Feeding suppression associated with a CB1R inverse agonist was abolished in mice that received a peripheral β-adrenergic inhibitor, chemical ablation of afferent sensory fibers, including afferent vagal fibers, and micro-injections of the NMDA glutamatergic receptor antagonist, MK-801, into the nucleus of the solitary tract. Moreover, metabolic benefits of Roux-en-Y gastric bypass in mice were dependent on a mechanism that included interactions between CB1Rs and sympathetic neurotransmission. Studies will be important to identify possible roles for CB1Rs in interactions between sympathetic and parasympathetic branches of the autonomic nervous system and their participation in control of food intake and energy metabolism.The pre-clinical studies in rodents discussed above suggest that the eCB system is an integral component of the gut-brain axis that controls food intake and becomes dysregulated in obesity. These investigations provide evidence of specific molecular and cellular mechanisms that underlie eCB-mediated gut-brain signaling, which may inform development of therapeutic strategies for the treatment of human obesity and related metabolic disorders. Indeed, human studies indicate that eCB levels are elevated in blood during consumption of palatable foods and in obesity.In particular, rimonabant—a systemically acting CB1R antagonist/inverse agonist—showed clinical promise for its anti-obesity effects that included reductions in body weight, waist circumference,drying cannabis and levels of circulating triglycerides, and increases in levels of high-density lipoprotein.
Unfortunately, rimonabant was associated with psychiatric side effects such as increased depression and anxiety, which precluded its approval by the Food and Drug Administration for the treatment of obesity in the Unites States. These effects were likely a result of its ability to access the brain and disrupt cognitive functions. On the other hand, CB1R antagonists that are designed to have low brain penetrance display similar anti-obesity effects as their brain-penetrant counterparts and may be a useful therapeutic strategy for safe and effective treatment of obesity and related metabolic disorders. Collectively, these investigations provide evidence that the eCB system in the gastrointestinal tract is a key component of the gut–brain axis that controls food intake and becomes dysregulated in diet-induced obesity. Exciting new studies suggest important interactions between the eCB system and the gut microbiome; however, future investigations will be important to identify molecular and cellular mechanisms in these interactions, and the impact on gut-brain signaling important for food intake and energy metabolism in health and metabolic disease. In addition, studies will be important to elucidate specific intracellular mechanisms that the eCB system recruits to control release of satiation peptides and other signaling molecules from the intestinal epithelium, including those involved in transduction of food-related signals to activation of vagal afferent neurons by “neuropods”. It is clear that eCBs have indirect and direct actions on vagal afferent neural signaling; however, it is unclear how gut-brain eCB signaling interacts with brain reward circuits in control of food intake and reward. Moreover, it will be important to identify how gut-brain eCB signaling participates in discrete aspects of food intake and reward, including satiation and satiety versus appetition.
Recreational stimulant use is a growing concern among young adults, with 4.4% and 5% to 35% of college students endorsing cocaine and recreational amphetamine use, respectively, and 16% of cocaine experimenters developing dependence within 10 years. To develop cost-effective prevention and intervention strategies, it is crucial to identify ultra–high risk recreational users. However, little is known about bio-behavioral markers forecasting trajectory of occasional stimulant use to stimulant use disorder. Previous stimulant use research is predominantly cross-sectional, comparing individuals with chronic stimulant use with healthy individuals; although findings from these studies highlight brain disruptions related to drug use, they cannot disentangle whether disruptions preceded or were a result of chronic use. Young adulthood is a period of increased independence, often providing more opportunities for risky behavior such as drug experimentation. Risky behavior can be defined as actions that may be subjectively desirable but are potentially harmful and is typically quantified in young adults by their degree of substance use, unprotected sex, health habits, and crime engagement. Risk taking often occurs in clusters of maladaptive behaviors, suggesting underlying impairments in decision making. Decision making involves several brain processes, including learning, inhibition, and outcome assessment, specifically appraising positive or negative valence of choices. Functional magnetic resonance imaging research indicates that individuals with SUD show impaired decision making associated with altered brain activation in executive control and reward processing regions. Decision making is thought to involve a cooperative relationship between an impulsive system activated by immediate rewards and an inhibitory control system. Through learning, the control network allows individuals to resist immediate attraction to rewards in favor of longer-term advantageous outcomes. In SUD, bio-behavioral indices of risk taking suggest an underlying imbalance between the control and impulsive systems.
The control system integral to decision making comprises prefrontal cortex , theorized as responsible for learning the relationship between stimuli and outcome, working memory, and inhibiting behavior. SUD samples exhibit frontal lobe impairments associated with compromised decision making and increased risk behavior. For example, cocaine abusers exhibit dorsolateral PFC hypoactivation during response inhibition and prediction of uncertain outcomes ; in cocaine dependence, orbitofrontal cortex and DLPFC attenuation are linked to reduced ability to differentiate between variable monetary gains. Similarly, methamphetamine users inaccurately process success or failure of available options, a pattern associated with orbitofrontal cortex/DLPFC hypoactivation. Working in conjunction with frontal regions is striatum, an area associated with reward processing ,plant benches selecting and initiating actions , and learning. During the Iowa Gambling Task , healthy individuals show stronger striatal activation to wins than to losses , but amphetam independent individuals demonstrate hypersensitive striatal responses to rewards. Cocaine and methamphetamine users also exhibit striatal hyperactivation but frontal hypoactivation during risky decision-making tasks such as the Iowa Gambling Task and the Balloon Analogue Risk Task that is linked to riskier behavioral performance. This suggests that such neural patterns during decision making promote favoring of risky incentives. Evidence from fMRI studies has led researchers to theorize that frontal lobe and striatum form a functional circuit with insular cortex and anterior cingulate cortex ; these regions coordinate to integrate emotional and autonomic information about rewards into goal-oriented behavior. ACC is proposed to be involved in emotion and behavior management based on its neural connections to both the emotion processing limbic system and the cognitive control center, PFC. Insula is proposed to play a role in interoceptive processing, wherein individuals integrate physiological cues to differentiate between risky and safe decisions and transform these cues into conscious feelings and behaviors. ACC and insula hypoactivation is evident in chronic stimulant users in response inhibition and error monitoring during decision making. Evidence for aberrant activity in key components of the PFC-limbic network has led researchers to suggest that weakened ability to accurately process information about options and control behaviors leads to favoring choices that offer immediate, rather than delayed, rewards. Cross-sectional studies of occasional stimulant users report decision-making impairments that parallel findings in stimulant-dependent individuals, including 1) weakened inhibitory control and reduced cognitive flexibility ; 2) neuropsychological impairments in executive functions ; and 3) frontal, striatal, and insular attenuation during a Risky Gains Task paired with reduced ability to differentiate between safe and risky decisions. Several research groups have recognized limitations of cross-sectional addiction research and have shifted toward a longitudinal approach to understand the transition to problematic substance use. Structural MRI studies show that decreased brain volume in frontocentral regions at age 14 years predicts binge drinking at age 16 and that frontostriatal regions are linked to heightened stimulant use in OSUs 1 to 2 years later. However, fMRI has been less applied to predict the development of SUD. The current longitudinal study used follow-up clinical and drug use data from OSUs 3 years after an fMRI scan to determine whether baseline behavioral and blood oxygen level–dependent responses during the RGT 1) differentiated young adults who became problem stimulant users from those who desisted from stimulant use during the 3-year interim and 2) predicted cumulative baseline and follow-up stimulant and marijuana use across OSUs, regardless of clinical status , to address concerns regarding significant rates of marijuana and stimulant co-use.
Analyses compared BOLD activity related to specific task requirements: decision contrasts compared BOLD activity during risk-taking choice trials versus safe choice trials; outcome contrasts compared BOLD activity on trials where each subject took a risk and subsequently earned a win or a loss. Categorical hypotheses were tested based on prior biobehavioral findings in stimulant- dependent individuals: 1) PSUs would exhibit riskier task performance than DSUs; 2) PSUs would show greater striatal BOLD signals than DSUs to outcomes, particularly in response to risky wins; and 3) PSUs would exhibit lower PFC, insular, and cingulate BOLD signals during decision making. Because dimensional analyses were exploratory, no a priori hypotheses were tested.Three hypotheses were tested. First, consistent with the prediction that PSUs would exhibit riskier task performance than DSUs, PSUs more frequently made a risky decision following a win compared with DSUs, while DSUs more frequently made a safe decision following a risky win. This pattern supports previous findings that PSUs are more reactive to rewards. Second, although it was predicted that PSUs would show greater activation in reward processing striatal regions to risky wins than to risky losses when compared with DSUs, our results demonstrated the opposite effect, with PSUs exhibiting lower striatal BOLD signals across outcomes than DSUs. However, this finding is consistent with a longitudinal study of sensation-seeking adolescents in which striatal hypoactivation predicted future problematic drug use; the authors theorized that lower striatal activity may lead to a compensatory mechanism in which one seeks out increased risk to gain greater stimulation, thereby balancing reward center hypoactivation. PSUs exhibited greater temporo-occipital BOLD signals to wins than to losses, findings consistent with a recent meta-analysis reporting that 86% of addiction-related neuroimaging studies demonstrate significant visual cortex activity to drug cues. Although the RGT did not test drug-related responses, our results demonstrate an analogous relationship to general reward cues, suggesting that PSUs may allocate greater visual attention to risky rewards than to risky losses. Middle temporal lobe is involved in memory of reward-based information critical for future oriented decision making, suggesting that PSUs may be less able to consolidate information about outcomes differently. Together, PSUs are characterized by visual attention and memory activation during risky rewards but blunted responsivity to loss outcomes. Our third prediction was supported in that PSUs exhibited lower PFC, insula, and cingulate BOLD signals than DSUs during risky feedback. These findings align with a recent study conducted by our research group demonstrating that during a task evaluating how individuals learn to make decisions, PSUs exhibited lower insula and ACC activation across all available outcomes than DSUs. Such patterns are consistent with previous reports of PFC, insula, and ACC attenuations in chronic stimulant users that are linked with decreased ability to adapt behavior using prior experiences/ reduced inhibitory control, interoceptive awareness, and conflict monitoring, respectively. Thus, young adults predisposed to SUD may have prior deficits in recruiting neural effort toward critical decision-making processes. Nonhypothesized group differences also emerged in thalamic, precuneus, and posterior cingulate regions that warrant discussion. PSUs showed relatively greater precuneus and posterior cingulate BOLD signals when making risky decisions than when making safe decisions when compared with DSUs. Such differences are consistent with previous findings in SUD samples that heightened activation of these areas during exteroceptive awareness may underlie the maintenance and exacerbation of substance use. Greater thalamic response to risky reward versus loss feedback in PSUs is consistent with research demonstrating that thalamic BOLD signals are linked to relapse in cocaine-dependent individuals. Thalamus acts as a relay center for the brain by sending sensory information to insula for further interoceptive processing ; hypoactivation to loss may reflect differences in relay and integration of information during decision making. With respect to baseline characteristics, DSUs endorsed higher baseline levels of state depression than PSUs, which may have affected RGT performance given that individuals with depression tend to be risk averse. However, given that mean scores for DSUs are substantially below the Beck Depression Inventory threshold for clinical depression [in nonclinical populations, scores above 20 indicate depression ; it is unlikely that DSUs performed in a manner consistent with samples with depression].