The Motivational And Habit Circuits Of The Brain:Determining Alterations In Addiction And Potential Therapeutic Modulation Via Losartan

Reward-oriented goal-directed and habitual behaviors are important for survival and everyday life,helping us to rapidly adapt to changing environments and reducing cognitive load in a stable environment,respectively.The neural basis for these behaviors is the motivational and habit circuits of the brain,which support functions that encompass value-driven processing,reward seeking,and automated cognitive and behavioral adaptions.Dysfunctional motivation-habit pathways have been associated with the development of psychiatric disorders such as substance addiction,obsessive-compulsive disorder,pathological gambling,and gaming addiction.Animal models suggest that the shift from motivational drive to compulsive addictive substance use is mediated by a shift from ventral to dorsal striatal dominance in the motivational and habit circuits.However,the specific process by which the neuroadaptive shift in the striatum leads to addiction in humans remains to be determined.Therefore,human translational studies are urgently needed to examine the role of the motivation-habit pathway,especially the ventral-dorsal striatal switch,in the the addictive process in human.Determining the dysregulation of the motivation-habit pathway in addiction and understanding its neural basis could help identify new and effective therapeutic targets that could further improve interventions for addiction.Animal models suggest that the renin-angiotensin antagonist losartan may modulate striatal and midbrain activity and initial human studies reported effects on behaviors associated with this circuits such as reward-and punishment-learning.However,the effects of a modulation of the renin-angiotensin system via losartan on neural activity,particularly on the motivational and habit circuits,have not been established.Against this background,the current experimental studies used magnetic resonance imaging(MRI)combined with psychopharmacological interventions and computational cognitive neuroscience approaches to examine,in four studies,the role of the ventral-dorsal striatum shift in the motivational and habit circuits in non-substance and substance addiction,the effects of losartan on the functional performance of the motivational and habit circuits during reward-punishment processing,and the effects of losartan on the spontaneous activity of the motivational and habit circuits.Study I,structural MRI with a dimensional approach in a non-clinical sample without a diagnosis of gaming disorder and confirmed a significant negative correlation between the severity of gaming disorder symptoms and striatal gray matter volume,and that this association was more pronounced in the ventral striatum,which is consistent with animal models as well as the hypothesis that the ventral striatum plays a dominant role during early stages of addiction and may mediate the initial dysregulation of reward-incentive related processes.Study I provided basic evidence that addictive behaviors in humans without the neurotoxic effects of addictive substances are still dominated by the striatum.Therefore,in Study II,combining a cue-reactivity task with MRI,we examined cannabis users who were recruited based on their addiction status as addicted and non-addicted,by comparing them with a well-matched healthy control group.Results revealed that cannabis cue exposure increased arousal and craving in users,and both cannabis user groups showed higher ventral striatal reactivity responses in response to cannabis cues,while dorsal striatal reactivity responses were specifically observed in addicted cannabis users.The findings from Studies I and II confirmed that dysregulation of the motivational and habit circuits is associated with the development of addiction.To explore the effects of losartan on the motivational and habit circuits,Study III combined a social incentive delay task that engages the motivation-habit pathway with a double-blind,between-group,placebo-controlled pharmacological experimental design with functional MRI and computational modeling to test whether losartan could modulate social reward and punishment processing via these circuits.It was found that losartan modulates the motivational significance of social rewards and punishments in the anticipation phase,while influencing subsequent affective evaluation of social stimuli.At the neural level,losartan enhanced coupling between the ventral striatum and the middle frontal gyrus during the anticipation phase of social reward.During the outcome feedback phase,losartan enhanced activity in the ventral tegmental area,as well as prediction error signals in the ventral tegmental area and dorsal striatum.These findings reveal a potential neurodynamic modulation of the motivational and habit circuits of losartan that enhances social reward motivation while decreasing sensitivity to social punishment.Another consideration for the clinical utility of losartan is its general effect on spontaneous brain activity.To this end,in Study IV,resting-state functional MRI was conducted to determine general effects of losartan on spontaneous neural activity by combining brain entropy,seed-based functional connectivity,and spectral dynamic causal modeling approaches.It was found that losartan decreases brain entropy in the ventral tegmental area and ventral striatum,as well as in a wide range of brain regions,including frontal and temporal lobes and subcortical structures,while losartan also increases brain entropy in a small number of brain regions,including the inferior frontal gyrus/insula and the fusiform gyrus.Higher brain entropy values indicate stronger and more flexible information processing capacity,suggesting that losartan inhibits intrinsic information processing capacity in key regions of the motivation-habit pathway.Using a spectral dynamic causal model to further examine the effect of losartan on the effective connectivity of the motivation-habit pathway,parametric empirical Bayesian analysis revealed that in terms of effective connectivity losartan mainly affects connectivity of the dorsal striatum.In conclusion,this paper systematically explored the role of the motivation-habit circuits in the development of nonsubstance and substance addiction through the above four experimental studies,and found that the shift of the ventral-dorsal striatum may be the neural mechanism promoting addiction development,which provides a theoretical framework and neural target to inform future addiction interventions and treatments.We also explored the impact of psychopharmacological interventions targeting the motivation-habit pathway with losartan as a means,and found that losartan can specifically affect the neural activity in the core brain regions of the motivation-habit pathway,such as the ventral tegmental area,ventral striatum,and dorsal striatum,by task-and resting-state functional MRI,providing a potential clinical application of losartan as intervention for addiction and other psychiatric disorders associated with dysregulation of the motivation-habit pathway.