The effects of local application of D2 selective dopaminergic drugs into the medial prefrontal cortex of rats in a delayed spatial choice task

Druzin, Michael; Kurzina, Natalia; Malinina, Evgenya P; Kozlov, A. P.

doi:10.1016/s0166-4328(99)00166-7

Cited by 59 publications

(45 citation statements)

References 63 publications

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“…There is evidence suggesting a D2 modulation of working memory (Druzin et al, 2000) and age-related PFC cognitive functions (Arnsten et al, 1995). The inhibitory D2 effects on pyramidal cell excitability may constitute important cellular mechanisms for selection of relevant information in the PFC.…”

Section: Discussionmentioning

confidence: 99%

Dopamine–Glutamate Interactions Controlling Prefrontal Cortical Pyramidal Cell Excitability Involve Multiple Signaling Mechanisms

Tseng¹,

O’Donnell²

2004

J. Neurosci.

357

270

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Although the importance of dopamine (DA) for prefrontal cortical (PFC) cognitive functions is widely recognized, the nature of DA actions in the PFC remains controversial. A critical component in DA actions is its modulation of glutamate transmission, which can be different when specific receptors are activated. To obtain a clear picture of cellular mechanisms involved in these interactions, we studied the effects of DA-glutamate coactivation on pyramidal cell excitability in brain slices obtained from developmentally mature rats using whole-cell patch-clamp recordings. Bath application of NMDA, AMPA, and the D1 agonist SKF38393 induced concentration-dependent excitability increases, whereas bath application of the D2 receptor agonist quinpirole induced a concentration-dependent excitability decrease. The NMDA-mediated response was potentiated by SKF38393. This NMDA-D1 synergism required postsynaptic intracellular Ca 2ϩ and protein kinase A (PKA) and was independent of membrane depolarization. On the other hand, the excitatory effects of both NMDA and AMPA were attenuated by a D2 agonist. Surprisingly, the D2-NMDA interaction was also blocked by the GABA A antagonists bicuculline and picrotoxin, suggesting that the inhibitory action of D2 receptors on NMDA-induced responses in the PFC may be mediated by GABAergic interneurons. In contrast, the D2-AMPA interaction involves inhibition of PKA and activation of phospholipase lipase C-IP 3 and intracellular Ca 2ϩ at a postsynaptic level. Thus, the modulatory actions of D1 and D2 receptors on PFC pyramidal cell excitability are mediated by multiple intracellular mechanisms and by activation of GABA A receptors, depending on the glutamate receptor subtypes involved.

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Section: Discussionmentioning

confidence: 99%

Dopamine–Glutamate Interactions Controlling Prefrontal Cortical Pyramidal Cell Excitability Involve Multiple Signaling Mechanisms

Tseng¹,

O’Donnell²

2004

J. Neurosci.

357

270

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“…Specifically, intra-PFC infusions of SKF 81297 at doses ranging from 0.06 to 0.3 mg have been shown to impair performance on delayed response tasks when the baseline levels of performance are good (ie, during shorter delays), but these same doses improved working memory during longer delays, when baseline levels of performance were poor (Zahrt et al, 1997;Phillips, 2001, Chudasama and. Similarly, infusions of a D2 agonist have also been shown to disrupt performance of a delayed response task conducted in a Umaze (Druzin et al, 2000). In the present study, we observed neither a disruption nor an improvement in set-shifting following infusions of 0.06 or 0.2 mg of SKF 81297, although we did observe a slight, nonsignificant reduction in the number of errors committed by rats that were required to make the more difficult shift from a visual-cue-to a response-based strategy.…”

Section: Regulation Of Set-shifting By Both Pfc D1 and D2 Receptorsmentioning

confidence: 99%

Multiple Dopamine Receptor Subtypes in the Medial Prefrontal Cortex of the Rat Regulate Set-Shifting

Floresco

Magyar

Ghods-Sharifi

et al. 2005

Neuropsychopharmacol

359

290

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Dopamine (DA) input to the prefrontal cortex (PFC), acting on D1 receptors, plays an essential role in mediating working memory functions. In comparison, less is known about the importance of distinct PFC DA receptor subtypes in mediating executive functions such as set-shifting. The present study assessed the effects of microinfusion of D2 and D4 receptor antagonists, and D1, D2, and D4 receptor agonists into the PFC on performance of a maze-based set-shifting task. In Experiment 1, rats were trained on a response discrimination task, and then on a visual-cue discrimination task requiring rats to suppress the use of the response strategy and approach the previously irrelevant cue to locate food. In Experiment 2, the order of training was reversed. Infusions of the D2 antagonist eticlopride, or the D4 agonist PD-168,077, impaired shifting from a response to a visual-cue discrimination strategy and vice versa, and caused a selective increase in perseverative errors. In contrast, infusions of the D4 antagonist L-745,870 improved set-shifting. Infusions of the D1 agonist SKF81297 or the D2 agonist quinpirole caused no reliable effect. These data, in combination with previous reports of impaired setshifting following D1 receptor blockade, suggest that multiple receptors in the PFC are essential for set-shifting and that the mechanisms by which PFC DA mediates behavioral flexibility may be different from those underlying working memory. These findings may have important implications for developing novel treatments for cognitive deficits observed in disorders such as attentional deficit and hyperactivity disorder and schizophrenia.

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“…Thus, it is apparent that PFC D 1 receptor modulation of working memory takes the form of an "inverted U-shaped" curve (Arnsten 1997;Zahrt et al 1997;Williams and Castner 2005) where too little or too much D 1 receptor stimulation can hamper patterns of activity in PFC neural networks that normally mediate efficient working memory processes. Although the effects of D 2 receptor stimulation on working memory have yet to be explored fully, one notable study showed that infusions of a D 2 agonist also disrupt performance on a delayed response task conducted in a U-maze, whereas infusions of the D 2 antagonist sulpiride improved performance (Druzin et al 2000). This finding indicates that under some conditions, D 2 receptor activity in the PFC may also modulate working memory functions, but their contribution to these processes are distinct from those regulated by D 1 receptors.…”

Section: Working Memorymentioning

confidence: 99%

“…Likewise, infusions of the D 2 agonist quinpirole did not alter performance during the set shift. This lack of effects was surprising, considering that stimulation of DA receptors in the PFC can alter working memory performance (Zahrt et al 1997;Druzin et al 2000;Floresco and Phillips 2001;Chudasama and Robbins 2004). However, another study utilizing a perceptual setshifting task designed by Birrell and Brown (2000) showed that infusion of the partial D 1 agonist SKF 38393 does not Fig.…”

Section: Behavioral Flexibilitymentioning

confidence: 99%

Mesocortical dopamine modulation of executive functions: beyond working memory

2006

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Whereas PFC D1 receptor activity is of primary importance in working memory, D1 and D2 receptors act in a cooperative manner to facilitate behavioral flexibility. We note that the principle of the "inverted U-shaped" function of D1 receptor activity mediating working memory does not necessarily apply to other PFC functions. DA in different subregions of the PFC also mediates decision-making assessed with delay discounting or effort-based procedures, and we report that D1, D2, and D4 receptors in the medial PFC contribute to decision-making when animals must bias the direction of behavior to avoid aversive stimuli, assessed with a conditioned punishment procedure. Thus, mesocortical DA modulation of distinct executive functions is subserved by dissociable profiles of DA receptor activity in the PFC.

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The effects of local application of D2 selective dopaminergic drugs into the medial prefrontal cortex of rats in a delayed spatial choice task

Cited by 59 publications

References 63 publications

Dopamine–Glutamate Interactions Controlling Prefrontal Cortical Pyramidal Cell Excitability Involve Multiple Signaling Mechanisms

Dopamine–Glutamate Interactions Controlling Prefrontal Cortical Pyramidal Cell Excitability Involve Multiple Signaling Mechanisms

Multiple Dopamine Receptor Subtypes in the Medial Prefrontal Cortex of the Rat Regulate Set-Shifting

Mesocortical dopamine modulation of executive functions: beyond working memory

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