Nicotine and Resting-State Functional Connectivity: Effects of Intermittent Doses

Abstract

Introduction: It is unknown how the timing between doses might affect nicotine's impact on neural activity. Our objective was to examine how the interdose interval affects nicotine's impact on resting-state functional connectivity (rsFC). Materials and Methods: Adult male Sprague-Dawley rats were administered nicotine daily (0.4 mg/ kg) over 6 days while control animals received saline vehicle. Functional magnetic resonance imaging was used to measure rsFC before and after a challenge dose of nicotine (0.4 mg/kg) delivered for the first time and 3, 6, 12, or 24 hr after the previous dose. Results: As the interval between nicotine doses increased from 3 to 24 hr, the strength of rsFC increased in some circuits, particularly the nucleus accumbens and prefrontal circuits, and decreased in others, namely the interpeduncular nucleus, hippocampus, caudoputamen, retrosplenial cortex, ventral tegmental, and the insular circuits. Conclusions: These data indicate that the effect that nicotine has on the brain is affected by the amount of time that has passed since the previous dose. The effect on rsFC of cumulative doses is not additive. This may have important implications for the study of nicotine addiction as it implies that the same dose of nicotine might have a different impact on the brain depending on the time elapsed from the previous exposure.

Altered neural connectivity in adult female rats exposed to early life social stress

“…Previous behavioral and neuroendocrine gene expression analyses of ECSS exposed animals have described depressed maternal care, decreased aggression, increased anxiety, and numerous behaviorally relevant changes in gene expression in stress and depression associated nuclei [5,6,15]. The present approach identified functional connectivity in the range of our previous rat studies [10,11,16] and those of other groups [17,18], and was sensitive to group differences even at modest connectivity levels. These rodent RSFC data support the hypotheses that the ECSS procedure has long term effects on neural connectivity in numerous social behavior, stress, and depression relevant brain nuclei and that socially focused pathological animal models involve robust changes in resting connectivity in multiple clinically relevant networks, including the limbic system, the reward system, and the introspective socioaffective and salience networks.…”

“…All fMRI data were processed and analyzed using Medical Image Visualization and Analysis (MIVA, http://ccni.wpi.edu), Statistical Parametric Mapping (SPM8) software (Wellcome Department of Cognitive Neurology, London, UK) and Matlab (The Mathworks Inc., Natick, MA, USA), following a similar processing pipeline addressed in our previous publications [3,4,10,11]. Anatomical and fMRI images were registered from multiple subjects to a fully segmented rat brain atlas (Swanson).…”

The power of using functional fMRI on small rodents to study brain pharmacology and disease

“…For example, a differential sensitivity to cocaine is seen in female rats not only as a result of hormonal changes during/throughout the estrous cycle, but also in association with changes in sexual receptivity and presence of pups ( Febo et al, 2011 ; Caffrey and Febo, 2014 ). FC analyses show connectivity effects in the brain which depend on the amount of time that has passed since the previous dosage of the drug, which implies that the same dose of nicotine might have a different impact on the brain depending on the time elapsed from the previous exposure ( Huang et al, 2015 ). Finally, long term effects of addiction are extensively studied.…”

Menthol enhances nicotine-induced locomotor sensitization and in vivo functional connectivity in adolescence

“…On the day following the open-field experiment (PND50±1), subsets of previously acclimated adolescent animals from two groups (nicotine-only, n =6, and nicotine with 5.38 mg/kg menthol, n =6) underwent fMRI imaging as previously described (Huang et al, 2015; Li et al, 2008; Liang et al, 2012a,b).…”

“…The effects of this exposure were assessed in relation to locomotor activity and functional connectivity as measured by magnetic resonance imaging. It was hypothesized that repeated nicotine and menthol co-administration would enhance locomotor sensitization, and that this behavioral effect would be accompanied by enhanced functional connectivity involving the nucleus accumbens and the ventral tegmental area, circuits previously identified as affected by nicotine in our laboratory (Huang et al, 2015; Li et al, 2008).…”