Yavin Shaham's research while affiliated with National Institute on Drug Abuse and other places

Publications (673)

Article
The high efficacy mu-opioid receptor (MOR) agonist methadone is an effective opioid use disorder (OUD) medication used exclusively in opioid-dependent patients. However, methadone has undesirable effects that limit its clinical efficacy. Intermediate efficacy MOR agonists may treat OUD with fewer undesirable effects. We compared the effects of meth...
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Rationale and objective Social factors play a critical role in drug addiction. We recently showed that rats will abstain from methamphetamine, cocaine, heroin, and remifentanil self-administration when given a choice between the addictive drug and operant social interaction. Here, we further characterized operant social interaction by determining t...
Preprint
Studies using rodent models have shown that relapse to drug or food seeking increases progressively during abstinence, a phenomenon termed ‘incubation of craving’. Mechanistic studies of incubation of craving have focused on specific neurobiological targets within pre- selected brain areas. Recent methodological advances in whole-brain immunohistoc...
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Studies using either continuous or intermittent access cocaine self-administration procedures showed that cocaine seeking increases during abstinence (incubation of cocaine craving), and that this effect is higher after intermittent cocaine access. Other studies showed that cocaine abstinence is characterized by the emergence of stress- and anxiety...
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Rationale Clinically relevant pain is often associated with functional impairment and behavioral depression, including depression of social behavior. Moreover, recovery of function is a major goal in pain treatment. We used a recently developed model of operant responding for social interaction in rats to evaluate the vulnerability of social behavi...
Article
A widely held dogma in the preclinical addiction field is that females are more vulnerable than males to drug craving and relapse. Here, we first review clinical studies on sex differences in psychostimulant and opioid craving and relapse. Next, we review preclinical studies on sex differences in psychostimulant and opioid reinstatement of drug see...
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Rationale and objectivesRecent studies reported that when given a mutually exclusive choice between cocaine and palatable food, most rats prefer the non-drug reward over cocaine. However, these studies used rat strains with limited genetic and behavioral diversity. Here, we used a unique outbred strain of rats (Heterogeneous Stock, HS) that mimic t...
Article
The prelimbic cortex (PrL) is involved in the organization of operant behaviors, but the relationship between longitudinal PrL neural activity and operant learning and performance is unknown. Here, we developed deep behavior mapping (DBM) to identify behavioral microstates in video recordings. We combined DBM with longitudinal calcium imaging to qu...
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Ketamine, a racemic mixture of (S)-ketamine and (R)-ketamine enantiomers, has been used as an anesthetic, analgesic and more recently, as an antidepressant. However, ketamine has known abuse liability (the tendency of a drug to be used in non-medical situations due to its psychoactive effects), which raises concerns for its therapeutic use. (S)-ket...
Article
Background Mouse models of social behavior fail to account for volitional aspects of social interaction and current neurobiological investigation of social behavior is performed almost exclusively using C57BL/6J mice, the background strain of most transgenic mice. Here, we introduce a mouse model of operant social self-administration and choice, us...
Article
Significance We recently introduced a rat model of incubation (time-dependent increase) of oxycodone craving after voluntary abstinence induced by negative consequences of drug seeking. We used resting-state functional MRI to determine whether longitudinal functional connectivity changes in orbitofrontal cortex (OFC) circuits would predict incubati...
Article
Background and purpose: Maintenance treatment with opioid agonists (buprenorphine, methadone) decreases opioid use and relapse. We recently modeled maintenance treatment in rats and found that chronic delivery of buprenorphine or the mu opioid receptor (MOR) partial agonist TRV130 decreases relapse to oxycodone seeking and taking. Here, we tested...
Article
Social reinforcement-based treatments are effective for many, but not all, people with addictions to drugs. We recently developed an operant rat model that mimics features of one such treatment, the community-reinforcement approach. In this model, rats uniformly choose social interaction over methamphetamine or heroin. Abstinence induced by social...
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Alcohol intake remains controlled in a majority of users but becomes “compulsive,” i.e., continues despite adverse consequences, in a minority who develop alcohol addiction. Here, using a footshock-punished alcohol self-administration procedure, we screened a large population of outbred rats to identify those showing compulsivity operationalized as...
Preprint
Rationale and objectives: Recent studies reported that when given a mutually exclusive choice between cocaine and palatable food, most rats prefer the non-drug reward over cocaine. However, these studies used rat strains with limited genetic and behavioral diversity. Here, we used a unique outbred strain of rats (Heterogeneous Stock, HS) that mimic...
Article
Full-text available
Rationale and objectivePain-related factors increase the risk for opioid addiction, and pain may function as a negative reinforcer to increase opioid taking and seeking. However, experimental pain-related manipulations generally do not increase opioid self-administration in rodents. This discrepancy may reflect insufficient learning of pain-relief...
Article
Relapse to drug use during abstinence is a defining feature of addiction. During the last several decades, this clinical scenario has been studied at the preclinical level using classic relapse/reinstatement models in which drug seeking is assessed after experimenter-imposed home-cage forced abstinence or extinction of the drug-reinforced respondin...
Article
Persistent susceptibility to cue-induced relapse is a cardinal feature of addiction. Discriminative stimuli (DSs) are one type of drug-associated cue that signal drug availability (DS+) or unavailability (DS−) and control drug seeking prior to relapse. We previously established a trial-based procedure in rats to isolate DSs from context, conditione...
Preprint
A widely held dogma in the preclinical addiction field is that females are more vulnerable than males to drug craving and relapse. Here, we first review clinical studies on sex differences in psychostimulant and opioid craving and relapse. Next, we review preclinical studies on sex differences in psychostimulant and opioid reinstatement of drug see...
Preprint
We recently developed a rat model of incubation of oxycodone craving where opioid seeking progressively increases after voluntary suppression of drug self-administration by adverse consequences of drug seeking. Here, we studied the role of ventral subiculum (vSub) neuronal ensembles in this incubation, using the activity marker Fos, muscimol-baclof...
Preprint
Rationale and Objective: Pain-related factors increase risk for opioid addiction, and opioid-induced pain relief may function as a negative reinforcer to increase opioid taking and seeking. However, experimental pain-related manipulations generally do not increase opioid self-administration in rodents. This discrepancy may reflect insufficient lear...
Article
Critical features of human addiction are increasingly being incorporated into complementary animal models, including escalation of drug intake, punished drug seeking and taking, intermittent drug access, choice between drug and non-drug rewards, and assessment of individual differences based on criteria in the fourth edition of the Diagnostic and S...
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Growing evidence during the last 15 years has implicated epigenetic mechanisms in the behavioral effects of addictive drugs. The main focus of these studies has been on epigenetic mechanisms of psychomotor sensitization and drug reinforcement, as assessed by the conditioned place preference and drug self-administration procedures. Some of these stu...
Article
Neuronal ensembles in ventromedial prefrontal cortex (vmPFC) play a role in both cocaine and palatable food seeking. However, it is unknown whether similar or different vmPFC neuronal ensembles mediate food and cocaine seeking. Here, we used the Daun02 inactivation procedure to assess whether the neuronal ensembles mediating food and cocaine seekin...
Article
We recently reported that social choice-induced voluntary abstinence prevents incubation of methamphetamine craving in rats. This inhibitory effect was associated with activation of protein kinase-Cδ (PKCδ)-expressing neurons in central amygdala lateral division (CeL). In contrast, incubation of craving after forced abstinence was associated with a...
Article
It is difficult to translate results from animal research on addiction to an understanding of the behavior of human drug users. Despite decades of basic research on neurobiological mechanisms of drug addiction, treatment options remain largely unchanged. A potential reason for this is that mechanistic studies using rodent models do not incorporate...
Article
Werecently developed a rat model of relapse to drug seeking after food choice-induced voluntary abstinence. Here, we used this model to study the role of the orbitofrontal cortex (OFC) and its afferent projections in relapse to fentanyl seeking. Wetrained male and female rats to self-administer palatable food pellets for 6 d (6h/d) and intravenous...
Article
Background Maintenance treatment with opioid agonists (buprenorphine, methadone) is effective for opioid addiction but does not eliminate opioid use in all patients. Here, we modeled maintenance treatment in rats that self-administered the prescription opioid oxycodone. The maintenance medication was either buprenorphine or the G-protein-biased mu...
Article
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 abstine...
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Full-text available
Cocaine-associated memories are persistent, but, on retrieval, become temporarily destabilized and vulnerable to disruptions, followed by reconsolidation. To explore the synaptic underpinnings for these memory dynamics, we studied AMPA receptor (AMPAR)-silent excitatory synapses, which are generated in the nucleus accumbens by cocaine self-administ...
Article
Recent studies suggest that the ventral medial prefrontal cortex (vmPFC) encodes both operant drug self-administration and extinction memories. Here, we examined whether these opposing memories are encoded by distinct neuronal ensembles within the vmPFC with different outputs to the nucleus accumbens (NAc) in male and female rats. Using cocaine sel...
Article
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 i...
Article
Inappropriate and pathological aggression plays a leading role in the suffering and death of millions of people, and further places an untenable strain on the caregivers and families of those afflicted. In some cases, such as addictive drugs, aggression can be highly rewarding (appetitive) and continually pursued despite short- and long-term negati...
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Full-text available
In abstinent drug addicts, cues formerly associated with drug-taking experiences gain relapse-inducing potency ('incubate') over time. Animal models of incubation may help develop treatments to prevent relapse, but these models have ubiquitously focused on the role of conditioned stimuli (CSs) signaling drug delivery. Discriminative stimuli (DSs) a...
Article
We recently developed a mouse model of appetitive operant aggression and reported that adult male outbred CD-1 mice lever-press for the opportunity to attack subordinate male mice and relapse to aggression seeking during abstinence. Here we studied the role of nucleus accumbens (NAc) dopamine receptor (Drd)1- and Drd2-expressing neurons in aggressi...
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Results from clinical studies suggest that drug relapse and craving are often provoked by exposure to drug-associated contexts. Since 2002, this phenomenon has been modeled in laboratory animals using the ABA renewal model. In the classical version of this model, rats with a history of drug self-administration in one context (A) undergo extinction...
Preprint
Full-text available
In abstinent drug addicts, cues formerly associated with drug-taking experiences gain relapse-inducing potency ('incubate') over time. Animal models of incubation may help develop treatments to prevent relapse, but these models have ubiquitously focused on the role of conditioned stimuli (CSs) signaling drug delivery. From a translational perspecti...
Article
Full-text available
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...
Article
The epidemic of addiction and overdose is real. Addiction among pain patients accounts for only a small proportion but a large number. Scientific opinion leaders can be most effective on two fronts, each relatively low-tech: dissemination and oversight of empirically established treatments, and promulgation of social-science-based strategies for po...
Article
Many preclinical studies examined cue‐induced relapse to heroin and cocaine seeking in animal models, but most of these studies examined only one drug at a time. In human addicts, however, polydrug use of cocaine and heroin is common. We used a polydrug self‐administration relapse model in rats to determine similarities and differences in brain are...
Article
Lifetime relapse rates remain a major obstacle in addressing the current opioid crisis. Relapse to opioid use can be modeled in rodent studies where drug self-administration is followed by a period of abstinence and a subsequent test for drug seeking. Abstinence can be achieved through extinction training, forced abstinence, or voluntary abstinence...
Article
Methamphetamine (Meth) seeking progressively increases after withdrawal (incubation of Meth craving), but the transcriptional mechanisms that contribute to this incubation are unknown. Here we used RNA-sequencing to analyze transcriptional profiles associated with incubation of Meth craving in central amygdala (CeA) and orbitofrontal cortex (OFC),...
Article
Relapse to nonmedical use of prescription opioids often occurs after exposure to places previously associated with drug use. Here, we describe a rat model of context‐induced reinstatement of oxycodone seeking after repeated cycles of drug self‐administration and extinction‐induced abstinence. We also determined the role of mu, delta, and kappa opio...
Article
Relapse to methamphetamine (Meth) seeking progressively increases after withdrawal from drug self-administration (incubation of Meth craving). We previously demonstrated a role of dorsomedial striatum (DMS) dopamine D1 receptors (D1Rs) in this incubation. Here, we studied the role of afferent glutamatergic projections into the DMS and local D1R– gl...
Article
Studies using the renewal procedure showed that basolateral amygdala (BLA) inactivation inhibits context-induced relapse to cocaine-seeking after extinction. Here, we determined whether BLA inactivation would also inhibit context-induced relapse after drug-reinforced responding is suppressed by punishment, an animal model of human relapse after sel...
Article
Background: Methamphetamine (meth) seeking progressively increases after withdrawal (incubation of meth craving). We previously demonstrated an association between histone deacetylase 5 (HDAC5) gene expression in the rat dorsal striatum and incubation of meth craving. Here we used viral constructs to study the causal role of dorsal striatum HDAC5...
Article
High rates of relapse to drug use during abstinence is a defining feature of human drug addiction. This clinical scenario has been studied at the preclinical level using different animal models in which relapse to drug seeking is assessed after cessation of operant drug self-administration in rodents and monkeys. In our Society for Neuroscience (SF...
Article
Despite decades of research on neurobiological mechanisms of psychostimulant addiction, the only effective treatment for many addicts is contingency management, a behavioral treatment that uses alternative non-drug reward to maintain abstinence. However, when contingency management is discontinued, most addicts relapse to drug use. The brain mechan...
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Full-text available
Results from preclinical rodent studies during the last 20 years implicated glutamate neurotransmission in different brain regions in drug self-administration and rodent models of relapse. These results, along with evidence for drug-induced neuroadaptations in glutamatergic neurons and receptors, suggested that addiction might be treatable by medic...
Article
Fentanyl is a potent synthetic opioid used extensively in humans for general anesthesia and analgesia. Fentanyl has emerged as a recreational drug, often in combination with heroin, and can result in lethality during overdose. Fentanyl is well characterized as an anesthetic, but the basic physiological effects of fentanyl in the brain when taken as...
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Learned associations between environmental stimuli and rewards drive goal-directed learning and motivated behavior. These memories are thought to be encoded by alterations within specific patterns of sparsely distributed neurons called neuronal ensembles that are activated selectively by reward-predictive stimuli. Here, we use the Fos promoter to i...
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Eating is a learned process. Our desires for specific foods arise through experience. Both electrical stimulation and optogenetic studies have shown that increased activity in the lateral hypothalamus (LH) promotes feeding. Current dogma is that these effects reflect a role for LH neurons in the control of the core motivation to feed, and their act...
Article
We recently developed a rat model of context-induced relapse to alcohol seeking after punishment-imposed abstinence to mimic relapse after self-imposed abstinence due to adverse consequences of drug use. Here, we determined the model's generality to cocaine and have begun to explore brain mechanisms of context-induced relapse to cocaine seeking aft...
Article
Kappa opioid receptors (KORs) and their endogenous ligand dynorphin are involved in stress-induced alcohol seeking but the mechanisms involved are largely unknown. We previously showed that systemic injections of the KOR agonist U50,488, which induce stress-like aversive states, reinstate alcohol seeking after extinction of the alcohol-reinforced r...
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Full-text available
Heroin use and overdose have increased in recent years as people transition from abusing prescription opiates to using the cheaper street drug. Despite a long history of research, many physiological effects of heroin and their underlying mechanisms remain unknown. Here, we used high-speed amperometry to examine the effects of intravenous heroin on...
Article
Background Nicotine craving and relapse often occurs after reactivation of nicotine reward memories. We recently developed a memory retrieval-reconsolidation interference procedure in which reactivation of nicotine reward memories by acute exposure to nicotine (the unconditioned stimulus, UCS) and then pharmacologically interfering with memory reco...
Article
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Background: Some people are highly motivated to seek aggressive encounters, and among those who have been incarcerated for such behavior, recidivism rates are high. These observations echo two core features of drug addiction: high motivation to seek addictive substances, despite adverse consequences, and high relapse rates. Here we used establishe...
Article
Importance: A relapse into nicotine addiction during abstinence often occurs after the reactivation of nicotine reward memories, either by acute exposure to nicotine (a smoking episode) or by smoking-associated conditioned stimuli (CS). Preclinical studies suggest that drug reward memories can undergo memory reconsolidation after being reactivated...
Article
We recently developed a rat model of incubation of methamphetamine craving after choice-based voluntary abstinence. Here, we studied the role of dorsolateral striatum (DLS) and dorsomedial striatum (DMS) in this incubation. We trained rats to selfadminister palatable food pellets (6 d, 6 h/d) and methamphetamine (12 d, 6 h/d). We then assessed rela...
Chapter
High rates of relapse to drug use during abstinence is a defining feature of drug addiction. In abstinent drug users, drug relapse is often precipitated by acute exposure to the self-administered drug, drug-associated cues, stress, as well as by short-term and protracted withdrawal symptoms. In this review, we discuss different animal models that h...