Differences in D2 dopamine receptor availability and reaction to novelty in socially housed male monkeys during abstinence from cocaine

Rationale

Studies in socially housed monkeys have demonstrated an influence of position in the social dominance hierarchy on brain dopamine D2 receptors and the reinforcing effects of cocaine that dissipates after long-term cocaine self-administration.

Objective

The aims of the study were to examine the effects of abstinence from cocaine on D2 receptors in socially housed monkeys and to extend behavioral characterizations to measures of reactivity to a novel object.

Materials and methods

Twelve socially housed male cynomolgus monkeys with extensive cocaine self-administration experience were used (average lifetime intakes ～270 and 215 mg/kg for dominant and subordinate monkeys, respectively). Abstinence lasted for approximately 8 months, after which D2 receptor availability was assessed using positron emission tomography and the D2 ligand [¹⁸F]fluoroclebopride. Reaction to novelty was also assessed in these subjects as well as nine individually housed monkeys.

Results

During abstinence, D2 receptor availability in the caudate nucleus was significantly higher in dominant versus subordinate monkeys. Average latency to touch a novel object was also significantly higher in dominant monkeys compared to subordinates or individually housed monkeys. In socially experienced monkeys, a significant positive correlation was observed between caudate nucleus D2 receptor availability and latencies to touch the novel object.

Conclusions

Although chronic cocaine self-administration blunts the ability of social dominance to alter D2 receptor availability and sensitivity to the reinforcing effects of cocaine, this influence reemerges during abstinence. In addition, the data suggest that prior experience with social dominance can lead to longer latencies in reaction to novelty—a personality trait associated with low vulnerability to cocaine abuse.     

High anxiety is a predisposing endophenotype for loss of control over cocaine, but not heroin, self-administration in rats

Rationale

Although high anxiety is commonly associated with drug addiction, its causal role in this disorder is unclear.

Objectives

In light of strong evidence for dissociable neural mechanisms underlying heroin and cocaine addiction, the present study investigated whether high anxiety predicts the propensity of rats to lose control over intravenous cocaine or heroin self-administration.

Methods

Sixty-four rats were assessed for anxiety in the elevated plus-maze, prior to extended access to intravenous cocaine or heroin self-administration.

Results

High-anxious rats, identified in the lower quartile of the population, showed a greater escalation of cocaine, but not heroin, self-administration compared with low-anxious rats selected in the upper quartile of the population. Anxiety scores were also positively correlated with the extent of escalation of cocaine self-administration.

Conclusions

The present data suggest that high anxiety predisposes rats to lose control over cocaine??but not heroin??intake. High anxiety may therefore be a vulnerability trait for the escalation of stimulant but not opiate self-administration.     

Sex differences in behavioral and neural cross-sensitization and escalated cocaine taking as a result of episodic social defeat stress in rats

Rationale

Episodic social defeat stress results in cross-sensitization to cocaine, characterized by augmentation of locomotor activity, dopamine (DA) levels in the nucleus accumbens (NAc), and cocaine self-administration during a 24-h “binge” in male rats. However, females are more vulnerable than males at each phase of cocaine addiction, and while these sex differences have been replicated in rats, the role of social stress in females remains largely neglected.

Objective

This study examined sex and estrous cycle differences in behavioral and dopaminergic cross-sensitization to cocaine, as well as cocaine taking in an unlimited-access self-administration “binge.”

Methods

Long-Evans rats underwent episodic social defeat and were assessed 10 days later for either (1) behavioral sensitization, as determined by locomotor activity in response to acute cocaine (10 mg/kg, i.p.), (2) neural sensitization, as determined by in vivo microdialysis of DA in the NAc shell in response to acute cocaine, or (3) intravenous self-administration of cocaine (0.3 mg/kg/infusion) in an unlimited-access “binge.”

Results

Social defeat stress resulted in behavioral and dopaminergic cross-sensitization in both sexes, but the effect was larger and longer lasting in stressed females. Furthermore, while stress engendered a longer “binge” in both sexes, females had a significantly longer “binge” duration than males.

Conclusions

These data suggest that socially stressed females exhibit a larger and longer lasting behavioral and neural cross-sensitization, as well as more dysregulated cocaine taking, than males possibly due to different alterations in the dopaminergic response in the NAc. Furthermore, estrogens appear to play a facilitatory role in both behavioral and dopaminergic sensitization.     

Exercise to reduce the escalation of cocaine self-administration in adolescent and adult rats

Rationale

Concurrent access to an exercise wheel decreases cocaine self-administration under short access (5 h/day for 5 days) conditions and suppresses cocaine-primed reinstatement in adult rats.

Objective

The effect of exercise (wheel running) on the escalation of cocaine intake during long access (LgA, 6 h/day for 26 days) conditions was evaluated.

Methods

Adolescent and adult female rats acquired wheel running, and behavior was allowed to stabilize for 3?days. They were then implanted with an iv catheter and allowed to self-administer cocaine (0.4?mg/kg, iv) during 6-h daily sessions for 16?days with concurrent access to either an unlocked or a locked running wheel. Subsequently, for ten additional sessions, wheel access conditions during cocaine self-administration sessions were reversed (i.e., locked wheels became unlocked and vice versa).

Results

In the adolescents, concurrent access to the unlocked exercise wheel decreased responding for cocaine and attenuated escalation of cocaine intake irrespective of whether the locked or unlocked condition came first. However, cocaine intake increased when the wheel was subsequently locked for the adolescents that had initial access to an unlocked wheel. Concurrent wheel access either before or after the locked wheel access did not reduce cocaine intake in adults.

Conclusions

Wheel running reduced cocaine intake during LgA conditions in adolescent but not adult rats, and concurrent access to the running wheel was necessary. These results suggest that exercise prevents cocaine seeking and that this effect is more pronounced in adolescents than adults.     

Nonhuman primate models of social behavior and cocaine abuse

Rationale

Although cocaine is often abused in social situations, very few animal studies examine the effects of cocaine in the context of social behavior.

Objectives

This review highlights studies investigating the behavioral effects of cocaine in the context of social housing conditions using nonhuman primates. In addition, this review presents recent findings examining the effects of self-administering cocaine on social behavior and the effects of manipulations hypothesized to be stressful or enriching on the interactions between cocaine reinforcement and social rank. The following dependent variables are examined: (1) cocaine-induced changes in social behavior and (2) cocaine self-administration in cynomolgus monkeys of varying social ranks. The independent variables examined include several environmental and pharmacological manipulations.

Conclusions

The studies reviewed here indicate that several variables can differentially affect cocaine self-administration when studied in a social context, rather than in individually housed animals. These variables include the social rank and sex of the individual, drug history, the nature of the “fear”-inducing manipulation, and the reliability of cortisol as an appropriate measure of “stress.” While the inclusion of socially housed animals necessitates larger sample sizes, animal models incorporating social behavior are more homologous to the human condition and should be implemented when possible.     

Disrupted social development enhances the motivation for cocaine in rats

Rationale

Early social experiences are of major importance for behavioural development. In particular, social play behaviour during post-weaning development is thought to facilitate the attainment of social, emotional and cognitive capacities. Conversely, social insults during development can cause long-lasting behavioural impairments and increase the vulnerability for psychiatric disorders, such as drug addiction.

Objectives

The aim of this study was to investigate whether a lack of social experiences during the juvenile and early adolescent stage, when social play behaviour is highly abundant, alters cocaine self-administration in rats.

Methods

Rats were socially isolated from postnatal days 21 to 42 followed by re-socialization until adulthood. Cocaine self-administration was then assessed under a fixed ratio and progressive ratio schedule of reinforcement. Next, cue, cocaine and stress-induced reinstatement of cocaine seeking was determined following extinction of self-administration.

Results

Early social isolation resulted in an enhanced acquisition of self-administration of a low dose (0.083 mg/infusion) of cocaine, but the sensitivity to cocaine reinforcement, assessed using a dose–response analysis, was not altered in isolated rats. Moreover, isolated rats displayed an increased motivation for cocaine under a progressive ratio schedule of reinforcement. Extinction and reinstatement of cocaine seeking was not affected by early social isolation.

Conclusions

Early social isolation causes a long-lasting increase in the motivation to self-administer cocaine. Thus, aberrations in post-weaning social development, such as the absence of social play, enhance the vulnerability for drug addiction later in life.     

The effects of varied extinction procedures on contingent cue-induced reinstatement in Sprague-Dawley rats

Rationale

Cue exposure therapy, which attempts to limit relapse by reducing reactivity to cocaine-paired cues through repeated exposures, has had limited success.

Objectives

The current experiments examined cocaine cue-induced anxiogenesis and investigated whether a model of cue exposure therapy would reduce reinstatement of cocaine seeking in rats with a history of cocaine self-administration.

Methods

Male rats experienced daily intravenous cocaine self-administration. Rats then experienced exposure to either the self-administration context or the context plus noncontingent presentations of cocaine-paired cues. Immediately following exposure, anxiety-like behavior was measured using elevated plus maze and defensive burying tests. In a second group of rats, self-administration was followed by 7 days of exposure to the context, context + noncontingent cue exposure, lever extinction, or cue + lever extinction. All animals then underwent two contingent cue-induced reinstatement tests separated by 7 days of lever extinction.

Results

Exposure to noncontingent cocaine-paired cues in the self-administration context increased anxiety-like behavior on the defensive burying test. Animals that experienced lever + cue extinction displayed the least cocaine seeking on the first reinstatement test, and lever extinction reduced cocaine seeking below context exposure or context + noncontingent cue exposure. All animals had similar levels of cocaine seeking on the second reinstatement test.

Conclusion

Noncontingent cue exposure causes anxiety, and noncontingent cue and context exposure are less effective at reducing contingent cue-induced reinstatement than lever or lever + cue extinction. These data indicate that active extinction of the drug-taking response may be critical for reduction of relapse proclivity in former cocaine users.     

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

Background

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.

Objective

The current study examined the effects of environmental enrichment on escalation of cocaine self-administration using an extended access procedure.

Methods

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.

Results

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.

Conclusions

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.     

Short and long access to cocaine self-administration activates tyrosine phosphatase STEP and attenuates GluN expression but differentially regulates GluA expression in the prefrontal cortex

Rationale

Dephosphorylation of extracellular signal-regulated kinase (ERK) and cyclic AMP response element binding protein (CREB) in the dorsomedial prefrontal cortex (dmPFC) at the end of short access (ShA) cocaine self-administration is implicated in cocaine seeking. However, what receptors and phosphatases mediate this effect and whether ERK/CREB and related phospho-proteins in the dmPFC react similarly during early withdrawal from long access (LgA) cocaine self-administration are unknown.

Objectives

The effects of ShA vs. LgA cocaine self-administration on the phosphorylation of protein phosphatase 2A (PP2A) and striatal-enriched protein tyrosine phosphatase (STEP), as well as GluN and GluA receptor subtype expression in the dmPFC during early withdrawal, were compared.

Methods

Rats self-administered cocaine or received saline during 2- or 6-h daily sessions for 10–11 days. Two hours after the final session, the dmPFC was dissected out and processed for immunoblotting.

Results

Similar to previous findings after ShA cocaine, phospho-ERK and phospho-CREB in the dmPFC were decreased after LgA cocaine. Cocaine elevated phospho-PP2A (deactivation) and decreased phospho-STEP (activation) in both ShA and LgA cocaine rats. GluN1, GluN2B, and phospho-GluN2B Tyr1472 in the dmPFC were decreased after ShA and LgA cocaine. Further, a significant reduction of GluA2, GluA1, and phospho-GluA1 Ser845 was found only in LgA rats.

Conclusions

Activation of phospho-STEP may underlie ERK and CREB dephosphorylation in the dmPFC as well as internalization and degradation of GluN complexes during early withdrawal from both ShA and LgA cocaine self-administration, whereas differential alteration of AMPA receptor subunits after ShA and LgA cocaine self-administration depends on cocaine intake.     

Performance on a strategy set shifting task in rats following adult or adolescent cocaine exposure

Rationale

Neuropsychological testing is widespread in adult cocaine abusers, but lacking in teens. Animal models may provide insight into age-related neuropsychological consequences of cocaine exposure.

Objectives

The objective of the present study is to determine whether developmental plasticity protects or hinders behavioral flexibility after cocaine exposure in adolescent vs. adult rats.

Methods

Using a yoked-triad design, one rat controlled cocaine delivery and the other two passively received cocaine or saline. Rats controlling cocaine delivery (1.0 mg/kg) self-administered for 18 sessions (starting P37 or P77), followed by 18 drug-free days. Rats next were tested in a strategy set shifting task, lasting 11–13 sessions.

Results

Cocaine self-administration did not differ between age groups. During initial set formation, adolescent-onset groups required more trials to reach criterion and made more errors than adult-onset groups. During the set shift phase, rats with adult-onset cocaine self-administration experience had higher proportions of correct trials and fewer perseverative + regressive errors than age-matched yoked-controls or rats with adolescent-onset cocaine self-administration experience. During reversal learning, rats with adult-onset cocaine experience (self-administered or passive) required fewer trials to reach criterion, and the self-administering rats made fewer perseverative + regressive errors than yoked-saline rats. Rats receiving adolescent-onset yoked-cocaine had more trial omissions and longer lever press reaction times than age-matched rats self-administering cocaine or receiving yoked-saline.

Conclusions

Prior cocaine self-administration may impair memory to reduce proactive interference during set shifting and reversal learning in adult-onset but not adolescent-onset rats (developmental plasticity protective). Passive cocaine may disrupt aspects of executive function in adolescent-onset but not adult-onset rats (developmental plasticity hinders).     

Escalation of cocaine intake with extended access in rats: dysregulated addiction or regulated acquisition?

Rationale

Understanding the neurobehavioral mechanisms underlying dysregulated cocaine intake is important for the development of new cocaine abuse therapies.

Objectives

The current study determined if cocaine escalation under extended access conditions (6-h access) is regulated by discrimination learning processes.

Methods

Rats were initially trained on cocaine self-administration (0.1 or 0.25?mg/kg/infusion) using a fixed ratio 1 (FR 1) schedule under 1-h access for 12 sessions. Some rats were then trained to self-administer cocaine under 1-h or 6-h access conditions exclusively for 14 additional sessions, while other rats were trained under both 1- and 6-h access conditions that were cued or noncued for 28 additional sessions (14 sessions for each 1- and 6-h access). Two additional groups of rats were initially trained to self-administer cocaine using an FR 1 schedule under 10-min access for 12 sessions; half of the animals were then switched to 60-min access conditions for 14 additional sessions.

Results

When access conditions were differentially cued, escalation of cocaine intake was evident in animals with both 1- and 6-h access conditions during the escalation phase. Escalation also was evident in animals initially trained with 10-min access and then switched to 60-min access.

Conclusions

The results demonstrate that dysregulated and regulated intakes can be expressed within the same animal, indicating that escalation is context-dependent. Furthermore, escalated cocaine intake can be expressed under 1-h access conditions. Overall, these results suggest that escalated cocaine intake may be representative of discrimination-dependent regulated intake rather than addiction-like, compulsive intake.     

Individual differences in the effects of environmental stimuli on cocaine choice in socially housed male cynomolgus monkeys

Rationale

Studies in laboratory animals have demonstrated an influence of environmentally derived stress and enrichment on the reinforcing effects of stimulants.

Objective

To characterize the effects of acute exposure to ethologically valid environmental stimuli on the reinforcing strength of cocaine relative to food in socially housed monkeys.

Materials and methods

Choice between cocaine and food was assessed in subsets of 16 socially housed (4/pen) male cynomolgus monkeys immediately after the following manipulations: (1) treats placed in home cage, (2) a 10-min exposure to a rubber snake, or (3) 3 to 7 days of living in a larger environment without cage mates.

Results

Placing treats in the home cage shifted the cocaine dose–response curve to the left in five monkeys tested and to the right in 4 of 12 animals. The rubber snake significantly shifted the cocaine choice curve to the left in dominant monkeys. Exposure to an enlarged environment decreased cocaine choice in 9 of 15 monkeys; this effect was transient and not related to social rank. Repeated testing did not affect cocaine choice.

Conclusions

Brief exposure to environmental events hypothesized to be stressors or enrichment altered cocaine choice, although not all individuals were affected and the effects were transient. Importantly, the data suggest that implementing positive changes in the environment produced effects that are clinically desirable. Understanding the behavioral and neurobiological mechanisms mediating sensitivity to environmental events in socially housed animals will lead to better treatment strategies for drug addiction.     

Effects of combined exercise and progesterone treatments on cocaine seeking in male and female rats

Background

Individually, both treatment with progesterone and concurrent access to an exercise wheel reduce cocaine self-administration under long-access conditions and suppress cocaine-primed reinstatement in female rats. In the present study, wheel running and progesterone (alone and combined) were assessed for their effects on reinstatement of cocaine-seeking primed by yohimbine, cocaine, and cocaine-paired cues.

Methods

Male and female rats were implanted with an intravenous catheter and allowed to self-administer cocaine (0.4 mg/kg/inf, iv) during 6-h sessions for 10 days. Subsequently, the groups of male and female rats were each divided into two groups that were given concurrent access to either a locked or unlocked running wheel under extinction conditions for 14 days. Next, all four groups were tested in a within-subjects design for reinstatement of cocaine-seeking precipitated by separate administration of cocaine-paired stimuli, yohimbine, or cocaine or the combination of yohimbine?+?cocaine-paired stimuli or cocaine?+?cocaine-paired stimuli. These priming conditions were tested in the presence of concurrent wheel access (W), pretreatment with progesterone (P), or both (W?+?P).

Results

In agreement with previous results, females responded more for cocaine than males during maintenance. Additionally, concurrent wheel running attenuated extinction responses and cocaine-primed reinstatement in females but not in males. Across all priming conditions, W?+?P reduced reinstatement compared to control conditions, and for cocaine-primed reinstatement in male rats, the combined W?+?P treatment was more effective than W or P alone.

Conclusion

Under certain conditions, combined behavioral (exercise) and pharmacological (progesterone) interventions were more successful at reducing cocaine-seeking behavior than either intervention alone.     

Effects of cocaine self-administration history under limited and extended access conditions on in vivo striatal dopamine neurochemistry and acoustic startle in rhesus monkeys

Rationale

The transition from infrequent and controlled cocaine use to dependence may involve enduring changes in neurobiology as a consequence of persistent drug use.

Objective

The present study utilized an intravenous drug self-administration protocol of increasing cocaine access to evaluate potential changes in dopamine function in vivo, including changes in sensitivity to psychostimulants.

Materials and methods

Drug-naïve rhesus monkeys were provided limited access (1 h) to cocaine self-administration for 60 days followed by 60 days under an extended access condition (4 h). Basal levels of striatal extracellular dopamine and its metabolites, as well as the effectiveness of cocaine and amphetamine to elevate dopamine, were determined with in vivo microdialysis before the initiation of cocaine self-administration and during limited and extended access. The effect of cocaine and amphetamine on the acoustic startle response was also examined to assess complementary behavioral changes as a function of drug history.

Results

Extended access to cocaine self-administration lead to increased daily intake compared to limited access conditions but did not result in escalated intake over time. However, cocaine- and amphetamine-induced increases in striatal dopamine were diminished as a function of cocaine self-administration history. Surprisingly, there was no effect of drug-taking history on sensitivity to psychostimulant-induced enhancement of startle amplitude.

Conclusions

The present experiments provide evidence of a hypofunctional dopamine system that is not associated with an escalation in drug intake or reflected in measures of acoustic startle.

     

The relationship between cocaine self-administration and actigraphy-based measures of sleep in adult rhesus monkeys

Rationale

Clinical trials show that chronic cocaine users suffer from sleep disturbances and preclinical research has shown that acute sleep deprivation increases the rate of cocaine self-administration in rats.

Objective

This study examined the effect of cocaine self-administration on behavioral indices of sleep and alternatively the effect of sleep disruption on cocaine-maintained responding by rhesus monkeys.

Methods

Seven adult rhesus monkeys, fitted with Actical® activity monitors, were trained to respond under a concurrent choice paradigm with food (three 1.0-g pellets) and cocaine (0.003–0.3 mg/kg) or saline presentation. For each monkey, the lowest preferred dose of cocaine (>80 % cocaine choice) was determined. Activity data were analyzed during lights out (2000-0600) to determine sleep efficiency, sleep latency, and total activity counts. Subsequently, the monkeys’ sleep was disrupted (every hour during lights-out period) the night prior to food–cocaine choice sessions.

Results

Self-administration of the preferred dose of cocaine resulted in a significant decrease in sleep efficiency, with a significant increase in total lights-out activity. Sleep disruption significantly altered behavioral indices of sleep, similar to those seen following cocaine self-administration. However, sleep disruption did not affect cocaine self-administration under concurrent choice conditions.

Conclusions

Based on these findings, cocaine self-administration does appear to disrupt behavioral indices of sleep, although it remains to be determined if treatments that improve sleep measures can affect future cocaine taking.     

Ketamine self-administration in the rat: evidence for a critical role of setting

Rationale

The abuse of ketamine has been reported to be on the rise over the past 15?years, but its abuse appears to be limited almost exclusively to the context of music and dance settings, indicating a major role of context in modulating its reinforcing effects. We have previously reported that amphetamine, cocaine, and heroin self-administration (SA) in the rat are differentially influenced by the setting in which testing takes place. The aim of the present study is to extend this pre-clinical model to ketamine.

Materials and methods

Independent groups of rats with intravenous catheters were given the possibility to self-administer different doses of ketamine (125, 250, and 500???g/kg per infusion) under two environmental conditions. Some animals were housed in the SA chambers (resident rats) whereas other rats were transported to the SA chambers only for the test sessions (non-resident rats). After training, within-subject dose effect curves (125, 250, 500, and 1,000???g/kg per infusion) and break-point (during a progressive ratio session) were calculated.

Results

Non-resident rats readily acquired ketamine self-administration. In contrast, resident rats self-administered only the highest dose of ketamine (500???g/kg), but still four times less than non-resident rats (11.0?±?6.0 vs 44.4?±?5.2 infusions during the last training session). No significant differences in break-point were found during the progressive ratio session.

Conclusions

The present study confirms at a preclinical level the importance of setting for ketamine SA and further validates a previously described animal model of drug?environment interaction.     

The behavioral economics of drug self-administration: A review and new analytical approach for within-session procedures

Rationale

Behavioral–economic demand curve analysis offers several useful measures of drug self-administration. Although generation of demand curves previously required multiple days, recent within-session procedures allow curve construction from a single 110-min cocaine self-administration session, making behavioral–economic analyses available to a broad range of self-administration experiments. However, a mathematical approach of curve fitting has not been reported for the within-session threshold procedure.

Objectives

We review demand curve analysis in drug self-administration experiments and provide a quantitative method for fitting curves to single-session data that incorporates relative stability of brain drug concentration.

Methods

Sprague–Dawley rats were trained to self-administer cocaine, and then tested with the threshold procedure in which the cocaine dose was sequentially decreased on a fixed ratio-1 schedule. Price points (responses/mg cocaine) outside of relatively stable brain cocaine concentrations were removed before curves were fit. Curve-fit accuracy was determined by the degree of correlation between graphical and calculated parameters for cocaine consumption at low price (Q ₀) and the price at which maximal responding occurred (P _max).

Results

Removing price points that occurred at relatively unstable brain cocaine concentrations generated precise estimates of Q ₀ and resulted in P _max values with significantly closer agreement with graphical P _max than conventional methods.

Conclusion

The exponential demand equation can be fit to single-session data using the threshold procedure for cocaine self-administration. Removing data points that occur during relatively unstable brain cocaine concentrations resulted in more accurate estimates of demand curve slope than graphical methods, permitting a more comprehensive analysis of drug self-administration via a behavioral–economic framework.     

Treatment of cocaine withdrawal anxiety with guanfacine: relationships to cocaine intake and reinstatement of cocaine seeking in rats

Rationale

Successful treatment of cocaine addiction is severely impeded by the propensity of users to relapse. Withdrawal severity may serve as a key predictor of susceptibility to relapse. Therefore, the identification and treatment of cocaine withdrawal symptoms such as anxiety may improve addiction treatment outcome.

Objectives

The current study examined the role of anxiety-like behavior during cocaine withdrawal and anxiolytic treatment in reinstatement of cocaine seeking in an animal model of relapse.

Methods

Male rats experienced daily IV cocaine self-administration. One group of animals received the norepinephrine α-2 agonist, guanfacine, or vehicle prior to anxiety testing 48 h after the last self-administration session. In the second group of rats, relationships between cocaine intake, anxiety-like behavior after withdrawal of cocaine, and reinstatement responding were investigated. The third and fourth groups of animals received guanfacine, yohimbine (norepinephrine α-2 antagonist), or vehicle once per day for 3 days 48 h after cessation of cocaine self-administration, followed by extinction and subsequent reinstatement induced by cocaine injections, cocaine-paired cues, and yohimbine administration.

Results

Cocaine-withdrawn rats at 48 h demonstrated higher levels of anxiety-like behavior as measured on a defensive burying task when compared to yoked saline controls, an effect reversed by guanfacine treatment. Cocaine intake was positively correlated with measures of anxiety-like behavior during early withdrawal, and this anxiety-like behavior was significantly correlated with subsequent cocaine-primed reinstatement. Yohimbine treatment during early withdrawal increased reinstatement to conditioned cues, while guanfacine treatment reduced reinstatement to yohimbine.

Conclusions

These studies suggest an important role for noradrenergic mediation of anxiety-like behavior that emerges after withdrawal of cocaine and potential risk of relapse as modeled by reinstatement, and suggest that treatment of anxiety symptoms during early abstinence may reduce the risk of relapse.     

Escalation of i.v. cocaine intake in peri-adolescent vs. adult rats selectively bred for high (HiS) vs. low (LoS) saccharin intake

Rationale

Adolescence marks a period of increased vulnerability to the development of substance use disorders. High sweet preference is a genetically mediated behavioral trait that also predicts vulnerability to substances of abuse. Previous research has shown that while adolescent rats selectively bred for high (HiS) saccharin intake acquire cocaine self-administration at the same rate as adult HiS rats, adolescent rats bred for low saccharin intake (LoS) acquire cocaine self-administration faster than adult LoS rats.

Objectives

This study was conducted to investigate the interaction of the addiction vulnerability factors of peri-adolescence and saccharin preference on cocaine intake using an animal model of escalation of cocaine consumption over 6-h/day sessions.

Methods

Peri-adolescent and adult HiS and LoS female rats self-administered i.v. cocaine (0.4 mg/kg/inf) during short-access (2-h/day) sessions for 2 days. Next, a long-access (6-h/day) period (LgA) commenced and lasted 16 days. Following LgA, session length was returned to 2-h/day for a second short access phase.

Results

LoS peri-adolescent rats escalated cocaine intake over the LgA period and consumed more drug than LoS adult rats; however, peri-adolescent and adult HiS rats consumed similar amounts of cocaine during this period. Additionally, adult HiS rats self-administered more cocaine than adult LoS rats during the LgA period, while there was no phenotypic difference between the rat lines during peri-adolescence for the LgA period. During the first short-access phase, peri-adolescent rats self-administered more cocaine than adult rats.

Conclusions

These results emphasize the importance of adolescent drug abuse prevention by illustrating that phenotypic protection from addiction may not be expressed until adulthood.     

Cocaine self-administration behaviors in ClockΔ19 mice

Rationale

A key role has been identified for the circadian locomotor output cycles kaput (Clock) gene in the regulation of drug reward. Mice bearing a dominant negative mutation in the Clock gene (ClockΔ19 mice) exhibit increased cocaine-induced conditioned place preference, reduced anxiety- and depression-like behavior, increased sensitivity to intracranial self-stimulation, and increased dopaminergic cell activity in the ventral tegmental area.

Objectives

We sought to determine if this hyperhedonic phenotype extends to cocaine self-administration and measures of motivation.

Methods

Two separate serial testing procedures were carried out (n?=?7–10/genotype/schedule). Testing began with acquisition of sucrose pellet self-administration, implantation of intravenous catheter, acquisition of cocaine self-administration, and dose–response testing (fixed ratio or progressive ratio). To evaluate diurnal variations in acquisition behavior, these sessions occurred at Zeitgeber 2 (ZT2) or ZT14.

Results

WT and ClockΔ19 mice exhibited similar learning and readily acquired food self-administration at both ZT2 and ZT14. However, only ClockΔ19 mice acquired cocaine self-administration at ZT2. A greater percentage of ClockΔ19 mice reached acquisition criteria at ZT2 and ZT14. ClockΔ19 mice self-administered more cocaine than WT mice. Using fixed ratio and progressive ratio schedules of reinforcement dose–response paradigms, we found that cocaine is a more efficacious reinforcer in ClockΔ19 mice than in WT mice.

Conclusion

Our results demonstrate that the Clock gene plays an important role in cocaine reinforcement and that decreased CLOCK function increases vulnerability for cocaine use.