Since its founding in 2017, the CCB has financially supported a variety of research investigations. While some of these projects are only just beginning, others, listed below, have been submitted to and published by neuroscience academic journals. Please note that future papers will be added to this list as they are published.
Ghrelin: From a gut hormone to a potential therapeutic target for alcohol use disorder.
CCB Fellow Mehdi Farokhnia published in Physiology and Behavior (epub Feburar 2019)
Abstract: Alcohol use disorder (AUD) is a leading cause of morbidity and mortality worldwide. However, treatment options, including pharmacotherapies, are limited in number and efficacy. Accumulating evidence suggests that elements of the gut-brain axis, such as neuroendocrine pathways and gut microbiome, are involved in the pathophysiology of AUD and, therefore, may be investigated as potential therapeutic targets. One pathway that has begun to be examined in this regard is the ghrelin system. Here, we review preclinical and clinical data on the relationship between ghrelin and alcohol-related outcomes, with a special focus on the role of the ghrelin system as a treatment target for AUD. Observational studies indicate that endogenous ghrelin levels are positively associated with craving for alcohol, subjective responses to alcohol, and brain activity in response to alcohol cues. Knockout rodent models suggest that deletion of the ghrelin peptide or receptor gene leads to reduction of alcohol intake and other alcohol-related outcomes. Different research groups have found that ghrelin administration increases, while ghrelin receptor (GHS-R1a) blockade reduces alcohol intake and other alcohol-related outcomes in rodents. Ghrelin administration in heavy-drinking individuals increases alcohol craving and self-administration and modulates brain activity in response to alcohol reward anticipation. PF-5190457, a GHS-R1a blocker, has been shown to be safe and tolerable when co-administered with alcohol. Furthermore, preliminary results suggest that this compound may reduce cue-elicited craving for alcohol in heavy-drinking individuals - a finding in need of replication. Collectively, the existing literature supports further examination of the ghrelin system as a therapeutic target for AUD. More research is also needed to understand the biobehavioral and molecular mechanisms underlying ghrelin's functions and to examine different interventional approaches to target the ghrelin system for AUD treatment.
D1 receptor hypersensitivity in mice with low striatal D2 receptors facilitates select cocaine behaviors.
CCB Fellow Lauren Dobbs published in Neuropsychopharmacology (epub December 2018)
Abstract: Vulnerability for cocaine abuse in humans is associated with low dopamine D2 receptor (D2R) availability in the striatum. The mechanisms driving this vulnerability are poorly understood. In this study, we found that downregulating D2R expression selectively in striatal indirect-pathway neurons triggers a multitude of changes in D1 receptors (D1R)-expressing direct-pathway neurons, which comprise the other main subpopulation of striatal projection neurons. These changes include a leftward shift in the dose response to D1-like agonist that indicates a behavioral D1R hypersensitivity, a shift from PKA to ERK intracellular signaling cascades upon D1R activation, and a reduction in the density of bridging collaterals from D1R-expressing neurons to pallidal areas. We hypothesize that the D1R hypersensitivity underlies abuse vulnerability by facilitating the behavioral responses to repeated cocaine, such as locomotor sensitization and drugs self-administration. We found evidence that littermate control mice develop D1R hypersensitivity after they are sensitized to cocaine. Indeed, D1-like agonist and cocaine cross-sensitize in control littermates and this effect was potentiated in mice lacking striatal D2Rs from indirect pathway neurons. To our surprise, mice with low striatal D2Rs acquired cocaine self-administration similarly to littermate controls and showed no significant change in motivation to take cocaine but lower seeking. These findings indicate that downregulation of striatal D2Rs triggers D1R hypersensitivity to facilitate cocaine locomotor sensitization, which by itself was not associated with greater cocaine taking or seeking under the conditions tested.
A competitive model for striatal action selection.
CCB Fellow Wambura Fobbs published in Brain Research (October 2018)
Abstract: The direct and indirect pathway striatal medium spiny neurons (dMSNs and iMSNs) have long been linked to action selection, but the precise roles of these neurons in this process remain unclear. Here, we review different models of striatal pathway function, focusing on the classic “go/no-go” model which posits that dMSNs facilitate movement while iMSNs inhibit movement, and the “complementary” model, which argues that dMSNs facilitate the selection of specific actions while iMSNs inhibit potentially conflicting actions. We discuss the merits and shortcomings of these models and propose a “competitive” model to explain the contribution of these two pathways to behavior. The “competitive” model argues that rather than inhibiting conflicting actions, iMSNs are tuned to the same actions that dMSNs facilitate, and the two populations “compete” to determine the animal’s behavioral response. This model provides a theoretical explanation for how these pathways work together to select actions. In addition, it provides a link between action selection and behavioral reinforcement, via modulating synaptic strength at inputs onto dMSNs and iMSNs. Finally, this model makes predictions about how imbalances in the activity of these pathways may underlie behavioral traits associated with psychiatric disorders. Understanding the roles of these striatal pathways in action selection may help to clarify the neuronal mechanisms of decision-making under normal and pathological conditions.
Volitional social interaction prevents drug addiction in rat models.
CCB Fellow Marco Venniro published in Nature Neuroscience (October 2018)
Abstract: Addiction treatment has not been appreciably improved by neuroscientific research. One problem is that mechanistic studies using rodent models do not incorporate volitional social factors, which play a critical role in human addiction. Here, using rats, we introduce an operant model of choice between drugs and social interaction. Independent of sex, drug class, drug dose, training conditions, abstinence duration, social housing, or addiction score in Diagnostic & Statistical Manual IV-based and intermittent access models, operant social reward prevented drug self-administration. This protection was lessened by delay or punishment of the social reward but neither measure was correlated with the addiction score. Social-choice-induced abstinence also prevented incubation of methamphetamine craving. This protective effect was associated with activation of central amygdala PKCδ-expressing inhibitory neurons and inhibition of anterior insular cortex activity. These findings highlight the need for incorporating social factors into neuroscience-based addiction research and support the wider implantation of socially based addiction treatments.
Novel models of drug relapse and craving after voluntary abstinence.
CCB Fellow Marco Venniro published in Neuropsychopharmacology (September 2018)
Abstract: Researchers introduced two novel models of choice-based voluntary abstinence and demonstrated the profound protective effects of positive social interaction on drug addiction and relapse in rat models. Findings support wider implementation of social-based behavioral treatments, which include not only the established community reinforcement approach, but also social-based psychotherapies and family-based social support systems to provide social support before and during drug-seeking episodes.
Why Do Mice Overeat High-Fat Diets? How High-Fat Diet Alters the Regulation of Daily Caloric Intake in Mice.
CCB Fellow Wambura Fobbs published in Obesity (Silver Spring) (June 2018)
Ad libitum high-fat diets (HFDs) spontaneously increase caloric intake in rodents, which correlates positively with weight gain. However, it remains unclear why rodents overeat HFDs. This paper investigated how changing the proportion of diet that came from HFDs might alter daily caloric intake in mice.
METHODS: Mice were given 25%, 50%, or 90% of their daily caloric need from an HFD, along with ad libitum access to a low-fat rodent chow diet. Food intake was measured daily to determine how these HFD supplements impacted total daily caloric intake. Follow-up experiments addressed the timing of HFD feeding.
RESULTS: HFD supplements did not alter total caloric intake or body weight. In a follow-up experiment, mice consumed approximately 50% of their daily caloric need from an HFD in 30 minutes during the light cycle, a time when mice do not normally consume food.
An HFD did not disrupt regulation of total daily caloric intake, even when up to 90% of total calories came from the HFD. However, HFDs increased daily caloric intake when provided ad libitum and were readily consumed by mice outside of their normal feeding cycle. Ad libitum HFDs appear to induce overconsumption beyond the mechanisms that regulate daily caloric intake.
If research you completed with the help of CCB funding is in the process of being submitted for publication, please include the following affiliation and acknowledgement statements in your paper:
Center on Compulsive Behaviors, Intramural Research Program, NIH, Bethesda, MD, USA
This study was funded by the Center on Compulsive Behaviors, NIH via NIH Director’s Challenge Award to (YOUR INITIALS HERE)