Cumulative Doses Of Cocaine Research Articles

Altered activity-based sleep measures in rhesus monkeys following cocaine self-administration and abstinence

BackgroundImpairments in sleep and cognitive function have been observed in patients with substance abuse disorders and may be potential factors contributing to drug relapse. In addition, sleep disruption may itself contribute to cognitive deficits. In the present study we examined the impact of prolonged cocaine self-administration and abstinence on actigraphy-based measures of night-time activity in rhesus macaques as an inferential measure of sleep, and determined whether sleep-efficiency correlated with cognitive impairments in the same subjects on drug free days. MethodsActigraphy data was obtained from a group of rhesus macaques intravenously self-administering cocaine (n=6) and a control group (n=5). Periods were evaluated during which the mean cumulative doses of cocaine were 3.0+0.0 and 4.5+0.2mg/kg/day for 4days (Tuesday–Thursday) each week. ResultsActigraphy-based sleep efficiency decreased during days of cocaine self-administration in a dose-dependent manner. Consistent with this observation, sleep became more fragmented. Activity-based sleep efficiency normalized during the weekend without cocaine prior to cognitive assessment on Monday. The magnitude of activity-based sleep disruption during self-administration did not correlate with the level of cognitive impairment on drug free days. With continued self-administration, the impact of cocaine on activity-based sleep efficiency declined indicating the development of tolerance. ConclusionsCocaine self-administration disrupted sleep efficiency in rhesus macaques as measured by actigraphy, but normalized quickly in the absence of cocaine. The cognitive impairment observed on drug free days was unlikely to be related to disruption of the nightly activity patterns on days of cocaine self-administration.

Access to high fat chow, but not sucrose or saccharin, enhances development of locomotor sensitization to cocaine in adolescent female rats (848.8)

Eating high fat chow enhances cocaine‐induced locomotion and sensitization in adolescent female rats; it is not known whether consumption of other preferred substances (e.g., sucrose or saccharin) also increases sensitivity to cocaine. It is also not known whether daily access to these feeding conditions is necessary to change sensitivity to cocaine, or if weekend access (i.e., 2/7 days per week) is sufficient. Adolescent female Sprague‐Dawley rats had free access to high (34.3%) fat or standard (5.7% fat) chow and free access to water, 10% sucrose solution, or 0.1% saccharin solution for 5 weeks. Rats that had weekend access to high fat chow, sucrose or saccharin had access to water and standard chow on other days. Cumulative doses of cocaine (1‐17.8 mg/kg) enhanced locomotion, and this effect increased in all groups after repeated tests. Although the rate of sensitization was comparable between groups, eating high fat chow daily (but not 2/7 days per week) significantly enhanced cocaine‐induced locomotion compared to controls. Neither daily nor weekend access to sucrose or saccharin enhanced cocaine‐induced sensitization. These results demonstrate that access to high fat chow, but not sucrose or saccharin, enhances development of locomotor sensitization to cocaine in adolescent female rats. As such, vulnerability to abuse cocaine might be increased in adolescent females that eat high fat food.Grant Funding Source: CPF supported by NIH Grant K05 DA017918 and KMS supported by NIH grant T32 DA031115

Effects of systemically administered cocaine on sensory responses to peri‐threshold vibrissae stimulation: individual cells, ensemble activity, and animal behaviour

Previous studies have shown that systemic administration of cocaine transiently alters stimulus-evoked responses of ventral posteromedial (VPM) thalamic neurons. Results from these single-unit electrophysiological studies revealed that cocaine was equally likely to augment or attenuate the magnitude of sensory evoked responses following threshold level stimulation of peripheral receptive fields. In an attempt to clarify the impact of cocaine administration on sensory signal processing, we examined the drug's effects on responses of individual neurons and ensembles of VPM thalamic neurons to sensory stimuli, and performance of subjects in a sensory detection behavioural task. Extracellular responses of single (n = 1 cell/rat) or multiple VPM thalamic neurons (n = 10-40 cells/rat) were monitored before and after cumulative doses of cocaine (0.25-2.0 mg/kg i.v.). Neuronal responses were characterized by assessing the response profile to a range of peri-threshold-level deflections of the optimal whisker on the contralateral face. Drug effects on stimulus-response curves, determined from quantitative analysis of spike train data, indicated that whereas cocaine elicits variable effects at the single cell level, the stimulus-evoked response of the recorded population was likely to increase following lower (0.25-1.0 mg/kg i.v.) doses of cocaine. Furthermore, cocaine preferentially enhanced responses to smaller magnitude deflections of vibrissa, altering the response profile from a mode that accurately conveyed stimulus strength to one that increased detection at the expense of discrimination. Finally, a similar pattern emerged in a behavioural paradigm involving rats trained to detect variable amplitude whisker pad stimulation, suggesting a common action of cocaine that may contribute to the drug's addictive properties.

Effects of ethanol on cocaine discrimination in rats

Ethanol and cocaine are frequently abused in combination, but little is known about how the subjective effects of the two drugs interact. The ability of ethanol and other GABA A-active compounds to alter the discriminative stimulus effects of cocaine was tested. Male Sprague–Dawley rats were trained to discriminate cocaine (10 mg/kg ip) from saline using either single- or cumulative-dosing methods. In single-dose testing, ethanol (0.1–0.5 g/kg) dose-dependently decreased cocaine-appropriate responding following the training dose of cocaine. Ethanol (0.5 g/kg) produced a rightward shift in the cocaine cumulative dose–effect curve. Ethanol (0.1–1.0 g/kg) failed to substitute for the discriminative stimulus effects of cocaine and the higher doses (1–2 g/kg) completely suppressed responding. Indirect GABA A agonists diazepam (benzodiazepine site) and pentobarbital (barbiturate site) did not block the discriminative stimulus effects of cumulative doses of cocaine. The GABA A antagonist pentylenetetrazol (PTZ) (10–40 mg/kg) did not substitute for cocaine. These findings suggest that ethanol can modulate the discriminative stimulus effects of cocaine, and that these effects may not be mediated by the actions of ethanol at the GABA A receptor.

Cocaine sensitization in the mouse using a cumulative dosing regime.

Many rodent models of cocaine sensitization use intermittent high doses of cocaine pretreatment followed by testing with a single moderate cocaine dose. The aim of the present study was to investigate the rate and extent of sensitization to the locomotor-stimulant effects of cocaine using multiple cocaine doses (5-40 mg/kg). Eight groups of male Swiss-Webster mice were pretreated with either single doses of cocaine (40 mg/kg) or saline in the home cage, or multiple doses in the test environment, for 4 days. On the fifth day they were tested for locomotor activity, following a single dose of saline and cumulative doses of cocaine (5-40 mg/kg at 10-minute intervals). All eight groups of mice developed context-dependent sensitization to the locomotor stimulant effects of cocaine. Subsequent testing, at 10-day intervals, revealed that sensitization was maximal after five test sessions of cumulative cocaine dosing, regardless of the pretreatment regime. The main determinant of the rate at which sensitization occurred was the frequency of cumulative cocaine dosing. However, both the potency and efficacy of cocaine were altered by different pretreatments associated with exposure to the locomotor activity chambers. This robust context-dependent sensitization was long lasting, and not abolished by a 5-day extinction procedure involving cumulative saline dosing in the locomotor activity chambers. In conclusion, cumulative dosing and its inherent handling, in combination with cocaine, induced marked sensitization not produced by cocaine alone.

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.

Cocaine-opioid interactions in groups of rats trained to discriminate different doses of cocaine.

The growing abuse of cocaine combined with morphine-like opiates ("speedballs") in human addicts has prompted efforts to characterize the roles of different opioid receptor subtypes in mediating their combined effects. Previous drug discrimination studies in rats have been inconsistent in showing significant interactions between cocaine and opioid agonists in subjects trained to discriminate a relatively high dose of cocaine from vehicle. It is known, however, that the training dose of cocaine can play a key role in drug-substitution and drug-interaction profiles and, therefore, training rats to discriminate a relatively low dose of cocaine may influence its interactions with opioid agonists. The objectives of this study were to examine the degree to which a relatively high (10 mg/kg) versus a relatively low (3.0 mg/kg) cocaine training dose influenced the interactions between cocaine and either the mu opioid agonist morphine or the kappa opioid agonist U50,488. Substitution tests with cumulative doses of cocaine, morphine and U50,488 were conducted, as were studies in which selected doses of morphine or U50,488 were administered prior to cumulative doses of cocaine. In substitution tests, cocaine was 2.9 times more potent under the low- than the high-dose training condition. Morphine substituted fully for cocaine in the majority of subjects trained to discriminate the low, but not the high, dose of cocaine. U50,488 engendered mainly saline-lever responses under both training conditions. In pretreatment studies, morphine enhanced and U50,488 attenuated the discriminative stimulus effects of cocaine in low-dose, but not high-dose, trained rats. In low-dose trained rats, cocaine was five- to eightfold more potent after morphine and three- to fourfold less potent after U50,488 pretreatments. The results demonstrate that cocaine-opioid interactions are dependent on the training dose of cocaine in rats and suggest an opposing influence of mu and kappa opioid receptors in modifying the discriminative stimulus effects of cocaine.

The interaction of cocaethylene and cocaine and of cocaethylene and alcohol on schedule-controlled responding in rats.

Cocaethylene is a unique metabolite of cocaine, produced only in the presence of alcohol. This metabolite is pharmacologically, physiologically and behaviorally active. Further, it has been reported to interact pharmacokinetically with both cocaine and alcohol, an interaction that may mediate, in part, the interaction of cocaine and alcohol. Although cocaethylene has been shown to interact with both cocaine and alcohol, behavioral assessments of these interactions are limited. To examine directly the behavioral interactions between cocaethylene and cocaine and between cocaethylene and alcohol, the present study assessed the effects produced by these combinations on schedule-controlled responding. Rats were first administered cumulative doses of cocaethylene, cocaine and alcohol to assess their effects alone on responding. Following this, doses of cocaethylene were combined with cumulative doses of cocaine or alcohol. Additionally, doses of cocaine or alcohol were given in combination with cumulative doses of cocaethylene. When administered alone, cocaethylene, cocaine and alcohol produced dose-related decreases in responding. Further, cocaethylene shifted the dose-response functions for both cocaine and alcohol to the left and down, while cocaine and alcohol shifted the dose-response function for cocaethylene to the left and down. An isobolographic analysis revealed that these interactions were additive in nature. The present study suggests behavioral interactions between cocaethylene and cocaine and between cocaethylene and alcohol. The contribution of cocaethylene to the enhanced effects produced by the co-administration of cocaine and alcohol was discussed.

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.

The interaction of cocaine and alcohol on schedule-controlled responding.

Within a number of physiological preparations, the effects of alcohol and cocaine in combination are reported to be greater than the effects of either drug given alone. Little has been reported, however, on the behavioral effects of the interaction. The present study investigated this issue by assessing the effects of cocaine and alcohol (alone and in combination) on schedule-controlled responding. Specifically, rats were trained to respond on an FR20 schedule for a water reinforcer. They were then administered cumulative doses of cocaine or alcohol. Following this, subjects were administered ineffective doses of alcohol prior to further dose-response assessments with cocaine and with ineffective doses of cocaine prior to further dose-response assessments with alcohol. Cocaine and alcohol alone produced dose-related decreases in responding. Furthermore, the dose-response function for cocaine was shifted to the left by alcohol and the dose-response function for alcohol was shifted to the left by cocaine. An isobolographic analysis revealed that the interaction between cocaine and alcohol was additive in nature. The possible bases for the interaction (e.g., changes in cocaine pharmacokinetics by alcohol and the formation of cocaethylene following co-administration of cocaine and alcohol) were discussed.

Relationship between the discriminative stimulus effects and plasma concentrations of intramuscular cocaine in rhesus monkeys

The relationship between the discriminative stimulus effects and plasma pharmacokinetics of cocaine was evaluated in six rhesus monkeys trained to discriminate cocaine (0.4 mg/kg, IM) from saline under a FR30 schedule of food presentation. The same monkeys were tested in two procedures. In a cumulative dosing procedure, five cumulative doses of cocaine (0.013-1.3 mg/kg) were administered and discriminative stimulus effects were evaluated 10 min after the administration of each dose. Cocaine plasma concentrations were measured in separate sessions using the same doses and interdose intervals. In a single dosing procedure, the time-courses of the discriminative stimulus effects and plasma concentrations of cocaine were assessed after the administration of cocaine (0.4 mg/kg). A close correspondence between cocaine's discriminative stimulus effects and plasma concentrations was obtained in both procedures. Cocaine was virtually undetectable in plasma at doses that produced saline-appropriate responding (0.013 and 0.04 mg/kg), whereas increasing plasma concentrations were measured at doses that produced primarily cocaine-appropriate responding (0.13 mg/kg or higher). The time-course of the discriminative stimulus effects of cocaine was characterized by a rapid onset (within 1-3 min post-cocaine) and offset (within 20-60 min post-cocaine). Peak plasma levels were obtained at 10 min post-cocaine. No differences in plasma concentrations were found 10 min after the administration of a cumulative versus a single dose of cocaine 0.4 mg/kg (mean, 75.8 and 74.0 ng/ml, respectively). Cocaine plasma concentrations lasted longer than its discriminative stimulus effects. The results of the present study confirm that the cumulative dosing procedure used yields plasma concentrations of cocaine that are similar to the concentrations obtained after single cocaine dosing.

Spinal antinociception mediated by a cocaine-sensitive dopaminergic supraspinal mechanism

The role of dopaminergic descending supraspinal processes in mediating the antinociceptive action of cocaine was studied in the rat using a combination of extracellular neuronal recording and behavioral techniques. Neurons in the superficial laminae (I-II) of the spinal dorsal horn with receptive fields on the tail were recorded in anesthetized rats using insulated metal microelectrodes. Stimulation of the receptive field with either high intensity transcutaneous electrical pulses or with an infrared CO 2 laser beam produced a biphasic increase in dorsal horn unit discharge. Conduction velocity estimates indicated that the early discharge corresponded to activity in Aδ whereas the late response corresponded to activity in C afferent fibers. Cumulative doses of cocaine (0.1–3.1 mg/kg i.v.) inhibited the late response to either electrical or laser stimulation in a dose-related manner. The early response to laser, but not electrical, stimulation was also suppressed by cocaine. Neurons in the spinal dorsal horn with receptive fields on the ipsilateral hindpaw were activated by natural noxious (pinch) or innocuous (tap) somatic stimulation. Cocaine selectively suppressed nociceptively evoked dorsal horn unit discharge. This antinociceptive effect was dose-related (0.3–3.1 mg/kg, i.v.) and antagonized by eticlopride (0.05–0.1 mg/kg, i.v.), a selective D2 dopamine receptor blocker. The same doses of cocaine failed to inhibit the responses of dorsal horn neurons to low threshold innocuous stimulation. Complete thoracic spinal cord transection eliminated the antinociceptive effect of cocaine on dorsal horn neurons and also eliminated the cocaine-induced attenuation of the tail-flick reflex. These data demonstrte that cocaine selectively inhibits nociceptive spinal reflexes and the nociceptive responses of dorsal horn neurons primarily by means of a D2 dopaminergic receptor mechanism. This antinociceptive effect of cocaine is independent of its local anesthetic activity and requires the integrity of the thoracic spinal cord, suggesting that the drug potentiates or activates supraspinal dopaminergic projections to the dorsal horn.

δ-Opioid receptor antagonists attenuate motor activity induced by amphetamine but not cocaine

Naloxone and naltrindole attenuate the locomotor response to amphetamine, implicating δ-opioid receptors in the opioid-antagonist/amphetamine interaction. To determine the role of δ-opioid receptor subtypes in this phenomenon, rats were pretreated with the following selective antagonists administered intracisternally: naltrindole, [D-Ala 2, Leu 5, Cys 6]enkephalin (DALCE, δ 1 receptor selective), naltrindole-5′-isothiocyanate ( δ 2 receptor selective). Cumulative dose-response curves to amphetamine were constructed (saline, 0.1, 0.4, 1.6 and 6.4 mg/kg s.c.), with injections every 30 min. Naltrindole was also tested against cumulative doses of cocaine (saline, 3.0, 10, 30 and 56 mg/kg i.p.). Gross and fine motor activity were recorded for 20 min, commencing 10 min postinjection. Amphetamine and cocaine dose dependently increased both gross and fine movements. Naltrindole (10 μg) attenuated the gross but not fine activity response to amphetamine, but 10 or 30 μg failed to influence the response to cocaine. Naltrindole-5′-isothiocyanate (30 μg) attenuated slighty but significantly the gross activity response to amphetamine, whereas DALCE (30 μg) was without effect. However, a combination of 10 μg each of DALCE and naltrindole-5′-isothiocyanate markedly attenuated the amphetamine-induced increases in gross movements without altering fine activity. These data provide further evidence for the involvement of δ-opioid receptors in the modulation of behavioral effects of amphetamine; both δ 1- and δ 2-opioid receptors appear to play a role. The differential effects of opioid antagonists on locomotor activity stimulated by amphetamine and cocaine suggests differences in the mechanism of action of these drugs not previously appreciated.

Modulation of the discriminative-stimulus effects of cocaine by buprenorphine

Modulation of the discriminative-stimulus effects of cocaine by the mixed-action opioid buprenorsphine was studied in squirrel monkeys trained to discriminate cocaine from saline, using a two-lever drug discrimination procedure. Lever pressing was maintained under a fixed-ratio 10 schedule of food presentation. During test sessions, monkeys received cumulative doses of cocaine after presession treatment with either saline or buprenorphine (0.001-0.01mg/kg). After pretreatment with saline, cocaine engendered dose-related increases in the percentage of cocaine-appropriate responses, reaching a maximum of 99-100 percent at doses of 0.3 or 1.0mg/kg. Pretreatment with buprenorphine shifted the cocaine dose-response function to the left, resulting in 98-100 percent cocaine-appropriate responding at doses of cocaine that previously engendered only saline-appropriate responding. When tested alone, buprenorphine did not occasion cocaine-appropriate responding at any dose. The results show that although buprenorphine does not itself have cocaine-like discriminative-stimulus effects, it can potentiate the discriminative-stimulus effects of cocaine.

Antagonism of behavioral effects of cocaine by selective dopamine receptor blockers

The cocaine-antagonist effects of SCH 39166, which selectively blocks D1 dopamine receptors, were compared with those of YM 09151-2, a selective D2 receptor blocker, and flupenthixol, a nonselective blocker of both dopamine receptor subtypes. Squirrel monkeys were studied under a fixed-interval schedule of stimulus-shock termination, and the effects of cumulative doses of cocaine were determined alone and after pretreatment with each dopamine receptor blocker. When administered alone, cocaine (0.01-1.78 mg/kg, IV) had biphasic effects on responding: intermediate doses increased response rate, whereas higher doses decreased response rate. The ED50 for cocaine (average does that produced a half-maximal increase in response rate) was 0.04 mg/kg. Pretreatment with SCH 39166 (0.03 and 0.1 mg/kg, IV) resulted in surmountable antagonism of both the rate-increasing and rate-decreasing effects of cocaine, the ED50 being increased by as much as 13-fold. Similar effects were observed after pretreatment with YM 09151-2 (0.001 and 0.003 mg/kg, IV) and flupenthixol (0.01 and 0.03 mg/kg, IV), which respectively produced up to a 13-fold and 32-fold increase in ED50. There also was evidence for reciprocal antagonism of the rate-decreasing effects of the three dopamine receptor blockers by cocaine. The results suggest a prominent role for D1 as well as D2 dopamine receptors in mediating the effects of cocaine on schedule-controlled behavior.