Assessment of a proposed “three-criteria” cocaine addiction model for use in reinstatement studies with rats

Stopponi

Front. Behav. Neurosci.

et al. 2019

Recent animal models of alcohol use disorder (AUD) are centered in capturing individual vulnerability differences in disease progression. Here, we used genetically selected Marchigian Sardinian alcohol-preferring (msP) and Wistars rats to apply a multidimensional model of AUD adapted from a previously described DSM-IV/DSM-5 multisymptomatic cocaine addiction model. As proof of concept, we hypothesized that msP rats, genetically selected for excessive drinking, would be more prone to develop dependence-like behavior compared to Wistars. Before exposure of animals to alcohol, we monitored basal anxiety in the elevated plus maze (EPM). Animals were then trained in prolonged operant alcohol self-administration, consisting of 30-min daily sessions for 60 days in total. Each session consisted of two 10-min periods of alcohol reinforcement separated by 10-min interval of non-reinforcement. Following training, we applied three criteria of individual vulnerability for AUD: (1) persistence of lever pressing for alcohol when it was not available; (2) motivation for alcohol in a progressive ratio (PR) schedule of reinforcement; and (3) resistance to punishment when alcohol delivery was anticipated by a foot-shock (0.3 mA). We obtained four groups corresponding to the number of criteria met (0–3 crit). Rats in the 0crit and 1crit groups were characterized as resilient, whereas rats in the 2crit and 3crit groups were characterized as prone to develop a dependent-like phenotype. As predicted, the 2–3crit groups were enriched with msP rats while the 0–1crit groups were enriched in Wistar rats. In further analysis, we calculated the global addiction score (GAS) per subject by the sum of the normalized score (z-score) of each criterion. Results showed GAS was highly correlated with animal distribution within the 3 criteria. Specifically, GAS was negative in the 0–1crit groups, and positive in the 2–3crit groups. A positive correlation between basal anxiety and quantity of alcohol intake was detected in msP rats but not Wistars. In conclusion, we demonstrated that the 0/3criteria model is a suitable approach to study individual differences in AUD and that msP rats, selected for excessive-alcohol drinking, show a higher propensity to develop AUD compared to non-preferring Wistars.

Section: Discussionmentioning

confidence: 99%

Sub-dimensions of Alcohol Use Disorder in Alcohol Preferring and Non-preferring Rats, a Comparative Study

Stopponi

Front. Behav. Neurosci.

et al. 2019

“…Furthermore, arguing against general learning deficits, abnormal punished reward-seeking in these mice were not accompanied by deficits in initial operant learning or in persistent reward-seeking during reward absence or progressive ratio responding for reward ( Deroche-Gamonet et al 2004; Radwanska and Kaczmarek 2012). In this context, recent studies in rats have found that chronic exposure to ethanol or cocaine causes changes in two or all three of these measures (Belin et al 2011; Deroche-Gamonet et al 2004; Jonkman et al 2012; Vendruscolo et al 2012) (but see Waters et al 2014). The behaviorally selective (punishment-specific) phenotypic profile shown by the GluN2B CxNULL mice demonstrates that while the mechanisms regulating these various measures are likely to be overlapping, they can also be dissociated.…”

Section: Discussionmentioning

confidence: 99%

Cortical GluN2B deletion attenuates punished suppression of food reward-seeking

2015

Rationale Compulsive behavior, which is a hallmark of psychiatric disorders such as addiction and obsessive-compulsive disorder, engages corticostriatal circuits. Previous studies indicate a role for corticostriatal N-methyl-D-aspartate receptors (NMDARs) in mediating compulsive-like responding for drugs of abuse, but the specific receptor subunits controlling reward-seeking in the face of punishment remain unclear. Objectives The current study assessed the involvement of corticostriatal GluN2B-containing NMDARs in measures of persistent and punished food reward-seeking. Methods Mice with genetic deletion of GluN2B in one of three distinct neuronal populations, cortical principal neurons, forebrain interneurons, or striatal medium spiny neurons, were tested for (1) sustained food reward-seeking when reward was absent, (2) reward-seeking under a progressive ratio schedule of reinforcement, and (3) persistent reward-seeking after a footshock punishment. Results Mutant mice with genetic deletion of GluN2B in cortical principal neurons demonstrated attenuated suppression of reward-seeking during punishment. These mice performed normally on other behavioral measures, including an assay for pain sensitivity. Mutants with interneuronal or striatal GluN2B deletions were normal on all behavioral assays. Conclusions Current findings offer novel evidence that loss of GluN2B-containing NMDARs expressed on principal neurons in the cortex results in reduced punished food rewardseeking. These data support the involvement of GluN2B subunit in cortical circuits regulating cognitive flexibility in a variety of settings, with implications for understanding the basis of inflexible behavior in neuropsychiatric disorders including obsessive-compulsive disorders (OCD) and addictions.

“…Indeed, some laboratories have failed to implement this model [98] that is technically challenging, as it requires the maintenance of patent catheters for more than 70 days on large cohorts (at least 40 rats, the smallest cohort out of which enough addicted rats can be reliably identified). Additionally, being based on a FR schedule, this model focuses on drug-taking behavior, whereas compulsivity is as much a disorder of drug seeking as it is of drug taking.…”

Section: Instrumental and Pavlovian Mechanisms Subserving Drug Use: Dmentioning

confidence: 99%

How Preclinical Models Evolved to Resemble the Diagnostic Criteria of Drug Addiction

Belin

Fouyssac

Bonci

et al. 2016

Biological Psychiatry

109

Drug addiction is a complex neuropsychiatric disorder that affects a subset of the individuals who take drugs. It is characterized by maladaptive drug-seeking habits that are maintained despite adverse consequences and intense drug craving. Despite extensive research, the pathophysiology and aetiology of addiction is only partially understood, due to the gap between current preclinical models of addiction and the clinical criteria of the disorder. Here we give a brief overview, based on selected methodologies, of how behavioral models have evolved over the last fifty years to the development of recent preclinical models of addiction that more closely mimic diagnostic criteria of addiction. These new models will hopefully increase our understanding of the complex neurobiological mechanisms whereby some individuals switch from controlled drug use to compulsive drug-seeking habits and relapse to these maladaptive habits. Additional, by paving the way to bridge the gap that exists between biobehavioral research on addiction and the human situation, these models may provide new perspectives for the development of novel and effective therapeutic strategies for drug addiction.