Rebecca S. Hofford

Environmental enrichment reduces methamphetamine cue-induced reinstatement but does not alter methamphetamine reward or VMAT2 function.

Environmental factors influence a variety of health-related outcomes. In general, being raised in an environment possessing social, sensory, and motor enrichment reduces the rewarding effects of various drugs, thus protecting against abuse vulnerability. However, in the case of methamphetamine (METH), which acts at the vesicular monoamine transporter 2 (VMAT2) to enhance dopamine release from the cytosol, previous evidence suggests that METH reward may not be altered by environmental enrichment. This study examined the influence of an enriched environment on measures of METH reward, METH seeking, and VMAT2 function. Rats were raised from weaning to adulthood in either an enriched environment (presence of social cohorts and novel objects) or an isolated environment (no cohorts or novel objects). Rats in these two conditions were subsequently tested for their acquisition of conditioned place preference (CPP), METH self-administration, maintenance of self-administration at various unit doses of METH (0.001-0.5mg/kg/infusion), and cue-induced reinstatement. VMAT2 function in striatum from these two groups also was assessed. No significant environment effects were found in CPP or METH self-administration, which paralleled a lack of effect in VMAT2 function between groups. However, cue-induced reinstatement was reduced by environmental enrichment. Together, these results suggest that environmental enrichment does not alter VMAT2 function involved in METH reward. However, the enrichment-induced decrease in cue-induced reinstatement indicates that enrichment may have a beneficial effect against relapse following a period of extinction via a neural mechanism other than striatal VMAT2 function.

Pharmacological manipulation of glucocorticoid receptors differentially affects cocaine self-administration in environmentally enriched and isolated rats

Social isolation rearing (isolated condition, IC) is used as a model of early life stress in rodents. Rats raised in this condition are often compared to rats raised in an environmentally enriched condition (EC). However, EC rats are repeatedly exposed to forced novelty, another classic stressor in rodents. These studies explored the relationship between cocaine self-administration and glucocorticoid receptor (GR) activation and measured total levels of GR protein in reward-related brain regions (medial prefrontal cortex, orbitofrontal cortex, nucleus accumbens, amygdala) in rats chronically exposed to these conditions. For experiment 1, rats were housed in EC or IC and were then trained to self-administer cocaine. Rats raised in these housing conditions were tested for their cocaine responding after pretreatment with the GR antagonist, RU486, or the GR agonist, corticosterone (CORT). For experiment 2, levels of GR from EC and IC rats were measured in brain regions implicated in drug abuse using Western blot analysis. Pretreatment with RU486 (20 mg/kg) decreased responding for a low unit dose of cocaine (0.03 mg/kg/infusion) in EC rats only. IC rats were unaffected by RU486 pretreatment, but earned significantly more cocaine than EC rats after pretreatment with CORT (10 mg/kg). No difference in GR expression was found between EC and IC rats in any brain area examined. These results, along with previous literature, suggest that enrichment enhances responsivity of the HPA axis related to cocaine reinforcement, but this effect is unlikely due simply to differential baseline GR expression in areas implicated in drug abuse.

Rearing environment differentially modulates cocaine self-administration after opioid pretreatment: A behavioral economic analysis

BACKGROUNDnResearch has shown that previous experiences during development, especially if stressful, can alter an organisms response to opioids later in life. Given the previous literature on opioid modulation of cocaine self-administration, the current study raised rats in either an enriched condition (EC) or isolated condition (IC) and employed behavioral economics to study the effects of naltrexone and morphine on cocaine self-administration.nnnMETHODSnEC and IC rats were trained to lever press for cocaine using a within-session demand procedure. This procedure measured cocaine consumption under changing cocaine price by decreasing the dose of cocaine earned throughout a session. Rats were able to self-administer cocaine on a FR1; every 10min the cocaine dose was systematically decreased (0.75-0.003mg/kg/infusion cocaine). After reaching stability on this procedure, rats were randomly pretreated with 0, 0.3, 1, or 3mg/kg naltrexone once every 3days, followed by random pretreatments of 0, 0.3, 1, or 3mg/kg morphine once every 3days. Economic demand functions were fit to each rats cocaine consumption from each pretreatment, and appropriate mathematical parameters were extracted and analyzed.nnnRESULTSnNaltrexone decreased the essential value of cocaine in IC rats only. However, morphine decreased the essential value of cocaine and the consumption of cocaine at zero price in both EC and IC rats.nnnCONCLUSIONnThese results indicate that environmental experiences during development should be considered when determining the efficacy of opioid drugs, especially for the treatment of substance abuse.

Sex differences in monoamines following amphetamine and social reward in adolescent rats.

Interaction with social peers may increase rates of drug self-administration, but a recent study from our laboratory showed that social interaction may serve as a type of alternative reward that competes with drug taking in adolescent male rats. Based on those previous results, the current study examined sex differences in preference for social interaction compared with amphetamine (AMPH) in adolescent rats using the conditioned place preference (CPP) paradigm. Similar to previous results with males, females showed AMPH CPP regardless of whether they were individual- or pair-housed. In contrast to males, however, females failed to show social CPP, and they did not prefer a peer-associated compartment over an AMPH-associated compartment in a free-choice test. In separate experiments, dopamine (DA) and serotonin (5-HT) metabolite levels were measured in adolescent males and females that were exposed acutely to peer interaction, no peer interaction, AMPH, or saline. In amygdala, levels of the DA metabolite dihydroxyphenylacetic acid (DOPAC) were altered more in response to peer interaction in males than females; in contrast, there was a greater amygdala DOPAC response to AMPH in females. Furthermore, there were greater changes in the 5-HT metabolite hydroxyindoleacetic acid (5-HIAA) in females than in males following social interaction. These results indicate that the ability of peer interactions to reduce drug reward is greater in adolescent males than females, perhaps due to a greater ability of social cues to activate limbic reward mechanisms in males or a greater ability of AMPH cues to activate limbic reward mechanisms in females.

The role of ‘jackpot’ stimuli in maladaptive decision-making: dissociable effects of D1/D2 receptor agonists and antagonists

RationaleLaboratory experiments often model risk through a choice between a large, uncertain (LU) reward against a small, certain (SC) reward as an index of an individual’s risk tolerance. An important factor generally lacking from these procedures are reward-associated cues that may modulate risk preferences.ObjectiveWe tested whether the addition of cues signaling ‘jackpot’ wins to LU choices would modulate risk preferences and if these cue effects were mediated by dopaminergic signaling.MethodsThree groups of rats chose between LU and SC rewards for which the LU probability of reward decreased across blocks. The unsignaled group received a non-informative stimulus of trial outcome. The signaled group received a jackpot signal prior to reward delivery and blackout on losses. The signaled-light group received a similar jackpot for wins, but a salient loss signal distinct from the win signal.ResultsPresenting win signals decreased the discounting of LU value for both signaled groups regardless of loss signal, while the unsignaled group showed discounting similar to previous research without cues. Pharmacological challenges with D1/D2 agonists and antagonists revealed that D1 antagonism increased and decreased sensitives to the relative probability of reward for unsignaled and signaled groups, respectively, while D2 agonists decreased sensitivities to the relative magnitude of reward.ConclusionThe results highlight how signals predictive of wins can promote maladaptive risk taking in individuals, while loss signals have reduced effect. Additionally, the presence of reward-predictive cues may change the underlying neurobehavioral mechanisms mediating decision-making under risk.

Effects of environmental enrichment on self-administration of the short-acting opioid remifentanil in male rats

BackgroundOpioid abuse is a major problem around the world. Identifying environmental factors that contribute to opioid abuse and addiction is necessary for decreasing this epidemic. In rodents, environmental enrichment protects against the development of low dose stimulant self-administration, but studies examining the effect of enrichment and isolation (compared to standard housing) on the development of intravenous opioid self-administration have not been conducted. The present study investigated the role of environmental enrichment on self-administration of the short-acting μ-opioid remifentanil.MethodsRats were raised in an enriched condition (Enr), standard condition (Std), or isolated condition (Iso) beginning at 21xa0days of age and were trained to lever press for 1 or 3xa0μg/kg/infusion remifentanil in young adulthood. Acquisition of self-administration and responding during increasing fixed ratio requirements were assessed, and a dose-response curve was generated.ResultsIn all phases, Enr rats lever pressed significantly less than Std and Iso rats, with Enr rats pressing between 9 and 40% the amount of Iso rats. Enr rats did not acquire remifentanil self-administration when trained with 1xa0μg/kg/infusion, did not increase responding over increasing FR when trained at either dose, and their dose-response curves were flattened compared to Std and Iso rats. When expressed as economic demand curves, Enr rats displayed a decrease in both essential value (higher α) and reinforcer intensity (Q0) compared to Std and Iso rats at the 1xa0μg/kg/infusion training dose.ConclusionEnvironmental enrichment reduced remifentanil intake, suggesting that social and environmental novelty may protect against opioid abuse.

Modified single prolonged stress reduces cocaine self-administration during acquisition regardless of rearing environment

&NA; Until recently, there were few rodent models available to study the interaction of post‐traumatic stress disorder (PTSD) and drug taking. Like PTSD, single prolonged stress (SPS) produces hypothalamic‐pituitary‐adrenal (HPA) axis dysfunction and alters psychostimulant self‐administration. Other stressors, such as isolation stress, also alter psychostimulant self‐administration. However, it is currently unknown if isolation housing combined with SPS can alter the acquisition or maintenance of cocaine self‐administration. The current study applied modified SPS (modSPS; two hours restraint immediately followed by cold swim stress) to rats raised in an isolation condition (Iso), enrichment condition (Enr), or standard condition (Std) to measure changes in cocaine self‐administration and HPA markers. Regardless of rearing condition, rats exposed to modSPS had greater corticosterone (CORT) release and reduced cocaine self‐administration during initial acquisition compared to non‐stressed controls. In addition, during initial acquisition, rats that received both Iso rearing and modSPS showed a more rapid increase in cocaine self‐administration across sessions compared to Enr and Std rats exposed to modSPS. Following initial acquisition, a dose response analysis showed that Iso rats were overall most sensitive to changes in cocaine unit dose; however, modSPS had no effect on the cocaine dose response curve. Further, there was no effect of either modSPS or differential rearing on expression of glucocorticoid receptor (GR) in hypothalamus, medial prefrontal cortex, amygdala, or nucleus accumbens. By using modSPS in combination with Iso housing, this study identified unique contributions of each stressor to acquisition of cocaine self‐administration. HighlightsEnriched, standard, and isolated rats underwent modified single prolonged stress.Exposure to modSPS attenuated cocaine self‐administration early in training.Corticosterone increased after modSPS but was not moderated by environment.ModSPS did not alter glucocorticoid receptor expression in hypo, mPFC, amyg, or NAc.