Dopamine uptake inhibitors and releasing agents differentiated by the use of synaptosomes and field-stimulated brain slices in vitro

Hunt, Peter; Raynaud, Jean‐Pierre; Leven, M.; Schacht, Ulrich

doi:10.1016/0006-2952(79)90217-x

Cited by 44 publications

(17 citation statements)

References 19 publications

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“…Haloperidol(1 .O mg/kg), a dopamine-receptor antagonist, causes an increase in evoked release of 22 + 3% in the nucleus accumbens and 23 f 9% in the caudate nucleus (n = 4). Benztropine (25 mg/kg), an inhibitor ofneuronal uptake of dopamine (Hunt et al, 1979), does not significantly change the time course of dopamine disappearance in the accumbens, and it has little effect on the amount of stimulated release (n = 4; Table l), in accord with previously published results regarding the caudate nucleus .…”

Section: Effect Of Pharmacological Agentssupporting

confidence: 81%

In vivo comparison of the regulation of releasable dopamine in the caudate nucleus and the nucleus accumbens of the rat brain

Kuhr¹,

Bigelow²,

Rm³

1986

J. Neurosci.

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In viva voltammetry has been used to measure the release of dopamine evoked by electrical stimulation of the medial forebrain bundle (MFB). Simultaneous measurements have been made with voltammetric-sensing electrodes ipsilateral to the stimulating electrode in the nucelus accumbens and the caudate nucleus of the anesthetized rat. During the stimulation, the species observed in both regions is voltammetrically identical to dopamine. Further evidence for the identity of dopamine is provided by anatomical, physiological, pharmacological, and postmortem data. Postmortem analysis of these brain regions after a single stimulation demonstrates that dopamine levels are unchanged, while dihydroxyphenylacetic acid (DOPAC) levels are increased in both regions. Systemic application of synthesis inhibitors results in a decrease in evoked release for each brain region. Amfonelic acid results in a restoration of stimulated release after synthesis inhibition. Evoked release is affected differently by pargyline in the two brain regions. The evoked release of dopamine is significantly elevated in the nucleus accumbens as a result of pargyline administration, but similar effects are not seen in the caudate nucleus. Tissue levels of dopamine are increased in both brain regions by pargyline, but the increase is significantly greater in the accumbens. Electrolytic lesions of the striatonigral pathway or systemic administration of picrotoxin eliminates the pargyline-induced difference in evoked release of dopamine. Amphetamine causes a reduction in stimulated release in the caudate nucleus with little effect on that observed in the nucleus accumbens. Administration of pargyline prior to amphetamine results in a diminution of release in both brain regions. Taken together, these data indicate that different factors affect regulation of the releasable pool of dopamine in the nucleus accumbens and caudate nucleus.Several major dopaminergic systems exist in the mammalian brain, including the nigrostriatal and mesolimbic systems. It is known that the mesolimbic system plays an important role in the regulation of normal brain function, and this role is distinct from that played by the nigrostriatal dopamine pathway (Mogenson and Yin, 1981;White and Wang, 1982). It has been shown by unit-recording techniques that these two regions respond in different manners to pharmacological stimuli thought to affect dopaminergic neurons (Rebec and Zimmerman, 1980; Reynolds et al., 1981). The behavioral responses elicited by electrical stimulation of these two pathways differ (van der Heyden, 1984). Lesions of the two regions also produce different behavioral responses (Kelly and Moore, 1976; Pycock and Marsden, 1978). Furthermore, anatomical differences have been shown at an ultrastructural level (Bouyer et al., 1984). A rec- Received June 10, 1985; revised Oct. 7, 1985; accepted Oct. 10, 1985. This work was supported by a grant from the National Science Foundation, Neurobiology Section.Correspondence should be addressed to R. M. Wigbtman, Department...

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Section: Effect Of Pharmacological Agentssupporting

confidence: 81%

In vivo comparison of the regulation of releasable dopamine in the caudate nucleus and the nucleus accumbens of the rat brain

Kuhr¹,

Bigelow²,

Rm³

1986

J. Neurosci.

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“…Additionally, because of the similarities in the effects of amphetamine, nomifensine and cocaine on the above ratio, 3MT rates of formation and total DA turnover, some of the effects of nomifensine and cocaine may be attributed to stimulation of DA release. This view is supported by a number of observations which suggest an ability of nomifensine to stimulate DA release (Braestrup & Scheel-Kruger, 1976;Broch, 1979;Kruk & Stamford, 1985;Hurd & Ungerstedt, 1989), especially when administered at relatively high doses (Hunt et al, 1979). These observations, together with the recent report of reduced cocaine-and amphetamineinduced spontaneous activity in rats pretreated with putative inhibitors of DA release (Calcagnetti & Schechter, 1992), provide additional support to the notion that some of the behavioural and neurochemical effects of cocaine and nomifensine can be attributed to stimulation of DA release.…”

Section: Discussionmentioning

confidence: 85%

“…Reduced intraneuronal metabolism of unreleased DA after amphetamine administration, at least in the nucleus accumbens and striatum, is supported by the failure of DA reuptake inhibitors to block the ability of amphetamine to lower DOPAC concentrations in the brain (Fuller & Snoddy, 1979). This view is also indirectly supported by the inability of DA reuptake inhibitors to attenuate DA release by amphetamine (Ross, 1977;Hunt et al, 1979). Therefore, accelerated efflux of newly synthesized DA and competition for DA reuptake sites by amphetamine (Fischer & Cho, 1979;Kuczenski, 1983;Sulzer et al, 1993) appear to be the primary mechanisms involved in its effects on DA transmission in the brain.…”

Section: Discussionmentioning

confidence: 99%

“…The uptake inhibitors employed here were selected because they either are or can potentially be abused, and because of their different biochemical (Gerhards et al, 1974;Nomikos et al, 1990), pharmacological (Hunt et al, 1974;Kuczenski, 1983) and electrophysiological effects (Bunney & Aghajanian, 1978). Thus, while the behavioural effects of amphetamine and, to a certain extent, nomifensine (Braestrup & ScheelKruger, 1976;Broch, 1979;Hunt et al, 1979;Schacht et al, 1982;Kruk & Stamford, 1985;Hurd & Ungerstedt, 1989) have been attributed to stimulation of DA release as well as to its reuptake inhibition, those behavioural effects exhibited by cocaine and GBR 12909 are believed to result primarily from their potent DA reuptake inhibitory effects (Heikkila et al, 1975;Van der Zee et al, 1980;Heikkila & Manzino, 1984;Ritz et al, 1987 The treatment schedules were as follows. Five groups of rats were used; one group was given saline and the other four groups were injected with one psychostimulant each at 0 min.…”

Section: Introductionmentioning

confidence: 99%

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Regional effects of amphetamine, cocaine, nomifensine and GBR 12909 on the dynamics of dopamine release and metabolism in the rat brain

Karoum

Chrapusta

Brinjak

et al. 1994

British J Pharmacology

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1 The effects of single-dose regimens of amphetamine, cocaine, nomifensine and GBR 12909 on the dynamics of dopamine (DA) release and metabolism were evaluated in the frontal cortex, hypothalamus, nucleus accumbens and striatum. The regimens selected are known to produce substantial behavioural effects. 2 3-Methoxytyramine (3MT) and 3,4-dihydroxyphenylacetic acid (DOPAC) rates of formation were used to assess DA metabolism by catechol-O-methyltransferase and monoamine oxidase respectively. The rate of formation of 3MT was used as an index of synaptic DA. The ratio and sum, respectively, of 3MT and DOPAC rates of formation were used to assess DA reuptake inhibition and turnover. 3 The effects of amphetamine on 3MT production and DOPAC steady-state levels were similar in all regions, suggesting similar pharmacodynamic actions. Amphetamine increased 3MT formation and steady-state levels, and reduced DOPAC steady-state levels. DOPAC formation was significantly reduced only in the nucleus accumbens and striatum. Total DA turnover remained unchanged except in the nucleus accumbens. Apparently, the amphetamine-induced increase in DA release occurred at the expense of intraneuronal DA metabolism and did not require stimulation of synthesis. 4 Nomifensine elevated 3MT formation in all regions. A similar effect was produced by cocaine except in the nucleus accumbens. GBR 12909 elevated 3MT production only in the hypothalamus, the striatum and the nucleus accumbens. 5 Cocaine selectively reduced DOPAC formation in the frontal cortex. Nomifensine increased and reduced, respectively, DOPAC formation in striatum and hypothalamus. GBR 12909 elevated DOPAC formation in all regions except the cortex, where pargyline did not reduce DOPAC levels in GBR 12909-treated rats. 6 Ratios and sum of 3MT and DOPAC rates of formation also exhibited wide regional variations for each drug. In contrast to the other drugs, the ratio was not increased after GBR 12909. Apparently, the DA uptake properties of this drug are poorly related to its in vivo effects on the ratio of 3MT production to that of DOPAC, which should increase when DA reuptake is inhibited. 7 Total DA turnover was increased by GBR 12909 in the hypothalamus, nucleus accumbens and striatum, while cocaine and nomifensine increased it only in the nucleus accumbens and striatum respectively. 8 It is concluded that: (a) 3MT and DOPAC rates of formation provide better indices of DA release and metabolism than do their steady-state concentrations. (b) Some effects of DA uptake blockers on DA transmission, especially those of nomifensine and cocaine, may be attributed to increased DA release. (c) Patterns of regional effects of psychostimulants on the dynamics of DA release and metabolism may be better biochemical correlates of stimulant-induced behaviours than would changes in any single region.

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“…To understand how methylphenidate normalizes the number of spontaneously active VTA DA neurons in prenatal ethanol-exposed animals, we have conducted a series of pharmacological experiments. The results show that nomifensine, which has a high degree of selectivity for the DA transporters at the dose administered (1 mg/kg i.p; Hunt et al, 1979) can restore the number of spontaneously active VTA DA neurons in prenatal ethanolexposed animals. This effect is similar to methylphenidate effect and supports that the normalization in the electrical activity of VTA DA neurons in prenatal ethanol-exposed animals is mediated through its effects on DA neurotransmission.…”

Section: Discussionmentioning

confidence: 91%

Methylphenidate Restores Ventral Tegmental Area Dopamine Neuron Activity in Prenatal Ethanol-Exposed Rats by Augmenting Dopamine Neurotransmission

Choong¹,

Shen²

2004

J Pharmacol Exp Ther

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Altered neurotransmission in the mesolimbic dopamine (DA) system has been suggested to be the underlying cause of attention problems commonly observed in children with fetal alcohol spectrum disorder (FASD). Methylphenidate is effective in treating attention problems in children with FASD. However, the underlying mechanism is currently unknown. We have shown previously that reduced ventral tegmental area (VTA) DA neuron activity in prenatal ethanol-exposed animals can be normalized by DA agonist treatment. In the present study, we investigated the possibility that similar mechanism mediates the effect of methylphenidate using the in vivo extracellular single-unit recording technique in anesthetized animals. We observed that reduced VTA DA neuron activity in prenatal ethanol-exposed animals was normalized by methylphenidate. The effect of methylphenidate was mediated by increased extracellular levels of DA instead of norepinephrine because this effect was not altered by the coadministration of prazosin, an ␣ 1 receptor antagonist, and was mimicked by the application of DA transporter blockers, nomifensine and 1-2(-[bis(4-flurophenyl)methoxy]ethyl)-4-(3-phenyl)piperazine dihydrochloride (GBR 12909). These observations support our hypothesis that depolarization inactivation is the cause of prenatal ethanol exposure-induced reduction in VTA DA neuron activity. We speculate that methylphenidate normalized the activity of VTA DA neurons by increasing extracellular DA levels in the VTA and the activation of somatodendritic DA autoreceptors. As a result, the depolarization inactivation was removed by hyperpolarization. The normalized VTA DA neuron activity in prenatal ethanol-exposed animals may contribute to a restoration of DA neurotransmission and the therapeutic effect of methylphenidate in attention problems in children with FASD.Prenatal ethanol exposure leads to abnormalities in the function of the midbrain dopamine (DA) system. For example, there is a reduction in DA uptake and receptor binding sites, DA content, and the DA metabolites in both the somatodendritic and terminal areas (Rathbun and Druse, 1985;Cooper and Rudeen, 1988;Druse et al., 1990) in prenatal ethanol-exposed animals. Prenatal ethanol exposure also can lead to changes in DA neuron morphology [e.g., smaller cell bodies and retarded dendritic growth in DA neurons (Shetty et al., 1993), DA receptor function (Shen et al., 1995;Wang and Shen, 2002), and DA receptor-mediated behavior (Hannigan and Randall, 1996)]. Recently, impairment in sustained attention, which could be modulated by DA (Davids et al., 2003), was also reported in prenatal ethanol-exposed animals (Hausknecht et al., 2003).In previous electrophysiological studies, we have demonstrated that prenatal ethanol exposure leads to a persistent reduction in the electrical activity of the midbrain DA neurons without a loss of DA neurons (Shen et al., 1999;Xu and Shen, 2001). Because the electrical activity controls the synthesis and release of DA (Gonon and Buda, 1985; SuaudChagny et ...

show abstract

Dopamine uptake inhibitors and releasing agents differentiated by the use of synaptosomes and field-stimulated brain slices in vitro

Cited by 44 publications

References 19 publications

In vivo comparison of the regulation of releasable dopamine in the caudate nucleus and the nucleus accumbens of the rat brain

In vivo comparison of the regulation of releasable dopamine in the caudate nucleus and the nucleus accumbens of the rat brain

Regional effects of amphetamine, cocaine, nomifensine and GBR 12909 on the dynamics of dopamine release and metabolism in the rat brain

Methylphenidate Restores Ventral Tegmental Area Dopamine Neuron Activity in Prenatal Ethanol-Exposed Rats by Augmenting Dopamine Neurotransmission

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