Various Doses Of Cocaine Research Articles

Effect of 6-hydroxydopamine lesions of the medial prefrontal cortex on intravenous cocaine self-administration under a progressive ratio schedule of reinforcement

Rats were trained to self-administer intravenous cocaine under a progressive ratio (PR) schedule of reinforcement. Under this schedule, an increasing number of lever responses had to be made to obtain each subsequent reinforcement (1.5 mg/kg per injection). Once stable responding was achieved with this schedule, bilateral 6-hydroxydopamine (6-OHDA) or vehicle-only injections were delivered into the medial prefrontal cortex (mPFC). Following recovery from surgery, the animals were given access to cocaine under the PR schedule. The effect of the lesion on self-administration behaviour was examined at various doses of cocaine (0.09–1.5 mg/kg per injection). 6-OHDA lesions of the mPFC had no effect on self-administration behaviour at the higher unit doses of cocaine. However, at the lower doses (0.09 and 0.19 mg/kg per injection), the lesion caused a significant increase in break point (BP), the number of responses made to obtain the last reinforcement of a self-administration session. The neurochemical results showed a significant reduction (57%) in mPFC levels of dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) (53%), with no changes in noradrenaline or serotonin levels. In contrast, the lesion caused no changes in DA or DOPAC levels in the nucleus accumbens (NACC) or striatum. These results indicate that the DAergic innervation of the mPFC cortex has a role in cocaine self-administration behaviour; however, whether this role is contingent on NACC DA function remains to be elucidated.

Cocaine-induced somatic growth deficit during the brain growth spurt is prevented by artificial-rearing

The brain growth spurt is a dynamic period of central nervous system development that has been shown to be particularly vulnerable to a variety of insults. This study was designed to assess the effects of various doses of cocaine during this potentially vulnerable period on survival rate, somatic growth, and brain development, utilizing an artificial-rearing paradigm. Three cocaine-treated groups received SC administration of either 40, 60, or 80 mg/kg/day of cocaine HCl from postnatal days 4 through 9. There were significant differences in survival rates among 60 and 80 mg/kg/day cocaine-treated animals as compared with gastrostomy controls. No statistically significant differences were found with regard to body and brain weights between the various cocaine-treated groups and the gastrostomy control group. Additionally, there was no evidence of cocaine's effect on forebrain, cerebellum, or brainstem weights when compared with individually corresponding controls. Taken together with our previous results, these data suggest that cocaine administration during the brain growth spurt period produces a dose-related increase in lethality, and the use of artificial-rearing method seems to lower the lethal threshold of cocaine among these neonates. However, no statistically significant effects of cocaine exposure on brain weight measures were obtained. The most important finding was that the cocaine-induced somatic growth retardation observed previously under normal-rearing conditions was eliminated by using a nutritionally controlled artificial-rearing paradigm, suggesting that cocaine-induced restriction of somatic growth may be a function of interference with normal feeding behavior, and therefore, a secondary effect of cocaine exposure during development.

Effects of cocaine on cardiac vagal tone before and during coronary artery occlusion: cocaine exacerbates the autonomic response to myocardial ischemia.

Cocaine is a potent sympathomimetic drug that can provoke lethal cardiac events. Cocaine-induced alterations in autonomic balance, particularly during myocardial ischemia, could contribute significantly to these adverse reactions. To test this hypothesis, we produced a 2-min left circumflex coronary artery (LCX) occlusion in unanesthetized mongrel dogs (n = 7) instrumented to measure left ventricular pressure (LVP), ventricular electrogram, and coronary blood flow (CBF) with and without various doses of cocaine (0.0, 0.5, 1, 2, and 4 mg/kg). At least 24 h elapsed between cocaine doses, which were given in random order. Time series analysis of heart rate (HR) variability was used as an index of cardiac vagal tone (0.24-1.04 Hz). Cocaine elicited dose-dependent increases in HR that were accompanied by corresponding decreases in cardiac vagal tone. The peak response was achieved approximately 1 min after cocaine was given and returned to precocaine values 15 (0.5 and 1 mg/kg), 30 (2 mg/kg), or 60 (4 mg/kg) min later. Myocardial ischemia elicited significant increases in HR and reductions in cardiac vagal tone that were accentuated by cocaine (1, 2, and 4 mg/kg); e.g., cocaine (2 mg/kg) elicited a greater HR (control 119.3 +/- 5.9, occlusion 149.7 +/- 9.6; cocaine 144 +/- 11.9, occlusion 178.3 +/- 10.4 beats/min) and vagal tone (control 5.6 +/- 0.7, occlusion 2.6 +/- 0.3; cocaine 5.2 +/- 0.7, occlusion 1.3 +/- 0.5 ln s2) response to 2-min coronary occlusion. beta-Adrenoceptor blockade (propranolol HCl 1 mg/kg) attenuated the HR response but elicited greater reduction (lower values were achieved) in vagal tone during coronary artery occlusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Cocaine alters behavior in the rat fetus.

Changes in motor behavior and sensory responsiveness were characterized in rat fetuses on gestational Day 21 after acute administration of various doses of cocaine. An increase in fetal motor activity was evident in the 3 highest doses (5, 10, and 20 mg/kg). Cocaine-exposed Ss showed reduced facial wiping in behavioral bioassays of cutaneous sensitivity (10 and 20 mg/kg) and chemosensory responsiveness (20 mg/kg). Changes in other behavioral measures indicated that fetuses detected and responded to these stimuli, suggesting that reduced facial wiping was due to a disruption of sensorimotor integration or motor coordination. Study of the fetus in vivo can provide insights into the mechanisms of cocaine's deleterious effects on central nervous system and behavioral development.

Failure of ondansetron to block the discriminative or reinforcing stimulus effects of cocaine in the rat

Ondansetron (GR38032F), a serotonin 5HT 3 antagonist, is active in numerous behavioral paradigms and neurochemical systems. Since 5HT 3 antagonists have been suggested as therapeutic agents for the treatment of drug abuse, the action of ondansetron on cocaine drug discrimination and self-administration paradigms in rats was investigated. Doses of ondansetron (0.001–1.0 mg/kg) had no effect on the discriminative stimulus properties of 10 mg/kg cocaine. In contrast, SCH23390, a dopamine D 1 antagonist known to block cocaine discrimination, acted as previously reported. Ondansetron did not augment the effects of SCH23390, but at higher doses, combinations of ondansetron and SCH23390 produced disruption of lever pressing in the presence of cocaine. Ondansetron (0.001–1.0 mg/kg) had no effect on the self-administration of various doses of cocaine, nor did it have any effect on reacquisition of cocaine self-administration in animals with a history of active administration followed by a period of abstinence. As before, SCH23390, known to block cocaine self-administration, acted as previously reported. Although other 5HT antagonists may prove to be efficacious in cocaine abuse, ondansetron appears unlikely to alter the subjective or rewarding stimulus properties of cocaine.

Effects of the putative dopamine autoreceptor antagonists (+)-AJ 76 and (+)-UH 232 on the discriminative stimulus properties of cocaine.

Recent evidence suggests that the putative dopamine (DA) autoreceptor antagonists, (+)-AJ 76 and (+)-UH 232, share some neurochemical and behavioral effects with both psychostimulants and neuroleptics. The ability of (+)-AJ 76 and (+)-UH 232 to mimic or antagonize the stimulus effects of cocaine was investigated in rats trained to discriminate 5 mg/kg (N = 8) or 10 mg/kg (N = 8) of cocaine from saline in a two-lever, water-reinforced, drug discrimination task. In the cocaine (10 mg/kg) group, administration of (+)-AJ 76 (2.5-20 mg/kg) engendered only a partial substitution for cocaine (maximum 60% cocaine-lever responses). Given in combination with cocaine (10 mg/kg), (+)-AJ 76 (2.5-40 mg/kg) did not significantly attenuate the cocaine cue. A fixed dose of (+)-AJ 76 (2.5 or 10 mg/kg) plus various doses of cocaine (1.25-5 mg/kg) did not alter the cocaine dose-response curve. (+)-UH 232 (2-16 mg/kg) produced primarily saline-appropriate responding in rats trained to discriminate 5 mg/kg of cocaine and was unable to block the interoceptive cocaine state when given in combination with cocaine (5 mg/kg). (+)-UH 232 (2 or 8 mg/kg) also did not alter the cocaine dose-response curve. These results suggest that (+)-AJ 76 and (+)-UH 232 elicit only weak or no cocaine-like stimulus effects and, unlike neuroleptics, do not attenuate the cocaine cue.

Serotonin 5-HT3 antagonists do not alter the discriminative stimulus properties of cocaine

The central nervous system (CNS) of the rat is known to contain serotonin (5-HT) type -3 receptors (5-HT3). Behavioral evidence suggests that 5-HT3 receptors interact with mesolimbic dopamine (DA) systems and that 5-HT3 antagonists can interfere with the hyperlocomotive effects of amphetamine and cocaine and the rewarding and stimulus effects of morphine, nicotine and ethanol. Cocaine, which blocks the reuptake of DA, norepinephrine (NE), and 5-HT in the CNS, also may be an antagonist at 5-HT3 receptors. The purpose of the present study was to determine whether systemic administration of the 5-HT3 antagonists ICS 205930 or MDL 72222 could mimic or block the discriminative stimulus properties of cocaine. Once rats (N = 16) were trained to discriminate cocaine (10 mg/kg) from saline, substitution tests with various doses of cocaine (0.313-10 mg/kg), ICS 205930 (2-24 mg/kg), and MDL 72222 (2-16 mg/kg) were conducted. Cocaine produced a dose-related increase in cocaine-appropriate responding while the 5-HT3 antagonists engendered primarily saline-lever responding. Neither ICS 205930 nor MDL 72222 were able to antagonize the stimulus effects of cocaine (5 mg/kg). Response rates were not significantly reduced when the 5-HT3 antagonists were given in combination with cocaine. The results indicate that although 5-HT3 antagonists can inhibit some of the unconditioned behavioral effects of psychomotor stimulants, the discriminative stimulus effects of cocaine remain intact.

Blockade of the discriminative stimulus effects of cocaine in rhesus monkeys with the D1 dopamine antagonists SCH-39166 and A-66359

Rhesus monkeys were trained in a 2-lever, food-reinforced drug discrimination paradigm to discriminate cocaine (0.2 or 0.4mg/kg, i.m., 10min pre-session) from saline. Before test sessions, in which responding on either lever was reinforced, the monkeys were injected with various doses of cocaine alone or in combination with the D(1) dopamine antagonists SCH-39166 or A-66359. Administration of cocaine alone (0.025-0.4mg/kg, i.m.) resulted in a dose-related increase in the percent of responses that occurred on the drug-appropriate lever. Both SCH-39166 (0.05-0.1mg/kg, i.m., 60min pre-session) and A-66359 (0.2-0.4mg/kg, i.m., 30min pre-session) reduced cocaine-appropriate responding from more than 80% to less than 20% at least at one dose combination in all monkeys. Also for both drugs and in all monkeys, the blockade was overcome by increasing the dose of cocaine. SCH-39166 was more potent and longer acting than A-66359. The results provide further evidence that D(1) dopamine receptors are involved in the discriminative stimulus effects of cocaine and that D(1) antagonists may block the subjective effects of cocaine.

The effects of cocaine on multivariate locomotor behavior and defecation

The present study utilized a multifactorial open-field analysis (Digiscan activity) to assess behavioral changes induced by various doses of cocaine known to stimulate locomotion. The measures that were implemented included ambulation, rearing, stereotypic behavior, rotational movements and changes in defecation levels. Thirty-two male Sprague-Dawley rats were habituated to Digiscan-16 Animal Activity Monitors (Omnitech Electronics, Columbus, OH) before being injected with 0.0, 10, 20 or 30 mg/kg cocaine. Rats were kept on a reversed light/dark schedule and tested in the middle of the dark cycle. It was found that cocaine consistently increased activity measures; most prominently affecting the rotational and ambulatory indices. Interestingly, this ‘activity print’ appeared to be dose-dependent and specific to cocaine. Open-field defecation levels were compared to home-cage levels as an additional behavioral correlate. Defecation decreased under all doses of cocaine as compared to control levels (saline injection). This result is attributed to cocaine's weakly sympathomimetic effect.

Effect of various doses of cocaine on endurance capacity in rats.

To determine the effects of a variety of doses of cocaine on endurance capacity, rats were injected intraperitoneally with either 0.1, 0.5, 2.5, 12.5, or 20 mg/kg body wt 20 min before running to exhaustion at 26 m/min up a 10% grade. Animals given saline ran 116 +/- 9 (SE) min. At doses of 12.5 and 20 mg/kg, cocaine reduced endurance time significantly (34 and 74%, respectively). At rest the drug had no effect on liver or fast-twitch muscle glycogen but significantly reduced (20-40%) soleus glycogen at the two highest doses. However, at exhaustion, the quantity of glycogen depleted in the fast-twitch red and white vastus muscles was similar in all groups despite the reduced run times of the animals receiving a higher dose implying a greater rate of glycogenolysis due to cocaine. Blood lactate in the 20 mg/kg group (9.9 +/- 1.2 mM) at exhaustion was nearly twice that of the saline controls at exhaustion (5.1 +/- 0.6). Before exercise plasma norepinephrine (at doses of 2.5, 12.5 and 20 mg/kg) was higher than saline controls and remained higher (20 mg/kg groups) at exhaustion. We conclude that high doses of cocaine cause rapid muscle glycogen depletion and early fatigue. The mechanism by which cocaine causes these effects is not clear.

Blockade of the discriminative stimulus effects of cocaine in rhesus monkeys with the D1 dopamine antagonist SCH 23390.

To investigate the role of D1 dopamine receptors in the discriminative stimulus effects of cocaine, two rhesus monkeys were trained in a two-lever, food-reinforced, drug discrimination paradigm to discriminate cocaine (0.2 mg/kg, IM) from saline. Administration of various doses of cocaine resulted in a dose-related increase in the percentage of responses that occurred on the drug-appropriate lever. Administration of the D1 antagonist SCH 23390 20 min before cocaine reduced drug-appropriate responding from 100% to 0% in all subjects and increased by 4-8-fold the cocaine dose necessary to induce drug-appropriate responding. A mutual antagonism of the rate-decreasing effects of cocaine and SCH 23390 was also observed. These findings suggest that D1 receptors play a significant role in the discriminative stimulus and rate-decreasing effects of cocaine.

Effect of repeated administration of various doses of cocaine and WIN 35,065-2 on locomotor behavior of mice

Cocaine and a cocaine analog, WIN 36,065-2, were administered daily for 3 or 4 days. Both compounds developed sensitization to their locomotor stimulatory effects, with similarly shaped dose-response curves. Dosages giving optimal sensitization were 25 mg/kg per day for cocaine and 3 mg/kg for WIN 35,065-2. At 40 mg/kg, cocaine produced less stimulation of locomotion on day 3 than on day 1. With doses of 6 and 10 mg/kg of WIN 35,065-2, tolerance to locomotor stimulation was observed. Monitoring by an observer revelead that after 40 mg/kg of cocaine the animals spent about the same amount of time expressing non-ambulatory behavior such as biting, sniffing, rearing, or resting on day 3 as on day 1. Therefore, in the 3 day period there was no increase in non-ambulatory behavior that could have produced the decrease in locomotor stimulation measured with the activity monitor. We assessed the possible involvement of the local anesthetic action of cocaine-like compounds in inhibiting locomotion by measuring the hypomotive effect over a 3 day period by repeated administration of the local anesthetic drugs tetracaine, lidocaine, norcocaine and benzoylpseudotropine. These compounds had the same hypomotive effects on day 1 and 3, suggesting that the decrements in locomotor stimulation observed with daily high doses of cocaine and WIN 35,065-2 involve mechanisms other than their local anesthetic action. The present results indicate that the size of the dose of a psychostimulant is a crucial variable in dosage schedules for studying the sensitization to its effect on locomotor behavior.