Appetitive Instrumental Learning Is Impaired by Inhibition of cAMP-Dependent Protein Kinase within the Nucleus Accumbens

Baldwin, Anne E.; Sadeghian, Kenneth; Holahan, Matthew R.; Kelley, Ann E.

doi:10.1006/nlme.2000.4002

Cited by 85 publications

(89 citation statements)

References 54 publications

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“…Because cAMP signaling is primarily mediated through binding PKA, manipulating cAMP binding sites on PKA is a widely accepted method to study cAMP transmission Baldwin et al, 2002;Beninger and Gerdjikov, 2004;Lynch and Taylor, 2005). The typical "cAMP antagonist," Rp-cyclic adenosine 3Ј,5Ј-phosphorothioate (Rp), is a competitive inhibitor for cAMP binding sites on PKA which maintains PKA in its inactive state (Schwede et al, 2000).…”

Section: Resultsmentioning

confidence: 99%

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Opposing Regulation of Pair Bond Formation by cAMP Signaling within the Nucleus Accumbens Shell

Aragona¹,

Wang²

2007

J. Neurosci.

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The formation of monogamous pair bonds, by prairie voles, is facilitated by activation of dopamine (DA) D 2 -like, but not D 1 -like, receptors within the nucleus accumbens (NAcc) shell. Because DA exerts opposing regulation of cAMP production depending on the subtype of receptor activated, we tested the hypothesis that DA regulation of pair bond formation is mediated via the cAMP signaling cascade. Consistent with activation of D 2 -like receptors, decreasing cAMP signaling, by blocking cAMP binding sites on protein kinase A (PKA), facilitated partner preference formation. Conversely, increasing cAMP signaling, by preventing the activation of inhibitory G-proteins, activating stimulatory G-proteins, or stimulating PKA prevented the formation of mating-induced partner preferences. These manipulations were effective in the shell, but not the core, of the NAcc. Together, these data demonstrate opposing regulation over pair bond formation by cAMP signaling within the NAcc shell.

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Section: Resultsmentioning

confidence: 99%

“…Further, a positive relationship has generally been found between cAMP signaling and food seeking (Beninger and Gerdjikov, 2004). For example, cAMP signaling in the NAcc core is important for the acquisition of food seeking (Baldwin et al, 2002). Thus, cAMP signaling within the NAcc mediates multiple aspects of goal-directed behavior.…”

Section: Discussionmentioning

confidence: 99%

Opposing Regulation of Pair Bond Formation by cAMP Signaling within the Nucleus Accumbens Shell

Aragona¹,

Wang²

2007

J. Neurosci.

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“…Notably, no effect of LY293558 was observed when administered post-trial, whereas other post-trial treatments, including inhibition of PKA or de novo protein synthesis (Baldwin et al 2002a;Hernandez et al 2002), have been shown to impair consolidation when administered at the same time point. Thus, it appears that AMPA/KA receptors may only be required during the encoding or acquisition phase of instrumental learning and are not obviously involved in consolidation (i.e., ongoing gene expression and protein synthesis) once the animal is removed from the stimulus situation.…”

Section: Discussionmentioning

confidence: 98%

“…The coincident detection of glutamate and dopamine signals has been shown to be required for long-term potentiation (Wickens et al 1996;Arbuthnott et al 2000;Floresco et al 2001;Kerr and Wickens 2001) by regulating the transcription and translation of plasticity-related immediate-early genes through various second messenger systems (Sharp et al 1995;Sutton and Beninger 1999;Berke and Hyman 2000;Horvitz 2002;Reynolds and Wickens 2002;Steward and Worley 2002;Kelley 2004). Indeed, post-training inhibition of cAMP-dependent protein kinase (PKA) (Baldwin et al 2002a) or inhibition of de novo protein synthesis within the NAc core (Hernandez et al 2002) prevents the consolidation, or longterm stabilization, of memory for response-outcome contingencies.…”

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confidence: 99%

AMPA/kainate, NMDA, and dopamine D1 receptor function in the nucleus accumbens core: A context-limited role in the encoding and consolidation of instrumental memory

Hernandez¹,

Andrzejewski²,

Sadeghian³

et al. 2005

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Neural integration of glutamate-and dopamine-coded signals within the nucleus accumbens (NAc) is a fundamental process governing cellular plasticity underlying reward-related learning. Intra-NAc core blockade of NMDA or D1 receptors in rats impairs instrumental learning (lever-pressing for sugar pellets), but it is not known during which phase of learning (acquisition or consolidation) these receptors are recruited, nor is it known what role AMPA/kainate receptors have in these processes. Here we show that pre-trial intra-NAc core administration of the NMDA, AMPA/KA, and D1 receptor antagonists AP-5 (1 µg/0.5 µL), LY293558 (0.01 or 0.1 µg/0.5 µL), and SCH23390 (1 µg/0.5 µL), respectively, impaired acquisition of a lever-pressing response, whereas post-trial administration left memory consolidation unaffected. An analysis of the microstructure of behavior while rats were under the influence of these drugs revealed that glutamatergic and dopaminergic signals contribute differentially to critical aspects of the initial, randomly emitted behaviors that enable reinforcement learning. Thus, glutamate and dopamine receptors are activated in a time-limited fashion-only being required while the animals are actively engaged in the learning context.In order to survive in changing environments, animals must be able to acquire, consolidate, and retrieve pertinent information regarding a given stimulus situation. The ability to learn associations between various stimuli and events, including motor actions, is the basis of instrumental learning (Rescorla 1991;Dickinson and Balleine 1994). Appetitive instrumental learning occurs when an animal associates its behavior with a favorable outcome such as food, sex, or the avoidance of pain. For instance, in a common experimental model of instrumental learning, a hungry rat learns to press a lever to obtain a food reward.The nucleus accumbens (NAc) and its associated circuitry have been linked to the acquisition of adaptive motor responses and the control of behaviors related to natural reinforcers (Setlow 1997;Parkinson et al. 2000;Corbit et al. 2001). Because of the rich glutamatergic and dopaminergic innervation of the NAc from regions associated with motivational, cognitive, and sensory processes, many studies have focused on the role of these neurotransmitter systems with respect to instrumental and incentive learning (Berridge and Robinson 1998;Cardinal et al. 2002;Beninger and Gerdjikov 2004;Kelley 2004). For example, blockade of glutamate (N-methyl-D-aspartate, NMDA) or dopamine D1 receptors within the NAc core potently impairs instrumental learning, and coinfusion of low, individually ineffective doses of AP-5 and SCH23390 also prevents learning, suggesting that convergence of both systems on post-synaptic neurons is required In the aforementioned studies, pre-trial blockade of NMDA and D1 receptors appeared to prevent the encoding (or acquisition) of information; however, it is possible that disruption of the consolidation phase of learning or retrieval could have contribut...

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“…The first 10 reinforcers were obtained on a fixed ratio 1 schedule, followed by a variable ratio 2 schedule, in which one, two, or three responses were reinforced in a 15-min session (35). Mice were required to retrieve each pellet before further reinforcement.…”

Section: Methodsmentioning

confidence: 99%

Loss of dendrite stabilization by the Abl-related gene (Arg) kinase regulates behavioral flexibility and sensitivity to cocaine

Gourley

Koleske

Taylor

2009

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

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Adolescence is characterized by increased vulnerability to developing neuropsychiatric disorders and involves a period of prefrontal cortical dendritic refinement and synaptic pruning that culminates in cytoskeletal stabilization in adulthood. The Abl-related gene (Arg) acts through p190RhoGAP to inhibit the RhoA GTPase and stabilize cortical dendritic arbors beginning in adolescence. Cortical axons, dendrites, and synapses develop normally in Argdeficient (arg ؊/؊ ) mice, but adult dendrites destabilize and regress; thus, arg ؊/؊ mice present a model of adolescent-onset dendritic simplification. We show that arg ؊/؊ mice are impaired in a reversal task and that deficits are grossly exacerbated by low-dose cocaine administration. Although ventral prefrontal dopamine D2 receptor levels predict ''perseverative'' error counts in wild-type mice, no such relationship is found in arg ؊/؊ mice. Moreover, arg ؊/؊ mice are insensitive to the disruptive effects of the D2/D3 antagonist haloperidol in reversal but show normal sensitivity to its locomotor-depressant actions. Arg deficiency and orbitofrontal cortical Arg inhibition via STI-571 infusion also enhance the psychomotor stimulant actions of cocaine. These findings provide evidence that stabilization of dendritic structure beginning in adolescence is critical for the development of adaptive and flexible behavior after cocaine exposure.A dolescence is a critical period of maturation for corticostriatal neurocircuitry and is characterized by increased risk taking, novelty seeking, and vulnerability to addictive drugs that, with repeated use, are associated with cognitive dysfunction in adulthood (1-3). In utero cocaine exposure has limited effects on cognitive performance in adult rodents (4-6), but adolescent and adult cocaine use is associated with poor inhibitory control, inflexible behavior, and drug-related compulsivity. Here, we use an animal model of late-onset dendritic simplification to test the hypothesis that the transition from dendritic refinement and synaptic pruning processes that occur in the adolescent prefrontal cortex (PFC), to the dendrite stabilization processes occurring in the adult PFC, is a period of vulnerability to cocaine.Numerous proteins regulate cortical dendrite development; to date, however, only a few have been implicated in cytoskeletal stability in adolescence and adulthood, serving primarily to antagonize inherent cytoskeletal retraction machinery. For example, activation of the master cytoskeletal regulator, RhoA (Rho), induces neurite retraction, a process required for pruning and refining neuronal connections during development. Rho activation in mature neurons, however, leads to synapse loss and dendritic regression in a wide variety of experimental systems (7-9). Recent studies have identified a Rho inhibitory pathway involving integrin adhesion receptors, the Abl family tyrosine kinase, Arg, and the Rho inhibitor, p190RhoGAP, that acts in dendritic spines of late adolescent mice to maintain synapses and promote dendrite stabi...

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Appetitive Instrumental Learning Is Impaired by Inhibition of cAMP-Dependent Protein Kinase within the Nucleus Accumbens

Cited by 85 publications

References 54 publications

Opposing Regulation of Pair Bond Formation by cAMP Signaling within the Nucleus Accumbens Shell

Opposing Regulation of Pair Bond Formation by cAMP Signaling within the Nucleus Accumbens Shell

AMPA/kainate, NMDA, and dopamine D1 receptor function in the nucleus accumbens core: A context-limited role in the encoding and consolidation of instrumental memory

Loss of dendrite stabilization by the Abl-related gene (Arg) kinase regulates behavioral flexibility and sensitivity to cocaine

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