Enriched Condition Rats Research Articles

Effects of Social Isolation on Perineuronal Nets in the Amygdala Following a Reward Omission Task in Female Rats.

Negative urgency is a facet of impulsivity associated with negative affect and risky behavior that may involve the amygdala. The current study determined if social isolation during development alters negative urgency and c-Fos activity in the basolateral amygdala (BLA). Female Sprague-Dawley rats were raised in an isolated condition (IC), a standard social condition (SC), or an enriched condition (EC) and then were tested for locomotor activity, novelty place preference, and negative urgency using a reward omission task. Following performance on the reward omission task, the brains were analyzed for c-Fos expression in Ca2+/calmodulin kinase II (CaMKII) and calbindin (CB) neurons, as well as in parvalbumin (PV) neurons associated with perineuronal nets (PNNs) in BLA. IC rats exhibited enhanced locomotion compared with both SC and EC rats, as well as enhanced novelty place preference compared with EC rats; only IC rats showed increased responding following omission of an expected reward (negative urgency). Following completion of the reward omission task, IC rats also displayed increased percent of c-Fos neurons in BLA associated with CaMKII, CB, and PV neurons compared with SC and EC rats. In IC rats, c-Fos activation in BLA occurred following the omission of an expected reward. Finally, IC rats displayed reduced PNN intensity associated with PV neurons compared with EC rats, but the percent of these neurons co-expressing c-Fos was greater in IC rats; SC rats were intermediate between IC and EC rats. Negative urgency was observed in IC rats, but not SC or EC rats. While multiple mechanisms are likely involved, this behavioral effect was associated with an isolation-induced increase in activity of excitatory neurons in BLA, as well as decreased PNN intensity surrounding GABAergic neurons in the same region.

Dynamic interactions of ceftriaxone and environmental variables suppress amphetamine seeking

Extrasynaptic glutamate within the nucleus accumbens (NAc) is a driver of relapse. Cocaine, ethanol, and methamphetamine reduce the expression of cystine-glutamate antiporter (xCT) and primary glial glutamate transporter 1 (GLT1) leading to increased extrasynaptic glutamate. Ceftriaxone (CTX) restores xCT and GLT1 expression and effectively suppresses cocaine and ethanol reinstatement, however, the effects of CTX on amphetamine (AMP) reinstatement are not determined. Rodents were reared in an enriched condition (EC), isolated (IC), or standard condition (SC) and trained in AMP self-administration (0.1 mg/kg/infusion). EC, IC, and SC rats received injections of SAL or CTX (200 mg/kg) after daily extinction sessions. Then rats were tested in cue- and AMP-induced reinstatement tests. We hypothesized that EC rearing would reduce reinstatement by altering GLT1 or xCT expression in the NAc and medial prefrontal cortex (mPFC). In Experiment 2, pair-housed rats received once-daily AMP (1.0 mg/kg i.p.) or SAL for eight days followed by once-daily CTX (200 mg/kg i.p.) or SAL injections for 10 days. CTX treatment reduced cue-induced drug seeking in EC rats but not IC or SC rats. In an AMP-induced reinstatement test, CTX reduced AMP-induced drug seeking in EC and SC rats, but not IC rats. Western blot analyses revealed that AMP self-administration and non-contingent repeated AMP exposure did not downregulate GLT1 or xCT in the NAc or mPFC. Therefore, the ability for EC housing to reduce amphetamine seeking may work through other mechanisms.

Environmental enrichment and drug value: a behavioral economic analysis in male rats.

Rats raised in an enriched condition (EC) show decreased stimulant self-administration relative to rats reared in an isolated condition (IC). However, few studies have examined the behavioral mechanisms underlying this environment-induced difference in self-administration. Because economic demand for drugs of abuse predicts addiction-like behavior in both humans and animals, we applied a behavioral economic analysis to cocaine self-administration data in EC and IC rats. During cocaine self-administration, the dose decreased across blocks of trials (0.75-0.003mg/kg/inf), which allowed for a determination of demand intensity and demand elasticity. Demand intensity did not differ between EC and IC rats; however, cocaine was more elastic in EC rats relative to IC rats (i.e. EC rats were less willing to respond for cocaine as the unit price increased). When EC rats were placed in an isolated condition, demand elasticity decreased, whereas elasticity increased for IC rats placed in an enriched condition. Additionally, we applied behavioral economic analyses to previously published self-administration data and found that our results replicate past findings with cocaine and methylphenidate. To determine if differences in demand elasticity are specific to drug reinforcement, a separate group of rats was tested in sucrose or saccharin self-administration. Results showed that sucrose and saccharin were more elastic in EC rats relative to IC rats, and demand intensity was lower for saccharin in EC rats relative to IC rats. Overall, drug and nondrug reinforcers are more elastic in EC rats, which may account for the protective effects of environmental enrichment against stimulant self-administration.

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

BackgroundResearch has shown that previous experiences during development, especially if stressful, can alter an organism’s 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. MethodsEC 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 rat’s cocaine consumption from each pretreatment, and appropriate mathematical parameters were extracted and analyzed. ResultsNaltrexone 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. ConclusionThese results indicate that environmental experiences during development should be considered when determining the efficacy of opioid drugs, especially for the treatment of substance abuse.

Prefrontal microRNA-221 Mediates Environmental Enrichment-Induced Increase of Locomotor Sensitivity to Nicotine

Background:Environmental enrichment alters susceptibility in developing drug addiction. We have demonstrated that rats raised in an enriched condition are more sensitive than rats raised in an impoverished condition to nicotine-induced locomotor activity, and this is associated with alterations of phosphorylated extracellular signal-regulated kinase 1/2 within the prefrontal cortex. This study determined the impact of microRNA-221 in the prefrontal cortex on phosphorylated extracellular signal-regulated kinase 1/2 and the enriched environment-dependent behavioral changes in response to nicotine.Methods:A microRNA array was conducted to profile microRNA expression in the prefrontal cortex of enriched condition and impoverished condition rats in response to repeated nicotine (0.35mg/kg, s.c.) administration. microRNA-221 in the prefrontal cortex, nucleus accumbens, and striatum was further verified by quantitative real-time PCR. Lentiviral-mediated overexpression of microRNA-221 in PC12 cells and the medial prefrontal cortex was performed to determine the effects of microRNA-221 on nicotine-mediated phosphorylated extracellular signal-regulated kinase 1/2, phosphorylated cAMP-response element-binding protein, and locomotor activity.Results:microRNA-221 was profoundly upregulated in the prefrontal cortex but not in nucleus accumbens and striatum of enriched condition rats relative to impoverished condition rats following repeated administration of nicotine. Overexpression of lentiviral-microRNA-221 attenuated nicotine-induced increase in phosphorylated extracellular signal-regulated kinase 1/2 in PC12 cells. Lentiviral-microRNA-221 overexpression in the medial prefrontal cortex further increased locomotor activity in impoverished condition but not in enriched condition rats in response to repeated nicotine administration. Accordingly, lentiviral-microRNA-221 attenuated nicotine-induced increases in phosphorylated extracellular signal-regulated kinase 1/2 and phosphorylated cAMP-response element-binding protein in the medial prefrontal cortex of impoverished condition but not enriched condition rats.Conclusion:These findings suggest that environmental enrichment, via upregulation of prefrontal microRNA-221 expression, suppresses the nicotine-induced activation of extracellular signal-regulated kinase and cAMP-response element-binding protein, which provides a potential mechanism underlying enhanced locomotor sensitivity to nicotine.

Effect of environmental enrichment on dopamine and serotonin transporters and glutamate neurotransmission in medial prefrontal and orbitofrontal cortex

Recent studies have reported that rats raised in an enriched condition (EC) have decreased dopamine transporter (DAT) function and expression in medial prefrontal cortex (mPFC), as well as increased d-amphetamine-induced glutamate release in nucleus accumbens compared to rats raised in an isolated condition (IC). In these previous studies, DAT function and expression were evaluated using mPFC pooled from four rats for each condition to obtain kinetic parameters due to sparse DAT expression in mPFC. In contrast, accumbal glutamate release was determined using individual rats. The current study extends the previous work and reports on the optimization of DAT and serotonin transporter (SERT) functional assays, as well as cell surface expression assays using both mPFC and orbitofrontal cortex (OFC) from individual EC or IC rats. In addition, the effect of d-amphetamine on glutamate release in mPFC and OFC of EC and IC rats was determined using in vivo microdialysis. Results show that environmental enrichment decreased maximal transport velocity (Vmax) for [3H]dopamine uptake in mPFC, but increased Vmax for [3H]dopamine uptake in OFC. Corresponding changes in DAT cell surface expression were not found. In contrast, Vmax for [3H]serotonin uptake and cellular localization of SERT in mPFC and OFC were not different between EC and IC rats. Further, acute d-amphetamine (2mg/kg, s.c.) increased extracellular glutamate concentrations in mPFC of EC rats only and in OFC of IC rats only. Overall, these results suggest that enrichment produces long-lasting alterations in mPFC and OFC DAT function via a trafficking-independent mechanism, as well as differential glutamate release in mPFC and OFC. Rearing-induced modulation of DAT function and glutamate release in prefrontal cortical subregions may contribute to the known protective effects of enrichment on drug abuse vulnerability.

Effects of environmental enrichment on ERK1/2 phosphorylation in the rat prefrontal cortex following nicotine-induced sensitization or nicotine self-administration.

Rats raised in an enriched condition (EC) exhibit alterations in the neurobiological and behavioral response to nicotine compared with rats reared in an impoverished condition (IC) or a standard condition (SC). The current study determined whether environmental enrichment differentially regulates extracellular signal-regulated kinase1/2 (ERK1/2) activity in the prefrontal cortex in rats following nicotine sensitization or nicotine self-administration. Under the saline control condition, EC rats displayed diminished baseline activity and greater sensitization to repeated administration of nicotine compared with IC and SC rats. After repeated saline injections, the basal levels of phosphorylated ERK1/2 (pERK1/2) were higher in EC compared with IC and SC rats, which was negatively correlated with their respective baseline activities. Repeated nicotine (0.35 mg/kg) injections induced pERK1/2 to similar levels in SC and IC rats; however, the induction of pERK1/2 in EC rats by nicotine was not significantly different from saline controls, owing to their high baseline. In the self-administration paradigm, EC rats self-administered less nicotine (0.03 mg/kg/infusion) relative to IC or SC rats on a fixed ratio-1 schedule of reinforcement. Accordingly, no differences in pERK1/2 were found between EC and IC rats self-administering saline, whereas nicotine self-administration resulted in an increase in pERK1/2 in IC rats but not in EC rats. Furthermore, the levels of pERK1/2 in EC and IC rats were positively correlated with their respective total number of nicotine infusions. Thus, these findings suggest that environmental enrichment alters the basal and nicotine-mediated pERK1/2, which may contribute to enrichment-induced behavioral alterations in response to nicotine.

Overexpression of DeltaFosB in nucleus accumbens mimics the protective addiction phenotype, but not the protective depression phenotype of environmental enrichment.

Environmental enrichment produces protective addiction and depression phenotypes in rats. ΔFosB is a transcription factor that regulates reward in the brain and is induced by psychological stress as well as drugs of abuse. However, the role played by ΔFosB in the protective phenotypes of environmental enrichment has not been well studied. Here, we demonstrate that ΔFosB is differentially regulated in rats reared in an isolated condition (IC) compared to those in an enriched condition (EC) in response to restraint stress or cocaine. Chronic stress or chronic cocaine treatment each elevates ΔFosB protein levels in the nucleus accumbens (NAc) of IC rats, but not of EC rats due to an already elevated basal accumulation of ΔFosB seen under EC conditions. Viral-mediated overexpression of ΔFosB in the NAc shell of pair-housed rats (i.e., independent of environmental enrichment/isolation) increases operant responding for sucrose when motivated by hunger, but decreases responding in satiated animals. Moreover, ΔFosB overexpression decreases cocaine self-administration, enhances extinction of cocaine seeking, and decreases cocaine-induced reinstatement of intravenous cocaine self-administration; all behavioral findings consistent with the enrichment phenotype. In contrast, however, ΔFosB overexpression did not alter responses of pair-housed rats in several tests of anxiety- and depression-related behavior. Thus, ΔFosB in the NAc the shell mimics the protective addiction phenotype, but not the protective depression phenotype of environmental enrichment.

Dynamic Proteomics of Nucleus Accumbens in Response to Acute Psychological Stress in Environmentally Enriched and Isolated Rats

Our prior research has shown that environmental enrichment (i.e. rats reared in an environment with novel objects, social contact with conspecifics) produces a protective antidepressant-like phenotype in rats and decreases neurobiological effects of acute psychological stress. Although CREB activity has been identified as a major player, the downstream molecular mechanisms remain largely unexplored. Thus, the current study investigates proteomic differences in the accumbens of rats raised in an enriched condition (EC) versus those raised in an isolated control condition (IC) under basal conditions and after 30 min of acute restraint stress. Results showed that under basal conditions, EC rats generally expressed less mitochondria-related proteins, particularly those involved in TCA cycle and electron transport compared to IC rats. After 30 min of acute stress, EC rats displayed increased expression of energy metabolism enzymes (among others) while IC rats exhibited decreased expression of similar proteins. Further, network and pathway analyses also identified links to AKT signaling proteins, 14-3-3 family proteins, heat-shock proteins, and ubiquitin-interacting proteins. The protein ENO1 showed marked differential expression and regulation; EC rats expressed higher levels under basal conditions that increased subsequent to stress, while the basal IC expression was lower and decreased further still after stress. The results of this study define differential protein expression in a protective rat model for major depression and additionally identify a dynamic and coordinated differential response to acute stress between the two groups. These results provide new avenues for exploration of the molecular determinants of depression and the response to acute stress.

Dose-dependent effects of differential rearing on amphetamine-induced hyperactivity

Differential rearing decreases psychostimulant-induced hyperactivity. In general, environmental enrichment decreases the locomotor response to low unit doses of psychostimuluants, whereas isolation increases the response. It is not clear whether the changes in locomotor activity are due to an enrichment-induced decrease or an isolation-induced increase. Therefore, the current experiments examined the ability of enrichment rearing, as compared with isolation and standard rearing, to attenuate amphetamine-induced hyperactivity following acute administration, repeated administration, and sensitization of a low (0.3 mg/kg) and moderate (1.0 mg/kg) dose of amphetamine. Rats were reared under enriched, isolated, or standard conditions. Enrichment slowed the acquisition of amphetamine-induced hyperactivity and attenuated the expression of amphetamine-induced sensitization, but only at the low unit dose. Enrichment did not protect against the expression of conditioned hyperactivity at either of the doses tested. The behavior of standard condition rats was generally closer to that of isolated condition rats than enriched condition rats, suggesting that the enrichment attenuates the response to amphetamine as opposed to isolation rearing increasing the response to amphetamine. These results suggest that the effects of enrichment are because of enrichment manipulation and not simply a contrast from the effects of isolation.

Distinct effects of enriched environment on dopamine clearance in nucleus accumbens shell and core following systemic nicotine administration

Environmental enrichment during development may reduce drug abuse liability by modulating dopamine transporter (DAT) function. Nucleus accumbens (NAc) shell and core respond differentially to regulate the rewarding properties and locomotor stimulant effects of psychostimulants. The current study evaluated dopamine (DA) clearance (CL(DA) ) in the NAc shell and core using in vivo voltammetry in rats raised in an enriched condition (EC) or an impoverished condition (IC) and determined the effect of nicotine (0.4 mg/kg) on CL(DA) . Baseline CL(DA) in NAc shell and core was not different between EC and IC rats. In the saline control group, CL(DA) in NAc shell was greater across time in IC when compared with EC rats, whereas CL(DA) in NAc core was greater in EC rats when compared with IC rats. Consistent with these findings, opposite effects of enrichment on DA clearance in shell and core were obtained following acute nicotine administration. In NAc shell, nicotine increased CL(DA) in EC rats, but not in IC rats. Conversely, in NAc core, nicotine increased CL(DA) in IC rats, but not in EC rats. The current results demonstrate that environmental enrichment differentially regulates the response to nicotine in NAc shell and core via alterations in DAT function, which may explain how environmental enrichment reduces the behavioral response to nicotine.

Environmental enrichment during development decreases intravenous self-administration of methylphenidate at low unit doses in rats

Despite the efficacy and widespread use of methylphenidate (MPH) as a treatment modality for attention deficit hyperactivity disorder, clinical and preclinical findings indicate that it has abuse potential. Environmental enrichment reduces susceptibility to cocaine and amphetamine self-administration and decreases impulsive behavior, but its effects on MPH self-administration are unknown. The present experiments sought to determine the influence of environmental enrichment on MPH self-administration. Male rats were raised in an enriched condition (EC) or isolated condition (IC). They were trained to self-administer MPH (0.3 mg/kg/infusion) and then exposed to varying doses of MPH on either a fixed-ratio (experiment 1) or a progressive-ratio (experiment 2) schedule of reinforcement. EC rats earned significantly fewer infusions of MPH at low doses (0.03 and 0.056 mg/kg/infusion) compared with IC rats under both schedules; however, no differences were observed at high unit doses (0.1-1.0 mg/kg/infusion). During saline substitution at the end of MPH self-administration, EC rats also responded less for saline compared with IC rats, indicative of more rapid extinction. As with other stimulant drugs with different mechanisms of action, environmental enrichment during development protects against self-administration of MPH at low unit doses but not at high unit doses.

Isolation rearing as a preclinical model of attention/deficit-hyperactivity disorder

Rats raised in an isolated condition (IC) are impulsive and hyperactive compared to rats raised in an enriched condition (EC), suggesting that isolation rearing may be a preclinical model of attention-deficit/hyperactivity disorder (ADHD). The current study determined if administration of methylphenidate (MPH), a dopamine transporter (DAT) blocker used in the treatment of ADHD, reduces the hyperactivity observed in IC rats toward levels observed in EC rats. Another goal was to determine if chronic MPH treatment differentially alters DAT function in EC and IC rats in medial prefrontal cortex (mPFC) or orbitofrontal cortex (OFC). IC and EC rats were treated with either MPH (1.5mg/kg, p.o.) or vehicle from postnatal days (PND) 28–51. On PND 28 and 51, rats were evaluated for MPH-induced locomotor activity. On PND 55–63, in vitro [3H]DA uptake assays were performed in mPFC and OFC. At both PND 28 and 51, IC rats were hyperactive compared to EC rats. At PND 28, MPH increased activity in EC rats only. At PND 51, MPH did not alter locomotor activity in IC or EC rats. Beginning at PND 55, basal uptake of [3H]dopamine in IC rats was higher in mPFC and lower in OFC compared to EC rats. The basal differences in DAT function were normalized by MPH treatment in mPFC, but not in OFC. These findings suggest that isolation rearing may not represent a valid predictive model for screening effective medications in the treatment of hyperactivity associated with ADHD.

Environmental-induced differences in corticosterone and glucocorticoid receptor blockade of amphetamine self-administration in rats.

Rats raised in isolation self-administer more amphetamine than rats raised in enrichment. This study examined whether differential rearing alters basal and amphetamine-stimulated corticosterone and whether blocking glucocorticoid receptors alters amphetamine self-administration in differentially reared rats. The rats were raised from 21 to 51 days of age in either an enriched condition (EC), social condition (SC), or isolated condition (IC). Following the repeated collection of basal blood samples, the rats were administered amphetamine (0.5 or 2.0 mg/kg, i.p.) or saline, and blood samples were collected again. In another experiment, EC and IC rats were trained to i.v. self-administer amphetamine (0.003 or 0.03 mg/kg/infusion) and then were pretreated with the glucocorticoid receptor antagonist RU-486 (5, 10, or 20 mg/kg; i.p.) or vehicle prior to the session. Basal-free corticosterone levels were ~4 times higher in IC rats than in either EC or SC rats with the first blood collection, but not with repeated collections. IC rats showed a more rapid amphetamine-induced increase in corticosterone levels than EC and SC rats. RU-486 pretreatment decreased amphetamine self-administration dose-dependently in both EC and IC rats; however, using an amphetamine unit dose of 0.03 mg/kg/infusion, the effect of RU-486 was blunted in IC rats (maximal decrease of ~40% in IC and ~90% in EC), suggesting an environment-induced difference in the role of glucocorticoid receptors in stimulant reinforcement. The increase in stimulant self-administration produced by social isolation may involve enhanced reactivity of the hypothalamo-pituitary-adrenal stress axis.

Experience-dependent changes in neuronal processing in the nucleus accumbens shell in a discriminative learning task in differentially housed rats

Environmental enrichment is associated with enhanced learning of complex tasks, attenuated seeking of natural and drug rewards, and altered function of the nucleus accumbens (NAcc), a brain region involved in goal-directed behavior. For example, during acquisition of a discriminative learning task, neurons in the NAcc core subregion are more responsive to discrete, goal-directed movements in rats raised in an enriched condition (EC) relative to an isolated condition (IC), but as learning materialized, this enhanced responsiveness shifts to the cues that predict these movements. Here, we report that these results do not extend to NAcc shell: neuronal responses in this subregion are similar in EC and IC rats during goal-directed movement and the presentation of associative cues both during and after task acquisition. With experience in this task, however, the overall proportion of task-related neuronal responses in NAcc shell decreases. The response pattern of shell neurons is also sensitive to the presence of contextual cues: shell neuronal firing reveals a significant shift from a predominant excitatory to a predominant inhibitory profile in probe trials when the cue that predicts sucrose availability is absent. Collectively, these data suggest that NAcc shell neurons encode cues associated with natural reward, are less responsive during appetitive behavior in familiar conditions, and are insensitive to appetitive learning differences expressed in rats reared in different environmental conditions.

Effect of environmental enrichment on methylphenidate-induced locomotion and dopamine transporter dynamics

Rats raised in an enriched condition (EC) are less sensitive to the locomotor effects of stimulant drugs than rats raised in an impoverished condition (IC). Methylphenidate (MPD), a primary pharmacotherapy for attention-deficit/hyperactivity disorder, has abuse potential. This study determined whether environmental enrichment differentially altered the effects of MPD on locomotor activity and dopamine (DA) transporter (DAT) function. Acute and repeated MPD (3 or 10mg/kg, s.c.) increased locomotion in EC, IC and social condition (SC) rats; however, EC rats showed a blunted response to repeated MPD (3mg/kg). The maximal velocity (Vmax) of [3H]DA uptake in the presence of the combination of phorbol 12-myristate 13-acetate, a protein kinase C (PKC) activator and okadaic acid, a protein phosphatase inhibitor was decreased in EC and IC rats by 68% and 40%, respectively, indicating that DAT in prefrontal cortex (PFC) is more sensitive to PKC-mediated down-regulation in EC rats. Acute MPD (10mg/kg) administration decreased the Vmax of [3H]DA uptake in PFC and striatum in EC rats, but not in IC rats. Furthermore, [3H]WIN 35,428 binding density was decreased in PFC of EC and IC rats, and in striatum of EC rats given repeated MPD (10mg/kg). These results demonstrate that environmental enrichment modulates DAT dynamics in PFC. However, since the change in DAT function was observed only following the high dose of MPH (10mg/kg), the attenuated locomotor response to repeated MPD (3mg/kg) in EC rats is not likely due to a specific DAT alteration in the brain regions examined.

Effect of environmental enrichment on escalation of cocaine self-administration in rats

Previous studies found that environmental enrichment protects against the initiation of stimulant self-administration in rats, but it is unclear if enrichment also protects against the escalation of stimulant use with long-term exposure. The current study examined the effects of environmental enrichment on escalation of cocaine self-administration using an extended access procedure. Rats were raised from 21 days in an enriched condition (EC) with social cohorts and novel objects, a social condition with only social cohorts (SC), a novelty condition (NC) with novel objects in isolated cages, or an isolated condition (IC) without social cohorts or novel objects. In young adulthood, EC, SC, NC, and IC rats were separated into short access (ShA) or long access (LgA) groups that received either 1 or 6 h, respectively, of daily cocaine self-administration (0.1 mg/kg/infusion) for 14 days. In a second experiment, EC and IC rats were used to assess differences in acquisition and escalation of cocaine self-administration at a 0.5 mg/kg/infusion unit dose. With ShA sessions, EC rats acquired cocaine self-administration at a slower rate than IC rats at both unit doses; however, with extended training, both groups eventually reached similar rates. At the 0.1 mg/kg/infusion dose, only NC and IC rats escalated in amount of intake when switched to the LgA sessions. At the 0.5 mg/kg/infusion dose, rates of cocaine self-administration escalated in LgA groups over 14 days regardless of EC or IC rearing condition; however, EC rats escalated at a faster rate, eventually reaching the same level of intake observed in IC rats. Although environmental enrichment protects against escalation of a low unit dose of cocaine, it may not protect against escalation with a higher unit dose. In addition, at a lower unit dose, this protective mechanism appears to be due to the presence of social cohorts rather than novel objects.

Environmental Enrichment Produces a Behavioral Phenotype Mediated by Low Cyclic Adenosine Monophosphate Response Element Binding (CREB) Activity in the Nucleus Accumbens

Previous research has shown that rats reared in an enriched condition (EC) are more sensitive to the acute effects of amphetamine than rats reared in an isolated condition (IC); yet, EC rats self-administer less amphetamine than IC rats. The present study used cocaine to further explore this environmental enrichment behavioral phenotype, as well as the underlying molecular mechanisms involved. Enriched condition and IC rats were studied in a broad battery of behavioral tests, including cocaine conditioned place preference (CPP) and self-administration and several measures of anxiety- and depression-related behavior. The involvement of the transcription factor, cyclic adenosine monophosphate (cAMP) response element binding protein (CREB), in mediating EC versus IC differences was investigated. Enriched condition rats exhibited less cocaine self-administration, despite showing enhanced cocaine CPP. Enriched condition rats also displayed less depression-like behavior but higher levels of anxiety-like behavior. This behavioral phenotype is consistent with low CREB activity in the nucleus accumbens, a key brain reward region. Indeed, EC rats have less phospho-CREB (the transcriptionally active form of the protein) in the nucleus accumbens than IC rats, and a selective knockdown of CREB in this brain region of normally reared rats, by use of a novel viral vector expressing a short hairpin RNA (shRNA) directed against CREB, reproduced the EC behavioral phenotype. These studies identify a potential molecular mechanism for how rearing environment-a nonpharmacological, nonsurgical manipulation-can modify a wide range of complex emotional behaviors.

Effects of mecamylamine on nicotine-induced conditioned hyperactivity and sensitization in differentially reared rats

Rats reared in an enriched condition (EC) display less sensitization to nicotine than rats reared in an impoverished condition (IC). However, it is unknown what effect differential rearing has on nicotine-induced conditioned hyperactivity. The present study determined whether differential rearing affects nicotine-induced conditioned hyperactivity. This study also examined the effects of mecamylamine on conditioned hyperactivity and sensitization. EC, IC, and social condition (SC) rats were reared from 21 to 51 days of age before receiving repeated nicotine injections (.4 mg/kg) prior to 1-h locomotor sessions. Following the conditioned-hyperactivity test, rats received additional training sessions followed by a drug-free rest period before the sensitization test. Mecamylamine (1.0 mg/kg) was administered prior to the conditioned-hyperactivity test and sensitization test. Nicotine treatment resulted in sensitization and conditioned hyperactivity in all differential rearing groups. EC rats displayed less locomotor activity in response to nicotine than both IC and SC rats. Pretreatment with mecamylamine blocked the expression of conditioned hyperactivity only in EC and SC rats and attenuated sensitization in all three rearing groups. These findings suggest that environmental enrichment may alter nicotinic acetylcholine receptors during development and may be a protective factor in the initiation and relapse of smoking behavior.

Impulsive choice and environmental enrichment: Effects of d-amphetamine and methylphenidate

Individual differences in impulsive choice and rearing in differential environments are factors that predict vulnerability to drug abuse. The present study determined if rearing influences impulsive choice, and if d-amphetamine or methylphenidate alters impulsive choice in differentially reared rats. Male Sprague-Dawley rats were raised from 21 days of age in either an enriched condition (EC) or an isolated condition (IC) and were tested as young adults on an adjusting delay task. In this task, two levers were available and a response on one lever yielded one 45 mg food pellet immediately, whereas a response on the other yielded three pellets after an adjusting delay. The delay was initially set at 6 s, and it decreased or increased by 1 s following responses on the immediate or delayed levers, respectively. A mean adjusted delay (MAD) was calculated upon completion of each daily session, and it served as the quantitative measure of impulsivity. Once MADs stabilized, rats were injected with saline, d-amphetamine (0.5, 1.0, or 2.0 mg/kg, s.c.), or methylphenidate (2.5, 5.0, or 10.0 mg/kg, s.c.) 15 min prior to adjusting delay sessions. EC rats had higher baseline MADs (were less impulsive) than IC rats. Additionally, administration of d-amphetamine, but not methylphenidate, dose-dependently increased impulsive choice (decreased MADs) in EC rats. In IC rats, d-amphetamine and methylphenidate dose-dependently decreased impulsivity (increased MADs). These results indicate that rearing environment influences impulsive choice and moderates the effect of psychostimulants on impulsive choice. Specifically, psychostimulants may decrease environment-dependent impulsive choice in individuals with high levels of impulsivity (e.g., those with ADHD), whereas they may increase impulsive choice in individuals with low levels of impulsivity.