Localized Nonablative Neuromodulatory Irradiation of the Nucleus Accumbens Ameliorates Voluntary Excessive Alcohol Consumption in Miniature Pigs.

Abstract

OBJECTIVES: We previously reported that low-dose (Dmax < 40 Gy, 7.5-mm collimator) focal irradiation could induce durable localized neuromodulation in the brains of miniature pigs without evidence of tissue damage (Yeh et al, 2021). It remained unclear whether this approach could be used for treating maladaptive behaviors. In this study, we evaluate the therapeutic neuromodulation potential of noninvasive, nonablative, bilateral irradiation of the nucleus accumbens (NAc) in a large-animal model of voluntary excessive alcohol intake. We hypothesize that focal irradiation within the NAc at a dose previously associated with focal metabolic changes would ameliorate the addictive-like behavior. MATERIALS AND METHODS: Over a 2-year interval, Lee Sung miniature pigs were acclimated to voluntarily consume ethyl alcohol in amounts exceeding the human binge drinking level (&#x223c;0.8 g/kg/day) in a progressive fixed-ratio (PFR) task (n = 3/5). Using magnetic resonance imaging (MRI)-guided targeting, these animals underwent bilateral NAc stereotactic irradiation (Dmax = 30 Gy, 5-mm collimator). After radiation, voluntary alcohol consumption in the PFR task was quantified for a period of 1 year. During this time, brain MRI was repeated at 3-month intervals to assess for radiation-induced structural abnormalities in the NAc. RESULTS: Voluntary alcohol consumption in the PFR task significantly decreased after bilateral focal irradiation of the NAc. A marked reduction in alcohol intake was evident after procedure, with a continued downward trend observed through the ninth month after surgery. In the 1-year follow-up period, voluntary alcohol intake remained below pretreatment. Notably, no signs of radiation-induced structural abnormalities in the NAc were observed. CONCLUSIONS: In a large-animal model, we indicated that low-dose, nonablative focal irradiation of the bilateral NAc can reduce chronic excessive voluntary alcohol consumption.