Nicotine-induced neuroplasticity in striatum is subregion-specific and reversed by motor training on the rotarod.

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.

Ghrelin signalling within the rat nucleus accumbens and skilled reach foraging.

Motivation alters behaviour in a complex manner and nucleus accumbens (NAc) shell has been implied as a key structure regulating such behaviour. Recent studies show that acute ghrelin signalling enhances motivation when assessed in a simple motor task. The aim of the present study was to define the role of ghrelin signalling on motivation in a more complex motor behaviour. Rats were tested in the Montoya staircase, an animal model of skilled reach foraging assessed by the number of sucrose pellets consumed. Electrophysiological recordings were conducted to explore the neurophysiological correlates of ghrelin signalling. The initial electrophysiological results displayed that ex vivo administration of ghrelin increased NAc shell output in brain slices from drug- and training-naïve rats. In rats with an acquired skilled reach performance, acute as well as repeated treatment with a ghrelin receptor (GHSR-1 A) antagonist (JMV2959) decreased the number of sucrose pellets consumed. Moreover, infusion of JMV2959 into NAc shell reduced this consumption. Sub-chronic, during ten days, JMV2959 treatment during training on the Montoya staircase reduced the number of pellets consumed, whereas ghrelin improved this behaviour. In addition, field potential and whole cell recordings were conducted in NAc shell of rats that had been treated with ghrelin or GHSR-1 A antagonist during training on the Montoya staircase. Sub-chronic administration of ghrelin during motor-skill learning selectively increased the frequency of inhibitory transmission in the NAc shell, resulting in a net suppression of accumbal output. Collectively these data suggest that ghrelin signalling in NAc shell enhances skilled reached foraging tentatively by increasing the motivation.

Acoustic white noise ameliorates reduced regional brain expression of CaMKII and ΔFosB in the spontaneously hypertensive rat model of ADHD.

Loud (≥70dBA) acoustic white noise improves cognitive performance in children with ADHD as well as skilled reach and rotarod performance in the spontaneously hypertensive (SH) rat model of ADHD. To investigate how acoustic noise influences the brain activity in the SH rat model of ADHD, immunohistochemical staining of two neuronal activity and plasticity markers, Ca2+/Calmodulin dependent protein kinase II (CaMKII) and ΔFosB, was evaluated in Wistar (n = 24) and SH (n = 16) rats after repeated exposure to acoustic noise or ambient silence. Other SH rats (n = 6) were treated with repeated methylphenidate (MPH). Expression of CaMKII was reduced in the tuberomammillary nucleus (TMN) of the SH rat compared to Wistar but not in the nucleus accumbens (nAc) or the dorsolateral prefrontal cortex (DL-PFC). In the TMN, the expression of CaMKII was increased by noise in both strains. ΔFosB expression was reduced in nAc, DL-PFC and the dorsolateral striatum (DLS) of the SH rat compared to Wistar. Exposure to acoustic white noise significantly increased ΔFosB expression in the nAc and DL-PFC but not in the DLS of SH rats. The results indicate that acoustic noise shifts a reduced neuronal activity in the nAc, TMN and DL-PFC in SH rats toward the normal levels of activity in outbred rats. This may explain why noise has benefit selectively in ADHD.

Acoustic noise improves motor learning in spontaneously hypertensive rats, a rat model of attention deficit hyperactivity disorder.

The spontaneously hypertensive (SH) rat model of ADHD displays impaired motor learning. We used this characteristic to study if the recently described acoustic noise benefit in learning in children with ADHD is also observed in the SH rat model. SH rats and a Wistar control strain were trained in skilled reach and rotarod running under either ambient noise or in 75 dBA white noise. In other animals the effect of methylphenidate (MPH) on motor learning was assessed with the same paradigms. To determine if acoustic noise influenced spontaneous motor activity, the effect of acoustic noise was also determined in the open field activity paradigm. We confirm impaired motor learning in the SH rat compared to Wistar SCA controls. Acoustic noise restored motor learning in SH rats learning the Montoya reach test and the rotarod test, but had no influence on learning in Wistar rats. Noise had no effect on open field activity in SH rats, but increased corner time in Wistar. MPH completely restored rotarod learning and performance but did not improve skilled reach in the SH rat. It is suggested that the acoustic noise benefit previously reported in children with ADHD is shared by the SH rat model of ADHD, and the effect is in the same range as that of stimulant treatment. Acoustic noise may be useful as a non-pharmacological alternative to stimulant medication in the treatment of ADHD.