAV delivering DNA encoding for channelrhodopsin. Entering the designated active corner of an open field arena resulted in photostimulation of the ILC terminals in the NAcSh. Self-stimulation occurred during two consecutive days of testing over three consecutive weeks: first for 10 Hz, then 20 Hz, then 30 Hz. Whole-cell recordings of medium spiny neurons in the NAcSh assessed both optogenetically evoked local field potentials and intrinsic excitability.ResultsAlthough both sexes learned to seek the active zone, within the first day, females entered the zone more than males, resulting in a greater amount of photostimulation. Increasing the frequency of optogenetic stimulation amplified female reward-seeking behavior. Males were less sensitive to ILC stimulation, with higher frequencies and repeated days required to increase male reward-seeking behavior. Unexpectedly, ex vivo optogenetic local field potentials in the NAcSh were greater in slices from male animals. In contrast, female medium-spiny neurons (MSNs) displayed significantly greater intrinsic neuronal excitability.ConclusionsTaken together, these data indicate that there are sex differences in the motivated behavior driven by glutamate within the ILC-NAcSh circuit. Though glutamatergic signaling was greater in males, heightened intrinsic excitability in females appears to drive this sex difference.

Project description:Ethanol (EtOH) is known to have excitatory effects on dopamine (DA) release, with moderate-to-high doses (0.5 to 2.5 g/kg) of acute EtOH enhancing DA neuron firing rates in the ventral tegmental area (VTA) and DA levels in the nucleus accumbens (NAc). EtOH has also been shown to reduce DA activity, with moderate doses (1 to 2 g/kg) attenuating electrically evoked release, and higher doses (5 g/kg) decreasing NAc DA levels, demonstrating a biphasic effect of EtOH on DA release. The purpose of the current study was to evaluate EtOH's inhibitory effects on NAc DA terminal release under low- and high-frequency stimulation conditions.Using fast-scan cyclic voltammetry in NAc slices from C57BL/6J mice, we examined EtOH's (40 to 160 mM) effects on DA release under several different stimulation parameters, varying frequency (5 to 125 Hz), number of pulses (1 to 10), and stimulation intensity (50 to 350 ?A). Additionally, calcium concentrations were manipulated under high-frequency stimulation conditions (20 Hz, 10 pulses, 350 ?A) to determine whether EtOH's effects were dependent upon calcium concentration, and by extension, the amount of DA release.Acute EtOH (40 to 160 mM) inhibited DA release to a greater extent under high-frequency, multiple-pulse stimulation conditions, with increased sensitivity at 5 and 10 pulses and frequencies of 20 Hz or higher. High-frequency, multiple-pulse stimulations also resulted in greater DA release compared with single-pulse release, which was controlled by reducing stimulation intensity. Under reduced DA conditions, high-frequency stimulations still showed increased EtOH sensitivity. Reducing calcium levels also decreased DA release at high-frequency stimulations, but did not affect EtOH sensitivity.EtOH appears to inhibit DA release at NAc terminals under high-frequency stimulation conditions that are similar to release events observed during phasic burst firing in DAergic neurons, suggesting that EtOH may provide inhibition of DA terminals selectively during phasic signaling, while leaving tonic DA terminal activity unaffected.

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Oestradiol influences on dopamine release from the nucleus accumbens shell: sex differences and the role of selective oestradiol receptor subtypes.

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Oestradiol influences on dopamine release from the nucleus accumbens shell: sex differences and the role of selective oestradiol receptor subtypes.

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