Cocaine-maintained Responding Research Articles

HIV-1 proteins dysregulate motivational processes and dopamine circuitry

Motivational alterations, such as apathy, in HIV-1+ individuals are associated with decreased performance on tasks involving frontal-subcortical circuitry. We used the HIV-1 transgenic (Tg) rat to assess effect of long-term HIV-1 protein exposure on motivated behavior using sucrose (1–30%, w/v) and cocaine (0.01–1.0 mg/kg/infusion) maintained responding with fixed-ratio (FR) and progressive-ratio (PR) schedules of reinforcement. For sucrose-reinforced responding, HIV-1 Tg rats displayed no change in EC50 relative to controls, suggesting no change in sucrose reinforcement but had a downward shifted concentration-response curves, suggesting a decrease in response vigor. Cocaine-maintained responding was attenuated in HIV-1 Tg rats (FR1 0.33 mg/kg/infusion and PR 1.0 mg/kg/infusion). Dose-response tests (PR) revealed that HIV-1 Tg animals responded significantly less than F344 control rats and failed to earn significantly more infusions of cocaine as the unit dose increased. When choosing between cocaine and sucrose, control rats initially chose sucrose but with time shifted to a cocaine preference. In contrast, HIV-1 disrupted choice behaviors. DAT function was altered in the striatum of HIV-1 Tg rats; however, prior cocaine self-administration produced a unique effect on dopamine homeostasis in the HIV-1 Tg striatum. These findings of altered goal directed behaviors may determine neurobiological mechanisms of apathy in HIV-1+ patients.

Effects of ethanol on cocaine self-administration in monkeys responding under a second-order schedule of reinforcement

BackgroundConcurrent alcohol use among cocaine abusers is common but the behavioral variables that promote co-abuse are not well understood. The present study examined the effects of intragastric (i.g.) ethanol (EtOH) administration in monkeys responding under a schedule of cocaine reinforcement in which extensive drug seeking was maintained by conditioned stimuli. MethodsFour adult male cynomolgus monkeys (Macaca fascicularis) were trained to respond under a second-order fixed-interval (FI) 600s (fixed-ratio (FR) 30:S) schedule of cocaine (0.003–0.56mg/kg/injection) presentation. Sessions ended after 5 injections or 90min had elapsed. Different EtOH doses (0.5–2.0g/kg, i.g.) were administered 30min before the session, typically on Tuesdays and Fridays. Blood ethanol concentrations (BECs) were also assessed. Pattern of FI responding was assessed by determining quarter-life (QL) values. ResultsCocaine self-administration was characterized as an inverted U-shaped function of dose; QL values increased monotonically with dose. EtOH pretreatments dose-dependently decreased self-administration at several cocaine doses in 3 of 4 monkeys. In one animal, EtOH increased low-dose cocaine-maintained responding. For all monkeys, QL values were increased by EtOH when low- and high-cocaine doses were self-administered, suggesting additive effects of EtOH and cocaine. Furthermore, BECs were not altered following cocaine self-administration. ConclusionsThe reductions in cocaine self-administration and the increases in QL values following EtOH, suggest that EtOH was enhancing cocaine-related conditioned reinforcement. A better understanding of the behavioral mechanisms that mediate the co-abuse of alcohol and cocaine will lead to improved treatments for both drugs.

Influence of experimental history on nicotine self-administration in squirrel monkeys.

Methods for establishing robust long-term self-administration of intravenous (i.v.) nicotine, the primary psychoactive agent in tobacco, are not well-established in laboratory animals. Here, we examine the use of a fading procedure to establish robust and consistent i.v. nicotine self-administration under second-order schedule conditions in squirrel monkeys. First, self-administration behavior was developed in two groups of male squirrel monkeys using a second-order fixed-interval 5-min schedule with fixed-ratio 5 units (FI 5-min (FR5: S)). Comparable performances were maintained by i.v. cocaine (0.032mg/kg/injection (inj); group A, n = 3) and the combination of food delivery (20-30% condensed milk) and 0.01mg/kg/inj i.v. nicotine (group B, n = 3). Subsequently, the concentration of condensed milk was gradually reduced to zero in the second group and self-administration behavior was maintained by i.v. nicotine alone. Next, self-administration of a range of doses of i.v. nicotine (0.001-0.032mg/kg/inj) and, in additional experiments, the minor tobacco alkaloid anatabine (0.01-0.18mg/kg/inj) was studied in both groups. Results show that nicotine and anatabine had reinforcing effects in both groups. However, optimal doses of nicotine and anatabine maintained significantly higher rates of i.v. self-administration behavior in subjects trained with the fading procedure than in subjects provided with a history of cocaine-maintained responding. These results illustrate conditions under which robust i.v. nicotine self-administration can be established in squirrel monkeys and the influence of prior experimental history in the expression of reinforcing effects of nicotine and anatabine.

Effects of L-methamphetamine treatment on cocaine- and food-maintained behavior in rhesus monkeys.

Monoamine releasers with prominent dopaminergic actions, e.g., D-methamphetamine (D-MA), significantly reduce cocaine use and craving in clinical and preclinical laboratory studies. However, D-MA and related drugs also display high abuse potential, which limits their acceptability as agonist replacement medications for the management of Cocaine Use Disorder. The L-isomer of methamphetamine (L-MA), unlike D-MA, has preferential noradrenergic actions and is used medicinally with low, if any, abuse liability. The present study was conducted to determine whether L-MA could serve as an agonist replacement medication by both mimicking interoceptive effects of cocaine and decreasing intravenous (IV) cocaine self-administration. Separate groups (N = 4-5) of rhesus monkeys were studied to determine whether L-MA could (1) substitute for cocaine in subjects that discriminated intramuscular (IM) cocaine (0.4 mg/kg) from saline and (2) decrease IV cocaine self-administration under a second-order FR2(VR16:S) schedule of reinforcement. L-MA, like D-MA but with approximately 5-fold lesser potency, substituted for cocaine in drug discrimination experiments in a dose-dependent manner. In IV self-administration studies, 5-10-day treatments with continuously infused L-MA (0.032-0.32 mg/kg/h, IV) dose-dependently decreased cocaine-maintained responding; the highest dosage reduced cocaine intake to levels of saline self-administration without appreciable effects on food-maintained responding. These results indicate that L-MA both shares discriminative stimulus effects with cocaine and reduces cocaine self-administration in a behaviorally selective manner. L-MA and other compounds with a similar pharmacological profile deserve further evaluation for the management of Cocaine Use Disorder.

Lorcaserin Reduces the Discriminative Stimulus and Reinforcing Effects of Cocaine in Rhesus Monkeys.

Cocaine abuse and obesity are serious public health problems, and studies suggest that both dopamine and serotonin systems are involved in regulating the consumption of drugs and food. Lorcaserin has serotonin (5-HT)2C receptor agonist actions, is approved by the U.S. Food and Drug Administration for treating obesity, and might be effective for treating cocaine abuse. These studies characterized the pharmacokinetic and behavioral profiles of lorcaserin (intragastric administration) and determined the effectiveness of lorcaserin to alter discriminative stimulus and reinforcing effects of cocaine (intravenous administration) in rhesus monkeys. Administered acutely, lorcaserin dose-dependently increased the occurrence of yawning while decreasing spontaneous activity and operant responding for food. These effects appeared within 30-60 minutes of administration and began to dissipate by 240 minutes, a time course closely matching plasma concentrations of lorcaserin. In monkeys discriminating cocaine from saline, lorcaserin alone did not occasion cocaine-appropriate responding but shifted the cocaine dose-response curve to the right and down in two of three monkeys. When administered acutely, lorcaserin dose-dependently decreased the rate at which monkeys responded for infusions of cocaine. When administered chronically, 3.2 mg/kg lorcaserin reduced the rate of cocaine-maintained responding by 50% for the duration of a 14-day treatment period. Together, these results show that lorcaserin attenuates the discriminative stimulus effects of cocaine after acute administration and the reinforcing effects of cocaine after acute and repeated administration, consistent with the view that it might have utility in treating cocaine abuse.

Treatment of cocaine addiction with amphetamine, a sleep-suppressant drug: associative learning, sleep patterns and clinical perspectives

Dear Editor Stimulants have shown promise as a treatment for cocaine dependence despite resistance in the field to using controlled substances as therapeutic agents for addictive disorders. Conceptually, the goal of substitution pharmacotherapy is to replace a drug of abuse with rapid onset and brief half-life with an agent that has a more gradual onset of action and long halflife to suppress withdrawal and drug craving, reducing the cycle of compulsive use (Grabowski et al. 2004; Mariani and Levin 2012). Within this context, the recent study by Zimmer and colleagues (2013) demonstrated that D-amphetamine treatment during the persistence of a previously established active cocaine self-administration, but not during passive cocaine infusions, resulted in a significant decrease in cocaine-maintained responding under a PR schedule of reinforcement. The authors discussed these findings in terms of associative processes between the drug effect and the environmental cues, culminating into drug-seeking behavior. This potential hypothesis needs to be viewed in relation to an important aspect of addiction, namely the potentiating effect of environmental cues previously paired with drug effects on the development of drug craving in humans (Carter and Tiffany 1999; Niaura et al. 1988). Because several stimuli can become conditioned to the drug for the abusers, the exposure to conditioned reinforcement may lead to relapse into drug-seeking behavior following a period of abstinence thought to play a crucial role in the addictive cycle. Despite these interesting findings by Zimmer and colleagues (2013), one cannot ignore the use of amphetamine by humans. As an alertness-enhancing and euphorigenic drug, amphetamine is frequently used when irregular work/rest patterns cause excessive sleepiness (Akersted and Ficca 1997; Parsons et al. 2006; Robinson and Becker 1986), characterizing it as a sleep deprivation-related drug. In addition, it has been repeatedly demonstrated that sleep deprivation shares similar neurobiological effects with psychostimulants (Demontis et al. 1990; Fadda et al. 1993; Nunes et al. 1994; Tufik 1981a, b). In this scenario, studies from our group have been conducted in order to investigate the relationship between sleep deprivation and addiction. Of note, we demonstrated that the sleep condition affects amphetamine-induced behavioral changes by specifically modulating its conditioned component. Context-dependent behavioral sensitization to amphetamine is potentiated by sleep deprivation procedures, and a sleep rebound period can attenuate it (Calzavara et al. 2008; Frussa-Filho et al. 2004). In the study under consideration, Zimmer et al. (2013) propose a continuous and passive infusion of amphetamine as a potential treatment to reduce the reinforcing effectiveness of cocaine. Nonetheless, this therapeutic approach would suppress the sleep pattern of addicts. Because it has been extensively demonstrated that sleep disorders, which may impair addiction treatment bymodulating the drug–environment conditioning, are concomitant features in patients with addictive disorders (Canellas and de Lecea 2012; Mahfoud et al. 2009), characterizing a vicious cycle, this prolonged substitution pharmacotherapy could be dangerous in the clinic. Indeed, regarding the authors’ findings, the role of the environment needs to be considered not only in the treatment of the contingent cocaine group but also in that of the noncontingent This letter is in memory of Dr. Roberto Frussa-Filho, who dedicated his entire life to Science, because aman is alivewhile his name is still spoken.

Effects of saikosaponin A on cocaine self-administration in rats

We have previously demonstrated that saikosaponin A (SSA) attenuated morphine self-administration behavior. In the present study, we evaluated the effects of SSA on cocaine-maintained responding using self-administration procedure. Rats self-administered cocaine (0.25mg/kg per infusion) under a fixed ratio 1 schedule of reinforcement during daily 3-h session. Once stable basal responses were obtained, rats were pretreated with each doses of SSA (1.0, 2.5, 5.0mg/kg) or its vehicle (5% Tween-80) by an intraperitoneal injection 30min before the start of self-administration testing. Additionally, different groups of rats received either the selective GABAB antagonist SCH 50911 or the GABAA antagonist bicuculline before systemic administration of SSA at dose of 2.5mg/kg. Results showed that SSA significantly reduced cocaine self-administration without affecting food consumption. SSA inhibition of cocaine reinforced-responding was blocked by SCH 50911, but not bicuculline. Results suggest that SSA may attenuate cocaine-reinforced behavior through activation of GABAB receptors.

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

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. 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. 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. 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. 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.

MGluR2-Positive Allosteric Modulators: Therapeutic Potential for Treating Cocaine Abuse?

mGluR2-Positive Allosteric Modulators: Therapeutic Potential for Treating Cocaine Abuse?

Nicotine and cocaine self-administration using a multiple schedule of intravenous drug and sucrose reinforcement in rats

There appears to be a relatively narrow range of contingencies in which intravenous (i.v) infusions of nicotine will maintain responding in rats. The schedule of reinforcement typically used when investigating i.v. nicotine self-administration is a simple fixed-ratio (FR) schedule. This study determined if responding in rats could be established using a multiple schedule of either i.v. cocaine or nicotine and sucrose reinforcement. Following training of individual components with each reinforcer, rats were placed on an FR15 60-s timeout multiple schedule of cocaine (0.3 mg/kg/infusion) and sucrose (45 mg pellets) reinforcement or an FR5 60-s timeout multiple schedule of nicotine (0.03 mg/kg/infusion) and sucrose (45 mg pellets) reinforcement. Both cocaine and nicotine maintained significant levels of responding under the multiple schedule. Pretreatment with the dopamine D1 antagonist SCH 23390 increased cocaine-maintained responding, but not sucrose responding. Acute pretreatment with the nicotinic antagonist mecamylamine or SCH 23390 specifically decreased nicotine self-administration. Extinction of the individual nicotine and sucrose components resulted in decreases in responding in each component under extinction. These results indicate that i.v. nicotine maintains responding under a multiple schedule. This procedure may be useful when studying the specificity of drug pretreatments on nicotine self-administration.

Effectiveness of analogs of the kappa opioid receptor antagonist (3R)-7-Hydroxy-N-((1S)-1-{[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl}-2-methylpropyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxamide (JDTic) to reduce U50,488-induced diuresis and stress-induced cocaine reinstatement in rats

The kappa opioid receptor (KOR) antagonist, JDTic, was reported to prevent stress-induced reinstatement of cocaine-maintained responding and to have antidepressant-like effects. Our objectives were to determine whether analogs of JDTic retained KOR antagonist activity and whether an orally effective analog prevented footshock-induced cocaine reinstatement. RTI-194 (i.g. 1-30 mg/kg, s.c. 0.3-10 mg/kg, and i.p. 30 mg/kg), RTI-212 (s.c. 0.3-10 mg/kg and i.p. 30 mg/kg), and RTI-230 (i.g. 3-30 mg/kg and i.p. 1-30 mg/kg) were evaluated for their ability to block diuresis induced by 10-mg/kg U50,488 in rats. RTI-194 was additionally evaluated i.g. (3-100 mg/kg) for its ability to prevent footshock-induced reinstatement of responding previously reinforced with 0.5-mg/kg/inf cocaine. RTI-194 significantly (p < 0.05) attenuated U50,488-induced diuresis when given i.g., s.c., and i.p. RTI-194s effectiveness increased 1 week following administration. RTI-212 was ineffective. RTI-230 was ineffective when given i.g., but blocked diuresis at 24 h and 8 days (1, 10, and 30 mg/kg), 15 days (10 and 30 mg/kg), 22 and 29 days (30 mg/kg) following i.p. administration. Footshock reinstated responding in vehicle-but not RTI-194 (30 and 100 mg/kg)-treated rats. RTI-194 and RTI-230 are effective KOR antagonists, and RTI-194 is now included with JDTic as the only reported compounds capable of antagonizing the KOR following oral administration. The failure of stress to reinstate cocaine seeking in rats treated with RTI-194 is consistent with results reported with JDTic, although it had less efficacy in lowering response levels than JDTic, suggesting a diminished overall effectiveness relative to it.

Effects of chronic d-amphetamine administration on the reinforcing strength of cocaine in rhesus monkeys

Agonist medications have been proven effective in treating opioid and nicotine dependence; results from clinical studies suggest that the indirect dopamine agonist d-amphetamine may reduce cocaine abuse. In preclinical studies, chronic d-amphetamine treatment decreased ongoing cocaine self-administration. The present study extended previous results by determining effects of chronic d-amphetamine treatment on the reinforcing strength of cocaine under conditions in which access to cocaine was suspended during d-amphetamine treatment. Daily operant conditioning sessions consisted of morning access to food pellets delivered under a 50-response fixed-ratio schedule and evening access to cocaine (0.005-0.48 mg/kg per injection, i.v.) under a progressive-ratio schedule. After responding maintained by 0.045 mg/kg per injection cocaine stabilized, self-administration sessions were suspended and d-amphetamine (0.01-0.1 mg/kg per hr, i.v.) was administered continuously for 5 days. On the following day, d-amphetamine treatment was discontinued and daily self-administration sessions resumed. Following termination of d-amphetamine treatment, food- and cocaine-maintained responding was decreased in a dose-related manner. Decreases in the reinforcing strength of cocaine were larger and lasted longer than effects on food reinforcement. However, cocaine self-administration was unaltered if 6 days elapsed between discontinuation of d-amphetamine treatment and the next cocaine self-administration session. The necessity of a self-administration session in the presence of d-amphetamine suggests that the protracted decrease in cocaine self-administration may be a manifestation of behavioral tolerance. Regarding treatment of cocaine dependence, data suggest that prolonged d-amphetamine treatment may be necessary to produce a sustained reduction in the reinforcing effects of cocaine.

The CB1 antagonist rimonabant (SR141716) blocks cue-induced reinstatement of cocaine seeking and other context and extinction phenomena predictive of relapse

Cannabinoid CB1 antagonists decrease self-administration of palatable food and several abused drugs in animals and modulate extinction of conditioned fear responses. Less is known, however, about whether and how CB1 antagonists might modulate the extinction of appetitive behavior. Therefore, this study examined the effects of the CB1 receptor antagonist rimonabant (SR141716) during extinction of responding maintained either by cocaine or by palatable foods (corn oil or Ensure), as well as responding elicited by stimulus cues that had been paired with the presentation of cocaine (i.e., cue-induced reinstatement) or a prime (presentation of cocaine or food). The effect of rimonabant on high rate responding in water-deprived mice trained to self-administer water was also examined. In mice self-administering cocaine, rimonabant attenuated cue-induced reinstatement of cocaine self-administration, the initial burst of responding during cocaine extinction and responding during spontaneous recovery. In mice self-administering corn oil, rimonabant decreased responding during extinction and also attenuated responding that had been reinstated by a priming presentation of corn oil. Moreover, mice treated with rimonabant required fewer daily sessions to reach criterion for extinction of cocaine-maintained responding than vehicle treated mice. Also, rimonabant had no effect on the rate of operant responding in mice trained to respond for water under an FR5 schedule of reinforcement. Taken together, these data suggest that in addition to attenuating the primary reinforcing effects of both palatable foods and drugs of abuse, CB1 receptor antagonism can attenuate context and cue reactivity during extinction learning and potentially enhance extinction learning in this way.

Characterization of PG‐619, a dopamine D3 receptor partial agonist, on cocaine self‐administration and drug‐elicited yawning in rhesus monkeys

The dopamine D3 receptor is a promising target for the development of novel treatment agents for addiction due to its restricted expression in limbic brain regions and involvement in reinforcement pathways (Newman et al., 2005). The present study examined the effects of PG‐619, a D3 receptor partial agonist, with 100‐fold selectivity for the D3 over D2 receptors (Grundt et al., 2007), on cocaine self‐administration (SA) and yawning in male rhesus monkeys with an extensive cocaine history (n=3). Monkeys self‐administered cocaine (0.003‐0.3 mg/kg) under a fixed‐ratio 30 schedule during daily 2‐hr sessions. Prior work found CJB 090, a D3 partial agonist with 60‐fold D3 selectivity, decreased cocaine‐maintained responding (Martelle et al., 2007). Acute doses of PG‐619 (0.1 ‐ 1.0 mg/kg, i.v., 10 min presession) did not significantly affect cocaine SA; higher doses of PG‐619 are currently being evaluated. In vivo potency of PG‐619 to elicit yawning was also examined. As with CJB 090, no doses of PG‐619 (0.1 ‐ 1.0 mg/kg) elicited yawning. The preliminary findings support prior work that D3 partial agonists do not have D3 agonist effects in vivo. Furthermore, the findings suggest greater selectivity of D3 over D2 receptors may result in substantial decreases in potency to affect cocaine SA, although bioavailability and pharmacokinetic factors may contribute to the behavioral profiles of these drugs. DA 12460 and NIDA‐IRP.

Assessment of Reinforcing Effects of Benztropine Analogs and Their Effects on Cocaine Self-Administration in Rats: Comparisons with Monoamine Uptake Inhibitors

Benztropine (BZT) analogs inhibit dopamine uptake but are less effective than cocaine in producing behavioral effects predicting abuse liability. The present study compared reinforcing effects of intravenous BZT analogs with those of standard monoamine uptake inhibitors and the effects of their oral pretreatment on cocaine self-administration. Responding of rats was maintained by cocaine [0.032-1.0 mg/kg/injection (inj)] or food reinforcement under fixed-ratio five-response schedules. Maximal rates of responding were maintained by 0.32 mg/kg/inj cocaine or substituted methylphenidate, with lower rates maintained at lower and higher doses. The N-methyl BZT analog, AHN 1-055 (3alpha-[bis(4'-fluorophenyl)methoxy]-tropane), also maintained responding (0.1 mg/kg/inj), although maximal rates were less than those with cocaine. Responding was not maintained above vehicle levels by the N-allyl, AHN 2-005 (N-allyl-3alpha-[bis(4'-fluorophenyl)methoxy]-tropane), and N-butyl, JHW 007 [N-(n-butyl)-3alpha-[bis(4'-fluorophenyl)methoxy]-tropane], BZT analogs, and it was not maintained with nisoxetine or citalopram. Presession treatment with methylphenidate (3.2-32 mg/kg) dose-dependently shifted the cocaine self-administration dose-effect curve leftward, whereas nisoxetine and citalopram effects were not significant. An intermediate dose of AHN 1-055 (32 mg/kg) increased responding maintained by low cocaine doses and decreased responding maintained by higher doses. A higher dose of AHN 1-055 completely suppressed cocaine-maintained responding. Both AHN 2-005 and JHW 007 dose-dependently (10-32 mg/kg) decreased cocaine self-administration, shifting its dose-effect curve down. Decreases in cocaine-maintained responding occurred at doses of methylphenidate and BZT analogs that left food-maintained responding unchanged. During a component in which injections were not available, methylphenidate and AHN 1-055, but not AHN 2-005 or JHW 007, increased response rates. These findings further support the low abuse liability of BZT analogs and their potential development as medications for cocaine abuse.

Cocaine self-administration on a hold-down schedule of reinforcement in rats

Although many contingencies operating in the natural environment include continuous dimensions of responses and reinforcers, previous studies of drug self-administration have almost exclusively used discrete dimensions of responses (e.g., a lever press) and reinforcers (e.g., 1.0 mg/kg/injection cocaine). Therefore, the present study provides an initial examination under experimental conditions with both responses and reinforcers measured along continuous dimensions. Cocaine-maintained responding was studied in rats under a novel, hold-down schedule of reinforcement wherein the duration of the response was directly related to the magnitude of the reinforcer. These conditions were established by activating the syringe pump when the lever was pressed down and turning the pump off when the lever was released. The concentration of cocaine available in the syringe was varied across sessions. Cocaine self-administration was readily maintained under these conditions and remained stable across sessions. Responding was concentration dependent, with the number of responses and total duration of the response inversely related to concentration, and overall session intake of cocaine was stable across concentrations. In general, the duration of the responses were less than 0.5 s and did not vary as a function of concentration. Stability of responding under these schedule conditions was acquired quickly. This schedule of reinforcement may be useful for comparing across drug classes, can be extended for use with other types of responses and reinforcers, and may be more representative of the natural world where response-reinforcer contingencies are more likely to be experienced along continuous, rather than discrete, dimensions.

Microinjection of the δ-opioid receptor selective antagonist naltrindole 5′-isothiocyanate site specifically affects cocaine self-administration in rats responding under a progressive ratio schedule of reinforcement

Whether the δ-opioid receptor (DOR) system can modulate behavioral effects of cocaine remains equivocal. We examined whether site- and subtype-selective blockade of DORs within the rat mesocorticolimbic system affects cocaine self-administration. The DOR antagonist naltrindole 5′-isothiocyanate (5′-NTII; 5 nmol) was microinjected into the nucleus accumbens (NAcc), ventral tegmental area (VTA), or amygdala (AMYG) in rats self-administering 1.5 mg/kg cocaine under a progressive ratio (PR) schedule. Intra-NAcc 5′-NTII significantly decreased cocaine self-administration, while 5′-NTII administration into the VTA significantly increased cocaine-maintained responding. 5′-NTII administration into the AMYG produced no effect. These data support a site-specific role of DORs in cocaine's behavioral effects.

Diverse effects of GABA-mimetic drugs on cocaine-evoked self-administration and discriminative stimulus effects in rats

Recent data indicate that gamma-aminobutyric acid (GABA) is a modulator of behavioral responses to cocaine. The efficacy of gabapentin (a cyclic GABA analogue), tiagabine (a GABA reuptake inhibitor), or vigabatrin (an inhibitor of GABA transaminase and reuptake) to alter cocaine-seeking behavior and discriminative effects was examined in rats. Rats were trained to press a lever for cocaine (0.5 mg/kg per infusion) paired with a cue (light + tone) using a fixed ratio (FR) 5 schedule of reinforcement. After extinction, the cocaine-seeking behavior was reinstated by cocaine priming (10 mg/kg). Another group of rats was trained to discriminate cocaine (10 mg/kg) from saline in a two-lever FR 20 task. Vigabatrin (150-250 mg/kg) decreased cocaine-maintained responding, whereas tiagabine (10 mg/kg) significantly reduced responses on the "active" lever. Vigabatrin (150-250 mg/kg) significantly decreased responding to the cocaine-priming dose and a nonsignificant attenuation of cocaine-induced reinstatement was seen after tiagabine (5-10 mg/kg). Gabapentin (10-30 mg/kg) failed to alter maintenance of cocaine self-administration or drug-induced reinstatement. Pretreatment with either gabapentin, tiagabine, or vigabatrin resulted in neither reinstatement of cocaine seeking nor alterations in cocaine discrimination. Our study demonstrates that vigabatrin (only at the 150 mg/kg dose) exerted inhibitory actions on cocaine-maintained responding and attenuated the reinstatement of extinguishing responding more effectively than gabapentin or tiagabine and with less evidence of motor impairment than the latter drugs. Present findings do not support a role for gabapentin or tiagabine for the possible treatment of cocaine relapse, whereas albeit limited effects of vigabatrin may be seen.

Effects of the CRF 1 antagonist antalarmin on cocaine self-administration and discrimination in rhesus monkeys

Cocaine stimulates the rapid release of ACTH, and by inference, CRF in several species, suggesting that the HPA “stress” axis may contribute to the abuse-related effects of cocaine. The effects of a systemically-active CRF 1 receptor antagonist, antalarmin, on cocaine self-administration and cocaine discrimination were examined in rhesus monkeys. Antalarmin's acute (1–10 mg/kg, IV) and chronic (3.2 mg/kg IV) effects on IV cocaine self-administration were studied. The acute effects of 3.2 mg/kg IV antalarmin on the cocaine self-administration dose–effect curve (0.001–0.10 mg/kg/inj) were also examined. The acute effects of antalarmin (5 and 10 mg/kg, IM) on the cocaine discrimination dose–effect curve (0.013–1.3 mg/kg) were examined. Antalarmin did not significantly decrease the reinforcing or the discriminative stimulus effects of cocaine. Acute antalarmin administration produced a dose-dependent but non-significant decrease in self-administration of 0.01 mg/kg/inj cocaine but did not alter the cocaine dose–effect curve. Chronic daily antalarmin treatment did not significantly decrease cocaine-maintained responding. Antalarmin did not significantly alter either the cocaine discrimination dose–effect curve or the time course of the cocaine-training dose. Antalarmin (10 mg/kg) produced sedation, suggesting that it was centrally active, however, it did not attenuate cocaine's abuse-related effects in rhesus monkeys.

The effects of eticlopride and the selective D 3-antagonist PNU 99194-A on food- and cocaine-maintained responding in rhesus monkeys

The dopamine D 3 receptor is mainly expressed in regions of the brain associated with the limbic system. D 3 receptor blockade may antagonize cocaine reinforcement while producing less severe extrapyramidal side effects than blockade of D 2 receptors. The purpose of the present studies was to evaluate the effects of a selective D 3 receptor antagonist and a non-selective D 2/D 3 receptor antagonist on food- and cocaine-maintained responding under two schedules of cocaine self-administration. Adult male rhesus monkeys were trained to respond under multiple schedules of food (1.0 g pellets) and cocaine (0.01–0.3 mg/kg/injection) presentation. In one experiment ( n = 4), the schedule was a fixed-interval (FI) 3-min and a second study ( n = 6) was conducted using a second-order fixed-ratio 5 (FI 6-min : S) schedule. The D 3 antagonist PNU 99194-A (0.3–3.0 mg/kg), which is 14-fold selective for D 3 relative to D 2 receptors, or the D 2/D 3 antagonist eticlopride (0.001–0.03 mg/kg) was administered immediately prior to the experimental session for at least 5 consecutive sessions. Under the multiple FI 3-min schedule of food and cocaine presentation, PNU 99194-A and eticlopride decreased food- and cocaine-maintained responding in a dose-dependent manner and irrespective of cocaine dose. Under the multiple second-order schedule of food and cocaine presentation, at least one dose of PNU 99194-A and eticlopride decreased cocaine- and food-maintained responding. These findings indicate that PNU 99194-A can decrease operant responding in monkeys, but not in a manner that would suggest selectivity of cocaine- over food-maintained responding. Future studies with more selective D 3 antagonists are needed to better address the role of this receptor subtype in cocaine addiction.