Brendan J. Tunstall

A Review of Preclinical Research Demonstrating that Drug and Non-Drug ReinforcersDifferentially Affect Behavior

This review describes and summarizes current preclinical research revealing important differences between drug and non-drug reinforcers in terms of their effects on behavior. Despite research showing that drugs are not especially strong reinforcers in animals, a number of other behavioral differences potentially relevant to addiction have been reported in studies that have compared drug and non-drug reinforcers. Several of these effects appear only after long-term access to drugs. These include an escalation of drug intake, an increased persistence in responding for the drug, and a decreased sensitivity to the effects of punishers or other suppressors of drug seeking. Further differences between drug and non-drug reinforcers include the effects that reinforcer-paired stimuli have on behavior. Drug cues, as compared to food cues, have been shown to exert greater control over reinforcer-seeking behavior after periods of abstinence. Similarly, behavior previously reinforced by drugs, but not food, has been shown to be susceptible to stress-induced reinstatement after extinction. The behavioral differences between drug and non-drug reinforcers reviewed here may identify special features of drugs that lead to addiction.

Drug specificity in drug versus food choice in male rats.

Although different classes of drug differ in their mechanisms of reinforcement and effects on behavior, little research has focused on differences in self-administration behaviors maintained by users of these drugs. Persistent drug choice despite available reinforcement alternatives has been proposed to model behavior relevant to addiction. The present study used a within-subjects procedure, where male rats (Long-Evans, N = 16) were given a choice between cocaine (1.0 mg/kg/infusion) and food (a single 45-mg grain pellet) or between heroin (0.02 mg/kg/infusion) and food in separate phases (drug order counterbalanced). All rats were initially trained to self-administer each drug, and the doses used were based on previous studies showing that small subsets of rats tend to prefer drug over food reinforcement. The goal of the present study was to determine whether rats that prefer cocaine would also prefer heroin. Choice sessions consisted of 2 forced-choice trials with each reinforcer, followed by 14 free-choice trials (all trials separated by 10-min intertrial interval). Replicating previous results, small subsets of rats preferred either cocaine (5 of the 16 rats) or heroin (2 of the 16 rats) to the food alternative. Although 1 of the 16 rats demonstrated a preference for both cocaine and heroin to the food alternative, there was no relationship between degree of cocaine and heroin preference in individual rats. The substance-specific pattern of drug preference observed suggests that at least in this animal model, the tendencies to prefer cocaine or heroin in preference to a nondrug alternative are distinct behavioral phenomena.

Essential values of cocaine and non-drug alternatives predict the choice between them

This study investigated the relationship between reinforcer value and choice between cocaine and two non‐drug alternative reinforcers in rats. The essential value (EV, a behavioral economic measure based on elasticity of demand) of intravenous cocaine and food (Experiment 1) or saccharin (Experiment 2) was determined in the first phase of each experiment. Food had higher EV than cocaine, whereas the EVs of cocaine and saccharin did not differ. In the second phase of each experiment, rats were allowed to make mutually exclusive choices between cocaine and the non‐drug alternative reinforcer. The main findings were that the EV of cocaine was a positive predictor of cocaine preference and the EV of food or saccharin was a negative predictor of cocaine preference. An analysis of within‐session patterns of choice behavior revealed sequential dependencies, whereby rats were more likely to choose cocaine on a particular trial after having chosen the non‐drug alternative on previous trials. When the time between choices was increased, these sequential dependencies disappeared. The results of these experiments are consistent with the suggestion that addiction‐like behavior involves both overvaluation of drug reinforcers and undervaluation of non‐drug reinforcers.

Dysregulation of brain stress systems mediates compulsive alcohol drinking

The transition from moderate to compulsive alcohol drinking is driven by increasingly dysfunctional reward and stress systems. We review behavioral and pharmacological studies of alcohol self-administration in rats that were mainly conducted within the framework of the alcohol vapor model of dependence. We discuss neurotransmitter systems that are implicated in alcohol drinking, with a focus on contrasting those neurotransmitter systems that drive behavior in the dependent vs. nondependent states. We hypothesize that the identification of systems that become increasingly dysfunctional in alcohol dependence will reveal possible targets for successful interventions to reduce the motivation that drives compulsive alcohol drinking. In our opinion, drugs that (1) normalize, rather than block, a hypofunctional reward system via restoration of the function of hypothalamic stress systems, and (2) desensitize extrahypothalamic stress systems have the potential to selectively and effectively curb compulsive alcohol drinking.

The Role of the Ghrelin System in Drug Addiction

In the past years, a significant volume of research has implicated the appetitive hormone ghrelin in the mechanisms underlying drug use and addiction. From a neuroscientific standpoint, ghrelin modulates both reward and stress pathways, two key drivers of substance use behaviors. Previous investigations support a connection between the ghrelin system and alcohol, stimulants, and tobacco use in both animals and humans, while the research on opioids and cannabis is scarce. In general, upregulation of the ghrelin system seems to enhance craving for drugs as well as substances use. On the other hand, acute and chronic exposure to drugs of abuse influences the ghrelin system at different levels. This chapter summarizes the literature on the relationship between the ghrelin system and substance-related behaviors. We also review recent work investigating the ghrelin system as a potential pharmacological target for treating substance use disorders and discuss the need for additional research.

Compulsive-Like Sufentanil Vapor Self-Administration in the Rat.

Opioid misuse is at historically high levels in the United States, with inhalation (ie, smoking and vaping) being one of the most common routes of consumption. We developed and validated a novel preclinical model of opioid self-administration by inhalation that does not require surgery and reliably produces somatic and motivational signs of dependence. Rats were trained to perform an operant response (nosepoke) to receive 10 s of vaporized sufentanil, a potent opioid, in 2 h daily sessions. Rats readily and concentration-dependently self-administered vaporized sufentanil. Rats exhibited a significant increase in responding for sufentanil when given the preferential μ-opioid receptor inverse agonist naloxone, suggesting the participation of μ-opioid receptors in the reinforcing properties of sufentanil vapor. Serum sufentanil concentrations significantly correlated with the number of sufentanil vapor deliveries. Rats that were given long access (LgA; 12 h/day) but not short access (ShA; 1 h/day) to vaporized sufentanil escalated their drug intake over time and exhibited both naloxone-precipitated somatic signs of opioid withdrawal and spontaneous withdrawal-induced mechanical hypersensitivity. After 6 months of forced drug abstinence, LgA rats returned to pre-escalation baseline levels of responding for sufentanil and mechanical sensitivity. Upon subsequent re-escalation (ie, after the return to extended access to sufentanil vapor), LgA rats again developed naloxone-precipitated somatic signs of withdrawal and spontaneous withdrawal-induced mechanical hypersensitivity. These findings demonstrate that the operant sufentanil vapor self-administration model has both face and construct validity and therefore will be useful for investigating the neurobiological basis of opioid addiction.

Atypical dopamine transporter inhibitors attenuate compulsive-like methamphetamine self-administration in rats

ABSTRACT Methamphetamine (METH) is a highly addictive drug, but no pharmacological treatment is yet available for METH use disorders. Similar to METH, the wake‐promoting drug (R)‐modafinil (R‐MOD) binds to the dopamine transporter (DAT). Unlike METH, R‐MOD is not a substrate for transport by DAT and has low abuse potential. We tested the hypothesis that the atypical DAT inhibitor R‐MOD and compounds that are derived from modafinil would decrease METH intake by reducing the actions of METH at the DAT. We tested the effects of systemic injections of R‐MOD and four novel modafinil‐derived ligands with increased DAT affinity (JJC8‐016, JJC8‐088, JJC8‐089, and JJC8‐091) on intravenous (i.v.) METH self‐administration in rats that were allowed short access (ShA; 1 h) or long access (LgA; 6 h) to the drug. ShA rats exhibited stable METH intake over sessions, whereas LgA rats exhibited an escalation of drug intake. R‐MOD decreased METH self‐administration in ShA and LgA rats (in the 1st hour only). JJC8‐091 and JJC8‐016 decreased METH self‐administration in both ShA and LgA rats. JJC8‐089 decreased METH self‐administration in LgA rats only, whereas JJC8‐088 had no effect on METH self‐administration in either ShA or LgA rats. These findings support the potential of atypical DAT inhibitors for the treatment of METH use disorders and suggest several novel compounds as candidate drugs. HighlightsThere is currently no available pharmacological treatment for METH use disorder.Rats allowed extended access to METH escalate their drug intake.R‐Modafinil and several modafinil analogues reduced escalated METH intake.Atypical DAT inhibitors have potential for treating METH use disorders.

Social Stress-Induced Alterations in CRF Signaling in the VTA Facilitate the Emergence of Addiction-like Behavior

Stress increases the vulnerability to addiction in humans (for review, see [Sinha, 2008][1]). In preclinical studies, stressors can enhance drug self-administration and induce relapse ([Miczek et al., 2008][2]; [Mantsch et al., 2016][3]). The brain region-specific molecular mechanisms that mediate