Cerebellar Vermis Involvement in Cocaine-Related Behaviors

Abstract

Although the cerebellum is increasingly being viewed as a brain area involved in cognition, it typically is excluded from circuitry considered to mediate stimulant-associated behaviors since it is low in dopamine. Yet, the primate cerebellar vermis (lobules II-III and VIII-IX) has been reported to contain axonal dopamine transporter immunoreactivity (DAT-IR). We hypothesized that DAT-IR-containing vermis areas would be activated in cocaine abusers by cocaine-related cues and, in healthy humans, would accumulate DAT-selective ligands. We used BOLD fMRI to determine whether cocaine-related cues activated DAT-IR-enriched vermis regions in cocaine abusers and positron emission tomography imaging of healthy humans to determine whether the DAT-selective ligand [ 11 C]altropane accumulated in those vermis regions. Cocaine-related cues selectively induced BOLD activation in lobules II-III and VIII-IX in cocaine users, and, at early time points after ligand administration, we found appreciable [ 11 C]altropane accumulation in lobules VIII-IX, possibly indicating DAT presence in this region. These data suggest that parts of cerebellar vermis mediate cocaine's persisting and acute effects. In light of prior findings illustrating vermis connections to midbrain dopamine cell body regions, established roles for the vermis as a locus of sensorimotor integration and motor planning, and findings of increased vermis activation in substance abusers during reward-related and other cognitive tasks, we propose that the vermis be considered one of the structures involved in cocaine-and other incentive-related behaviors.

The cerebellum in drug craving

“…Neuroimaging findings showed that presenting cocaine addicts with visual or auditory cues resulted in greater activity in the anterior and posterior vermis (Anderson et al, 2006). In the same way, widespread activation of the vermis and cerebellar hemispheres was found when drug users were exposed to tactile marijuana cues (a pipe) (Filbey et al, 2009).…”

“…Interestingly, the vast majority of human imaging studies in which the cerebellum has been found to be active when craving is experienced were done by exposing addicts to drug-associated cues (Grant et al, 1996;Bonson et al, 2002;Kilts et al, 2001;Anderson et al, 2006;Filbey et al, 2009;Smolka et al, 2006;Tomasi et al, 2015). Similarly, animal research has demonstrated the selective activation of the cerebellum in rodents that express a preference towards cocaine-related cues (Carbo-Gas et al, 2014ab).…”

“…Of note, one of the most influential addiction theories posits that such disease is driven by the attribution of excessive incentive salience to drugs and drug-associated cues (Robinson and Berridge, 1993). Data showing cerebellar activations when salient stimuli or cues are presented no matter their valence point to the involvement of this structure in such process (Moulton et al, 2011;Killgore et al, 2003;Anderson et al, 2006). Moreover, resting-state functional connectivity studies have allowed to unravel a functional network termed as the "salience network", which showed responsivity to salient events with independence of the sensory modality (Downar et al, 2002).…”

“…Numerous human neuroimaging studies have demonstrated activation in the cerebellum during the presentation of drug-associated cues (Anderson et al, 2006;Filbey et al, 2009;Grant et al, 1996). In almost every study, craving was elicited by the presentation of the cue.…”

“…Interestingly, activation of the cerebellum was a common finding in the aforementioned imaging studies (Anderson et al, 2006;Bonson et al, 2002;Filbey et al, 2009;Grant et al, 1996;Kilts et al, 2001;Smolka et al, 2006;Tomasi et al, 2015). However, this region has been habitually overlooked probably because of the firmly established view of the cerebellum as a region exclusively committed to motor-related functions.…”