Effects Of Chronic Cocaine Exposure Research Articles

Effect of chronic cocaine exposure on the hemodynamic response to vasopressors in sheep.

The purpose of this study was to determine how chronic cocaine exposure affects the hemodynamic response to epinephrine, dopamine, phenylephrine, and ephedrine in awake sheep. The hemodynamic response to dopamine (10 microg/kg), phenylephrine (1.5 microg/kg), and ephedrine (0.15 mg/kg) boluses was determined at baseline before low-dosage cocaine exposure and again after 15 and 18 days of cocaine exposure. The hemodynamic response to epinephrine (0.15 microg/kg), phenylephrine (1.5 microg/kg), and ephedrine (0.15 mg/kg) was determined at baseline before high-dosage cocaine exposure and again after 15 and 18 days of cocaine exposure. Chronic cocaine exposure abolished the mean arterial pressure and heart rate responses to dopamine but did not alter the responses to epinephrine, phenylephrine, or ephedrine. In awake sheep, chronic cocaine exposure markedly impairs the hemodynamic response to dopamine but not to epinephrine, phenylephrine, or ephedrine.

Cocaine’s Effects on Neuroendocrine Systems: Clinical and Preclinical Studies

This review examines the effects of cocaine on the neuroendocrine system and summarizes findings from clinical studies of cocaine abusers and preclinical studies in rodents and rhesus monkeys. The effects of acute and chronic cocaine administration on anterior pituitary, gonadal, and adrenal hormones are described, and the functional consequences of chronic cocaine exposure are discussed. Many of cocaine’s acute effects on the endocrine system are consistent with its actions as a monoamine reuptake inhibitor. Acute cocaine administration stimulates release of gonadotropins, ACTH, and cortisol or corticosterone and suppresses prolactin levels. It has been difficult to detect changes in basal levels of most hormones or alterations in hormone responsiveness to a challenge dose of cocaine or other agents after chronic cocaine treatment. Interpretation of clinical data is often complicated by polydrug abuse involving opiates and alcohol as well as cocaine. However, preclinical studies of the effects of chronic cocaine exposure on integrated neuroendocrine function have revealed disruptions of the estrous cycle in rats and the menstrual cycle in rhesus monkeys. Furthermore, the menstrual cycle disorders observed in rhesus monkeys parallel those reported in women who abuse cocaine. Much remains to be learned about cocaine’s interactions with the endocrine system and the consequences of cocaine abuse for reproductive function.

Chronic cocaine administration does not modify haemodynamic responses to isoflurane anaesthesia in sheep.

Cocaine use is epidemic in the developed world, resulting in numerous patients presenting for surgery and anaesthesia with a history of chronic cocaine exposure. The purpose of this study was to determine the effect of chronic cocaine exposure on the cardiovascular response to isoflurane general anaesthesia. The changes in mean arterial pressure (MAP), heart rate (HR), cardiac output (CO), central venous pressure (CVP), pulmonary capillary wedge pressure (PCWP) and systemic vascular resistance (SVR) with increasing concentration of isoflurane (1%, 1.7%, and 2.4% end tidal) were determined at baseline in six sheep. The animals then received a continuous cocaine infusion (0.2 mg.kg-1.hr-1) and twice daily cocaine boluses (4 mg.kg-1) for 17 days followed on day 18 by a cocaine binge consisting of eight cocaine boluses (4 mg.kg-1) administered at one hour intervals. The haemodynamic studies conducted at baseline prior to cocaine exposure were then repeated on days 15 and 18. Increasing concentrations of isoflurane produced the expected dose-dependent cardiovascular depression, but this was not altered by cocaine exposure. Although chronic cocaine exposure has been shown to increase isoflurane minimum alveolar concentration by 25% in sheep; chronic cocaine exposure does not result in tolerance of the cardiovascular depression produced by isoflurane.

The effect of chronic cocaine exposure throughout pregnancy on maternal and infant outcomes in the rhesus monkey.

To explore the effects of gestational cocaine exposure in a nonhuman primate model, pregnant rhesus monkeys were either treated (N = 10) with escalating doses of cocaine up to 7.5 mg/kg (IM), three times per day, 5 consecutive days per week, prior to conception and throughout gestation, or were not treated (N = 10) with cocaine at all. Substantial levels of both cocaine and its major metabolite, benzoylecgonine, were observed in samples of hair taken at birth from mothers and infants of the cocaine-treated group. Despite these differences in cocaine exposure, the experimental groups did not differ significantly with respect to maternal outcome, as measured by body weight again during pregnancy and length of pregnancy. On the other hand, the experimental groups did differ significantly with respect to infant outcome, as measured at birth by body weight, overall length, and crown circumference, all of which were decreased in the cocaine-treated group. A variety of reflexes tested at birth were normal in the cocaine-treated group. It was concluded that, in a rhesus monkey model, chronic cocaine exposure throughout pregnancy had no significant effect on maternal outcome, but did significantly affect infant outcome as assessed in this investigation.

Changes in serotonin and norepinephrine uptake sites after chronic cocaine: pre- vs. post-withdrawal effects

Although acute cocaine is a strong reuptake inhibitor at dopamine (DA), norepinephrine (NE) and serotonin (5-HT) synapses, the effects of chronic cocaine on 5-HT and NE transporters have received less attention than its effects on DA transporters. In the present study, quantitative autoradiography was used to map effects of chronic cocaine exposure on the binding of [ 3H]nisoxetine and [ 3H]cyanoimipramine to NE and 5-HT transporters, respectively. Female Wistar rats were given increasing concentrations of cocaine in the drinking water for 4 weeks (mean dose during the final two weeks: ∼ 25 mg/kg body weight) and sacrificed either on the 30th day of cocaine administration or at one of two time points after withdrawal (4 days or 30 days). In animals sacrificed while on cocaine, [ 3H]cyanoimipramine binding was significantly elevated in the infralimbic cortex (+ 13%, P < 0.05), n. accumbens (+ 16%, P < 0.05, P < 0.05), lateral septal n. (+21%, P < 0.05), pedunculopontine n. (+ 16%, P < 0.05), and vestibular n. (+19%, P < 0.05). These changes were no longer observed when brains were examined either 4 days or 30 days after cessation of cocaine. In animals sacrificed while on cocaine, [ 3H]nisoxetine binding was decreased in the bed n. of the stria terminalis (—18%, P < 0.05), the lateral parabrachial area (—35%, P < 0.05) and the inferior olive (—26%, P < 0.05). In animals sacrificed 4 days after cessation of cocaine, these effects were no longer apparent, except for a 16% reduction in the inferior olive ( P < 0.05). In this 4-day withdrawal group, a significant increase in [ 3H]nisoxetine binding was seen in the paraventricular n. of the hypothalamus (PVN, +33%, P < 0.05). This PVN change was still seen in the group sacrificed 30 days after cessation of cocaine (+44%, P < 0.02). Binding of [ 3H]WIN 35,428 to dopamine transporters was unaltered in this group. Taken together, these observations indicate that chronic cocaine has different effects on brain 5-HT and NE transporters, both while the animals are on cocaine and after withdrawal. They support the notion that increased 5-HT uptake in limbic forebrain may play a role in behavioral /psychiatric effects of chronic cocaine. They are also consistent with previous indications that chronic cocaine does not induce degeneration of nerve terminals in noradrenergic or serotonergic neurons. The persistent increase in [ 3H]nisoxetine binding in the paraventricular hypothalamus suggests the possibility of neuroendocrine changes after withdrawal from chronic cocaine use.

Chronic cocaine administration reversibly increases isoflurane minimum alveolar concentration in sheep.

Significant numbers of patients are seen for surgery and anesthesia with a history of chronic cocaine use. However, little is known about how cocaine use influences anesthetic physiology and pharmacology. The purpose of this study was to investigate the effect of chronic cocaine exposure on the minimum alveolar concentration (MAC) of isoflurane in sheep. Isoflurane MAC was determined at baseline in 12 sheep using a standard protocol. The animals were subsequently exposed to cocaine for 18 days. Cocaine exposure consisted of a continuous subcutaneous cocaine infusion at 0.2 mg.kg-1.h-1, twice daily 4-mg/kg intravenous boluses and repeated hourly 4 mg/kg cocaine boluses for 8 h on day 18. Minimum alveolar concentration determinations were repeated again on days 15, 18, and on day 28 after 10 days of cocaine abstinence. Compared to baseline MAC (1.53 +/- 0.12%) cocaine exposure significantly increased isoflurane MAC on days 15 (1.91 +/- 0.14%) and 18 (1.78 +/- 0.13%; P = .005). MAC decreased after discontinuation of cocaine and was not different from baseline on day 28 (1.67 +/- 0.11). In sheep, chronic cocaine exposure resulted in a reversible increase in isoflurane MAC. This finding contrasts with studies of other central nervous system stimulants, which have demonstrated a decrease in MAC after chronic drug exposure.

Effect of chronic cocaine exposure on carotid artery reactivity in neonatal rabbits

Chronic cocaine abuse by pregnant women results in chronic neonatal drug exposure. In adults, chronic cocaine use alters neurotransmitter concentrations and receptor dose-response relationships. Similar changes may also occur in the neonatal cerebrovasculature after in utero cocaine exposure. This study examined the effect of chronic cocaine exposure on internal carotid artery reactivity to norepinephrine, serotonin, acetylcholine, sodium nitroprusside, adenosine, and cocaine in neonatal rabbits. Internal carotid artery rings were isolated from 16 to 20 day old rabbits that had received cocaine (20 mg/kg IP BID, mn = 8) or saline (n = 8) from 5 days of age and were studied in organ baths using standard in vitro techniques. Chronic treatment with cocaine decreased the half-maximal relaxant response (ED 50) to adenosine (control 6.9 ± 1.8 vs cocaine 3.5 ± 0.99 μM, p = 0.05). The half-maximal contractile responses (EC 50) to norepinephrine and serotonin and the half-maximal relaxant responses (ED 50) to acetylcholine and sodium nitroprusside were similar between groups. The threshhold concentration of cocaine that induced vessel contraction was altered by chronic cocaine exposure (control group 10 −6 M vs chronic cocaine group 10 −4 M). We conclude that chronic cocaine exposure sensitizes carotid arteries to the relaxant effects of adenosine. In addition, chronic cocaine exposure desensitizes carotid arteries to the contractile effects of acute cocaine. These vasoreactivity changes may underlie altered cerebrovascular responses to asphyxia and play a role in the pathogenesis of postnatally acquired brain injury in critically ill “crack” babies.

The effect of chronic cocaine exposure during pregnancy on maternal and infant outcomes in the rhesus monkey.

To explore the effects of gestational cocaine exposure in a nonhuman primate model, pregnant rhesus monkeys were treated from about 1 month of gestation until term with either 0 (N = 3), 0.3 (N = 3), 1.0 (N = 3), or escalating doses up to 8.5 (N = 3) mg/kg (IM), three times per day, 5 consecutive days per week. Despite these differences in cocaine exposure, the experimental groups did not differ significantly with respect to maternal outcome, as measured by body weight gain during pregnancy and length of pregnancy. A clear dose-response relationship was observed between the cumulative dose of cocaine administered during gestation and the levels of both cocaine and its major metabolite, benzoylecgonine, in samples of infant hair taken at birth. However, the experimental groups did not differ significantly with respect to infant outcome, as measured at birth by body weight, overall length, crown-to-rump length, rump-to-heel length, biparietal diameter, and crown circumference. Furthermore, the experimental groups did not differ significantly with respect to the integrity of a variety of infant reflexes tested at birth. It was concluded that, in a rhesus monkey model, chronic cocaine exposure during pregnancy had no significant effect on maternal and infant outcomes as assessed in this investigation.

The effect of chronic cocaine exposure during pregnancy on the acquisition of operant behaviors by rhesus monkey offspring.

To explore possible long-term effects of gestational cocaine exposure in a nonhuman primate model, pregnant rhesus monkeys were treated from about 1 month of gestation until term with either 0 (N = 3), 0.3 (N = 3), 1.0 (N = 3), or escalating doses up to 8.5 (N = 3) mg/kg (IM), three times per day, 5 consecutive days per week. Despite these differences in cocaine exposure, the experimental groups did not differ significantly with respect to the postnatal growth of offspring over an 18-month period following birth. Beginning at 6 months of age, the behavior of offspring was monitored using an operant test battery that included five food-reinforced tasks designed to model aspects of learning, color and position discrimination, time estimation, short-term memory and attention, and motivation. Although the acquisition of each operant behavior by offspring progressed significantly during training between 6 and 18 months of age, this acquisition was not differentially affected by gestational cocaine exposure. It was concluded that, in a rhesus monkey model, chronic cocaine exposure during pregnancy had no significant effect on the offsprings' acquisition of operant behaviors.

Cocaine and the porcine coronary microcirculation: Effects of chronic cocaine exposure and hypercholesterolemia

To examine the acute effect of cocaine on the coronary microcirculation and whether chronic cocaine administration with or without a concomitant high-cholesterol diet affects beta-adrenoceptor and endothelial functions in the coronary microcirculation. Prospective experimental study. Laboratory and animal research facility. Yorkshire pigs. Pigs were fed a high (2%)-cholesterol diet or a regular diet for 3 months. Animals in both groups received cocaine chronically (7 mg/kg/day, IM). Control animals were fed a regular diet. Responses of the porcine coronary arterioles (90 to 190 microns in diameter) were examined in vitro in a pressurized (40 mmHg) no-flow state using a video-imaging apparatus. Acute application of cocaine caused a significant contraction with a mean maximal diameter decrease of 14% +/- 5%, which was markedly reduced by muscarinic blockade but not significantly affected by alpha 1-adrenergic blockade. Lidocaine or procainamide had no vasoconstrictor effect. Chronic exposure of animals to cocaine diminished contractile responses to cocaine and reduced relaxation responses to the nonselective beta-adrenergic receptor agonist isoproterenol. Phenylephrine caused a minimal (< 4%) contraction of vessels in all groups. Chronic cocaine administration with concomitant high-cholesterol feeding attenuated endothelium-dependent relaxations to serotonin, whereas endothelium-dependent relaxations to bradykinin were unaffected. Endothelium-independent relaxations to sodium nitroprusside were similar in all groups. These results suggest that cocaine can exert a direct vasoconstrictor effect on the porcine coronary microcirculation via a muscarinic mechanism. Chronic exposure to cocaine significantly decreases beta-adrenoceptor-mediated relaxation and blunts endothelium-dependent relaxation to a small degree.

Effects of repeated cocaine injections on cochlear function

The effects of repeated cocaine administration on cochlear function were evaluated by measuring amplitude-intensity and latency-intensity functions of the whole-nerve action potential of the auditory nerve. Whole-nerve action potential input/output functions obtained using tone-pips of 0.5, 1, 2, 4 and 8 kHz in a group of cocaine-treated subjects were compared with those obtained in saline-treated animals. All measurements were made 24 h after the last treatment. Amplitudes of whole-nerve action potentials were enhanced in the cocaine-treated animals compared to the control group. No statistically significant differences in latency-intensity functions were seen after cocaine treatment. The effect of chronic cocaine exposure also was examined on catecholamine innervation in the cochlea using immunohistochemical techniques. The density of adrenergic innervation was reduced in the cocaine-treated animals.

Effect of chronic cocaine on reproduction in female house mice

The effect of chronic cocaine exposure on the reproductive success of juvenile female house mice was studied. We followed two generations of female mice to examine the consequence of cocaine treatment on developmental and reproductive parameters such as weight gain, first estrus, impregnation, fertility, and maternal success. Twenty-two-day-old female mice were given cocaine at a daily total of 40 mg/kg body weight, delivered by two SC injections of 20 mg/kg each, until they were mated and inseminated by experienced males. The treatment attenuated weight gain and delayed puberty in the females but had no discernible effect on their pups. Administration of cocaine to lactating mothers decreased the weaning weight of their pups. Juvenile females previously nursed by mothers receiving cocaine and receiving 40 mg/kg cocaine daily themselves were impregnated at older ages than controls. Nevertheless, once these juveniles reached puberty, they mated succesfully and their reproductive parameters did not differ from those of control mice. Thus, chronic cocaine treatment of juvenile female mice slows body growth and development but has little effect of the offspring produced later when they reached adulthood.

Effects of cocaine on dopamine receptor gene expression: A study in the postmortem human brain

The effects of chronic cocaine exposure on dopamine D 1 and D 2 receptor gene expression in the human brain were studied in postmortem samples from chronic cocaine abusing and matched control subjects. Using in situ hybridization and receptor autoradiography to examine messenger ribonucleic acid (RNA) and binding sites, respectively, neither D 1 nor D 2 receptor expression was found to be changed in the nucleus accumbens, caudate, putamen, or substantia nigra of the cocaine-exposed subjects. Although chronic cocaine exposure can produce alterations in dopaminergic neurotransmission, sustained compensatory changes in dopamine receptor expression do not appear to occur in the human.