Extracellular Concentration and In Vivo Recovery of Dopamine in the Nucleus Accumbens Using Microdialysis

Parsons, Loren H.; Justice, Joseph B.

doi:10.1111/j.1471-4159.1992.tb09298.x

Cited by 260 publications

(189 citation statements)

References 17 publications

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“…Dopamine receptors exhibit differing affinity states for dopamine, termed high-affinity and low-affinity states. The low-affinity K i for dopamine for the cloned rat D3 receptor is in the range of 27-44 nM (Sokoloff et al, 1990(Sokoloff et al, , 1992Levesque et al, 1992;Burris et al, 1995), close to basal extracellular dopamine (3-5 nM (Kalivas and Duffy, 1993;Parsons and Justice, 1992)) and basal synaptic dopamine concentrations ((50 nM (Ross, 1991)). In contrast, the low-affinity state K i 's for D1 and D2 receptors are significantly higher.…”

Section: Discussion 'D3 Dopamine Receptor Hypothesis' Of Sensitizationmentioning

confidence: 78%

Altered Behavioral Response to Dopamine D3 Receptor Agonists 7-OH-DPAT and PD 128907 Following Repetitive Amphetamine Administration

Richtand

Welge

Levant

et al. 2003

Neuropsychopharmacol

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Behavioral sensitization, the progressive and enduring enhancement of certain behaviors following repetitive drug use, is mediated in part by dopaminergic pathways. Increased locomotor response to drug treatment, a sensitizable behavior, is modulated by an opposing balance of dopamine receptor subtypes, with D1/D2 dopamine receptor stimulation increasing and D3 dopamine receptor activation inhibiting amphetamine-induced locomotion. We hypothesize that tolerance of D3 receptor locomotor inhibition contributes to behavioral sensitization. In order to test the hypothesis that expression of behavioral sensitization results in part from release of D3 receptor-mediated inhibition, thereby resulting in decreased response to D3 receptor agonists, we examined the effect of repetitive amphetamine administration on the behavioral response to the D3 receptor preferring agonists 7-OH-DPAT and PD 128907. D3-selective effects have recently been described for both drugs at a low dose. At 1 week following completion of a repetitive treatment regimen, amphetamine-pretreated rats displayed a decreased response to D3-selective doses of both 7-OH-DPAT and PD 128907, when compared to animals receiving saline pretreatment. Moreover, in addition to the quantitative alteration in response, there was a change in the inter-relation between response to amphetamine and D3 agonist. A highly significant inverse relation between locomotor inhibitory response to PD 128907 and the locomotor-stimulant response to amphetamine was observed prior to amphetamine treatment. In contrast, 10 days following repetitive amphetamine treatment, the relation between response to PD 128907 and amphetamine was not detected. The observed behavioral alteration could not be accounted for by changes in D3 receptor binding in ventral striatum. These findings suggest a persistent release of D3 receptor-mediated inhibitory influence contributes to the expression of behavioral sensitization to amphetamine.

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Section: Discussion 'D3 Dopamine Receptor Hypothesis' Of Sensitizationmentioning

confidence: 78%

Altered Behavioral Response to Dopamine D3 Receptor Agonists 7-OH-DPAT and PD 128907 Following Repetitive Amphetamine Administration

Richtand

Welge

Levant

et al. 2003

Neuropsychopharmacol

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“…The D3 receptor has highest affinity for dopamine, with low-affinity state K i ¼ 30 nM (Sokoloff et al, 1992), close to basal extracellular (3-5 nM; Kalivas and Duffy, 1993;Parsons and Justice, 1992) and synaptic dopamine concentrations (50 nM; Ross, 1991). In contrast, D1 and D2 receptor affinity for dopamine are far lower: D2 K i (nM) ¼ 2000 and D1 K i (nM) ¼ 2300 (Sokoloff et al, 1992).…”

Section: D3 Dopamine Receptor Theory Of Sensitizationmentioning

confidence: 92%

Behavioral Sensitization, Alternative Splicing, and D3 Dopamine Receptor-Mediated Inhibitory Function

Richtand

2006

Neuropsychopharmacol

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Behavioral sensitization, the progressive and enduring augmentation of certain behaviors following repetitive drug use, alters rodent locomotion in a long-standing manner. The same dopamine pathways playing an important role in drug dependence and psychosis also play a critical role in sensitization. Individual dopamine receptor subtypes have markedly different functional responses to stimulation, with D3 dopamine receptor stimulation inhibiting rodent locomotion. The D3 receptor has highest affinity of the dopamine receptor subtypes for dopamine, and is occupied to a greater degree following stimulant drug administration. D3 receptor activity may be regulated through the expression of an alternatively spliced, truncated receptor isoform (termed 'D3nf') altering receptor localization and function via dimerization with the full-length subunit. The expected physiological response to repetitive drug administration is tolerance. Tolerance of D3 receptor inhibition of locomotion would contribute to sensitization to stimulant drugs. We hypothesize that repetitive D3 receptor stimulation contributes to the development of behavioral sensitization through decreased responsivity of D3-receptor-mediated locomotor inhibition. Increased D3nf expression may direct altered receptor localization and subsequent release of D3-receptormediated inhibition, contributing to the expression of sensitization. These hypotheses follow directly from the affinities of the receptor subtypes for dopamine; dopamine concentrations following stimulant administration; the effects of individual dopamine receptor subtype stimulation on locomotion; and the expected homeostatic response of the system to perturbation by drug. Clarifying these mechanisms underlying sensitization may suggest new interventions for neuropsychiatric conditions in which dopamine plays an important role, including psychosis, drug dependence, and Parkinson's disease. This information may also elucidate a previously unrecognized mechanism regulating receptor trafficking and desensitization.

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“…The basal level of synaptic dopamine in the rat nucleus accumbens has been estimated to be 4 nM. 35 At a firing frequency of five impulses per second, the synaptic dopamine in rat striatum has been estimated to be about 200 nM in the first few millisec and then to rapidly fall to 1-2 nM within 200 millisec. 36 The resting synaptic dopamine concentration in the human striatum has been indirectly estimated to be about 45 nM.…”

Section: Therapeutic Levels Of Antipsychotic Drugs Occupy High Levelsmentioning

confidence: 99%

Antipsychotic drugs which elicit little or no Parkinsonism bind more loosely than dopamine to brain D2 receptors, yet occupy high levels of these receptors

1998

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This review addresses two questions. First, why does clozapine apparently occupy low levels of dopamine D2 receptors in patients, in contrast to all other antipsychotic drugs which occupy 70-80% of brain dopamine D2 receptors? Second, what is the receptor basis of action of antipsychotic drugs which elicit low levels of Parkinsonism?Antipsychotic doses of clozapine occupy between 0% and 50% of D2 receptors, as measured in patients by a variety of radioligands. It has recently been found, however, that the percent occupancy of a receptor by a drug depends on the radioligand used to measure that receptor. Based on this new finding, this review concludes that clozapine clinically occupies high levels of D2 receptors in the absence of any radioligand. This occupancy is estimated to be of the order of 70-80% in the dopamine-rich region of the human striatum, and even higher in the limbic D2-containing regions which are low in endogenous synaptic dopamine. This conclusion arises from two different approaches. One approach is to relate the reported clozapine occupancies in the human striatum with the dissociation constants of the various radioligands at the D2 receptor. This relation extrapolates to approximately 70-80% occupancy by clozapine when clozapine competes with endogenous dopamine at the D2 receptor. The second approach is to calculate the D2 occupancy of each antipsychotic drug, using the average spinal fluid concentration and the correct dissociation constant of the antipsychotic, thereby revealing that all antipsychotic drugs, including clozapine, occupy approximately 70-80% of dopamine D2 receptors in the human striatum, and possibly higher in the limbic regions.As determined by the new dissociation constants, antipsychotic drugs which elicit Parkinsonism (trifluperazine, chlorpromazine, raclopride, haloperidol, fluphenazine, risperidone) bind more tightly than dopamine to D2, while those antipsychotic drugs which elicit little or no Parkinsonism (melperone, seroquel, perlapine, clozapine, remoxipride, molindone, sulpiride, olanzapine, sertindole) bind more loosely than dopamine to D2 receptors. Compared to the tightly bound antipsychotic drugs, the more loosely bound antipsychotics generally require higher clinical doses, require fewer days for clinical adjustment, but may dissociate from the D2 receptor more rapidly and could lead to clinical relapse somewhat earlier than that found with the traditional tightly bound antipsychotic drugs.

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Extracellular Concentration and In Vivo Recovery of Dopamine in the Nucleus Accumbens Using Microdialysis

Cited by 260 publications

References 17 publications

Altered Behavioral Response to Dopamine D3 Receptor Agonists 7-OH-DPAT and PD 128907 Following Repetitive Amphetamine Administration

Altered Behavioral Response to Dopamine D3 Receptor Agonists 7-OH-DPAT and PD 128907 Following Repetitive Amphetamine Administration

Behavioral Sensitization, Alternative Splicing, and D3 Dopamine Receptor-Mediated Inhibitory Function

Antipsychotic drugs which elicit little or no Parkinsonism bind more loosely than dopamine to brain D2 receptors, yet occupy high levels of these receptors

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