Persistent changes in exploration and hyperactivity coexist with cognitive impairment in mice withdrawn from chronic cocaine

Mañas‐Padilla, M. Carmen; Ávila‐Gámiz, Fabiola; Gil-Rodríguez, Sara; Guevara‐Miranda, David Ladrón de; Fonseca, Fernando Rodrı́guez de; Santín, Luis J.; Castilla‐Ortega, Estela

doi:10.1016/j.physbeh.2021.113542

Cited by 9 publications

(23 citation statements)

References 26 publications

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“…A previous study found a similar reduction following contingency reversal after intra-DMS infusion of a cholinergic M2/M4 receptor agonist (Bradfield et al ., 2013). This reduction in nose-poking is not likely to reflect reduced locomotion since cocaine withdrawal has been shown to increase, rather than decrease, this activity (Mañas-Padilla et al, 2021). The reduction in nose-poking is also unlikely to result from a cocaine-induced decrease in motivation because both the cocaine and saline groups showed equal increases in their responses during initial learning as the reinforcement schedule became progressively more challenging (FR1→RR20).…”

Section: Discussionmentioning

confidence: 99%

Drug Reinforcement Impairs Cognitive Flexibility by Inhibiting Striatal Cholinergic Neurons

Gangal

Xie

Cheng

et al. 2022

Preprint

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The mechanisms underlying the reduction in cognitive flexibility associated with reinforcement of addictive substance use are unknown. This reinforcement is mediated by substance-induced synaptic plasticity in direct-pathway medium spiny neurons (dMSNs) that project to the substantia nigra (SNr). Cognitive flexibility is mediated by cholinergic interneurons (CINs), which receive extensive local inhibition from the striatum. Here, we report that cocaine or alcohol administration caused a long-lasting potentiation of local inhibitory dMSN-->CIN transmission in the dorsomedial striatum (DMS), a brain region critical for goal-directed behavior and cognitive flexibility. This dMSN-->CIN potentiation reduced CIN firing activity. Furthermore, chemogenetic and time-locked optogenetic inhibition of DMS CINs suppressed cognitive flexibility in an instrumental reversal learning task. Importantly, rabies-mediated tracing and physiological studies revealed that SNr-projecting dMSNs, which mediate reinforcement, sent axonal collaterals to inhibit DMS CINs, which mediate flexibility. Our findings demonstrate that the local inhibitory dMSN-->CIN circuit mediates a reinforcement-induced reduction in cognitive flexibility.

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Section: Discussionmentioning

confidence: 99%

Drug Reinforcement Impairs Cognitive Flexibility by Inhibiting Striatal Cholinergic Neurons

Gangal

Xie

Cheng

et al. 2022

Preprint

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“…This dosage regimen was chosen because it has been shown to induce persistent cognitive and exploratory alterations. 9 , 10 , 11 …”

Section: Methodsmentioning

confidence: 99%

“…According with other studies (reviewed in Mañas‐Padilla et al 8 ), we have previously shown that young male mice exposed to 12–14 days of repeated cocaine administration display behavioural alterations that persist after protracted cocaine abstinence. 9 , 10 , 11 Mainly, mice abstinent from chronic cocaine exposure are impaired in hippocampal‐dependent memory, evidenced by object or place recognition and spatial navigation tasks, 9 , 10 , 11 and they may demonstrate exacerbated exploratory activity and motor activation when they are exposed to challenging situations or novel environments. 10 In this regard, the hippocampus is a brain region widely communicated with main addiction‐related brain areas that has a key role for declarative memory, emotional behaviour and response to novel stimuli; and it modulates the hyperlocomotive effects of cocaine—through excitatory connections with the accumbens.…”

Section: Introductionmentioning

confidence: 99%

“… 9 , 10 , 11 Mainly, mice abstinent from chronic cocaine exposure are impaired in hippocampal‐dependent memory, evidenced by object or place recognition and spatial navigation tasks, 9 , 10 , 11 and they may demonstrate exacerbated exploratory activity and motor activation when they are exposed to challenging situations or novel environments. 10 In this regard, the hippocampus is a brain region widely communicated with main addiction‐related brain areas that has a key role for declarative memory, emotional behaviour and response to novel stimuli; and it modulates the hyperlocomotive effects of cocaine—through excitatory connections with the accumbens. 12 , 13 Therefore, the hippocampus is a strong candidate to modulate the cocaine‐induced behavioural symptoms, and so, strategies that stimulate hippocampal plasticity may be valuable in the therapies destined to treat the cocaine abuse.…”

Section: Introductionmentioning

confidence: 99%

“…Interestingly, cocaine‐abstinent mice show normal AHN levels in basal conditions; but they show a dysregulation—either an abnormal increase or decrease—of their number of hippocampal immature neurons when they are exposed to behavioural tasks. 9 , 10 , 11 Therefore, they could be benefited of a pro‐AHN intervention such as EE. The present study aims to investigate whether EE improves the emotional and cognitive symptoms caused by chronic cocaine administration and, whether EE modulates the AHN in cocaine‐abstinent mice.…”

Section: Introductionmentioning

confidence: 99%

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Environmental enrichment alleviates cognitive and psychomotor alterations and increases adult hippocampal neurogenesis in cocaine withdrawn mice

et al. 2022

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Cocaine is a widely used psychostimulant drug whose repeated exposure induces persistent cognitive/emotional dysregulation, which could be a predictor of relapse in users. However, there is scarce evidence on effective treatments to alleviate these symptoms. Environmental enrichment (EE) has been shown to be associated with improved synaptic function and cellular plasticity changes related to adult hippocampal neurogenesis (AHN), resulting in cognitive enhancement. Therefore, EE could mitigate the negative impact of chronic administration of cocaine in mice and reduce the emotional and cognitive symptoms present during cocaine abstinence. In this study, mice were chronically administered with cocaine for 14 days, and control mice received saline. After the last cocaine or saline dose, mice were submitted to control or EE housing conditions, and they stayed undisturbed for 28 days. Subsequently, mice were evaluated with a battery of behavioural tests for exploratory activity, emotional behaviour, and cognitive performance. EE attenuated hyperlocomotion, induced anxiolytic‐like behaviour and alleviated cognitive impairment in spatial memory in the cocaine‐abstinent mice. The EE protocol notably upregulated AHN in both control and cocaine‐treated mice, though cocaine slightly reduced the number of immature neurons. Altogether, these results demonstrate that EE could enhance hippocampal neuroplasticity ameliorating the behavioural and cognitive consequences of repeated administration of cocaine. Therefore, environmental stimulation may be a useful strategy in the treatment cocaine addiction.

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Temozolomide treatment inhibits spontaneous motivation for exploring a complex object in mice: A potential role of adult hippocampal neurogenesis in “curiosity”

Mañas‐Padilla

Melgar‐Locatelli

Vicente

et al. 2022

J of Comparative Neurology

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Intrinsic exploratory biases are an innate motivation for exploring certain types of stimuli or environments over others, and they may be associated with cognitive, emotional, and even personality‐like traits. However, their neurobiological basis has been scarcely investigated. Considering the involvement of the hippocampus in novelty recognition and in spatial and pattern separation tasks, this work researched the role of adult hippocampal neurogenesis (AHN) in intrinsic exploratory bias for a perceptually complex object in mice. Spontaneous object preference tasks revealed that both male and female C57BL/6J mice showed a consistent unconditioned preference for exploring “complex”—irregular—objects over simpler ones. Furthermore, increasing objects’ complexity resulted in an augmented time of object exploration. In a different experiment, male mice received either vehicle or the DNA alkylating agent temozolomide (TMZ) for 4 weeks, a pharmacological treatment that reduced AHN as evidenced by immunohistochemistry. After assessment in a behavioral test battery, the TMZ‐treated mice did not show any alterations in general exploratory and anxiety‐like responses. However, when tested in the spontaneous object preference task, the TMZ‐treated mice did not display enhanced exploration of the complex object, as evidenced both by a reduced exploration time—specifically for the complex object—and a lack of preference for the complex object over the simple one. This study supports a novel role of AHN in intrinsic exploratory bias for perceptual complexity. Moreover, the spontaneous complex object preference task as a rodent model of “curiosity” is discussed.

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Persistent changes in exploration and hyperactivity coexist with cognitive impairment in mice withdrawn from chronic cocaine

Cited by 9 publications

References 26 publications

Drug Reinforcement Impairs Cognitive Flexibility by Inhibiting Striatal Cholinergic Neurons

Drug Reinforcement Impairs Cognitive Flexibility by Inhibiting Striatal Cholinergic Neurons

Environmental enrichment alleviates cognitive and psychomotor alterations and increases adult hippocampal neurogenesis in cocaine withdrawn mice

Temozolomide treatment inhibits spontaneous motivation for exploring a complex object in mice: A potential role of adult hippocampal neurogenesis in “curiosity”

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