Effects Of Acute Cocaine Administration Research Articles

Ontogeny of behavioral sensitization to cocaine

The ontogeny of the behavioral effects of acute cocaine administration and behavioral sensitization to cocaine in rat pups was investigated. Acute behavior stimulating effects of cocaine were observed in pups as young as 7 postnatal days (PND) old, although they needed a higher dose of cocaine than adult rats to evoke the same motor effects. An adult dose-response curve pattern of stereotypy and locomotion to acute cocaine treatment was observed at PND 21, and of rearing at PND 28. Rats aged PND 7, 14, 21, 28, and 56 received repeated injections of saline or cocaine (15 mg/kg) twice a day for 5 consecutive days. After a 3-week period of abstinence, sensitization to a challenge dose of cocaine was assessed. Cocaine-induced stereotyped behavior was enhanced significantly only in rats in which cocaine pretreatment was initiated on PND 21, 28, and 56, but not earlier on PND 7 and 14. Adult female rats given repeated cocaine injections on PND 56–60 showed significantly greater sensitization than males, but no such sex difference was observed in pups given cocaine repeatedly on PND 21–25 or 28–32. These results show clearly that cocaine-induced behavioral sensitization in rats occurred only when subchronic cocaine administration was commenced on PND 21 or later.

Behavioral effects of acute and chronic cocaine administration in male and female rats: effects of fixed-ratio schedule parameters.

Intact and gonadectomized male and female rats pressed a lever to obtain food on different fixed-ratio (FR) schedules in a three-component multiple schedule. The values of a small, intermediate and large FR schedule were individually determined and were higher for intact male rats than for most subjects in the other groups. Acute cocaine administration (1.0-30.0mg/kg) dose-dependently decreased response rates maintained by all three schedules, but responding maintained by the large FR schedule was more sensitive to the rate-decreasing effects of acute cocaine administration. Response rates of intact male rats were less sensitive to the rate-decreasing effects of cocaine than those of the other groups, at least at higher doses during the small and intermediate FR schedules. Cocaine's dose-effect curve was redetermined after chronic administration of a behaviorally active dose of cocaine. Differences between groups of subjects were not evident. Behavioral tolerance was consistently observed when responding was maintained by the small FR schedule. Effects varied between subjects within groups when responding was maintained by the intermediate FR schedule, but behavioral tolerance was frequently observed. Behavioral sensitization was evident during the large FR schedule, but these data were difficult to interpret because of a considerable shift in response rates after vehicle administration. The data suggest that the comparison of drug effects in male and female rats requires a systematic analysis of the contribution of behavioral parameters. They also provide additional evidence for the notion that reference to reinforcement-loss alone is not sufficient to explain the development of tolerance to the behavioral effects of cocaine.

The effects of acute cocaine administration on the DOI-induced head-twitch response in reserpinized mice

Previously it was shown that acute cocaine administration dose dependently reduces the 5-HT 2-receptor-mediated DOI [(±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane]-induced head-twitch response (HTR) in mice via indirect stimulation of the inhibitory adrenergic α 2- and serotonergic 5-HT 1A receptors. In addition, the inhibitory capacity of cocaine was enhanced fourfold in mice with 5-HT 2-receptor supersensitivity induced by a single injection of DOI 48 h prior to experimentation. The aim of the present investigation was to determine the inhibitory capacity of cocaine in reserpinized mice. A single injection of reserpine 48 h prior to DOI administration caused supersensitivity in the DOI-induced HTR. Two reserpine injections did not further enhance this supersensitivity effect. Once reserpinized 5-HT 2-receptor supersensitive animals were less responsive to the inhibitory effects of cocaine on the DOI-induced behavior than were the mice, as reported previously, that were made supersensitive by DOI pretreatment. The inhibitory capacity of cocaine was further attenuated when mice were reserpinized twice prior to determination of its effects on the DOI-induced behavior. Taken together with previously published data, the present investigation lends further support for the importance of endogenous levels of 5-HT and norepinephrine on the ability of cocaine to attenuate the DOI-induced HTR.

Characterization of dopamine transporter and locomotor effects of cocaine, GBR 12909, epidepride, and SCH 23390 in C57BL and DBA mice

C57BL/6 and DBA/2 mice were used to examine genetic differences in locomotor activating effects of acute cocaine administration and to determine whether differences were mediated by dopaminergic systems. C57BL/6 mice were less activated than DBA/2 mice at 5 and 10 min after 10 and 15 mg/kg cocaine. HPLC analysis showed equivalent brain cocaine concentrations in the two strains at 5 and 10 min after 10, 15, or 20 mg/kg doses. The selective dopamine uptake inhibitor, GBR 12909, at 5 and 7.5 mg/kg, produced greater locomotor activation in DBA/2 mice than in C57BL/6 mice. However, binding studies with the selective dopamine uptake ligand [ 3H]GBR 12935, revealed no between-strain difference in K d or B max in caudate putamen (CP) or nucleus accumbens (NA) membranes. Competition assays using unlabeled dopamine to compete for [ 3H]GBR 12935 binding in CP or NA membranes showed no between-strain difference by brain region. The specific D 1 or D 2 antagonists, SCH 23390 or epidepride, respectively, produced dose-dependent decreases in locomotor activity but there were no between-strain differences. However, epidepride, at a dose of 0.003 mg/kg, completely reversed cocaine-induced (15 mg/kg) activation in both strains. These findings show that C57BL/6 and DBA/2 mice differ in dopamine-related behaviors and suggest that dopaminergic processes may mediate genetic differences in cocaine sensitivity.

Effect of acute cocaine injection on the extracellular level of dopamine, blood flow, and oxygen pressure in brain of newborn piglets.

The present study examined the effects of acute cocaine administration on oxygen pressure in the vasculature of the cortex as well as on blood flow and extracellular levels of dopamine in the striatum of newborn piglets. The oxygen-dependent quenching of phosphorescence was used to continuously monitor oxygen pressure in the vasculature of the cortex. Following acute cocaine injection (1.5 mg/kg iv) the cortical oxygen pressure rapidly decreased from 36.3 +/- 1.2 to 32.9 +/- 1.4 Torr and remained at the lower level during the 120 min of postinjection period during which measurements were made. Blood flow in striatum, as determined by laser Doppler, was decreased by 8-10% at 5 min after injection of cocaine. This decrease in blood flow was statistically significant up to 40 min postinjection. Extracellular dopamine, measured using in vivo microdialysis, showed a large increase after cocaine injection. The dopamine level increased from 14 +/- 7 to 88 +/- 21 pmol/ml by 15 min after drug administration, then decreased to 45 +/- 11 pmol/ml and remained stable for the 120 min post-injection period. The mechanism(s) by which the increase in the extracellular level of dopamine occurred may include a direct effect of cocaine on the dopamine transporter and/or an indirect effect due to the decrease in cerebral oxygenation and blood flow. The increase in extracellular dopamine can be responsible for several alterations in neuronal metabolism with potentially deleterious effects on neuronal function.

The effects of acute cocaine administration on auditory event-related potentials in rats

Cocaine administration has been shown to affect several sites in the limbic forebrain. The nucleus accumbens has been implicated as an important site for the reinforcing aspects of this drug whereas, the amygdala and hippocampus may be more involved in drug conditioning and/or drug induced changes in the perception of stimuli. In the present study, auditory event-related potentials (ERPs) were utilized to explore the effects of cocaine on sensory processing in several limbic sites. Eleven adult male Wistar rats were stereotaxically implanted with electrodes aimed at the dentate gyrus, dorsal hippocampus (CA1–CA2), amygdala, and nucleus accumbens. The rats received intraperitoneal injections of either saline, 2.5, 5.0, 10.0 or 20 mg/kg of cocaine. The ERPs were recorded in response to an auditory ‘oddball’ paradigm consisting of frequently and infrequently presented tones. Cocaine was found to produce a dose dependent decrease in the variance of the amplitude of several ERP components in the amygdala and the hippocampal formation but not in the accumbens. Cocaine also produced a decrease in the latency of the N1 component in the amygdala. No significant changes were observed in the amplitude of the ERP components following any of the cocaine doses studied, suggesting that cocaine may not increase the salience of auditory stimuli in these structures. The observed reduction in the variance of the ERPs may suggest an increased focussing of the animals' attention to the auditory stimuli. These studies also suggest that the sensory/cognitive aspects involved in cocaine's actions, as quantified by ERPs, may primarily involve the hippocampal formation and the amygdala, but not the nucleus accumbens.

Acute Effects of Cocaine on Ornithine Decarboxylase Activity in Fetal and Neonatal Rat Heart: Evidence for Cardiotoxicity

Fetal exposure to cocaine is associated with increased perinatal cardiac risk. In the current study, we examined the effects of acute cocaine administration on ornithine decarboxylase (ODC) activity in fetal and neonatal rat heart. ODC is a key regulatory enzyme in the control of cell differentiation and growth, and rapid changes in ODC are associated with the response to cell injury. Administration of 30 mg/kg s.c. of cocaine to pregnant rats on the 20th day of gestation caused acute elevation of fetal cardiac ODC that persisted throughout the ensuing 24 h. In contrast, the same dose given directly to neonatal rats the day after birth evoked only a short-term (1-h) stimulation of ODC that was reversed by 4 h after treatment. By 4 days of age and subsequently, cocaine was unable to elicit acute stimulation of heart ODC and only evoked inhibition of enzyme activity. Elevated progesterone levels during pregnancy have been shown to sensitize the maternal myocardium to cocaine-induced catecholaminergic effects; the greater sensitivity of fetal heart ODC to cocaine, as compared to neonatal heart, supports the hypothesis that similar enhancement of fetal cardiac irritability can contribute to cocaine-induced cell damage.

Differential effects of cocaine on high and low response rates maintained with and without rate requirements1

Keypecking was maintained by a multiple (tandem random-interval 45-s, differential reinforcement of low rate 3-s) (tandem random-interval 45-s, differential reinforcement of high rate 0.2-s) schedule of food reinforcement in three pigeons. During non-drug sessions these schedule contingencies effectively controlled high and low response rates under approximately equal reinforcement frequencies. The behavioural effects of acute cocaine administration were assessed in the presence and absence of the response rate requirements (i.e. DRL, DRH contingencies). In the absence of response rate requirements cocaine administration consistently decreased high response rates. Low response rates tended to increase after the lower doses of cocaine, while thèy decreased consistently after the higher doses. High response rates decreased less after the lower doses of cocaine, in two of the three pigeons, when cocaine was administered in the presence of the rate requirements than when cocaine was administered in the absence of the rate requirements, while low rates increased less. Rate of reinforcement remained relatively constant across different lower doses of cocaine in the absence of high-rate requirements, but decreased in the presence of the high-rate requirements. Higher doses of cocaine consistently decreased reinforcement rate. These results support the notion that the behavioral effects of drugs may be a function of the extent to which response rates are directly controlled by schedule variables.

Cocaine elevates striatal dopamine efflux in spontaneously hypertensive and Wistar-Fyoto rats

The effects of acute cocaine administration on central dopaminergic systems were examined in the striata of spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats with the use of an in vivo microdialysis technique. Increased extracellular levels of dopamine were observed for 45 to 75 minutes following acute cocaine administration in both halothane-anesthetized and conscious SHR and WKY. However, no significant differences were noted between anesthetized and conscious SHR and WKY in either baseline levels or cocaine-induced changes in extracellular levels of dopamine and its metabolites. A positive, linear correlation between extracellular levels of dopamine and cocaine was demonstrated for the 60-min period following acute cocaine administration in both SHR and WKY. The slopes of the linear regression plots obtained from the data of each 15-min sample was slightly, but significantly, higher in conscious SHR than in conscious WKY. The present results suggest a transient and dose-related stimulation of striatal dopamine release following acute cocaine administration and a linear relationship between striatal extracellular levels of dopamine and cocaine in both SHR and WKY.

Sex differences in locomotor activity after acute and chronic cocaine administration

Adult, intact and gonadectomized male and female Wistar rats (n = 9) were exposed to an automated open field to assess the behavioral effects of acute cocaine administration (saline, 1.0 and 10.0 mg/kg subcutaneous). The subjects were exposed to the open field for 10 min, removed to be injected and returned to the open field for another 30 min. Three saline and two drug sessions were run in counterbalanced order. Locomotor activity in intact and castrated male rats and ovariectomized female rats decreased following injection, irrespective of the dose of cocaine. The locomotor activity of intact female rats was higher than that of any other group of subjects. It decreased during the session after saline and 1.0 mg/kg cocaine, but increased towards the end of the 30 min session after 10.0 mg/kg. Rearing measures paralleled the observations on locomotor activity. To determine the effects of chronic, home-cage, cocaine administration, five of the subjects in each group were injected with 10.0 mg/kg cocaine for 9 consecutive days. The remaining four subjects received saline injections. On day 10, all subjects were re-exposed to the open-field for 10 min, removed, injected with 10.0 mg/kg cocaine and returned to the open field for another 30 min. Chronic home cage cocaine administration produced an increase in cocaine's effects on locomotor activity and rearing in intact female rats only. However, behavioral sensitization was also observed in intact female rats who had been treated with saline for 9 consecutive days, suggesting that behavioral sensitization to cocaine in intact female rats may develop very rapidly and independent of environmental context.

Cocaine Effects on Luteinizing Hormone-Releasing Hormone-Stimulated Anterior Pituitary Hormones in Female Rhesus Monkey*

The effects of acute cocaine administration on synthetic LHRH-stimulated anterior pituitary hormones (LH, FSH, and PRL) were studied in 6 female rhesus monkeys during the follicular phase of the menstrual cycle (days 4-7). Integrated plasma samples were collected every 10 min for 40 min before iv administration of cocaine (0.4 or 0.8 mg/kg) or an equal volume of vehicle control solution. Synthetic LHRH (100 micrograms, iv) was administered 10 min after cocaine or placebo-cocaine administration, and 10 plasma samples were collected for an additional 100 min. LHRH stimulated a significant increase in LH within 10 min after placebo-cocaine administration (P less than 0.05) and after each dose of cocaine (P less than 0.0001). Cocaine (0.4 mg/kg) significantly enhanced LHRH stimulation of LH compared to placebo or 0.8 mg/kg cocaine administration (P less than 0.01). FSH increased significantly within 20-30 min after LHRH alone (P less than 0.008) and after 0.4 mg/kg cocaine (P less than 0.0001). LHRH-stimulated FSH levels also were significantly higher after 0.4 mg/kg cocaine than after placebo or 0.8 mg/kg cocaine (P less than 0.01). These data indicate that cocaine does not suppress LHRH stimulation of pituitary gonadotropins, and low doses of cocaine significantly enhance LH and FSH release. Consequently, cocaine does not compromise anterior-pituitary function at the level of the gonadotroph and may stimulate hypothalamic release of endogenous LHRH. PRL levels were unchanged by LHRH and placebo-cocaine administration. After LHRH and cocaine administration, PRL levels decreased significantly (P less than 0.05-0.01) and remained suppressed throughout the 110-min postcocaine sampling period. These data indicate that cocaine's significant suppression of PRL is not blocked by LHRH. These findings are consistent with dopaminergic inhibitory control of PRL and suggest that cocaine's inhibition of dopamine reuptake down-regulates pituitary lactotroph activity in rhesus monkey.

Effect of Acute Cocaine Administration on the Cholinergic Enzyme Levels of Specific Brain Regions in the Rat

Adult male Sprague-Dawley rats weighing between 170 and 204 g and maintained under controlled lighting and temperature conditions were used in this experiment. One group of animals was treated with 30 mg/kg of cocaine hydrochloride and the other group with saline. Rats were decapitated 20 min after cocaine injection and their brains were removed and the different regions including the medulla, pons, midbrain, cerebellum, hypothalamus, thalamus, hippocampus, and the cortex were dissected. All brain regions were assayed for choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) activities. The results obtained indicated that the administration of cocaine was associated with significant increases (p less than 0.01) in AChE activity in the medulla, pons, midbrain, hypothalamus, thalamus, and also in the hippocampus (p less than 0.05). A significant decrease in ChAT activity was found in the pons (p less than 0.01), hypothalamus, and thalamus (p less than 0.05), while a significant increase in ChAT activity was found in the cortex (p less than 0.05). The results suggest that the changes in general activity followed by stereotypic behavior may be related to the changes in the levels of cholinergic enzymes in specific brain regions.

Effects of cocaine on conflict behavior in the rat

The present studies examined the effects of acute cocaine administration, chronic cocaine administration and cocaine withdrawal on behavior in the Conditioned Suppression of Drinking (CSD) conflict paradigm, an animal model for the study of anxiety. In daily 10-minute sessions, water deprived rats were trained to drink from a tube that was occasionally electrified (0.25 mA), electrification being signalled by a tone. Within 3–4 weeks, control (i.e., non-drug) CSD behavior stabilized (30–50 shocks and 10–12 ml/session) and drug studies were initiated. Acute administration of cocaine (30-minute pretreatment) produced a selective pro-conflict effect only at a dose of 10 mg/kg cocaine, with lower doses (2.5, 5 mg/kg) exerting no effect on CSD behavior and a higher dose (20 mg/kg) depressing both punished and unpunished responding. In a second experiment, cocaine (10 mg/kg, IP, 2/day) or saline was administered to separate groups of subjects for 7 weeks. In this chronic treatment study, CSD testing was conducted 12 hours after each evening cocaine administration. Although it had no effect on CSD behavior during the first week of treatment, this chronic cocaine administration produced a significant and selective pro-conflict effect which was stable during the period from Weeks 2–7. In a final experiment, a high dose of cocaine (20 mg/kg, 3/day) or saline was given to separate groups of subjects for 2 weeks and the behavioral effects of these treatments and their subsequent termination were examined. In this study, CSD testing was conducted 8 hours after each evening cocaine treatment. During the first week of high dose cocaine treatment, a decrease in punished responding was observed; this parameter returned to baseline levels by Week 2. Discontinuation of this high dose chronic cocaine treatment resulted in a selective decrease in punished responding. This pro-conflict effect was greatest at 3 days, and lasted for 6 days after the last cocaine dose. These data are consistent with clinical findings demonstrating the anxiogenic effects of both acute and chronic cocaine treatment as well as cocaine withdrawal and suggest that conflict paradigms such as the CSD may be useful for the study of cocaine-induced anxiety states.

Effect of acute cocaine administration on the metabolism of antipyrine in vivo

Effect of acute cocaine administration on the metabolism of antipyrine in vivo