Dopamine D1 receptor involvement in latent inhibition and overshadowing

Nelson, Andrew John Dudley; Thur, Karen E.; Cassaday, Helen J.

doi:10.1017/s1461145711001751

Cited by 16 publications

(18 citation statements)

References 42 publications

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“…There is a possibility that this finding is sex-specific as male Drd 1 −/− could not be evaluated in these conditions, as they do not show robust LI. Recently, it has been shown in male rat studies that the D1 antagonist SCH23390 can reverse AMP effects on LI (Nelson et al , 2012), suggesting that these effects may not be specific to mice or females. Previous rat studies have shown that LI disruption by nicotine is also reversed by D 1 antagonists.…”

Section: Discussionmentioning

confidence: 99%

D-Amphetamine and Antipsychotic Drug Effects on Latent Inhibition in Mice Lacking Dopamine D2 Receptors

Bay-Richter

O'Callaghan

Mathur

et al. 2013

Neuropsychopharmacol

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Drugs that induce psychosis, such as 𝒟-amphetamine (AMP), and those that alleviate it, such as antipsychotics, are suggested to exert behavioral effects via dopamine receptor D2 (D2). All antipsychotic drugs are D2 antagonists, but D2 antagonism underlies the severe and debilitating side effects of these drugs; it is therefore important to know whether D2 is necessary for their behavioral effects. Using D2-null mice (Drd2−/−), we first investigated whether D2 is required for AMP disruption of latent inhibition (LI). LI is a process of learning to ignore irrelevant stimuli. Disruption of LI by AMP models impaired attention and abnormal salience allocation consequent to dysregulated dopamine relevant to schizophrenia. AMP disruption of LI was seen in both wild-type (WT) and Drd2−/−. This was in contrast to AMP-induced locomotor hyperactivity, which was reduced in Drd2−/−. AMP disruption of LI was attenuated in mice lacking dopamine receptor D1 (Drd1−/−), suggesting that D1 may play a role in AMP disruption of LI. Further supporting this possibility, we found that D1 antagonist SKF83566 attenuated AMP disruption of LI in WT. Remarkably, both haloperidol and clozapine attenuated AMP disruption of LI in Drd2−/−. This demonstrates that antipsychotic drugs can attenuate AMP disruption of learning to ignore irrelevant stimuli in the absence of D2 receptors. Data suggest that D2 is not essential either for AMP to disrupt or for antipsychotic drugs to reverse AMP disruption of learning to ignore irrelevant stimuli and further that D1 merits investigation in the mediation of AMP disruption of these processes.

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Section: Discussionmentioning

confidence: 99%

D-Amphetamine and Antipsychotic Drug Effects on Latent Inhibition in Mice Lacking Dopamine D2 Receptors

Bay-Richter

O'Callaghan

Mathur

et al. 2013

Neuropsychopharmacol

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“…Rats were trained, conditioned, and tested after 20–23 h of water restriction (fully described previously: Norman and Cassaday, 2003; Nelson et al, 2012; Pezze et al, 2016). …”

Section: Methodsmentioning

confidence: 99%

Scopolamine Impairs Appetitive But Not Aversive Trace Conditioning: Role of the Medial Prefrontal Cortex

2017

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The muscarinic acetylcholine receptor is an important modulator of medial prefrontal cortex (mPFC) functions, such as the working memory required to bridge a trace interval in associative leaning. Aversive and appetitive trace conditioning procedures were used to examine the effects of scopolamine (0.1 and 0.5 mg/kg, i.p.) in male rats. Follow-up experiments tested the effects of microinfusion of 0.15 μg of scopolamine (0.075 μg of in 0.5 μl/side) in infralimbic (IL) versus prelimbic regions of rat mPFC, in appetitive trace and locomotor activity (LMA) procedures. Systemic scopolamine was without effect in an aversive trace conditioning procedure, but impaired appetitive conditioning at a 2 s trace interval. This effect was demonstrated as reduced responding during presentations of the conditioned stimulus (CS) and during the interstimulus interval (ISI). There was no such effect on responding during food (unconditioned stimulus, US) responding or in the intertrial interval (ITI). In contrast, systemic scopolamine dose-relatedly increased LMA. Trace conditioning was similarly impaired at the 2 s trace (shown as reduced responding to the CS and during the ISI, but not during US presentations or in the ITI) after infusion in mPFC, whereas LMA was increased (after infusion in IL only). Therefore, our results point to the importance of cholinergic modulation in mPFC for trace conditioning and show that the observed effects cannot be attributed to reduced activity.SIGNIFICANCE STATEMENT Events are very often separated in time, in which case working memory is necessary to condition their association in “trace conditioning.” The present study used conditioning variants motivated aversively with foot shock and appetitively with food. The drug scopolamine was used to block muscarinic acetylcholine receptors involved in working memory. The results show that reduced cholinergic transmission in medial prefrontal cortex (mPFC) impaired appetitive trace conditioning at a 2 s trace interval. However, scopolamine was without effect in the aversive procedure, revealing the importance of procedural differences to the demonstration of the drug effect. The finding that blockade of muscarinic receptors in mPFC impaired trace conditioning shows that these receptors are critical modulators of short-term working memory.

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“…The results from phase II in the above experiment suggest that pairing optogenetic stimulation of DA axons in mPFC with CSs had no direct behavioral consequence, or that the task was not sensitive to its effects. Previous evidence suggests that DA can modulate latent inhibition: the ability to ignore a stimulus previously presented without reinforcement (25)(26)(27)(28). We thus further explored the possibility that CS 2 -DA pairing could bias the animal's subsequent learning, by performing additional tests on the same mice.…”

Section: Significancementioning

confidence: 99%

Phasic dopamine release in the medial prefrontal cortex enhances stimulus discrimination

Popescu

Zhou

Poo

2016

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

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Phasic dopamine (DA) release is believed to guide associative learning. Most studies have focused on projections from the ventral tegmental area (VTA) to the striatum, and the action of DA in other VTA target regions remains unclear. Using optogenetic activation of VTA projections, we examined DA function in the medial prefrontal cortex (mPFC). We found that mice perceived optogenetically induced DA release in mPFC as neither rewarding nor aversive, and did not change their previously learned behavior in response to DA transients. However, repetitive temporal pairing of an auditory conditioned stimulus (CS) with mPFC DA release resulted in faster learning of a subsequent task involving discrimination of the same CS against unpaired stimuli. Similar results were obtained using both appetitive and aversive unconditioned stimuli, supporting the notion that DA transients in mPFC do not represent valence. Using extracellular recordings, we found that CS-DA pairings increased firing of mPFC neurons in response to CSs, and administration of D 1 or D 2 DAreceptor antagonists in mPFC during learning impaired stimulus discrimination. We conclude that DA transients tune mPFC neurons for the recognition of behaviorally relevant events during learning.learning | attention | dopamine T he firing activity of dopamine (DA) neurons in the ventral tegmental area (VTA) is consistent with a role of reward prediction error signal, which is believed to guide behavioral adaptation through DA release in target brain regions (1-7). Experiments using optogenetic manipulations have established a causal link between the activity of DA neurons in VTA and the reinforcing signal that mediates learning and conditioning (8-10). Stimulation of VTA, however, results in transient DA release in many target areas, and it is unclear how each of these regions contributes to learning. For example, compared with the striatum, the medial prefrontal cortex (mPFC) receives fewer DA projections (11), expresses fewer DA reuptake transporters (12), and exhibits an overall lower level of DA (13,14). Nevertheless, pharmacological studies have implicated DA as a powerful neuromodulator of mPFC, able to influence many cognitive functions that support learning (15-21). Furthermore, DA neurons in VTA projecting to either the striatum or mPFC have distinct intrinsic neuronal properties and receive distinct inputs (22-24); thus, they are likely to serve different roles. It remains unclear what function phasic DA release might have in mPFC, whether it carries any valence, or how it affects stimulus-specific learning.In this study, we addressed specifically the role of phasic DA release in stimulus-response association. Using optogenetically timed release of DA from VTA neuronal projections in mPFC, we found that DA transients enhance the firing of mPFC neurons in response to the paired conditioned stimuli (CSs), whereas blocking DA receptors in mPFC during learning impairs stimulus discrimination. Furthermore, pairing a CS with optogenetic stimulation of DA fibers in ...

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Dopamine D1 receptor involvement in latent inhibition and overshadowing

Cited by 16 publications

References 42 publications

D-Amphetamine and Antipsychotic Drug Effects on Latent Inhibition in Mice Lacking Dopamine D2 Receptors

D-Amphetamine and Antipsychotic Drug Effects on Latent Inhibition in Mice Lacking Dopamine D2 Receptors

Scopolamine Impairs Appetitive But Not Aversive Trace Conditioning: Role of the Medial Prefrontal Cortex

Phasic dopamine release in the medial prefrontal cortex enhances stimulus discrimination

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