CCB Publications

Effects of oral, smoked, and vaporized cannabis on endocrine pathways related to appetite and metabolism: a randomized, double-blind, placebo-controlled, human laboratory study.
CCB Fellow Mehdi Farokhnia published in Translational Psychiatry (February 2020)

Abstract: As perspectives on cannabis continue to shift, understanding the physiological and behavioral effects of cannabis use is of paramount importance. Previous data suggest that cannabis use influences food intake, appetite, and metabolism, yet human research in this regard remains scant. The present study investigated the effects of cannabis administration, via different routes, on peripheral concentrations of appetitive and metabolic hormones in a sample of cannabis users. This was a randomized, crossover, double-blind, placebo-controlled study. Twenty participants underwent four experimental sessions during which oral cannabis, smoked cannabis, vaporized cannabis, or placebo was administered. Active compounds contained 6.9 ± 0.95% (~50.6 mg) Δ9-tetrahydrocannabinol (THC). Repeated blood samples were obtained, and the following endocrine markers were measured: total ghrelin, acyl-ghrelin, leptin, glucagon-like peptide-1 (GLP-1), and insulin. Results showed a significant drug main effect (p = 0.001), as well as a significant drug × time-point interaction effect (p = 0.01) on insulin. The spike in blood insulin concentrations observed under the placebo condition (probably due to the intake of brownie) was blunted by cannabis administration. A significant drug main effect (p = 0.001), as well as a trend-level drug × time-point interaction effect (p = 0.08) was also detected for GLP-1, suggesting that GLP-1 concentrations were lower under cannabis, compared to the placebo condition. Finally, a significant drug main effect (p = 0.01) was found for total ghrelin, suggesting that total ghrelin concentrations during the oral cannabis session were higher than the smoked and vaporized cannabis sessions. In conclusion, cannabis administration in this study modulated blood concentrations of some appetitive and metabolic hormones, chiefly insulin, in cannabis users. Understanding the mechanisms underpinning these effects may provide additional information on the cross-talk between cannabinoids and physiological pathways related to appetite and metabolism.

Continuous Representations of Speed by Striatal Medium Spiny Neurons.
CCB Alumni Wambura Fobbs published in Journal of Neuroscience (February 2020)

Abstract: The striatum is critical for controlling motor output. However, it remains unclear how striatal output neurons encode and facilitate movement. A prominent theory suggests that striatal units encode movements in bursts of activity near specific events, such as the start or end of actions. These bursts are theorized to gate or permit specific motor actions, thereby encoding and facilitating complex sequences of actions. An alternative theory has suggested that striatal neurons encode continuous changes in sensory or motor information with graded changes in firing rate. Supporting this theory, many striatal neurons exhibit such graded changes without bursting near specific actions. Here, we evaluated these two theories in the same recordings of mice (both male and female). We recorded single-unit and multiunit activity from the dorsomedial striatum of mice as they spontaneously explored an arena. We observed both types of encoding, although continuous encoding was more prevalent than bursting near movement initiation or termination. The majority of recorded units did not exhibit positive linear relationships with speed but instead exhibited nonlinear relationships that peaked at a range of locomotor speeds. Bulk calcium recordings of identified direct and indirect pathway neurons revealed similar speed tuning profiles, indicating that the heterogeneity in response profiles was not due to this genetic distinction. We conclude that continuous encoding of speed is a central component of movement encoding in the striatum.
SIGNIFICANCE STATEMENT The striatum is a structure that is linked to volitional movements and is a primary site of pathology in movement disorders. It remains unclear how striatal neurons encode motor parameters and use them to facilitate movement. Here, we evaluated two models for this: a “discrete encoding model” in which striatal neurons facilitate movements with brief burst of activity near the start and end of movements, and a “continuous encoding model”, in which striatal neurons encode the sensory or motor state of the animal with continuous changes in firing. We found evidence primarily in support of the continuous encoding model. This may have implications for understanding the striatal control of movement, as well as informing therapeutic approaches for treating movement disorders.

Effect of the dopamine stabilizer (-)-OSU6162 on potentiated incubation of opioid craving after electric barrier-induced voluntary abstinence..
CCB Fellow Ida Fredriksson published in Neuropsychopharmacology (January 2020)

Abstract: In the classical incubation of drug craving rat model, drug seeking is assessed after homecage forced abstinence. However, human abstinence is often voluntary because negative consequences of drug seeking outweigh the desire for the drug. Here, we developed a rat model of incubation of opioid craving after electric barrier-induced voluntary abstinence and determined whether the dopamine stabilizer (-)-OSU6162 would decrease this new form of incubation. We trained male and female rats to self-administer oxycodone (0.1 mg/kg/infusion, 6 h/day) for 14 days. We then exposed them to either homecage forced abstinence or voluntary abstinence induced by an electric barrier of increasing intensity near the drug-paired lever. On abstinence days 1, 15, or 30, we tested the rats for oxycodone seeking without shock and drug. We also examined the effect of (-)-OSU6162 (7.5 and 15 mg/kg) on oxycodone seeking on abstinence day 1 or after 15 days of either voluntary or forced abstinence. Independent of sex, the time-dependent increase in oxycodone seeking after cessation of opioid self-administration (incubation of opioid craving) was stronger after voluntary abstinence than after forced abstinence. In males, (-)-OSU6162 decreased incubated (day 15) but not non-incubated (day 1) oxycodone seeking after either voluntary or forced abstinence. In females, (-)-OSU6162 modestly decreased incubated oxycodone seeking after voluntary but not forced abstinence. Results suggest that voluntary abstinence induced by negative consequences of drug seeking can paradoxically potentiate opioid craving and relapse. We propose the dopamine stabilizer (-)-OSU6162 may serve as an adjunct pharmacological treatment to prevent relapse in male opioid users.

Taking action: empathy and social interaction in rats.
CCB Fellow Marco Venniro published in Neuropsychopharmacology (January 2020)

Abstract: Imagine you are walking and notice a person crying on the sidewalk visibly in distress. This individual is not familiar to you and has not requested any assistance, so you understandably hesitate to approach. A likely question you may ask yourself in that moment of indecision is whether you would like a stranger to offer support if you found yourself in a similar situation. Do you ultimately stop to offer emotional support? The ability to understand the circumstances of someone other than yourself is defined as empathy. Empathy is a complex behavior that facilitates the formation of social connections through interpersonal socialization and aid. A lack of empathy can contribute to the psychopathology of several neuropsychiatric diseases, including autism spectrum disorder and substance use disorder. Therefore, it is crucial to understand the psychological processes and neurobiological substrates of empathic behavior.

Prefrontal regulation of punished ethanol self-administration.
Collaboration of CCB Fellows Michael Authement and Patrick Piantadosi published in Biological Psychiatry (November 2019)

Abstract:
Background A clinical hallmark of alcohol use disorder is persistent drinking despite potential adverse consequences. The ventromedial prefrontal cortex (vmPFC) and dorsomedial prefrontal cortex (dmPFC) are positioned to exert top-down control over subcortical regions, such as the nucleus accumbens shell (NAcS) and basolateral amygdala, which encode positive and negative valence of ethanol (EtOH)-related stimuli. Prior rodent studies have implicated these regions in regulation of punished EtOH self-administration (EtOH-SA).
Methods We conducted in vivo electrophysiological recordings in mouse vmPFC and dmPFC to obtain neuronal correlates of footshock-punished EtOH-SA. Ex vivo recordings were performed in NAcS D1 receptor-expressing medium spiny neurons receiving vmPFC input to examine punishment-related plasticity in this pathway. Optogenetic photosilencing was employed to assess the functional contribution of the vmPFC, dmPFC, vmPFC projections to NAcS, or vmPFC projections to basolateral amygdala, to punished EtOH-SA.
Results Punishment reduced EtOH lever pressing and elicited aborted presses (lever approach followed by rapid retraction). Neurons in the vmPFC and dmPFC exhibited phasic firing to EtOH lever presses and aborts, but only in the vmPFC was there a population-level shift in coding from lever presses to aborts with punishment. Closed-loop vmPFC, but not dmPFC, photosilencing on a postpunishment probe test negated the reduction in EtOH lever presses but not in aborts. Punishment was associated with altered plasticity at vmPFC inputs to D1 receptor-expressing medium spiny neurons in the NAcS. Photosilencing vmPFC projections to the NAcS, but not to the basolateral amygdala, partially reversed suppression of EtOH lever presses on probe testing.
Conclusions These findings demonstrate a key role for the vmPFC in regulating EtOH-SA after punishment, with implications for understanding the neural basis of compulsive drinking in alcohol use disorder.

Real-time value integration during economic choice is regulated by orbitofrontal cortex.
CCB Fellow Matthew Gardner published in Current Biology (December 2019)

Abstract: Neural correlates implicate the orbitofrontal cortex (OFC) in value-based or economic decision making. Yet inactivation of OFC in rats performing a rodent version of the standard economic choice task is without effect, a finding more in accord with ideas that the OFC is primarily necessary for behavior when new information must be taken into account. Neural activity in the OFC spontaneously updates to reflect new information, particularly about outcomes, and the OFC is necessary for adjustments to learned behavior only under these conditions. Here, we merge these two independent lines of research by inactivating lateral OFC during an economic choice that requires new information about the value of the predicted outcomes to be incorporated into an already established choice. Outcome value was changed by pre-feeding the rats one of two food options before testing. In control rats, this pre-feeding resulted in divergent changes in choice behavior that depended on the rats' prior preference for the pre-fed food. Optogenetic inactivation of the OFC disrupted this bi-directional effect of pre-feeding without affecting other measures that describe the underlying choice behavior. This finding unifies the role of the OFC in economic choice with its role in a host of other behaviors, causally demonstrating that the OFC is not necessary for economic choice per se-unless that choice incorporates new information about the outcomes.

Delta glutamate receptor conductance drives excitation of dorsal raphe neurons.
CCB Fellow Stephanie Gantz published on bioRxiv

Abstract: The delta glutamate receptors, GluD1_R and GluD2_R, are mysterious members of the ionotropic glutamate receptor family in that they are not gated by glutamate. One theory is that they are scaffolding proteins or synaptic organizers strictly, rather than ion conducting channels. Although mutant forms and wild type channels have been reported to conduct, conduction, gating, and biophysical properties of native GluD1_R remain unexplored. Here we show that the inward current induced by activation of α1-adrenergic receptors (α1-A_Rs) in the dorsal raphe nucleus (DR) is mediated by GluD1_R. Native GluD1_R channels are functional ion channels that are constitutively active under basal conditions and α1-A_Rs increase the tonic current. This inward current is responsible for the α1-A_R-dependent induction of persistent pacemaker-type firing of neurons in the DR. Given the extensive distribution of these receptors, the ionotropic nature of GluD_R is proposed to be widespread in the nervous system.

Operant social reward decreases incubation of heroin craving in male and female rats.
CCB Fellow Marco Venniro published in Biological Psychiatry (December 2018)

Abstract: Background: We recently reported that operant social choice-induced voluntary abstinence prevents incubation of methamphetamine craving. Here, we determined whether social choice-induced voluntary abstinence would prevent incubation of heroin craving. We also introduce a fully automatic social reward self-administration model that eliminates the intense workload and rat-human interaction of the original semiautomatic model.
Methods: In experiment 1, we trained male and female rats for social self-administration (6 days) and then for heroin self-administration (12 days). Next, we assessed relapse to heroin seeking after 1 and 15 abstinence days. Between tests, the rats underwent either forced or social choice-induced abstinence. In experiment 2, we developed a fully automatic social self-administration procedure by introducing a screen between the self-administration chamber and the social-peer chamber; the screen allows physical contact but prevents rats from crossing chambers. Next, we compared incubation of craving in rats with a history of standard (no-screen) or automatic (screen) social self-administration and social choice-induced abstinence.
Results: The time-dependent increase in heroin seeking after cessation of drug self-administration (incubation of craving) was lower after social choice-induced abstinence than after forced abstinence. There were no differences in social self-administration, social choice-induced abstinence, and incubation of craving in rats trained in the standard semiautomatic procedure versus the novel fully automatic procedure.
Conclusions: Our study demonstrates the protective effect of rewarding social interaction on heroin self-administration and incubation of heroin craving and introduces a fully automatic social self-administration and choice procedure to investigate the role of volitional social interaction in drug addiction and other psychiatric disorders.

Circuit mechanisms of neurodegenerative diseases: a new frontier with miniature microscopy.
CCB Fellow Craig Werner, a mini review published in Frontiers in Neuroscience (October 2019)

Abstract: Neurodegenerative diseases (NDDs), such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD), are devastating age-associated brain disorders. Significant efforts have been made to uncover the molecular and cellular pathogenic mechanisms that underlie NDDs. However, our understanding of the neural circuit mechanisms that mediate NDDs and associated symptomatic features have been hindered by technological limitations. Our inability to identify and track individual neurons longitudinally in subcortical brain regions that are preferentially targeted in NDDs has left gaping holes in our knowledge of NDDs. Recent development and advancement of the miniature fluorescence microscope (miniscope) has opened up new avenues for examining spatially and temporally coordinated activity from hundreds of cells in deep brain structures in freely moving rodents. In the present mini-review, we examine the capabilities of current and future miniscope tools and discuss the innovative applications of miniscope imaging techniques that can push the boundaries of our understanding of neural circuit mechanisms of NDDs into new territories.

Accelerated intermittent theta-burst stimulation as a treatment for cocaine use disorder: a proof-of-concept study.
CCB Fellow Vaughn Steele, published in Frontiers in Neuroscience (October 2019)

Abstract: There are no effective treatments for cocaine use disorder (CUD), a chronic, relapsing brain disease characterized by dysregulated circuits related to cue reactivity, reward processing, response inhibition, and executive control. Transcranial magnetic stimulation (TMS) has the potential to modulate circuits and networks implicated in neuropsychiatric disorders, including addiction. Although acute applications of TMS have reduced craving in urine-negative cocaine users, the tolerability and safety of administering accelerated TMS to cocaine-positive individuals is unknown. As such, we performed a proof-of-concept study employing an intermittent theta-burst stimulation (iTBS) protocol in an actively cocaine-using sample. Although our main goal was to assess the tolerability and safety of administering three iTBS sessions daily, we also hypothesized that iTBS would reduce cocaine use in this non-treatment seeking cohort. We recruited 19 individuals with CUD to receive three open-label iTBS sessions per day, with approximately a 60-min interval between sessions, for 10 days over a 2-week period (30 total iTBS sessions). iTBS was delivered to left dorsolateral prefrontal cortex (dlPFC) with neuronavigation guidance. Compliance and safety were assessed throughout the trial. Cocaine use behavior was assessed before, during, and after the intervention and at 1- and 4-week follow-up visits. Of the 335 iTBS sessions applied, 73% were performed on participants with cocaine-positive urine tests. Nine of the 14 participants who initiated treatment received at least 26 of 30 iTBS sessions and returned for the 4-week follow-up visit. These individuals reduced their weekly cocaine consumption by 78% in amount of dollars spent and 70% in days of use relative to pre-iTBS cocaine use patterns. Similarly, individuals reduced their weekly consumption of nicotine, alcohol, and THC, suggesting iTBS modulated a common circuit across drugs of abuse. iTBS was well-tolerated, despite the expected occasional headaches. A single participant developed a transient neurological event of uncertain etiology on iTBS day 9 and cocaine-induced psychosis 2 weeks after discontinuation. It thus appears that accelerated iTBS to left dlPFC administered in active, chronic cocaine users is both feasible and tolerable in actively using cocaine participants with preliminary indications of efficacy in reducing both the amount and frequency of cocaine (and other off target drug) use. The neural underpinnings of these behavioral changes could help in the future development of effective treatment of CUD.

Altered cortical structure and psychiatric symptom risk in adolescents exposed to maternal stress in utero: A retrospective investigation.
CCB Fellow Valerie Darcey co-authored the publication in Behavioural Brain Research (August 2019)

Abstract: Maternal exposure to stress during pregnancy is associated with increased risk for cognitive and behavioral sequelae in offspring. Animal research demonstrates exposure to stress during gestation has effects on brain structure. In humans, however, little is known about the enduring effects of in utero exposure to maternal stress on brain morphology. We examine whether maternal report of stressful events during pregnancy is associated with brain structure and behavior in adolescents.
We compare gray matter morphometry of typically-developing early adolescents (11—14 years of age, mean 12.7) at a single timepoint, based on presence/absence of retrospectively-assessed maternal report of negative major life event stress (MLES) during pregnancy: prenatal stress (PS; n = 28), comparison group (CG; n = 55). The Drug Use Screening Inventory Revised (DUSI-R) assessed adolescent risk for problematic behaviors. Exclusionary criteria included pre-term birth, low birth weight, and maternal substance use during pregnancy. Groups were equivalent for demographic (age, sex, IQ, SES, race/ethnicity), and birth measures (weight, length).
Compared to CG peers, adolescents in the PS group exhibited increased gray matter density in bilateral posterior parietal cortex (PPC): bilateral intraparietal sulcus, left superior parietal lobule and inferior parietal lobule. Additionally, the PS group displayed greater risk for psychiatric symptoms and family system dysfunction, as assessed via DUSI-R subscales.
These preliminary findings suggest that prenatal exposure to maternal MLES may exact enduring associations on offspring brain morphology and psychiatric risk, highlighting the importance of capturing these data in prospective longitudinal research studies (beginning at birth) to elucidate these associations.

Reduced Segregation Between Cognitive and Emotional Processes in Cannabis Dependence.
CCB Alumni Peter Manza published in Cerebral Cortex (June 2019)

Abstract: Addiction is characterized by an erosion of cognitive control toward drug taking that is accentuated by negative emotional states. Here we tested the hypothesis that enhanced interference on cognitive control reflects a loss of segregation between cognition and emotion in addiction. We analyzed Human Connectome Project data from 1206 young adults, including 89 with cannabis dependence (CD). Two composite factors, one for cognition and one for emotion, were derived using principal component (PC) analyses. Component scores for these PCs were significantly associated in the CD group, such that negative emotionality correlated with poor cognition. However, the corresponding component scores were uncorrelated in matched controls and nondependent recreational cannabis users (n = 87). In CD, but not controls or recreational users, functional magnetic resonance imaging activations to emotional stimuli (angry/fearful faces > shapes) correlated with activations to cognitive demand (working memory; 2-back > 0-back). Canonical correlation analyses linked individual differences in cognitive and emotional component scores with brain activations. In CD, there was substantial overlap between cognitive and emotional brain–behavior associations, but in controls, associations were more restricted to the cognitive domain. These findings support our hypothesis of impaired segregation between cognitive and emotional processes in CD that might contribute to poor cognitive control under conditions of increased emotional demand.

Pharmacotherapy for hoarding disorder: How did the picture change since its excision from OCD?.
CCB Fellow Daria Piancentino published in Current Neuropharmacology

Abstract: This brief review deals with the various issues that contributed to the creation of the new Diagnostic and Statistical Manual condition of hoarding disorder (HD) and attempts at reviewing its pharmacotherapy. It appears that after the newly founded diagnosis appeared in the literature as an autonomous entity, distinct from obsessive-compulsive disorder, drug trials are not being conducted and the disorder is left in the hands of psychotherapists, who on their part, report fair results in some core dimensions of HD. The few trials on HD specifically regard the serotonin-noradrenaline reuptake inhibitor venlafaxine, and, possibly due to the suggestion of a common biological background of HD with attention-deficit/hyperactivity disorder, the psychostimulant methylphenidate and the noradrenaline reuptake inhibitor atomoxetine. For all these drugs, positive results have been reported, but the evidence level of these studies is low, due to small samples and non-blind designs. Regretfully, there are currently no future studies aiming at seriously testing drugs in HD.

Heightened defensive responses following subtotal lesions of macaque orbitofrontal cortex.
CCB Fellow Maia Pujara published in Journal of Neuroscience (May 2019)

Abstract: Anxiety disorders are characterized by excessive attention to threat. Several brain areas, including the orbitofrontal cortex (OFC), have been associated with threat processing, with more recent work implicating specialized roles for the medial and lateral subregions of the OFC in mediating specific symptoms of anxiety disorders. Virtually no causal work, however, has evaluated the role of these OFC subregions in regulating behavioral responses under threat. To address this gap, we compared male rhesus monkeys (Macaca mulatta) with bilateral excitotoxic lesions restricted to either the lateral OFC (lOFC), targeting Walker's areas 11 and 13, or the medial OFC (mOFC), targeting Walker's area 14, to a group of unoperated controls on behavioral responses to the presentation of a fake rubber snake, fake spider, and neutral stimuli. Both lesion groups showed heightened defensive and reduced approach responses, accompanied by longer latencies to retrieve a food reward, in the presence of the threatening stimuli. Compared to unoperated controls, the mOFC lesion group also showed longer latencies to reach for rewards and a greater proportion of defensive responses (e.g., piloerection) in the presence of neutral stimuli. Thus, monkeys with mOFC lesions displayed a greater tendency to express defensive responses even in the absence of threat. Overall, our data reveal that both the mOFC and lOFC contribute to the attenuation of defensive responses. Notably, these findings, obtained following selective, excitotoxic lesions of the OFC, are diametrically opposed to the effects of aspiration lesions of OFC observed in macaques.
SIGNIFICANCE STATEMENT Engaging in adaptive defensive responses under threat promotes biological fitness. The orbitofrontal cortex (OFC) has been implicated in regulating defensive responses to threat, with distinct subregions likely playing different roles. Here we tested the effects of excitotoxic damage restricted to either the lateral or medial subdivisions of the OFC in rhesus macaques. We found significantly heightened defense and reduced approach responses to threatening stimuli in both lesion groups. While lateral OFC lesions led to an increase in defense responses to the threatening stimuli, medial OFC lesions produced increases in defense responses to both threatening and neutral stimuli. Our findings provide insights into the neural regulation of defensive responses to threat and inform the etiology and treatment of anxiety disorders in humans.

High–risk social drinkers and heavy drinkers display similar rates of alcohol consumption.
CCB Alumni Matthew Sloan published in Addiction Biology (March 2019)

Abstract: Alcohol consumption is often assessed over weeks to months, but few attempts have been made to characterize alcohol consumption rates at the level of an individual drinking session. Here, we aimed to compare the rate of alcohol consumption in social drinkers at high risk for alcohol use disorder (AUD) and heavy drinkers. One hundred and sixty social drinkers and 48 heavy drinkers participated in an alcohol self–administration study. Social drinkers were classified as low risk or high risk for AUD based on sex, impulsivity, and family history of alcoholism. Participants received a priming dose of intravenous alcohol to assess alcohol–induced craving and completed a 125–minute intravenous alcohol self‐administration session to assess rate of achieving a binge–level exposure (blood alcohol concentration greater than or equal to 80 mg%). There were no differences between rates of binging in high–risk and heavy drinkers (hazard ratio = 0.87; 95% CI, 0.48—1.56). Heavy drinkers reported higher levels of craving than high–risk and low–risk drinkers at baseline. However, following a priming dose of alcohol, there were no longer differences in craving between high–risk and heavy drinkers. These results indicate that high–risk social drinkers demonstrate binging behavior that is similar to heavy drinkers, which may be driven by alcohol–induced craving. Prospective studies are needed to elucidate whether these patterns of craving and consumption in high–risk social drinkers are predictive of future AUD.

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)

Abstract:
OBJECTIVE: 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.

CONCLUSIONS: 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.