The Classification of Dopamine Receptors: Relationship to Radioligand Binding

Creese, Ian; Sibley, David R.; Hamblin, Mark W.; Leff, Stuart E.

doi:10.1146/annurev.ne.06.030183.000355

Cited by 393 publications

(127 citation statements)

References 71 publications

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“…Whereas we do not discount a potential role for other neurotransmitters, we argue that the smaller range of DA dips (compared with bursts) is likely compensated for by the far greater sensitivity of D 2 (compared with D 1 ) receptors to low DA levels (Creese, Sibley, Hamblin, & Leff, 1983;Goto & Grace, 2005;Grace, 2001;Schultz, 1998). Thus, smaller DA dips would be sufficient to support No-Go learning via D 2 receptors, whereas larger phasic bursts would be needed to support Go learning via D 1 receptors.…”

Section: Learningcontrasting

confidence: 76%

A mechanistic account of striatal dopamine function in human cognition: Psychopharmacological studies with cabergoline and haloperidol.

Frank¹,

O’Reilly²

2006

Behavioral Neuroscience

435

490

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The authors test a neurocomputational model of dopamine function in cognition by administering to healthy participants low doses of D 2 agents cabergoline and haloperidol. The model suggests that DA dynamically modulates the balance of Go and No-Go basal ganglia pathways during cognitive learning and performance. Cabergoline impaired, while haloperidol enhanced, Go learning from positive reinforcement, consistent with presynaptic drug effects. Cabergoline also caused an overall bias toward Go responding, consistent with postsynaptic action. These same effects extended to working memory and attentional domains, supporting the idea that the basal ganglia/dopamine system modulates the updating of prefrontal representations. Drug effects interacted with baseline working memory span in all tasks. Taken together, the results support a unified account of the role of dopamine in modulating cognitive processes that depend on the basal ganglia.Keywords: basal ganglia, dopamine, cognition, computational, psychopharmacologyThe basal ganglia (BG) participate in various aspects of cognition and behavior by interacting with and modulating multiple areas of frontal cortex (Alexander, DeLong, & Strick, 1986). Similarly, the neurotransmitter dopamine (DA) plays a modulatory role in cognition through extensive diffuse projections from midbrain DA nuclei to the BG and frontal cortical areas (Fallon & Moore, 1978;Gerfen, 1992;Joel & Weiner, 2000). Several neurological conditions implicate DA dysfunction, including Parkinson's disease, attention deficit/hyperactivity disorder (ADHD), and schizophrenia (Abi-Dargham et al., 2000;Dougherty et al., 1999;Ilgin et al., 2001;Kish, Shannak, & Hornykiewicz, 1988;McGowan, Lawrence, Sales, Quested, & Graby, 2004;Nieoullon, 2002;Seeman, 1987;Weiner & Joel, 2002;Weinberger, 1987). Notably, the cognitive deficits observed in all of these conditions are qualitatively similar to those observed in patients with damage to prefrontal cortex (PFC; Barch et al., 2001;Brown & Marsden, 1990;Cools, Barker, Sahakian, & Robbins, 2001;Perlstein, Dixit, Carter, Noll, & Cohen, 2003;Willcutt et al., 2005). Consequently, the overwhelming tendency in the literature is to attribute patient cognitive deficits to dopaminergic dysfunction within PFC. This is a potentially valid attribution, given that selective disruption to prefrontal DA in monkeys gives rise to cognitive deficits that are similar to those observed under full excitotoxic PFC lesions (Sawaguchi & Goldman-Rakic, 1991; Williams & GoldmanRakic, 1995). However, there is growing evidence in both animals and humans that DA dysfunction within the BG alone can lead to frontal-like cognitive deficits (Collins, Wilkinson, Everitt, Robbins, & Roberts, 2000;Crofts et al., 2001;Frank, 2005;J. O. Rinne et al., 2000).Psychopharmacological studies that transiently manipulate the DA system in healthy individuals can potentially inform the cause of DA-related cognitive deficits. In particular, drugs that target the D 2 receptor, which is predominantly expressed in BG re...

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Section: Learningcontrasting

confidence: 76%

A mechanistic account of striatal dopamine function in human cognition: Psychopharmacological studies with cabergoline and haloperidol.

Frank¹,

O’Reilly²

2006

Behavioral Neuroscience

435

490

View full text Add to dashboard Cite

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“…Several theorists argue that although DA bursts support positivereinforcement learning, the firing rate changes associated with DA dips do not have sufficient dynamic range to be functionally effective (2,40). The present findings suggest that striatal D2 receptors are indeed effective in avoidance learning, potentially because of their enhanced sensitivity to low DA levels and their potent role in synaptic plasticity (11,41,42). This function seems to depend highly on DRD2 genotype and associated striatal D2 receptor density.…”

Section: Discussionmentioning

confidence: 50%

Genetic triple dissociation reveals multiple roles for dopamine in reinforcement learning

Frank

Moustafa²,

Haughey³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

638

836

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What are the genetic and neural components that support adaptive learning from positive and negative outcomes? Here, we show with genetic analyses that three independent dopaminergic mechanisms contribute to reward and avoidance learning in humans. A polymorphism in the DARPP-32 gene, associated with striatal dopamine function, predicted relatively better probabilistic reward learning. Conversely, the C957T polymorphism of the DRD2 gene, associated with striatal D2 receptor function, predicted the degree to which participants learned to avoid choices that had been probabilistically associated with negative outcomes. The Val/Met polymorphism of the COMT gene, associated with prefrontal cortical dopamine function, predicted participants' ability to rapidly adapt behavior on a trial-to-trial basis. These findings support a neurocomputational dissociation between striatal and prefrontal dopaminergic mechanisms in reinforcement learning. Computational maximum likelihood analyses reveal independent gene effects on three reinforcement learning parameters that can explain the observed dissociations.basal ganglia ͉ prefrontal cortex ͉ computational model

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“…It has been hypothesized that caudate neurons have two classes of dopaminergic receptors (Creese et al, 1983;Kebabian and Calne, 1979). The D2 receptors are most closely associated with DA synapses, and they have higher affinity for haloperidol than D 1 types.…”

Section: Discussionmentioning

confidence: 99%

Investigation of the failure of parenterally administered haloperidol to antagonize dopamine released from micropipettes in the caudate

Johnson¹,

Hoffer²,

Freedman³

1986

J. Neurosci.

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An anomaly in the experimental data underlying the theory that neuroleptics act by blockade of dopaminergic neurotransmission is the repeatedly demonstrated failure in several laboratories of parenterally administered neuroleptics to antagonize electrophysiologic actions of locally applied dopamine (DA) in striaturn. This failure is enigmatic since many investigators have successfully demonstrated antagonism when both dopamine and neuroleptic are applied directly to striatal neurons by microiontophoresis. We used multibarrel micropipettes to pressure-eject DA agonists onto rat caudate neurons while observing the ability of parenterally administered haloperidol to block the inhibitory actions of dopaminergic agonists on neuronal activity. Experiments performed at times of maximal behavioral effect of haloperidol did not demonstrate agonist-antagonist interaction. This result has been obtained by four other teams of investigators. A variety of pharmacologic manipulations were employed to help solve this enigma. Acute treatment with reserpine and a-methyl-paratyrosine, performed to minimize any possible interference by endogenous DA, did not permit blockade of dopamine by haloperidol. To see if this failure of antagonism could be generalized to other DA agonists, apomorphine, amphetamine, and phencyclidine (PCP) were also investigated. Although the direct dopaminergic agonist apomorphine was not antagonized by haloperidol, the indirect DA agonist PCP was successfully antagonized. Amphetamine, which has both direct and indirect actions when applied locally, was not antagonized. Antagonism of direct agonists was demonstrated in rats with unilateral 6-hydroxydopamine-induced lesions of the nigrostriatal pathway. In these preparations, parenterally administered haloperidol reversed the receptor-mediated supersensitivity to the inhibitory effects of locally applied DA and apomorphine. These data suggest that in caudate there exist postsynaptic receptors that are more sensitive to haloperidol than those receptors usually activated by DA released into the neuronal milieu from micropipettes. We suggest that PCP's indirect action on endogenous DA in presynaptic terminals results in specific interaction with these receptors. We further suggest that the postsynaptic receptors most sensitive to blockade by haloperidol may also be those receptors that increase in number following denervation. Failure to demonstrate antagonism of direct DA agonists in the absence of supersensitivity suggests that locally applied DA does not normally contact postsynaptic dopami-

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The Classification of Dopamine Receptors: Relationship to Radioligand Binding

Cited by 393 publications

References 71 publications

A mechanistic account of striatal dopamine function in human cognition: Psychopharmacological studies with cabergoline and haloperidol.

A mechanistic account of striatal dopamine function in human cognition: Psychopharmacological studies with cabergoline and haloperidol.

Genetic triple dissociation reveals multiple roles for dopamine in reinforcement learning

Investigation of the failure of parenterally administered haloperidol to antagonize dopamine released from micropipettes in the caudate

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