Francesca M. Filbeya, et alCraving is one of the primary behavioral components of drug addiction, and cue-elicited craving is an especially powerful form of this construct. While cue-elicited craving and its underlying neurobiological mechanisms have been extensively studied with respect to alcohol and other drugs of abuse, the same cannot be said for marijuana. Cue-elicited craving for other drugs of abuse is associated with increased activity in a number of brain areas, particularly the reward pathway. This study used functional magnetic resonance imaging (fMRI) to examine cue-elicited craving for marijuana. Thirty-eight regular marijuana users abstained from use for 72 h and were presented with tactile marijuana-related and neutral cues while undergoing a fMRI scan. Several structures in the reward pathway, including the ventral tegmental area, thalamus, anterior cingulate, insula, and amygdala, demonstrated greater blood oxygen level dependent (BOLD) activation in response to the marijuana cue as compared with the neutral cue.

These regions underlie motivated behavior and the attribution of incentive salience. Activation of the orbitofrontal cortex and nucleus accumbens was also positively correlated with problems
related to marijuana use, such that greater BOLD activation was associated with greater number of items on a marijuana problem scale. Thus, cue-elicited craving for marijuana activates the reward neurocircuitry associated with the neuropathology of addiction, and the magnitude of activation of these structures is associated with severity of cannabis-related problems. These findings may inform the development of treatment strategies for cannabis
dependence.

The relationship between craving and drug use behavior is an integral piece of the addiction puzzle. Craving is considered the intense desire for a rewarding object or experience. Cue elicited
craving, induced by exposure to alcohol- or drug-related cues, is a particularly potent form of craving. Previous investigators have reported that subjective craving increases after exposure to cues specific to a variety of drugs of abuse, including cocaine (e.g., tactile cues, videos, i.v. administration, images, guided imagery) heroin (e.g., images) alcohol (e.g., alcohol taste, images, alcohol-related words), and tobacco (e.g., visual and tactile presentations) .

Cue-elicited craving for alcohol and tobacco in particular have important clinical implications and have been the focus of psychosocial and pharmacological intervention efforts.

The advent of functional neuro-imaging has allowed studies of cue-elicited craving to elucidate the neurobiological mechanisms that accompany increased craving. Such neuro-imaging studies
have associated craving with increased activation of reward pathways . The reward circuits involve the dopamine projection from the ventral tegmental area (VTA) to striatal areas (e.g., nucleus accumbens) and the prefrontal cortex (PFC), the repeated activation of which underlies the attribution of incentive salience to otherwise neutral stimuli . Other reward-related areas, including the insula and cingulated gyrus show increased activity with the presentation of drug-related stimuli. Presentation of these stimuli is also associated with increased activity in brain structures that underlie reward and emotion regulation, such as the thalamus and amygdala.

The few published studies of cue-elicited craving for marijuana suggest that it is a reliable and valid phenomenon, analogous to cue-elicited craving for other drugs of abuse. Marijuana-related cues presented in a variety of sensory modalities, elicit increases in self-reported craving. For example, auditory-presented imagery scripts induce craving in marijuana smokers, and the magnitude of this craving varies as a function of the amount of marijuana-related content presented in the script . Craving also increases when abstinent frequent marijuana users are exposed to an auditory script that is paired with a tactile cue, such as a used marijuana pipe or bong .

Importantly, in this paradigm, cue presentation increases craving beyond the effects induced by abstinence. Additionally, marijuana related visual cues elicit greater craving in chronic heavy users than in controls; physiologically, users demonstrate greater skin conductance and larger late positivity of visual event-related brain potentials than controls in response to these stimuli .

The present study was designed to examine the effects of marijuana-related cues on the activation of reward circuitry, and to examine the relationship between these effects and the behavioral symptoms of cannabis dependence. We hypothesized that among regular marijuana users, marijuana-related cues compared with neutral cues, would elicit greater blood oxygen level dependent (BOLD) activity in reward structures (i.e., VTA, striatum, anterior cingulate, and insula). Furthermore, we hypothesized that the magnitude of this response would be associated with the number of problems related to marijuana use.

Results

Compared with the neutral cue, presentation of the marijuana cue elicited significantly greater BOLD activation in a large cluster encompassing several areas, including the VTA, dorsal anterior cingulate cortex, cerebellum, thalamus, pre- and postcentral gyri, inferior frontal gyrus/insula, thalamus, amygdala,

fusiform gyrus, pre- and postcentral gyri, inferior parietal lobe, and superior temporal gyrus (cluster-corrected z_2.3, P_0.05)

BOLD response in several of these differentially activated areas was also significantly positively correlated with total marijuana problem scale (MPS) score (cluster-corrected z _ 2.3, P _ 0.05). These areas included the orbitofrontal cortex (OFC) and nucleus accumbens (NAc) The analyses of correlations with the Structured Clinical Interview for DSM Disorders (SCID) total symptom count, subjective urge ratings, frequency, and duration of use did not meet the significance threshold.

Source: 13016–13021 _ PNAS _ August 4, 2009 _ vol. 106 _ no. 31 www.pnas.org_cgi_doi_10.1073_pnas.0903863106