Presynaptic autoinhibition of the electrically evoked dopamine release studied in the rat olfactory tubercle byin vivo electrochemistry

doi:10.1016/0306-4522(91)90277-U

Neuroscience

Volume 45, Issue 3, 1991, Pages 641-652

https://doi.org/10.1016/0306-4522(91)90277-U Get rights and content

Abstract

Evoked dopamine release was monitoredin vivo from the olfactory tubercle of anaesthetized rats by differential pulse amperometry combined with carbon fibre electrodes which, in most cases, were electrochemically treated. Dopamine release was evoked by electrical stimulation of the ascending dopaminergic pathway.

The dopamine release evoked by burst stimulation (20 s with a mean frequency of 6 Hz) was dose-dependently decreased byd,l-apomorphine (25–800 μg/kg, s.c.) or by quinpirole (50 μg/kg, s.c.) while the opposite effect was observed with haloperidol (12.5 μg/kg–0.5 mg/kg, s.c.) or withd,l-sulpiride (2–200 mg/kg, s.c.). Neither the D₁ agonist SKF 38393 (10 mg/kg, s.c.) nor the D₁ antagonist SCH 23390 (0.5 mg/kg, s.c.) affected the evoked dopamine release. Moreover, sulpiride competitively antagonized the effects of apomorphine. The relative amplitude of the apomorphine inhibition was inversely correlated with the stimulation frequency (6 or 9 Hz). The increase induced either by haloperidol or by sulpiride was positively related to the stimulation frequency (from 3 to 9 Hz) and reached a stable value (+ 700% of the pre-drug-evoked dopamine release) with higher frequencies (from 9 to 20 Hz). This increase also depended on the duration of the stimulation: both single-train (10 pulses) or burst stimulations for 20 s, whose frequency inside the trains was in both cases 14 Hz, evoked a dopamine release which was minimally affected by sulpiride or haloperidol.

In conclusion, in physiological conditions the amplitude of the impulse flow-dependent dopamine release is regulated by the extrasynaptic extracellular dopamine concentration which varies from 10 to 100 nM. This presynaptic autoinhibition is mediated by autoreceptors of the D₂ type and is involved in the nonlinear relationship between impulse flow and dopamine release.

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Another strategy could be to target the regulation of dopamine system. Activation of dopamine D2 autoreceptors expressed on dopamine neurons (Fig. 5) reduces dopamine neuron firing and dopamine release (Mercuri et al., 1997; Suaud-Chagny et al., 1991). It is thought that apomorphine used at a low dose can be used to target dopamine autoreceptors whilst avoiding significant stimulation of post-synaptic D2 receptors (Meltzer, 1980).
Antipsychotic drugs are central to the treatment of schizophrenia and other psychotic disorders but are ineffective for some patients and associated with side-effects and nonadherence in others. We review the in vitro, pre-clinical, clinical and molecular imaging evidence on the mode of action of antipsychotics and their side-effects. This identifies the key role of striatal dopamine D2 receptor blockade for clinical response, but also for endocrine and motor side-effects, indicating a therapeutic window for D2 blockade. We consider how partial D2/3 receptor agonists fit within this framework, and the role of off-target effects of antipsychotics, particularly at serotonergic, histaminergic, cholinergic, and adrenergic receptors for efficacy and side-effects such as weight gain, sedation and dysphoria. We review the neurobiology of schizophrenia relevant to the mode of action of antipsychotics, and for the identification of new treatment targets. This shows elevated striatal dopamine synthesis and release capacity in dorsal regions of the striatum underlies the positive symptoms of psychosis and suggests reduced dopamine release in cortical regions contributes to cognitive and negative symptoms. Current drugs act downstream of the major dopamine abnormalities in schizophrenia, and potentially worsen cortical dopamine function. We consider new approaches including targeting dopamine synthesis and storage, autoreceptors, and trace amine receptors, and the cannabinoid, muscarinic, GABAergic and glutamatergic regulation of dopamine neurons, as well as post-synaptic modulation through phosphodiesterase inhibitors. Finally, we consider treatments for cognitive and negative symptoms such dopamine agonists, nicotinic agents and AMPA modulators before discussing immunological approaches which may be disease modifying.
This article is part of the issue entitled ‘Special Issue on Antipsychotics’.
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When the receptor is stimulated by endogenous dopamine, this provides an important negative feedback mechanism (Carlsson and Lindqvist, 1963) that controls neuronal firing (Lane and Blaha, 1986; Mercuri et al., 1985) and the synthesis and release of dopamine (Chesselet, 1984). The activation of this dopamine-driven auto-inhibition (Benoit-Marand et al., 2001; Suaud-Chagny et al., 1991) results in decreased behavioural activity with dimensional relevance to positive symptoms of schizophrenia in animals (Amato et al., 2006; Amato et al., 2008; Lomanowska et al., 2004) and therefore speculatively, decreased positive symptoms of psychosis in humans. From this theoretical standpoint, dopamine itself underlies not only psychosis onset in schizophrenia, but also, the therapeutic effect of antipsychotic drugs.
All antipsychotics bind to the dopamine D2 receptor. An “optimal” level of D2 receptor blockade with antipsychotics is thought to ameliorate the positive symptoms of schizophrenia. However, persistent D2 receptor blockade is associated with a deteriorating clinical response in a subset of patients. Interestingly, antipsychotics with a weaker D2 receptor binding profile appear somewhat superior in this respect. This evidence challenges the hypothesis that D2 receptor blockade is the sole mechanism of antipsychotic efficacy and points to consistent inter-individual responses to antipsychotic treatment.
Here, we hypothesize that clinically effective doses of antipsychotics would lead to the formation of a D2 receptor “reserve” that is likely composed of presynaptic dopamine D2 autoreceptors. The majority of the remaining postsynaptic dopamine receptors are instead occupied by antipsychotics. Endogenous dopamine would then mainly interact with this D2 autoreceptor reserve, thereby reducing the presynaptic synthesis and release of dopamine and resulting in an indirect antipsychotic effect. This new proposal reconciles conceptual and empirical gaps encountered when clinical outcomes are compared to the pharmacology of antipsychotics.
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Striatal [DA]o increases with systemic or intra-striatal administration of D2 antagonists, and decreases with intra-striatal infusion of a D2 agonist [251]. In vivo electrochemical studies indicate that basal [DA]o is sufficient for tonic stimulation of D2 autoreceptors, and inhibition of action potential-dependent DA release [252,253]. Mice lacking D2 receptors allowed evaluation of dynamic autoreceptor regulation [224].
Dopamine (DA) transmission is governed by processes that regulate release from axonal boutons in the forebrain and the somatodendritic compartment in midbrain, and by clearance by the DA transporter, diffusion, and extracellular metabolism. We review how axonal DA release is regulated by neuronal activity and by autoreceptors and heteroreceptors, and address how quantal release events are regulated in size and frequency. In brain regions densely innervated by DA axons, DA clearance is due predominantly to uptake by the DA transporter, whereas in cortex, midbrain, and other regions with relatively sparse DA inputs, the norepinephrine transporter and diffusion are involved. We discuss the role of DA uptake in restricting the sphere of influence of DA and in temporal accumulation of extracellular DA levels upon successive action potentials. The tonic discharge activity of DA neurons may be translated into a tonic extracellular DA level, whereas their bursting activity can generate discrete extracellular DA transients.
Regulation of Extracellular Dopamine: Release and Uptake
2016, Handbook of Behavioral Neuroscience
Citation Excerpt :
Striatal [DA]o increases with systemic or intrastriatal administration of D2 antagonists and decreases with intrastriatal infusion of a D2 agonist (Imperato and Di Chiara, 1985, 1988; Westerink and De Vries,1989). In vivo electrochemical studies indicate that basal [DA]o is sufficient for tonic stimulation of D2 autoreceptors, and inhibition of action potential-dependent DA release (May and Wightman, 1989; Suaud-Chagny et al., 1991). Mice lacking D2 receptors allowed evaluation of dynamic autoreceptor regulation (Benoit-Marand et al., 2001).
Dopamine (DA) transmission is governed by processes that regulate release from axonal boutons in the forebrain and the somatodendritic compartment in midbrain, and by clearance by the DA transporter, diffusion, and extracellular metabolism. We review how axonal DA release is regulated by neuronal activity and by autoreceptors and heteroreceptors, and address how quantal release events are regulated in size and frequency. In brain regions densely innervated by DA axons, DA clearance is due predominantly to uptake by the DA transporter, whereas in cortex, midbrain, and other regions with relatively sparse DA inputs, the noradrenaline transporter and diffusion are involved. We discuss the role of DA uptake in restricting the sphere of influence of DA and in temporal accumulation of extracellular DA levels upon successive action potentials. The tonic discharge activity of DA neurons may be translated into a tonic extracellular DA level, whereas their bursting activity can generate discrete extracellular DA transients.
The role of D2-autoreceptors in regulating dopamine neuron activity and transmission
2014, Neuroscience
Citation Excerpt :
Autoreceptors regulate the activity of dopamine cells through several mechanisms. Pre-synaptic autoreceptors on nerve terminals regulate dopamine transmission by inhibiting the probability of vesicular dopamine release (Suaud-Chagny et al., 1991; Benoit-Marand et al., 2001; Phillips et al., 2002), decreasing dopamine synthesis (Kehr et al., 1972; Wolf and Roth, 1990) and altering the uptake of dopamine (Fig. 1) (Cass and Gerhardt, 1994; Wu et al., 2002; Truong et al., 2004). Somatodendritic D2-autoreceptors on VTA and SNc neurons inhibit the excitability of dopamine neurons and modulate the firing rate by activating a hyperpolarizing potassium GIRK current (Aghajanian and Bunney, 1977; Lacey et al., 1987; Mercuri et al., 1997; Beckstead et al., 2004; Courtney et al., 2012).
Dopamine D2-autoreceptors play a key role in regulating the activity of dopamine neurons and control the synthesis, release and uptake of dopamine. These G_i/o-coupled inhibitory receptors play a major part in shaping dopamine transmission. Found at both somatodendritic and axonal sites, autoreceptors regulate the firing patterns of dopamine neurons and control the timing and amount of dopamine released from their terminals in target regions. Alterations in the expression and activity of autoreceptors are thought to contribute to Parkinson’s disease as well as schizophrenia, drug addiction and attention-deficit hyperactivity disorder (ADHD), which emphasizes the importance of D2-autoreceptors in regulating the dopamine system. This review will summarize the cellular actions of dopamine autoreceptors and discuss recent advances that have furthered our understanding of the mechanisms by which D2-receptors control dopamine transmission.
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Striatal dopamine neurotransmission is critical for normal voluntary movement, affect and cognition. Dysfunctions of its regulation are implicated in a broad range of behaviors and disorders including Parkinson’s disease, schizophrenia and drug abuse. Extracellular dopamine levels result from a dynamic equilibrium between release and reuptake by dopaminergic terminals. Both processes are regulated by multiple mechanisms. Here we review data characterizing how dopamine levels are regulated by presynaptic autoreceptors and heteroreceptors, an area intensively investigated due to advances in real time electrochemical detection of extracellular dopamine, i.e., fast-scan cyclic voltammetry and amperometry, and the development of mutant mouse lines with deletions for specific receptors.

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^*: Permanent address: Institute of Experimental Endocrinology, Slovak Academy of Sciences, 83306 Bratislava, Czechoslovakia.

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Abstract

Reference (31)

Stimulation of rat spontaneous locomotion by low doses of haloperidol and (−)-sulpiride: importance of animal selection and measurement technique

Eur. J. Pharmac.

Activity of A9 and A10 dopaminergic neurons in unrestrained rats: further characterization and effects of apomorphine and cholecystokinin

Brain Res.

Non-linear relationship between impulse flow and dopamme released by rat midbrain dopaminergic neurons as studied byin vivo electrochemistry

Neuroscience

Regulation of dopamine release by impulse flow and by autoreceptors as studied byin vivo voltammetry in the rat striatum

Neuroscience

Effects of locally applied D-1 and D-2 receptor agonists and antagonists studied with brain dialysis

Eur. J. Pharmac.

The D-l antagonist SCH 23390 stimulates while the D-1 agonist SKF 38393 fails to affect dopamine release in the dorsal caudate of freely moving rats

Eur. J. Pharmac.

Lack of direct evidence for adrenergic and dopaminergic autoreceptors

Trends pharmac. Sci.

Striatal dopamine uptake in the rat:in vivo analysis by fast cyclic voltammetry

Neurosci. Lett.

The influence of stimulus parameters on the potentiation of Striatal dopamine release by metoclopramide:in vivo voltammetric data

Eur. J. Pharmac.

Pharmacology of electrically evoked dopamine release studied in the rat olfactory tubercle byin vivo electrochemistry

Eur. J. Pharmac.

On the mechanism of neuroleptic induced increase in Striatal dopamine release: brain dialysis provides direct evidence for mediation by autoreceptors localized on nerve terminals

Neurosci. Lett.

Control of dopamine extracellular concentration in rat striatum by impulse flow and uptake

Brain Res. Rev.

Frequency-dependent release of acetylcholine and dopamine from rabbit striatum: its modulation by dopaminergic receptors

J. Neurochem.

Drug-induced changes in the release of³H-monoamines from field stimulated rat brain slices

Acta physiol. scand.

Control of dopamme release by autoreceptors and by impulse flow as studied byin vivo voltammetry

Cited by (50)

Antipsychotics: Mechanisms underlying clinical response and side-effects and novel treatment approaches based on pathophysiology

Dopamine, the antipsychotic molecule: A perspective on mechanisms underlying antipsychotic response variability

Striatal dopamine neurotransmission: Regulation of release and uptake

Regulation of Extracellular Dopamine: Release and Uptake

The role of D2-autoreceptors in regulating dopamine neuron activity and transmission

Regulation of striatal dopamine release by presynaptic auto- and heteroreceptors

Presynaptic autoinhibition of the electrically evoked dopamine release studied in the rat olfactory tubercle byin vivo electrochemistry

Abstract

Eur. J. Pharmac.

Brain Res.

Neuroscience

Neuroscience

Eur. J. Pharmac.

Eur. J. Pharmac.

Trends pharmac. Sci.

Neurosci. Lett.

Eur. J. Pharmac.

Eur. J. Pharmac.

Neurosci. Lett.

Brain Res. Rev.

Frequency-dependent release of acetylcholine and dopamine from rabbit striatum: its modulation by dopaminergic receptors

J. Neurochem.

Drug-induced changes in the release of3H-monoamines from field stimulated rat brain slices

Acta physiol. scand.

Control of dopamme release by autoreceptors and by impulse flow as studied byin vivo voltammetry

Drug-induced changes in the release of³H-monoamines from field stimulated rat brain slices