Abstract
Nicotine is recognized as one of the most addictive drugs, which in part could be attributed to progressive neuroadaptations and rewiring of dorsal striatal circuits. Since motor‐skill learning produces neuroplasticity in the same circuits, we postulate that rotarod training could be sufficient to block nicotine‐induced rewiring and thereby prevent long‐lasting impairments of neuronal functioning. To test this hypothesis, Wistar rats were subjected to 15 days of treatment with either nicotine (0.36 mg/kg) or vehicle. After treatment, a subset of animals was trained on the rotarod. Ex vivo electrophysiology was performed 1 week after the nicotine treatment period and after up to 3 months of withdrawal to define neurophysiological transformations in circuits of the striatum and amygdala. Our data demonstrate that nicotine alters striatal neurotransmission in a distinct temporal and spatial sequence, where acute transformations are initiated in dorsomedial striatum (DMS) and nucleus accumbens (nAc) core. Following 3 months of withdrawal, synaptic plasticity in the form of endocannabinoid‐mediated long‐term depression (eCB‐LTD) is impaired in the dorsolateral striatum (DLS), and neurotransmission is altered in DLS, nAc shell, and the central nucleus of the amygdala (CeA). Training on the rotarod, performed after nicotine treatment, blocks neurophysiological transformations in striatal subregions, and prevents nicotine‐induced impairment of eCB‐LTD. These datasets suggest that nicotine‐induced rewiring of striatal circuits can be extinguished by other behaviors that induce neuroplasticity. It remains to be determined if motor‐skill training could be used to prevent escalating patterns of drug use in experienced users or facilitate the recovery from addiction.
Highlights
Tobacco use is a leading preventable cause of death worldwide
One hemisphere of the slice was constantly perfused with prewarmed artificial cerebrospinal fluid (aCSF) (30°C, 2 mL/min), and field population spikes (PSs) were evoked with a stimulating electrode and registered with a recording electrode in subregions of the striatum and amygdala
There was no significant effect by nicotine treatment on synaptic depression induced by the dopamine D2 receptor agonist quinpirole, neither after 1 week withdrawal (DMS: F 1,19 = 1.84, P = .19; dorsolateral striatum (DLS): F 1,22 = 0.53, P = .49) (Figure S1)
Summary
Tobacco use is a leading preventable cause of death worldwide. Even though the use of conventional cigarettes has decreased during the last 20 years, smoking is still a major health problem. The introduction of electronic cigarettes (e‐cigarettes) has once again increased nicotine use globally, and there is an association between initial e‐cigarette use and cigarette smoking later in life.[1] In order to reduce smoking prevalence, there is a need for more basic research that defines the effects by nicotine on neuronal circuits, and studies outlining how nicotine‐mediated maladaptation of neuronal function can be prevented. Studies of motor‐skill consolidation have led up to the postulate that neuroadaptations initially occurring in the DMS are transferred to the DLS where they may become permanent.[9,15,16] If nicotine‐ induced striatal rewiring depends on antecedent activity in the DMS, motor‐skill learning on the rotarod might in this regard act to counterbalance nicotine‐induced neurophysiological transformations and/or prevent progressive neuroadaptations. Based on this line of reasoning, we hypothesize that a period of training on the rotarod would prevent the progressive rewiring of neuronal circuits and extinguish the cascade of neurophysiological adaptations elicited by nicotine
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