Cocaine Dose-response Function Research Articles

Methylphenidate treatment beyond adolescence maintains increased cocaine self-administration in the spontaneously hypertensive rat model of attention deficit/hyperactivity disorder

Past research with the spontaneously hypertensive rat (SHR) model of attention deficit/hyperactivity disorder showed that adolescent methylphenidate treatment enhanced cocaine abuse risk in SHR during adulthood. The acquisition of cocaine self-administration was faster, and cocaine dose–response functions were shifted upward under fixed-ratio and progressive ratio schedules compared to adult SHR that received adolescent vehicle treatment or to control strains that received adolescent methylphenidate treatment. The current study determined if extending treatment beyond adolescence would ameliorate long-term consequences of adolescent methylphenidate treatment on cocaine abuse risk in adult SHR. Treatments (vehicle or 1.5mg/kg/day oral methylphenidate) began on postnatal day 28. Groups of male SHR were treated with vehicle during adolescence and adulthood, with methylphenidate during adolescence and vehicle during adulthood, or with methylphenidate during adolescence and adulthood. The group receiving adolescent-only methylphenidate was switched to vehicle on P56. Cocaine self-administration began on postnatal day 77, and groups receiving methylphenidate during adolescence and adulthood were treated either 1-h before or 1-h after daily sessions. At baseline under a fixed-ratio 1 schedule, cocaine self-administration (2h sessions; 0.3mg/kg unit dose) did not differ among the four treatment groups. Under a progressive ratio schedule (4.5h maximum session length; 0.01–1.0mg/kg unit doses), breakpoints for self-administered cocaine in SHR receiving the adult methylphenidate treatment 1-h pre-session were not different from the vehicle control group. However, compared to the vehicle control group, breakpoints for self-administered cocaine at the 0.3 and 1.0mg/kg unit doses were greater in adult SHR that received adolescent-only methylphenidate or received methylphenidate that was continued into adulthood and administered 1-h post-session. These findings suggest that extending methylphenidate treatment beyond adolescence does not ameliorate explicitly the long-term consequences of adolescent methylphenidate treatment. Pre-session methylphenidate may mask temporarily the detection of an increase in cocaine self-administration following chronic methylphenidate treatment.

Dopamine β-Hydroxylase Inhibitors Enhance the Discriminative Stimulus Effects of Cocaine in Rats

Inhibitors of dopamine β-hydroxylase (DBH), the enzyme that converts dopamine (DA) to norepinephrine (NE) in noradrenergic cells, have shown promise for the treatment of cocaine abuse disorders. However, the mechanisms underlying the beneficial effects of these compounds have not been fully elucidated. We used the drug discrimination paradigm to determine the impact of DBH inhibitors on the interoceptive stimulus properties of cocaine. Sprague-Dawley rats were trained to discriminate cocaine (5.6 mg/kg) from saline using a multicomponent, food-reinforced discrimination procedure. On test days, subjects were pretreated with the nonselective DBH inhibitor disulfiram (0-100.0 mg/kg i.p.) or the selective DBH inhibitor nepicastat (0-56.0 mg/kg i.p.) 2 hours prior to a test session either alone or in combination with cumulatively administered cocaine (0-5.6 mg/kg i.p.). Neither disulfiram nor nepicastat substituted for the cocaine stimulus when tested up to doses that nonspecifically reduced responding. However, in combination studies, pretreatment with either disulfiram or nepicastat produced leftward shifts in the cocaine dose-response function and also conferred cocaine-like stimulus effects to the selective NE transporter inhibitor, reboxetine (0.3-5.6 mg/kg i.p.). These results indicate that pharmacological inhibition of DBH does not produce cocaine-like interoceptive stimulus effects alone, but functionally enhances the interoceptive stimulus effects of cocaine, possibly due to facilitated increases in DA released from noradrenergic terminals. These findings suggest that DBH inhibitors have low abuse liability and provide support to clinical reports that some subjective effects produced by cocaine, particularly aversive effects, are enhanced after DBH inhibition.

Methylphenidate Treatment in Adolescent Rats with an Attention Deficit/Hyperactivity Disorder Phenotype: Cocaine Addiction Vulnerability and Dopamine Transporter Function

Appropriate animal models of attention deficit/hyperactivity disorder (ADHD) and drug reinforcement allow investigation of possible underlying biological bases of ADHD and its comorbidity with cocaine addiction. Toward this end, spontaneously hypertensive rats (SHRs) exhibiting an ADHD phenotype were compared with Wistar-Kyoto (WKY) and Wistar (WIS) rats. Initially, 1.5 mg/kg oral methylphenidate or vehicle was administered between postnatal days 28 and 55, and acquisition of visual discrimination learning was examined. After discontinuing adolescent treatments, adult rats were evaluated for cocaine self-administration and dopamine transporter (DAT) function in the prefrontal cortex (PFC) and striatum. During adolescence, SHRs showed deficits in visual discrimination relative to WKY and WIS rats when non-medicated. Methylphenidate improved visual discrimination only in SHRs. Compared with WKY and WIS rats, SHRs with previous methylphenidate treatment acquired cocaine self-administration faster, identified cocaine as a highly efficacious reinforcer by displaying an upward shift in the cocaine dose-response function, and showed the greatest motivation to self-administer cocaine by exhibiting the highest progressive ratio breakpoints. In the PFC, the maximal dopamine uptake (V(max)) at DAT was decreased in SHRs and increased in WKY and WIS rats by previous methylphenidate treatment. The affinity (K(m)) for dopamine at DAT in the PFC was not different between strains, nor was V(max) or K(m) altered in the striatum by previous methylphenidate treatment in any strain. Methylphenidate-induced decreases in dopamine clearance by DAT in the PFC may underlie increased cocaine self-administration in SHRs. These preclinical findings suggest that caution should be exercised when methylphenidate is prescribed for first-time treatment of ADHD in adolescent patients, as cocaine addiction vulnerability may be augmented.

Asymmetric generalization and interaction profiles in rhesus monkeys discriminating intravenous cocaine or intravenous heroin from vehicle.

Many polydrug abusers combine cocaine with heroin in the form of a "speedball." This study investigated the discriminative stimulus (DS) effects of speedballs in rhesus monkeys trained to discriminate either intravenous cocaine or intravenous heroin from vehicle. Initial substitution tests revealed an asymmetry in the generalization profile of dopamine and opioid agonists such that mu agonists partially substituted for cocaine, but direct and indirect dopamine agonists did not substitute for heroin. Subsequent speedball tests in which drug mixtures were administered by coinjecting the component drugs while keeping the dose-ratio constant revealed an additional asymmetry. In cocaine-trained monkeys, coadministration of cocaine and heroin produced leftward shifts in the cocaine dose-response function. Heroin's cocaine-enhancing effects were mimicked by the mu agonists fentanyl and methadone and less consistently by the delta agonist (+)-4-[(alphaR)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (SNC 80) and reversed by the mu antagonist naltrexone and the delta antagonist naltrindole. In heroin-trained monkeys, coadministration of cocaine and heroin attenuated the DS effects of heroin. Cocaine's heroin-attenuating effects were mimicked by the D1-like agonist 6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine (SKF 81297) and the D2-like agonist R-(-)-propylnorapomorphine and reversed by the D1-like antagonist (6aS-trans)-11-chloro-6,6a,7,8,9,13b-hexahydro-7-methyl-5H- benzo[d] aphtha[2,1-b]azepin-12-ol hydrobromide (SCH 39166) and the D2-like antagonist raclopride. Attenuation of the effects of heroin was accompanied by decreases in response rate. These results suggest that heroin enhances the DS effects of cocaine via mu, and to a lesser extent delta, receptor mechanisms; whereas cocaine-induced inhibition of the DS effects of heroin probably was due at least in part to masking of the heroin DS presumably via stimulation of both D1- and D2-like receptors.

Attenuation of cocaine-induced reinstatement of drug seeking in squirrel monkeys: kappa opioid and serotonergic mechanisms.

Kappa agonists can attenuate reinstatement of cocaine-seeking behavior induced by cocaine priming. The mechanisms underlying this effect have not been characterized fully but may have a serotonergic component as kappa agonists also increase the release of serotonin (5-hydroxytryptamine, 5-HT). This study investigated the role of kappa opioid receptor and 5-HT mechanisms in kappa agonist-induced attenuation of cocaine priming in monkeys. Squirrel monkeys were trained to self-administer cocaine (0.18-0.3 mg/kg/injection) under a second-order schedule in which drug seeking was maintained jointly by cocaine injections and a cocaine-paired visual stimulus. In extinction sessions, saline was substituted for cocaine, and the cocaine-paired stimulus was omitted. During test sessions, only saline was available for self-administration, and response-contingent presentations of the cocaine-paired stimulus were restored. Priming injections of cocaine (0.1-1.0 mg/kg) induced reinstatement of drug seeking. Maximal levels of responding were similar to those maintained by active cocaine self-administration. Pretreatment with the kappa agonists enadoline (0.01 mg/kg) and spiradoline (0.3 mg/kg) or the 5-HT transport inhibitors fluoxetine (5.6 mg/kg) and citalopram (10.0 mg/kg) attenuated the priming effects of cocaine, shifting the cocaine dose-response function rightward and downward. Inhibition of cocaine-induced reinstatement of drug seeking by spiradoline and fluoxetine was reversed by R(+)8-hydroxy-2-(di-n-propylamino)tetralin (0.03 mg/kg), a 5HT(1A) agonist that inhibits 5-HT release. The effects of spiradoline also were reversed by the kappa antagonist nor-binaltorphimine (10.0 mg/kg). Results suggest that the capacity of kappa opioid agonists to increase extracellular 5-HT levels may at least partially underlie kappa agonist-induced modulation of cocaine seeking.

Self-administration of cocaine-pentobarbital mixtures by rhesus monkeys

A number of experiments have evaluated self-administration of the combination of a stimulant and an opioid. Less is known about the combination of a stimulant and a CNS depressant. The present experiment was designed to examine self-administration of the mixture of cocaine and pentobarbital (PB). Rhesus monkeys ( n = 4) prepared with i.v. catheters were allowed to self-administer cocaine or saline under a progressive-ratio schedule. When responding was stable, doses of cocaine and PB, alone or in combination, were made available in test sessions. Cocaine functioned as a positive reinforcer in a dose-related manner in all monkeys. PB functioned as a relatively weaker reinforcer in one of four monkeys. Self-administration of intermediate doses of cocaine (0.025–0.1 mg/kg per injection) was decreased when mixed with PB (0.05–0.2 mg/kg per injection); full maximum responding was re-established when cocaine dose was increased. The magnitude of the shift to the right in the cocaine dose–response function was directly related to PB dose. When PB was given as an i.v. pretreatment there was no effect on cocaine self-administration up to a sedative dose of PB (5.6 mg/kg), suggesting that responding was not non-specifically suppressed by PB. Thus, simultaneous self-administration of PB diminished the potency but not the strength of cocaine as a reinforcer, potentially encouraging self-administration of larger doses of cocaine.

Effects of Dose and Session Duration on Cocaine Self-Administration in Rats

Previous studies showed that an extended 6-h session duration produced an increasing rate of cocaine self-administration in rats. The present study further investigated the effect of dose and session duration on cocaine self-administration. Eight groups of rats (4 doses x 2 session durations) self-administered one of four cocaine doses (0.25, 0.5, 1, and 2 mg/kg/injection) in either 1- or 6-h sessions under a fixed-ratio schedule. In another experiment, two other groups of rats self-administered 0.5 mg/kg/injection of cocaine in either 3- or 12-h sessions. Cocaine self-administration increased at all doses in 6-h sessions but not in 1-h sessions. Cocaine intake (milligram/kilogram) reached an asymptote earlier at a higher dose, but the rate of responding increased faster when the dose was lower. In ShA rats, the cocaine dose-response function was higher in rats at the two higher unit doses than at the lower doses. Cocaine self-administration increased in 6- and 12-h sessions, but not in 1- and 3-h sessions. The increase in self-administration was faster and greater in 12-h sessions than 6-h sessions. The data suggest that cocaine self-administration increases at various doses with prolonged access and that an increase in the rate of responding is positively and inversely associated with session duration and unit dose, respectively. Results also imply that cocaine intake reaches a ceiling faster at high doses even under short session duration. Therefore, high doses or prolonged access to cocaine are more likely to result in a pattern of cocaine intake that reflects compulsive use.

Sex differences in the escalation of oral phencyclidine (PCP) self-administration under FR and PR schedules in rhesus monkeys

Studies with male rats indicate that long access (LgA) vs short access (ShA) to i.v. cocaine and heroin self-administration leads to an escalation of drug intake and a subsequent upward shift of the dose-response function. The purpose of this experiment was to extend these results to male and female rhesus monkeys and oral phencyclidine (PCP) self-administration under fixed-ratio (FR) and progressive-ratio (PR) schedules. Adult rhesus monkeys (seven females and nine males) orally self-administered PCP (0.25 mg/ml) and water under concurrent FR 16 FR 16 schedules during daily ShA 3-h sessions. Since females weighed less than males, each liquid delivery (0.6 ml) represented a higher unit dose mg/kg for females than males, but drug concentration mg/ml remained constant. Concurrent PR PR schedules were then used to obtain a concentration-response function (0.125, 0.25, 0.5, and 1.0 mg/ml). Next, PCP and water were available during LgA 6-h sessions under concurrent FR 16 FR 16 schedules for 21 days. The monkeys were then retested under the concurrent FR 16 FR 16 and PR PR conditions during ShA sessions. Under the initial ShA concurrent FR 16 FR 16 schedules, females and males did not differ on PCP deliveries or intake (mg/kg); however, during LgA, males and females had more PCP deliveries compared with ShA. During LgA, males exceeded females in PCP deliveries, but females were higher than males in mg/kg PCP intake. Also, PCP (but not water) deliveries and mg/kg PCP intake significantly increased from the first 3 days to the last 3 days of the 21-day LgA period in both males and females. The subsequent ShA FR 16 FR 16 performance did not differ by sex, but it was significantly elevated above the first ShA period in both sexes. The concentration-response function for PCP break point under the PR PR schedules and PCP intake (mg/kg) were significantly shifted upward during the second (vs first) ShA period, and females' mg/kg intake significantly exceeded males'. Male and female rhesus monkeys both showed escalation of PCP self-administration during LgA to PCP and during ShA that occurred after (vs before) LgA. Both showed vertical upward shifts in the concentration x intake (mg/kg) function under the PR schedule, and females exceeded males on this measure. These findings with PCP and monkeys are consistent with vertical upward shifts of cocaine dose-response functions in previous escalation studies in male rats and reports of sex differences (F>M) during several other phases of drug abuse.

Attenuation of relapse to cocaine seeking by dopamine D1 receptor agonists and antagonists in non-human primates

Dopamine D(1) receptor agonists and antagonists attenuate reinstatement of cocaine seeking in a non-human primate model of relapse. The mechanisms by which these different classes of D(1) receptor drugs produce these similar effects on cocaine seeking are unknown. This study investigated how D(1) receptor agonists and antagonists alter the shape and position of the dose-response function for reinstatement of drug seeking induced by a cocaine prime accompanied by restoration of the cocaine-paired stimulus. Squirrel monkeys were given extensive histories of cocaine self-administration under a second-order fixed-interval, fixed-ratio schedule of i.v. drug injection. Drug seeking was then extinguished by replacing cocaine with vehicle and eliminating the cocaine-paired stimulus. In subsequent test sessions, in which the cocaine-paired stimulus was re-introduced, priming injections of cocaine alone or combined with the different D(1) receptor high- and low-efficacy agonists and antagonists (SKF 82958, SKF 81297, SKF 83959, ecopipam; n=3-4 per drug condition) were tested for their ability to reinstate extinguished cocaine seeking. Cocaine priming accompanied by the restoration of the cocaine-paired stimulus induced a dose-dependent reinstatement of drug seeking. When combined with cocaine, all D(1) receptor agonists and antagonists produced rightward and downward shifts in the cocaine dose-response function. However, combined pretreatment of SKF81297 (agonist) and ecopipam (antagonist) inhibited cocaine seeking less than either drug individually. These findings suggest that D(1) receptor high- and low-efficacy agonists as well as antagonists attenuate reinstatement of cocaine seeking in part via pharmacologically opposing actions at a common population of D(1) receptors.

Temporal factors affecting cocaine-opioid interactions: a cocaine drug discrimination study in rats.

Increasing concomitant abuse of cocaine and morphine-like opioids has prompted a number of studies aimed at understanding how these drugs interact. The present study was designed to determine if variations in opioid pretreatment time would affect how mu opioid agonists interact with cocaine. Rats were trained to discriminate 10 mg/kg cocaine from saline. One group of subjects (n=6) received morphine (5.6 mg/kg) 0.5 h, 1 h or 4 h prior to cumulative doses of cocaine (0.1-17.8 mg/kg). These pretreatment times were selected to overlap with states of acute opioid tolerance (approximately 1 h) or acute opioid dependence (approximately 4 h) as demonstrated by previous studies. A second group (n=6) was administered naloxone (0.3 mg/kg) 5 min prior to cumulative cocaine doses, with or without a 4-h morphine (5.6 mg/kg) or methadone (3.0 mg/kg) pretreatment. In a third procedure, the same subjects used in the second experiment were also tested for time-dependent changes in the analgesic effect of morphine using a hot-plate assay. Morphine pretreatment 1 h prior to assessment of the cocaine dose-response function significantly enhanced the discriminative stimulus effects of cocaine. However, neither 0.5-h or 4-h morphine pretreatment had any effect. In contrast, when naloxone was administered 4 h following either morphine or methadone and 5 min prior to assessment of the cocaine dose-response curve, the discriminative stimulus effects of cocaine were significantly attenuated. In assessing morphine-induced analgesia, paw-lick latency was significantly longer at 1 h and shorter at 4 h following morphine administration. The results illustrate the importance of temporal parameters for interactions between cocaine and mu opioid agonists.

Neuroactive steroids attenuate cocaine-induced sucrose intake in rats, but not cocaine-induced hyperactivity in mice

Neuroactive steroids, including the potent anticonvulsants ganaxolone (3alpha-hydroxy-3beta-methyl-5alpha-pregnan-20-one) and Co 2-1068 (3beta-(4acetyl-phenyl)ethynyl-3alpha,21-dihydroxy-5beta+ ++-20-one-21-hemisuccinate), have recently been shown to protect against cocaine-induced seizures. The purpose of the present experiments was to determine whether ganaxolone and Co 2-1068 attenuate acute behavioral effects of cocaine unrelated to seizures. In the first experiment, the locomotor effects of Co 2-1068 (10-100 mg/ kg), pentobarbital (10-100 mg/kg) and haloperidol (0.03-0.3 mg/kg), alone or in combination with cocaine (5.6-30 mg/kg), were determined in mice. In the second experiment, the effects on sucrose intake of ganaxolone (4-16 mg/kg), Co 2-1068 (8-64 mg/kg), pentobarbital (4-32 mg/kg), and haloperidol (0.04-0.4 mg/kg), alone or in combination with cocaine (4-16 mg/kg), were determined in rats. Cocaine caused a dose-related increase in locomotor activity in mice, whereas Co 2-1068, pentobarbital and haloperidol caused dose-related decreases. The dopamine antagonist haloperidol, at a dose that had no effect on activity by itself, but not Co 2-1068 or pentobarbital, attenuated the cocaine-induced increase in locomotor activity. Cocaine, ganaxolone, Co 2-1068, and haloperidol produced dose-related decreases in sucrose intake in rats; the effects of pentobarbital on sucrose intake were variable. As with locomotor effects, haloperidol attenuated the cocaine-induced decrease in sucrose intake. In addition, cocaine-induced decreases in sucrose intake were attenuated by ganaxolone and Co 2-1068. Pentobarbital had no statistically significant effect on the cocaine dose-response function. These results suggest that the interaction of neuroactive steroids with cocaine extends to pharmacologic actions beyond anticonvulsant efficacy, but that the blockade of behavioral effects of cocaine by neuroactive steroids does not apply to all acute behaviors.

Effects of Ethanol Hangover on the Operant Self-Administration of Cocaine in Rats

To assess the interaction of experimentally induced ethanol hangover and cocaine self-administration, rats maintained to self-administer cocaine (0.5 mg/kg/inj) were given either saline or 2 or 4 g/kg ethanol (10% w/v, IP) 15 h prior to cocaine access (dose range tested 0.03–1.0 mg/kg/inj). Cocaine was shown to be dose-dependently self-administered in a significant inverted U-shaped function. EtOH hangover had a significant effect on the dose-dependent effects of cocaine, resulting in a general flattening of the inverted U-shaped function with increasing intensity of hangover. A significant dose-dependent reduction in the number of reinforcer deliveries occurred at the peak of the cocaine dose–response function (0.06 mg/kg/inj) following the 2 and 4 g/kg EtOH pretreatment doses when compared to saline pretreatment. These data suggest that hangover may alter the ability for moderate doses of cocaine to “prime” and maintain stable self-administration behavior.

Opioid enhancement of the discriminative stimulus effects of cocaine: evidence for involvement of mu and delta opioid receptors.

Previous research in squirrel monkeys has shown enhancement of the discriminative stimulus effects of cocaine by mu-opioid agonists, but not by the delta agonist BW373U86. To examine further the role of mu and delta receptor stimulation in the ability of opioid drugs to modulate the discriminative stimulus effects of cocaine, the present study assessed the effects of cocaine alone and combined with SNC 80, a selective high-efficacy delta agonist, and fentanyl, a selective high-efficacy mu agonist. Five adult male squirrel monkeys were trained to discriminate i.m. injections of 0.3 mg/kg cocaine from saline under a fixed-ratio 10 schedule of food presentation. Cumulative doses of cocaine (0.03-1.0 mg/kg) engendered dose-related increases in drug-lever responding to a maximum of 100%, with a decrease in response rate observed at 1.0 mg/kg. Cumulative doses of SNC 80 (0.03-1.0 mg/kg) or fentanyl (0.001-0.01 mg/kg) resulted in a maximum of 22% and 48% drug-lever responding, respectively, accompanied by pronounced decreases in response rate. Administration of either SNC 80 (0.1-1.0 mg/kg) or fentanyl (0.001-0.01 mg/kg) prior to cumulative doses of cocaine produced dose-dependent leftward shifts in the cocaine dose-response function. When the selective delta antagonist naltrindole (1.0 mg/kg) was combined with SNC 80 (1.0 mg/kg) or fentanyl (0.01 mg/kg) prior to cumulative doses of cocaine, the leftward shift of the cocaine dose-response function produced by SNC 80 was blocked, whereas the leftward shift produced by fentanyl was not. By contrast, the mu antagonist naltrexone (0.3 mg/kg) blocked the cocaine-enhancing effects of fentanyl, but not of SNC 80. Combinations of SNC 80 (0.03-0.3 mg/kg) with fentanyl (0.001-0.003 mg/kg) resulted in leftward shifts in the cocaine dose-response function that were comparable in magnitude to the shifts in the cocaine dose-response function produced by either drug alone. These results suggest that opioid enhancement of the discriminative stimulus effects of cocaine is mediated independently by delta- and mu-receptor mechanisms.

Transition from moderate to excessive drug intake: change in hedonic set point.

Differential access to cocaine self-administration produced two patterns of drug intake in rats. With 1 hour of access per session, drug intake remained low and stable. In contrast, with 6 hours of access, drug intake gradually escalated over days. After escalation, drug consumption was characterized by an increased early drug loading and an upward shift in the cocaine dose-response function, suggesting an increase in hedonic set point. After 1 month of abstinence, escalation of cocaine intake was reinstated to a higher level than before. These findings may provide an animal model for studying the development of excessive drug intake and the basis of addiction.

Effects of lesions of the nucleus basalis magnocellularis on the acquisition of cocaine self-administration in rats.

The nucleus basalis magnocellularis (NBM) is one element in the limbic cortical-ventral striatal circuitry that has been implicated in reinforcement processes. The present study examined the involvement of the cholinergic neurons of the NBM in mediating aspects of cocaine reinforcement. Lesions of the NBM were made by injecting 0.01 M AMPA into the subpallidal basal forebrain. Following 4 days' recovery, rats were implanted chronically with catheters in the jugular vein. In three separate experiments, rats were trained to acquire cocaine self-administration under a FR1 schedule of reinforcement at doses of 0.25, 0.083 and 0.028 mg/injection. A dose-effect function was also determined at the end of the acquisition experiments using five different doses of cocaine (0.009, 0.028, 0.083, 0.25, 0.50 mg/injection) and saline which were presented once daily in a Latin square design. There were no significant differences between groups in the acquisition of cocaine self-administration at any of the three doses studied (0.028, 0.083 and 0.25 mg/injection), although at the lowest dose, lesioned animals responded at greater levels on both active and inactive levers. However, a shift to the left in the cocaine dose-response function was observed revealing that the lesioned group self-administered significantly higher amounts of low doses of cocaine than control rats. These data suggest that the integrity of the NBM is not a critical determinant of the reinforcing effects of cocaine during the acquisition of self-administration of the drug, but that NBM-dependent cholinergic mechanisms may nevertheless interact with the neural substrates mediating the reinforcing properties of cocaine. The data are relevant to recent hypotheses of functional interactions between the dopaminergic system and the cholinergic NBM.

Self-administration of cocaine and heroin combinations by rhesus monkeys responding under a progressive-ratio schedule.

The present study examined the reinforcing effects of cocaine and heroin, alone and combined, in rhesus monkeys (n = 4) responding under a progressive-ratio (PR) schedule. The PR schedule consisted of five components, each made up of four trials (i.e., 20 trials total), with each trial in a component having the same response requirement. The initial response requirement was fixed-ratio (FR) 120, which doubled across components to a maximum of FR1920. A trial ended with an injection or the expiration of a 15-min limited hold and the inter-trial interval was 30 min. Cocaine dose-response functions (13-400 micrograms/kg per injection) for injections/ session were monophasic, i.e., increased with dose until responding reached an asymptote or a peak. Heroin dose-response functions (1.6-100 micrograms/kg per injection) for injections/session were biphasic functions. i.e., increased to a peak and then decreased, whereas heroin dose-response functions for response rate were monophasic and reached an asymptote. When cocaine (1.6-200 micrograms/kg per injection) was combined with heroin (0.4-6.4 micrograms/kg per injection), low doses of cocaine (3.2-25 micrograms/kg per injection) and heroin (0.4-1.6 micrograms/kg per injection) that did not maintain behavior when tested alone did so when tested in combination. Combination with heroin resulted in a leftward shift in the cocaine dose-response functions, indicating that heroin increased the potency of cocaine as a reinforcer. This heroin-induced increase in cocaine's reinforcing potency may be a contributing factor to abuse of cocaine and heroin combinations (i.e., "speedballs") in humans. However, maximum injections/session for cocaine combined with heroin were not different from cocaine alone, suggesting that the reinforcing efficacy of combinations of cocaine and heroin were not higher than that of cocaine alone.

Differential modulation of behavioral effects of cocaine by low- and high-efficacy D1 agonists.

Dopamine D1 agonists differing in efficacy with respect to stimulation of adenylate cyclase activity and other in vitro and in vivo criteria were evaluated for their capacity to modulate the behavioral effects of cocaine in squirrel monkeys. Monkeys were trained either to respond on a fixed-ratio schedule in which lever pressing terminated a stimulus associated with electric shock or to discriminate cocaine from vehicle using a two-lever drug-discrimination procedure. When administered in combination with cocaine, D1 agonists displaying relatively low efficacy (SKF 38393, SKF 75670) attenuated both the rate-altering effects of cocaine on fixed-ratio responding and the discriminative-stimulus effects of cocaine, resulting in overall rightward shifts of the cocaine dose-response functions. Maximal attenuation of the behavioral effects of cocaine by the D1 partial agonists was comparable to that produced by the D1 antagonist SCH 39166. In contrast, D1 agonists displaying relatively high efficacy (SKF 81297, SKF 82958, SKF 83189) either had little effect on or accentuated the rate-altering and discriminative-stimulus effects of cocaine. The results show that D1 partial agonists can act as functional cocaine antagonists and may be viable candidate medications for the management of cocaine addiction.

The application of differential outcomes to a cocaine???saline discrimination procedure

This study examined the effects of differential outcomes on the speed of acquisition of a cocaine vs saline discrimination. Two groups of male Sprague-Dawley rats were trained to discriminate 8.0 mg/kg cocaine from saline. The experimental group was exposed to differential outcomes, where correct responses following the different injections (discriminative stimuli) were correlated with a particular outcome (either sweetened condensed milk or tap water). The control group received either sweetened condensed milk or tap water at random following cocaine and saline injections. Acquisition of schedule control and three progressively difficult testing criteria were examined. The differential outcomes group came under schedule control and reached the three progressively difficult testing criteria in significantly fewer sessions than the control group. To determine whether differential outcomes during training influenced the generalization to other doses of cocaine, substitution tests were administered with several other doses of cocaine (0.0-10.0 mg/kg) to both groups. Similar cocaine dose-response functions were observed with the differential outcome group and the control group and there was not a statistically significant effect of differential outcomes on the cocaine generalization curve.

Excitotoxic lesions of the basolateral amygdala impair the acquisition of cocaine-seeking behaviour under a second-order schedule of reinforcement

In these experiments we sought to establish the intravenous (i.v.) self-administration of cocaine under a second-order schedule of reinforcement in order: (i) to obtain reliable, drug-free levels of responding with cocaine as a reinforcer, and (ii) to enable investigation of the neural mechanisms by which arbitrary cues gain motivational salience and, as conditioned reinforcers, control over drug-seeking behaviour. Initially, each infusion of cocaine was made contingent upon a response on one of two identical levers and was paired with a 20-s light conditioned stimulus (CS). Responses on the second lever were recorded, but had no programmed consequence. When rats acquired stable rates of self-administration, a second-order schedule of the type FRx(FRy:S) was introduced, with values of "x" being increased progressively to 10 and then "y" from 2 through 8. Priming (i.e. non-contingent) infusions of cocaine were never given. Once the first infusion was obtained under the second-order schedule, further infusions were made contingent on each response (to a maximum of ten infusions/day). Each stage was repeated daily until the first infusion of each session was achieved within a 5-min criterion. Rats with bilateral, excitotoxic lesions of the basolateral amygdala readily acquired the i.v. self-administration of cocaine under a continuous reinforcement schedule, initially administering more infusions and maintaining a slightly elevated level of self-administration than controls. Despite increased numbers of CS/drug pairings, basolateral amygdala-lesioned rats were severely impaired in the acquisition of the second-order schedule of i.v. cocaine reinforcement. Lesioned rats showed a cocaine dose-response function that was shifted upwards relative to control subjects. There was no significant difference between drug-naive amygdala-lesioned and control animals in the locomotor response to intraperitoneal injections of cocaine. These experiments indicate the feasibility and utility of second-order schedules in studying the neurobehavioural basis of cocaine-seeking behaviour. They suggest a dissociation in the neural mechanisms underlying cocaine-taking and cocaine seeking behaviour, and demonstrate the potential importance of the basolateral amygdala in the processes by which previously neutral stimuli gain control over drug-seeking behaviour.

Effects of exposure regimen on changes in sensitivity to the effects of cocaine on schedule-controlled behavior in rhesus monkeys

It has been reported that conditions of drug exposure can influence changes in sensitivity to cocaine upon repeated administration. In the present experiment, the behavioral effects of prolonged exposure to continuous or intermittent infusion of cocaine were compared in rhesus monkeys responding under a multiple component fixed-ratio (FR) schedule of food presentation. In order to quantify changes in sensitivity to cocaine, cumulative dose-response functions for acute cocaine were determined using a multiple schedule comprised of six 10-minute components separated by time-out periods of 3 minutes. Initially, cocaine decreased responding in a dose-related manner. Continuous infusion of cocaine (4 mg/kg per day) for a period of 4 weeks resulted in a 2- to 4-fold shift to the right in the cocaine dose-response function, i.e., tolerance developed. In contrast, when the same daily dose of cocaine was injected intermittently (1.0 mg/kg per injection) four times/day to different monkeys, there was no change in the effects of cocaine on responding. The present results support the notion that the dosing regimen is an important determinant of changes in sensitivity to the behavioral effects of cocaine. Additionally, since sensitization failed to develop upon intermittent administration of cocaine, behavioral baseline may play a role in changes in sensitivity to cocaine.