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1.  Limited physical contact through a mesh barrier is sufficient for social reward-conditioned place preference in adolescent male rats 
Physiology & behavior  2011;105(3):749-756.
Adolescence is a period of enhanced sensitivity to social influences and vulnerability to drug abuse. Social reward in adolescent rats has been demonstrated with the conditioned place preference (CPP) model, but it is not clear whether limited contact with another rat without play is sufficient to produce reward. We investigated this issue using an apparatus containing two main compartments each with a wire mesh barrier that allowed rats placed on either side of the barrier to have limited physical contact. Adolescent male rats were given two conditioning sessions/day for 2 or 8 days following baseline preference tests. Rats were placed into their preferred side alone for one daily 10-min session and into their initially non-preferred side (i.e., CS) for the other session during which they either had restricted or unrestricted physical access to another rat (Rat/Mesh or Rat/Phys, respectively) or to a tennis ball (Ball/Mesh or Ball/Phys, respectively) unconditioned stimulus (US). Only the Rat/Phys group exhibited CPP after 2 CS-US pairings; however, after 8 CS-US pairings, the Rat/Mesh and Ball/Phys groups also exhibited CPP. During conditioning, the rat US elicited more robust approach and contact behavior compared to the ball, regardless of physical or restricted access. The incidence of contact and/or approach increased as the number of exposures increased. The results suggest that the rank order of US reward efficacy was physical contact with a rat > limited contact with a rat > physical contact with a ball, and that rough-and-tumble play is not necessary to establish social reward-CPP. The findings have important implications for emerging drug self-administration models in which two rats self-administering drug intravenously have limited physical contact via a mesh barrier shared between their respective operant conditioning chambers.
doi:10.1016/j.physbeh.2011.10.001
PMCID: PMC3975131  PMID: 22008744
rough-and-tumble play behavior; place conditioning; adolescence; drug self-administration
2.  A New Criterion for Acquisition of Nicotine Self-administration in Rats* 
Drug and alcohol dependence  2012;124(0):63-69.
Background
Acquisition of nicotine self-administration in rodents is relatively difficult to establish and measures of acquisition rate are sometimes confounded by manipulations used to facilitate the process. This study examined acquisition of nicotine self-administration without such manipulations and used mathematical modeling to define the criterion for acquisition.
Methods
Rats were given 20 daily 2-h sessions occurring 6 days/week in chambers equipped with active and inactive levers. Each active lever press resulted in nicotine reinforcement (0–0.6 mg/kg, IV) and retraction of both levers for a 20-s time out, whereas inactive lever presses had no consequences. Acquisition was defined for individual rats by the higher likelihood of reinforcers obtained across sessions fitting a logistic over a constant function according to the corrected Akaike information criterion (AICc).
Results
For rats that acquired self-administration, an AICc-based multi-model comparison demonstrated that the asymptote (highest number of reinforcers/session) and mid-point of the acquisition curve (h; the number of sessions necessary to reach half the asymptote) varied by nicotine dose, with both exhibiting a negative relationship (the higher the dose, the lower number of reinforcers and the lower h).
Conclusions
The modeling approach used in this study provides a way of defining acquisition of nicotine self-administration that takes advantage of all data from individual subjects and the procedure used is sensitive to dose differences in the absence of manipulations that influence acquisition (e.g., food restriction, prior food reinforcement, conditioned reinforcers).
doi:10.1016/j.drugalcdep.2011.12.011
PMCID: PMC3975132  PMID: 22243759
Nicotine; Self-administration; Akaike Information Criterion; Acquisition
3.  Novel Cues Reinstate Cocaine-Seeking Behavior and Induce Fos Protein Expression as Effectively as Conditioned Cues 
Neuropsychopharmacology  2012;37(9):2109-2120.
Cue reinstatement of extinguished cocaine-seeking behavior is a widely used model of cue-elicited craving in abstinent human addicts. This study examined Fos protein expression in response to cocaine cues or to novel cues as a control for activation produced by test novelty. Rats were trained to self-administer cocaine paired with either a light or a tone cue, or received yoked saline and cue presentations, and then underwent daily extinction training. They were then tested for reinstatement of extinguished cocaine-seeking behavior elicited by response-contingent presentations of either the cocaine-paired cue or a novel cue (that is, tone for those trained with a light or vice versa). Surprisingly, conditioned and novel cues both reinstated responding and increased Fos similarly in most brain regions. Exceptions included the anterior cingulate, which was sensitive to test cue modality in saline controls and the dorsomedial caudate-putamen, where Fos was correlated with responding in the novel, but not conditioned, cue groups. In subsequent experiments, we observed a similar pattern of reinstatement in rats trained and tested for sucrose-seeking behavior, whereas rats trained and tested with the cues only reinstated to a novel, and not a familiar, light or tone. The results suggest that novel cues reinstate responding to a similar extent as conditioned cues regardless of whether animals have a reinforcement history with cocaine or sucrose, and that both types of cues activate similar brain circuits. Several explanations as to why converging processes may drive drug and novel cue reinforcement and seeking behavior are discussed.
doi:10.1038/npp.2012.60
PMCID: PMC3398726  PMID: 22534624
cocaine; self-administration; drug-seeking behavior; novelty; reinstatement; immediate early gene; cocaine; self-administration; drug-seeking behavior; novelty; reinstatement; immediate early gene
4.  Environmental enrichment counters cocaine abstinence-induced stress and brain reactivity to cocaine cues but fails to prevent the incubation effect 
Addiction Biology  2011;17(2):365-377.
Environmental enrichment (EE) during a period of forced abstinence attenuates incentive motivational effects of cocaine-paired stimuli. Here we examined whether EE during forced abstinence from cocaine self-administration would prevent time-dependent increases in cue-elicited cocaine-seeking behavior (i.e., the incubation effect). Rats were trained to self-administer cocaine, which was paired with light/tone cues, for 15 days while living in isolated conditions (IC). Controls received yoked saline infusions. Subsequently, rats were assigned to live in either continued IC or EE for either 1 or 21 days of forced abstinence prior to a test for cocaine-seeking behavior. During testing, responding resulted only in presentation of the light/tone cues. Contrary to our prediction, cocaine-seeking behavior increased over time regardless of living condition during abstinence; however, EE attenuated cocaine-seeking behavior relative to IC regardless of length of abstinence. Brains were harvested and trunk blood was collected immediately after the 60-min test and later assayed. Results indicated that short-term EE elevated hippocampal brain-derived neurotrophic factor and reduced plasma corticosterone compared to IC. Furthermore, 21 days of EE during forced abstinence prevented increases in the cue-elicited amygdala phosphorylated extracellular signal-regulated kinase expression that was observed in IC rats. These findings suggest that EE attenuates incentive motivational effects of cocaine cues through a mechanism other than preventing the incubation effect, perhaps involving reduction of stress and neural activity in response to cocaine-paired cues during acute withdrawal.
doi:10.1111/j.1369-1600.2011.00358.x
PMCID: PMC3220742  PMID: 21812872
brain-derived neurotrophic factor (BDNF); craving; corticosterone; drug-seeking behavior; extracellular signal-regulated kinase (ERK); incentive motivation
5.  Mood symptoms contribute to working memory decrement in active-duty soldiers being treated for posttraumatic stress disorder 
Brain and Behavior  2012;2(4):357-364.
A significant proportion of military veterans of operations in Afghanistan and Iraq have been diagnosed with posttraumatic stress disorder (PTSD). Growing evidence suggests that neuropsychological deficits are a symptom of PTSD. The current study investigated neurocognitive functioning among soldiers diagnosed with PTSD. Specifically, active-duty soldiers with and without a diagnosis of PTSD were assessed for performance on tests of attention and working memory. In addition, factors such as combat experience, depression, anxiety, PTSD symptom severity, and alcohol consumption were explored as possible mediators of group differences in neurocognitive functioning. Twenty-three active-duty soldiers diagnosed with PTSD were matched with 23 healthy Soldier controls; all were administered the Attention Network Task (ANT), Backward Digit Span (BDS) task, Beck Depression Inventory, Beck Anxiety Inventory, PTSD Checklist—Military Version, Combat Exposure Scale, and Modified Drinking Behavior Questionnaire. Soldiers diagnosed with PTSD performed significantly worse on the working memory task (BDS) than healthy controls, and reported greater levels of PTSD symptoms, combat exposure, depression, and anxiety. However, after controlling for depression and anxiety symptoms, the relationship between PTSD and working memory was no longer present. The results indicate that PTSD is accompanied by deficits in working memory, which appear to be partially attributed to anxiety and depression symptoms.
doi:10.1002/brb3.53
PMCID: PMC3432958  PMID: 22950039
Anxiety; depression; digit span; memory; military; neurocognitive
6.  Anti-craving effects of environmental enrichment 
We hypothesized that environmental enrichment in rats may reduce cocaine-seeking behaviour elicited by cocaine-priming injections and by cocaine-associated cues. Rats trained to self-administer cocaine while housed in isolated conditions were then assigned to live in isolation or an enriched environment for 21 d of forced abstinence. Subsequently, extinction and reinstatement of cocaine-seeking behaviour (operant responses without cocaine available) were assessed. Expt 1 showed that enrichment resulted in less cocaine-seeking behaviour during extinction and cue-elicited reinstatement compared to continued isolation housing, but had no effect on cocaine-primed reinstatement. A subsequent experiment, which included a pair-housed group to control for potential isolation stress, again demonstrated that enrichment attenuated cocaine seeking during extinction, but not cocaine-primed reinstatement, relative to both isolation and pair-housed conditions. The findings suggest that enrichment reduces the impact of cocaine-associated environmental stimuli, and hence it may be a useful intervention for attenuating cue-elicited craving in humans.
doi:10.1017/S1461145709990472
PMCID: PMC2832121  PMID: 19691875
Cocaine; drug-seeking behaviour; environmental enrichment; reinstatement; self-administration
7.  Synergistic interaction between nicotine and social rewards in adolescent male rats 
Psychopharmacology  2009;204(3):391-402.
Rationale
Smoking typically begins during adolescence and is largely reinforced by social cues. During adolescence in rats, sensitivity to both social cues and drugs of abuse is enhanced.
Objectives
We have previously demonstrated in adolescent male rats that a low dose of cocaine interacts with social reward to produce an enhanced conditioned place preference (CPP) relative to either reward given alone. The present study further examined the nature of drug:social reward interactions using nicotine.
Methods
Dose-effect functions for nicotine-CPP were established using two different routes of administration (vehicle, 0.1, 0.3, and 0.6 mg/kg, SC and vehicle, 0.01, 0.03, and 0.06 mg/kg, IV). The effects of nicotine on social reward-CPP and social play behavior were next examined using parameters presumed to be sub-threshold for establishing social reward- and nicotine-CPP.
Results
Dose-dependent nicotine-CPP was observed using both routes of administration. Two pairings of the initially non-preferred side of the apparatus with either SC nicotine or another adolescent rat failed to produce CPP when examined alone, but together produced a robust CPP despite nicotine reducing social play. This interaction effect was not observed with the IV nicotine. A final experiment demonstrated that the enhancement of CPP with the combination of rewards was not due to additive effects of weak, sub-threshold conditioning.
Conclusions
These findings suggest that nicotine and social rewards interact synergistically in adolescent rats resulting in a greater, perhaps qualitatively different, reward than either reward given alone. Understanding drug:social reward interactions may provide new directions for development of preventions and interventions of adolescent smoking.
doi:10.1007/s00213-009-1470-2
PMCID: PMC2831774  PMID: 19224200
Adolescence; Conditioned Place Preference; Place conditioning; Drug Conditioning; Intravenous nicotine
8.  c-Fos expression associated with reinstatement of cocaine-seeking behavior by response-contingent conditioned cues 
Synapse (New York, N.Y.)  2009;63(10):823-835.
Summary
The capability of cocaine cues to generate craving in cocaine-dependent humans, even after extended abstinence, is modeled in rats using cue reinstatement of extinguished cocaine-seeking behavior. We investigated neural activity associated with incentive motivational effects of cocaine cues using c-fos mRNA and Fos protein expression as markers. Unlike preceding studies, we used response-contingent presentation of discrete cues to elicit cocaine seeking. Rats were first trained to press a lever, resulting in cocaine reinforcement and light and tone cues. Rats then underwent extinction training, during which lever presses decreased. On the test day, rats either received response-contingent cocaine cues or received no cues. The cues reinstated extinguished cocaine-seeking behavior on the test day. In general, cue-elicited c-fos mRNA and protein expression were similar and both were enhanced in the prefrontal cortex, ventral tegmental area (VTA), dorsal striatum and nucleus accumbens. Cues elicited more widespread Fos protein expression relative to our previous research in which cues were presented non-contingently without prior extinction training, including increases in the VTA, substantia nigra, ventral subiculum, and lateral entorhinal cortex. We also observed a correlation between cocaine-seeking behavior and Fos in the agranular insula (AgI) and basolateral amygdala (BLA). The findings suggest that connections between BLA and AgI play a role in cue-elicited incentive motivation for cocaine and that reinstatement of cocaine seeking by response-contingent cues activates a similar corticolimbic circuit as that observed with other modes of cue presentation; however, activation of midbrain and ventral hippocampal regions may be unique to reinstatement by response-contingent cues.
doi:10.1002/syn.20666
PMCID: PMC2748778  PMID: 19533625
drug craving; addiction; drug conditioning; reinstatement; cocaine; immediate early gene; extinction
9.  Social Reward-Conditioned Place Preference: A Model Revealing an Interaction between Cocaine and Social Context Rewards in Rats 
Drug and alcohol dependence  2008;96(3):202-212.
A recent thrust in drug abuse research is the influence of social interactions on drug effects. Therefore, the present study examined conditioned place preference (CPP) as a model for assessing interactions between drug and social rewards in adolescent rats. Parameters for establishing social reward-CPP were examined, including the number of conditioning sessions/day (1 or 2), the total number of sessions (2, 4, or 16), and the duration of sessions (10 or 30 min). Subsequently, the effects of cocaine or dextromethorphan on social reward-CPP and play behavior were examined. The results demonstrate that social reward-CPP (i.e., preference shift for an environment paired previously with a rat) was similar using either 1 or 2 conditioning sessions/day and either 10 or 30 min sessions; however, social reward-CPP increased as the number of social pairings increased. Additionally, a low dose of cocaine (2 mg/kg, IP) and a low number of social pairings (2 pairings) failed to produce CPP when examined alone, but together produced a robust CPP, demonstrating an interaction between these rewards. The non-rewarding drug, dextromethorphan (30 mg/kg, IP), failed to enhance social reward-CPP, suggesting that drug-enhanced social reward-CPP is specific to rewarding drugs. Surprisingly, there was no relationship between play behaviors and preference shift in drug-naïve animals. Furthermore, cocaine inhibited play behavior despite enhancing social reward-CPP, suggesting that aspects of social interaction other than play behavior likely contribute to social reward. The findings have important implications for understanding the influence of social context on cocaine reward during adolescence.
doi:10.1016/j.drugalcdep.2008.02.013
PMCID: PMC2488154  PMID: 18430522
Social Interaction; Conditioned Place Preference; Adolescence; Cocaine; Drug reward

Results 1-9 (9)