Inhibiting cyclin-dependent kinase 5 in the nucleus accumbens enhances the expression of amphetamine-induced locomotor conditioning

Singer, Bryan F.; Forneris, Justin; Vezina, Paul

doi:10.1016/j.bbr.2014.08.055

Cited by 6 publications

(10 citation statements)

References 23 publications

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“…However, it is also possible that the different neuronal events underlying the induction and expression of conditioning were differentially affected by changes in Cdk5 and Kal7 in these experiments, rendering the effects ultimately observed difficult to interpret. Supporting this possibility, we recently found that, unlike the results obtained in the present experiments, inhibiting NAcc Cdk5 not during exposure but immediately before testing enhanced the expression of amphetamine-induced locomotor conditioning and sensitization (Singer et al , in review). …”

Section: Discussionsupporting

confidence: 65%

Locomotor conditioning by amphetamine requires cyclin-dependent kinase 5 signaling in the nucleus accumbens

et al. 2014

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Intermittent systemic exposure to psychostimulants such as amphetamine leads to several forms of long-lasting behavioral plasticity including nonassociative sensitization and associative conditioning. In the nucleus accumbens (NAcc), the protein serine/threonine kinase cyclin-dependent kinase 5 (Cdk5) and its phosphorylation target, the guanine-nucleotide exchange factor kalirin-7 (Kal7), may contribute to the neuroadaptations underlying each of these forms of plasticity. Pharmacological inhibition of Cdk5 in the NAcc prevents the increases in dendritic spine density in this site and enhances the locomotor sensitization normally observed following repeated cocaine. Mice lacking the Kal7 gene display similar phenotypes suggesting that locomotor sensitization and increased NAcc spine density need not be positively correlated. As increases in spine density may relate to the formation of associative memories and both Cdk5 and Kal7 regulate the generation of spines following repeated drug exposure, we hypothesized that either inhibiting Cdk5 or preventing its phosphorylation of Kal7 in the NAcc may prevent the induction of drug conditioning. In the present experiments, blockade in rats of NAcc Cdk5 activity with roscovitine (40 nmol/0.5μl/side) prior to each of 4 injections of amphetamine (1.5 mg/kg; i.p.) prevented the accrual of contextual locomotor conditioning but spared the induction of locomotor sensitization as revealed on tests conducted one week later. Similarly, transient viral expression in the NAcc exclusively during amphetamine exposure of a threoninealanine mutant form of Kal7 [mKal7(T1590A)] that is not phosphorylated by Cdk5 also prevented the accrual of contextual conditioning and spared the induction of sensitization. These results indicate that signaling via Cdk5 and Kal7 in the NAcc is necessary for the formation of context-drug associations, potentially through the modulation of dendritic spine dynamics in this site.

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Section: Discussionsupporting

confidence: 65%

Locomotor conditioning by amphetamine requires cyclin-dependent kinase 5 signaling in the nucleus accumbens

et al. 2014

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“…As expected, rats that showed conditioned behavioral responding (Paired, IP AMPH) also showed conditioned increases in c-Fos expression in the NAcc shell (Figure 3c; one-way ANOVA, c-Fos/NeuN, % Control; F 2, 10 = 5.18, po0.05; Scheffé post hoc, Paired (264.25 ± 30.88 cells/rat) vs Unpaired (180.60 ± 16.17 cells/rat) or Control (216.50 ± 25.91 cells/rat), po0.05). This effect was not expected nor was it observed in the NAcc core (data not shown; one-way ANOVA, c-Fos/NeuN, F 2, 23 = 0.57, NS) as contextual stimuli are processed in the NAcc shell and not the NAcc core (Cruz et al, 2014a;Singer et al, 2014aSinger et al, , 2014b. Importantly, Paired rats that previously received intra-VTA amphetamine displayed neither conditioned locomotion nor increases in c-Fos expression in the NAcc shell (Figure 3d; one-way ANOVA, c-Fos/NeuN, % Control; F 2, 14 = 0.18, NS; Paired (590.33 ± 58.72 cells/rat), Unpaired (676.00 ± 62.73 cells/rat), Control (575.50 ± 44.76 cells/rat)).…”

Section: Associative Conditioningmentioning

confidence: 83%

“…This leads to the development of conditioned drugseeking behavior in the presence of cues, thereby increasing chances of reinforcement. Interestingly, the development of associative conditioning parallels the formation of nonassociative sensitized behavioral and neurochemical responding to amphetamine (Singer et al, 2009(Singer et al, , 2014aVezina and Leyton, 2009) and both have been implicated in escalated drug use in humans and animal models Vezina, 2013, 2014).…”

Section: Introductionmentioning

confidence: 99%

Drug-Paired Contextual Stimuli Increase Dendritic Spine Dynamics in Select Nucleus Accumbens Neurons

Singer

Bubula

et al. 2016

Neuropsychopharmacol

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Repeated exposure to amphetamine leads to both associative conditioning and nonassociative sensitization. Here we assessed the contribution of neuronal ensembles in the nucleus accumbens (NAcc) to these behaviors. Animals exposed to amphetamine IP or in the ventral tegmental area (VTA) showed a sensitized locomotor response when challenged with amphetamine weeks later. Both exposure routes also increased ΔFosB levels in the NAcc. Further characterization of these ΔFosB+ neurons, however, revealed that amphetamine had no effect on dendritic spine density or size, indicating that these neurons do not undergo changes in dendritic spine morphology that accompany the expression of nonassociative sensitization. Additional experiments determined how neurons in the NAcc contribute to the expression of associative conditioning. A discrimination learning procedure was used to expose rats to IP or VTA amphetamine either Paired or Unpaired with an open field. As expected, compared with Controls, Paired rats administered IP amphetamine subsequently showed a conditioned locomotor response when challenged with saline in the open field, an effect accompanied by an increase in c-Fos+ neurons in the medial NAcc. Further characterization of these c-Fos+ cells revealed that Paired rats showed an increase in the density of dendritic spines and the frequency of medium-sized spines in the NAcc. In contrast, Paired rats previously exposed to VTA amphetamine showed neither conditioned locomotion nor conditioned c-Fos+ expression. Together, these results suggest a role for c-Fos+ neurons in the medial NAcc and rapid changes in the morphology of their dendritic spines in the expression of conditioning evoked by amphetaminepaired contextual stimuli.

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“…Behavioral training and testing were conducted as previously described (Singer et al, 2016, 2014a, 2014b). Briefly, rats were conditioned using a discrimination learning paradigm over the course of five consecutive 3-day blocks.…”

Section: Methodsmentioning

confidence: 99%

“…Protein expression was examined specifically in the NAcc shell because this site is known to process contextual, as opposed to discrete, stimulus information (Bossert et al, 2013, 2007; Everitt and Robbins, 2005; Singer et al, 2014a, 2014b). Contextual cues also elicit rapid changes in dendritic spine morphology in the NAcc shell (Singer et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Stimuli associated with the presence or absence of amphetamine regulate cytoskeletal signaling and behavior

Singer

Bubula

Przybycien-Szymanska

et al. 2016

European Neuropsychopharmacology

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Drug-paired stimuli rapidly enlarge dendritic spines in the nucleus accumbens (NAcc). While increases in spine size and shape are supported by rearrangement of the actin cytoskeleton and facilitate the synaptic expression of AMPA-type glutamate receptors, it remains unclear whether drug-related stimuli can influence signaling pathways known to regulate these changes in spine morphology. These pathways were studied in rats trained on a discrimination learning paradigm using subcellular fractionation and protein immunoblotting to isolate proteins within dendritic spine compartments in the NAcc shell. An open field chamber was repeatedly associated with amphetamine in one group (Paired) and explicitly unpaired with amphetamine in another (Unpaired). Rats in a third group were exposed to the open field but never administered amphetamine (Control). When administered saline and returned to the open field one week later, Paired rats as expected displayed a conditioned locomotor response relative to rats in the other two groups. NAcc shell tissues were harvested immediately after this 30-minute test. Re-exposing Paired rats to the drug-paired excitatory context significantly decreased p-GluA2(S880), an effect consistent with reduced internalization of this subunit and increased spine proliferation in these rats. In contrast, re-exposing Unpaired rats to the drug-unpaired context, capable of inhibiting conditioned responding in these animals, significantly decreased levels of both actin binding protein Arp2/3 and p-cofilin, consistent with spine volatility, shrinkage, and inhibition of spine proliferation in these rats. These findings show that contextual stimuli previously associated with either the presence or absence of amphetamine differentially regulate cytoskeletal signaling pathways in the NAcc.

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Inhibiting cyclin-dependent kinase 5 in the nucleus accumbens enhances the expression of amphetamine-induced locomotor conditioning

Cited by 6 publications

References 23 publications

Locomotor conditioning by amphetamine requires cyclin-dependent kinase 5 signaling in the nucleus accumbens

Locomotor conditioning by amphetamine requires cyclin-dependent kinase 5 signaling in the nucleus accumbens

Drug-Paired Contextual Stimuli Increase Dendritic Spine Dynamics in Select Nucleus Accumbens Neurons

Stimuli associated with the presence or absence of amphetamine regulate cytoskeletal signaling and behavior

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