Evidence for enhanced neurobehavioral vulnerability to nicotine during periadolescence in rats

Epidemiological studies indicate that there is an increased likelihood for the development of nicotine addiction when cigarette smoking starts early during adolescence. These observations suggest that adolescence could be a “critical ” ontogenetic period, during which drugs of abuse have distinct effects responsible for the development of dependence later in life. We compared the long-term behavioral and molecular effects of repeated nicotine treatment during either periadolescence or postadolescence in rats. It was found that exposure to nicotine during periadolescence, but not a similar exposure in the postadolescent period, increased the intravenous self-administration of nicotine and the expression of distinct subunits of the ligand-gated acetylcholine receptor in adult animals. Both these changes indicated an increased sensitivity to the addictive properties of nicotine. In conclusion, adolescence seems to be a critical developmental period, characterized by enhanced neurobehavioral vulnerability to nicotine. Key words: nicotine; adolescence; intravenous; self-administration; acetylcholine receptor; PC

Oral dosing of rodents using a palatable tablet

Rationale: Delivering orally bioavailable drugs to rodents is an important component to investigating that route of administration in novel treatments for humans. However, the traditional method of oral gavage requires training, is stressful, and can induce oesophageal damage in rodents. Objectives: To demonstrate a novel administrative technique – palatable gelatine tablets – as a stress-free route of oral delivery. Methods: 24 male Lister hooded rats were sacrificed for brain tissue analysis at varying time-points after jelly administration of 30 mg/kg of the wake-promoting drug modafinil. A second group of 22 female rats were tested on locomotor activity after 30 mg/kg modafinil, or after vehicle jellies, with the locomotor data compared to the brain tissue concentrations at the corresponding times. Results: Modafinil was present in the brain tissue at all time-points, reducing in concentration over time. The pattern of brain tissue modafinil concentration is comparable to previously reported results following oral gavage. Modafinil-treated rats were more active than control rats, with greater activity during the later time-periods – similar to that previously reported following intraperitoneal injection of 40 mg/kg modafinil. Conclusions: Palatable jelly tablets are an effective route of administration of thermally-stable orally-bioavailable compounds, eliminating the stress/discomfort and health risk of oral gavage and presenting as an alternative to previously reported palatable routes of administration where high protein and fat levels may adversely affect appetite for food reward, and uptake rate in the gastrointestinal tract.Publisher PDFPeer reviewe

Maternal Environment Influences Cocaine Intake in Adulthood in a Genotype-Dependent Manner

Background: Accumulating epidemiological evidence points to the role of genetic background as a modulator of the capacity of adverse early experiences to give rise to mental illness. However, direct evidence of such gene-environment interaction in the context of substance abuse is scarce. In the present study we investigated whether the impact of early life experiences on cocaine intake in adulthood depends on genetic background. In addition, we studied other behavioral dimensions associated with drug abuse, i.e. anxiety- and depression-related behaviors. Methodology/Principal Findings: For this purpose, we manipulated the maternal environment of two inbred mouse strains, the C57BL/6J and DBA/2J by fostering them with non-related mothers, i.e. the C3H/HeN and AKR strains. These mother strains show respectively high and low pup-oriented behavior. As adults, C57BL/6J and DBA/2J were tested either for cocaine intravenous self-administration or in the elevated plus-maze and forced swim test (FST). We found that the impact of maternal environment on cocaine use and a depression-related behavior depends upon genotype, as cocaine self-administration and behavior in the FST were influenced by maternal environment in DBA/2J, but not in C57BL/6J mice. Anxiety was not influenced by maternal environment in either strain. Conclusions/Significance: Our experimental approach could contribute to the identification of the psychobiological factor

Stressor- and Corticotropin releasing Factor-induced Reinstatement and Active Stress-related Behavioral Responses are Augmented Following Long-access Cocaine Self-administration by Rats

Rationale Stressful events during periods of drug abstinence likely contribute to relapse in cocaine-dependent individuals. Excessive cocaine use may increase susceptibility to stressor-induced relapse through alterations in brain corticotropin-releasing factor (CRF) responsiveness. Objectives This study examined stressor- and CRF-induced cocaine seeking and other stress-related behaviors in rats with different histories of cocaine self-administration (SA). Materials and methods Rats self-administered cocaine under short-access (ShA; 2 h daily) or long-access (LgA; 6 h daily) conditions for 14 days or were provided access to saline and were tested for reinstatement by a stressor (electric footshock), cocaine or an icv injection of CRF and for behavioral responsiveness on the elevated plus maze, in a novel environment and in the light–dark box after a 14- to 17-day extinction/withdrawal period. Results LgA rats showed escalating patterns of cocaine SA and were more susceptible to reinstatement by cocaine, EFS, or icv CRF than ShA rats. Overall, cocaine SA increased activity in the center field of a novel environment, on the open arms of the elevated plus maze, and in the light compartment of a light–dark box. In most cases, the effects of cocaine SA were dependent on the pattern/amount of cocaine intake with statistically significant differences from saline self-administering controls only observed in LgA rats. Conclusions When examined after several weeks of extinction/ withdrawal, cocaine SA promotes a more active pattern of behavior during times of stress that is associated with a heightened susceptibility to stressor-induced cocaine-seeking behavior and may be the consequence of augmented CRF regulation of addiction-related neurocircuitry

Imbalanced decision hierarchy in addicts emerging from drug-hijacked dopamine spiraling circuit

Despite explicitly wanting to quit, long-term addicts find themselves powerless to resist drugs, despite knowing that drug-taking may be a harmful course of action. Such inconsistency between the explicit knowledge of negative consequences and the compulsive behavioral patterns represents a cognitive/behavioral conflict that is a central characteristic of addiction. Neurobiologically, differential cue-induced activity in distinct striatal subregions, as well as the dopamine connectivity spiraling from ventral striatal regions to the dorsal regions, play critical roles in compulsive drug seeking. However, the functional mechanism that integrates these neuropharmacological observations with the above-mentioned cognitive/behavioral conflict is unknown. Here we provide a formal computational explanation for the drug-induced cognitive inconsistency that is apparent in the addicts' “self-described mistake”. We show that addictive drugs gradually produce a motivational bias toward drug-seeking at low-level habitual decision processes, despite the low abstract cognitive valuation of this behavior. This pathology emerges within the hierarchical reinforcement learning framework when chronic exposure to the drug pharmacologically produces pathologicaly persistent phasic dopamine signals. Thereby the drug hijacks the dopaminergic spirals that cascade the reinforcement signals down the ventro-dorsal cortico-striatal hierarchy. Neurobiologically, our theory accounts for rapid development of drug cue-elicited dopamine efflux in the ventral striatum and a delayed response in the dorsal striatum. Our theory also shows how this response pattern depends critically on the dopamine spiraling circuitry. Behaviorally, our framework explains gradual insensitivity of drug-seeking to drug-associated punishments, the blocking phenomenon for drug outcomes, and the persistent preference for drugs over natural rewards by addicts. The model suggests testable predictions and beyond that, sets the stage for a view of addiction as a pathology of hierarchical decision-making processes. This view is complementary to the traditional interpretation of addiction as interaction between habitual and goal-directed decision systems

Anti-relapse neurons in the infralimbic cortex of rats drive relapse-suppression by drug omission cues

Drug addiction is a chronic relapsing disorder of compulsive drug use. Studies of the neurobehavioral factors that promote drug relapse have yet to produce an effective treatment. Here we take a different approach and examine the factors that suppress – rather than promote – relapse. Adapting Pavlovian procedures to suppress operant drug response, we determined the anti-relapse action of environmental cues that signal drug omission (unavailability) in rats. Under laboratory conditions linked to compulsive drug use and heightened relapse risk, drug omission cues suppressed three major modes of relapse-promotion (drug-predictive cues, stress, and drug exposure) for cocaine and alcohol. This relapse-suppression is partially driven by omission cue-reactive neurons, which constitute small subsets of glutamatergic and GABAergic cells, in the infralimbic cortex. Future studies of such neural activity-based cellular units (neuronal ensembles/memory engram cells) for relapse-suppression can be used to identify alternate targets for addiction medicine through functional characterization of anti-relapse mechanisms

Cocaine Is Low on the Value Ladder of Rats: Possible Evidence for Resilience to Addiction

International audienceBACKGROUND:Assessing the relative value of cocaine and how it changes with chronic drug use represents a long-standing goal in addiction research. Surprisingly, recent experiments in rats--by far the most frequently used animal model in this field--suggest that the value of cocaine is lower than previously thought.METHODOLOGY/PRINCIPAL FINDINGS:Here we report a series of choice experiments that better define the relative position of cocaine on the value ladder of rats (i.e., preference rank-ordering of different rewards). Rats were allowed to choose either taking cocaine or drinking water sweetened with saccharin--a nondrug alternative that is not biologically essential. By systematically varying the cost and concentration of sweet water, we found that cocaine is low on the value ladder of the large majority of rats, near the lowest concentrations of sweet water. In addition, a retrospective analysis of all experiments over the past 5 years revealed that no matter how heavy was past cocaine use most rats readily give up cocaine use in favor of the nondrug alternative. Only a minority, fewer than 15% at the heaviest level of past cocaine use, continued to take cocaine, even when hungry and offered a natural sugar that could relieve their need of calories.CONCLUSIONS/SIGNIFICANCE:This pattern of results (cocaine abstinence in most rats; cocaine preference in few rats) maps well onto the epidemiology of human cocaine addiction and suggests that only a minority of rats would be vulnerable to cocaine addiction while the large majority would be resilient despite extensive drug use. Resilience to drug addiction has long been suspected in humans but could not be firmly established, mostly because it is difficult to control retrospectively for differences in drug self-exposure and/or availability in human drug users. This conclusion has important implications for preclinical research on the neurobiology of cocaine addiction and for future medication development