Gestational exposure to cocaine or pharmacologically related compounds: effects on behavior and striatal dopamine receptors

Gestational cocaine (COC) exposure has been reported to alter behavior and possibly dopamine (DA) receptors. In this paper, we further examined the effects of prenatal COC (40 mg/kg, s.c.) on DA receptor binding and the behavioral response to quinpirole, a DA D2 receptor agonist. In an attempt to elucidate possible mechanisms of such effects, we exposed pregnant dams to specific reuptake blockers; fluoxetine 12.5 mg/kg, a serotonin reuptake blocker; desipramine 10 mg/kg, a norepinephrine reuptake blocker; GBR-12909 10 mg/kg, a DA reuptake blocker; or to a local anesthetic, lidocaine 40 mg/kg. Drugs were administered once daily over gestational days 8-20. Control dams were injected with saline (SAL) or pair-fed to the COC group. Quinpirole challenge was performed in the offspring on post natal day 19. Two pups per litter were injected (s.c.) with 0.03 or 0.09 mg/kg quinpirole-HCl on post-natal day 19. The remaining pups in each litter were sacrificed for analysis of striatal DA receptors. Results showed that only COC exposure altered the behavioral response to the quinpirole challenge by increasing quinpirole-induced stereotypy and motor activity relative to SAL controls. DA receptor analysis showed no alteration in K(D) or B(MAX) for striatal D1 or D2 sites in any group. These results suggest that prenatal COC exposure produces alterations in function of the D2 receptor complex which are not reflected in K(D) or B(MAX) and that these effects are not fully mimicked by exposure to specific monoamine reuptake blockers or a local anesthetic.     

Transplacental cocaine exposure: a mouse model demonstrating neuroanatomic and behavioral abnormalities

Between 10% and 15% of infants born in urban America today have been exposed to cocaine in utero. Clinical studies have suggested that impairment of brain growth is the single best marker of significant prenatal cocaine exposure, and postnatal developmental compromise seen in a subset of affected children as a consequence of that exposure. We have developed an animal model, in mice, of prenatal cocaine exposure that has allowed us to dissociate the direct effects of cocaine in altering fetal development from the indirect effects associated with cocaine-induced malnutrition. We find that transplacental cocaine exposure independently impairs fetal brain and body growth and results in behavioral deficits and permanent alterations in neocortical cytoarchitecture in exposed offspring.     

Effects of prenatal exposure to cocaine on Morris water maze performance in adult rats.

The spatial memory of adult rats prenatally exposed to cocaine and that of control offspring was assessed using the Morris water maze. Offspring were derived from Sprague Dawley dams that received subcutaneous injection of 40 mg/kg/3 cc cocaine hydrochloride (C40) daily on gestational Days 8-20, pair-fed dams injected with saline, or nontreated control dams. After acquisition, the platform was moved to a new location (reversal phase). Probe trials were conducted at the end of acquisition and reversal training. On the 1st acquisition day, adult male and female offspring prenatally exposed to cocaine required significantly more time and traversed a greater distance to find the hidden platform than did control offspring. Despite these initial differences observed in C40 offspring performance, all of the rats were performing at equivalent levels at the time probe trials were conducted. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Prenatal cocaine alters social competition of infant, adolescent, and adult rats

This series of experiments examined whether gestational cocaine exposure alters later social behavior exhibited during competition for biologically relevant stimuli. Rat offspring were derived from dams that received subcutaneous injections of 40 mg/kg/3cc cocaine HCl daily on gestational Days 8-20, pair-fed dams injected with saline, or nontreated control dams. Offspring competed with peers for access to a nipple in infancy, and to water in adolescence or adulthood. Prenatal cocaine exposure resulted in a decreased ability of cocaine-exposed infant rats to compete successfully for a nipple. Although adolescent and adult cocaine-exposed rats were no less successful than controls when competing for water, they exhibited a notable increase in aggression toward competitors during testing. Data provide evidence of alterations in social behavior and social competition as a result of prenatal cocaine exposure.     

Possible mechanisms of salt-induced hypertension in Dahl salt-sensitive rats

The effects of acute and chronic administration of cocaine on the antinociception and tolerance to the antinociceptive actions of mu-(morphine), kappa-(U-50,488H), and delta-([D-Pen2,D-Pen5]enkephalin; DPDPE), opioid receptor agonists were determined in male Swiss-Webster mice. Intraperitoneal injection of 40 mg/kg of cocaine by itself produced weak antinociceptive response as measured by the tail-fick test but the lower doses were ineffective. Administration of morphine (10 mg/kg, SC), U-50,488H (25 mg/kg, IP) or DPDPE (10 microg/mouse, ICV) produced antinociception in mice. Cocaine (20 mg/kg) potentiated the antinociceptive action of morphine and DPDPE but had no effect on U-50,488H-induced antinociception. Administration of morphine (20 mg/kg, SC), U-50,488H (25 mg/kg, IP) or DPDPE (20 microg/mouse, ICV) twice a day for 4 days resulted in the development of tolerance to their antinociceptive actions. Tolerance to the antinociceptive actions of morphine and U-50,488H was inhibited by concurrent treatment with 20 or 40 mg/kg doses of cocaine; however, tolerance to the antinociceptive action of DPDPE was not modified by cocaine. It is concluded that cocaine selectively potentiates the antinociceptive action of mu- and delta- but not of the kappa-opioid receptor agonist. On the other hand, cocaine inhibits the development of tolerance to the antinociceptive actions of mu- and kappa- but not of delta-opioid receptor agonists in mice.     

5-HT3 receptor modulation of behavior during withdrawal from continuous or intermittent cocaine

The present experiments examined alterations in 5-HT3 receptors during withdrawal from continuous or intermittent cocaine. Rats were pretreated with 40 mg/kg/day cocaine for 14 days by either SC injections or osmotic minipumps. The rats were then withdrawn from the pretreatment regimen for 7 days. In Experiment 1, rats received 0-16 mg/kg IP injections of ondansetron, a selective 5-HT3 receptor antagonist. In Experiment 2, the rats received 0-16 mg/kg IP ondansetron in combination with a 15 mg/kg IP injection of cocaine. In Experiment 3, the subjects received 0-16 mg/kg IP injections of ondansetron in combination with a 7.5 mg/kg IP injection of cocaine. Following these injections, the subjects' behavior was rated using the Ellinwood and Balster (18) rating scale. The results of Experiment 1 indicated that ondansetron had no effect on the behavior of the subjects, nor was there a differential effect of pretreatment regimen the effects of ondansetron. The results of Experiment 2 indicated that ondansetron had no effect on cocaine-induced locomotion in the saline control rats, but did have a slight, statistically significant, suppressive effect in the injection rats. In contrast, ondansetron had a robust facilitative effect on cocaine-induced locomotion in the continuous infusion rats. The results of Experiment 3 indicated that ondansetron had no effect on cocaine-induced locomotion in the saline control rats or the cocaine injection pretreatment subjects. In the continuous infusion subjects, ondansetron did have a slight, statistically significant, facilitative effect on cocaine-induced locomotion.(ABSTRACT TRUNCATED AT 250 WORDS)     

Intravenous gestational cocaine in rats: effects on offspring development and weanling behavior

Pregnant rats were injected with cocaine (CN; 6 mg/kg) or an equal volume of saline (SAL), via the tail vein, on gestation days 8-20. A third group was untreated (UT). Maternal weight gain was not affected by dam treatment despite slight differences in food intake. Litter characteristics (e.g., litter size, pup weight) did not differ among groups. Indices of fetal mortality were not affected by the treatments. Developmental tests, initiated on postnatal day (PND) 2, indicated slight delays in the negative geotaxic response and eye opening in cocaine-exposed pups. Open-field and tail-flick tests were performed on PND 21. Pups were acutely injected with cocaine (10 mg/kg, IP), saline, or received no treatment before placement in a novel open field; morphine (1.5 mg/kg, SC) or saline was injected prior to the tail flick test. Pups from CN dams exhibited a significant decrease in spontaneous exploratory behavior compared to both controls, and a time-dependent increase in rearing compared to pups from UT dams. The acute cocaine injection prior to placement in the open field did not alter locomotion or rearing among dam treatment groups. However, the acute cocaine injection did increase stereotypy ratings for female pups from CN dams compared to similarly treated males, and females from SAL and UT dams. No differences were observed among groups in the tail-flick test. These data suggest that the IV route of administration provides a viable method of cocaine delivery in pregnant rats, and provides further evidence of the developmental and behavioral teratogenicity of prenatal cocaine exposure.     

Interactive effects of prenatal cocaine and nicotine exposure on maternal toxicity, postnatal development and behavior in the rat

Two experiments were performed to investigate the interactive effects of prenatal coadministration of cocaine hydrochloride (C) and nicotine tartrate (N). Experiment I was designed to determine doses of C and N that could be coadministered without altering maternal gestational parameters and/or fetal viability. Exposure of Sprague-Dawley rats to combined high-dose C (20 mg/kg) and high-dose N (5.0 mg/kg) on gestation days 8-21 was not more toxic to dam or fetus that that of exposure to C alone. Experiment II investigated pregnancy outcome, postnatal development, and behavior of the offspring following drug exposure to either high-dose cocaine (20 mg/kg: CS), high-dose nicotine (5.0 mg/kg: NS), or both (NC) on gestation days 8-21. N was administered by osmotic minipump and C by sc injection. Saline-injected dams, fitted with saline-fitted pumps (SS), and untreated dams, pair-fed (PF) to NC females, served as controls. Alterations in maternal variables were limited to a 10-15% decrease in food consumption in NC and CS groups. Pregnancy outcome and birth statistics were unaffected by prenatal treatment, as was offspring body weight during the first four postnatal weeks. However, the development of surface righting was delayed inC CS pups, and only CS offspring were underresponsive to the stimulatory effects of dopamine agonists on activity and stereotypy. Behavioral responses to N challenge were similar in all groups. In addition, only CS offspring showed altered behavioral responses in a spontaneous alternation task. Treatment effects on dopamine D1 and D2 binding in the caudate nucleus were not observed. The combination of N and C did not exacerbate any of the behavioral changes seen in CS offspring. These results support the hypothesis that C is a behavioral teratogen in rodents, and suggest that in the present model, nicotine can mitigate some of the consequences of in utero exposure to cocaine.     

Alterations in the reinforcing efficacy of cocaine in adult rats following prenatal exposure to cocaine.

Adult male rats gestationally exposed to cocaine and nonexposed control offspring were examined for differences in operant responding for cocaine and sucrose reinforcement. Offspring were derived from dams that had received subcutaneous injections of 40 mg/kg/3cc cocaine hydrochloride daily on gestational Days 8–20 and nontreated control dams. Although no prenatal treatment differences were seen when the animals lever pressed for sucrose pellets on a progressive-ratio (PR) schedule, adult offspring prenatally exposed to cocaine were observed to exhibit an enhanced rate of cocaine intravenous self-administration on a fixed-ratio 5 (FR-5) schedule along with a marked decrease in break point on the PR reinforcement schedule. These results suggest that the reinforcing efficacy of cocaine may be reduced in animals with a prenatal history of cocaine exposure. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Neurochemical and neurobehavioral effects of repeated gestational exposure to chlorpyrifos in maternal and developing rats

Acute exposure to the organophosphate pesticide chlorpyrifos (CPF) on gestation day 12 (GD12, 200 mg/kg/ml, SC) causes extensive neurochemical changes in maternal brain but lesser changes in fetal brain. In the present study, we examined the relative neurotoxicity of repeated, lower-level CPF exposures during gestation in rats. Pregnant Sprague-Dawley rats were exposed to CPF (6.25, 12.5, or 25 mg/kg per day, SC) from GD12-19 and sampled at either GD16, GD20, or postnatal day 3 (PND3) for measurement of various maternal and developmental neurochemical markers. In contrast to the high acute dose exposure, no maternal toxicity was noted with repeated lower-level dosing. Extensive acetylcholinesterase (AChE) inhibition (83-90%) was noted in maternal brain at all three time points following repeated exposures (25 mg/kg). Higher AChE inhibition (58%) was noted in fetal brain at GD20 compared to 19-25% on PND3 in treated pups cross-fostered to control dams and in control pups cross-fostered to treated dams following repeated exposures (25 mg/kg per day). Whereas similar reductions in brain muscarinic receptor binding were noted at GD20 and PND3 in dams and developing brain between acute and repeated dosing regimens, greater changes in [3H]CD and [3H]cytisine binding were evident following repeated exposures. Righting reflex and cliff avoidance tests were markedly altered following repeated exposures. The results suggest that lower-level repeated exposures to CPF cause extensive neurochemical and neurobehavioral changes in developing rats in the absence of maternal toxicity.     

Two genetically selected strains of rats exhibit hypersensitivity or resistance to cocaine-induced fatal arrhythmias

We identified for the first time two genetically selected strains of rats that differ markedly in sensitivity to cocaine-induced life-threatening cardiac arrhythmias and arrest. The two strains of rats, designated as Fast and Slow, were bred for sensitivity (Fast) or resistance (Slow) to electrically kindled seizures. Studies were performed on halothane-anesthetized, mechanically ventilated rats. Animals were given cocaine (3 or 4 mg/kg/min i.v.) until they died. Arrhythmias (atrioventricular conduction block) developed at much lower cumulative cocaine doses in Slow-kindling rats than in Fast-kindling rats (15 +/- 1 versus 42 +/- 3 mg/kg, p <.01). The lethal cocaine dose (the dose that caused cardiac arrest) was also markedly lower in Slow than in Fast strains (32 +/- 2 versus 62 +/- 6 mg/kg, p <.01). These differences between the two strains were not significantly altered by pretreatment of animals with either ganglionic blockers, hexamethonium (20 mg/kg i.v.) or chlorisondamine (5 mg/kg i.v.), or a nonselective beta adrenergic receptor blocker, propranolol (1 mg/kg i.v.). A nonselective alpha adrenergic receptor blocker, phentolamine (10 mg/kg i.v.), however, abolished the differences between the Fast and Slow strains in the doses of cocaine required to produced atrioventricular conduction block and cardiac arrest. The results provide the first evidence of genetically determined susceptibility or resistance to cocaine-induced cardiotoxicity. There appears to be a genetically determined difference in the alpha adrenergic receptor system between the two strains that is responsible for the differential sensitivity to cocaine-induced arrhythmias and cardiac arrest.     

Effects of prenatal exposure to 5-fluoro-2'-deoxyuridine on developing central nervous system and reproductive function in male offspring of mice

The effect of 5-fluoro-2'-deoxyuridine (FrdU) on the developing brain and postpubertal reproductive function of male mouse offspring treated prenatally was investigated. FrdU was administered intraperitoneally to pregnant ICR mice at 1.5, 3, 6, 12.5, 25, and 50 mg/kg/day on days 8 through 13 of gestation or 12.5, 25, and 50 mg/kg/day on days 14 through 18 of gestation. Dams were allowed to deliver spontaneously. Dams treated with FrdU at 12.5, 25, and 50 mg/kg/day on days 8 through 13 of gestation did not deliver because of entire intrauterine death of embryos. Male offspring were aged for 10 or 15 weeks and then cohabited with untreated female mice for assessment of reproductive performance. Histological examination of the testis, epididymis, prostate, and seminal vesicle of offspring at 12 weeks of age, and sperm analysis of offspring at 12 or 17 weeks of age were performed. Dose-dependent decreases in body weight gain were noticed throughout the life of offspring. A marked decrease in the copulation rate was noted in the group treated with FrdU at 6 mg/kg/day on days 8 through 13 of gestation. However, neither histological examination of testes and sex-accessory glands nor sperm analysis revealed adverse effects of FrdU on the reproductive function in the male offspring of dams treated with FrdU at 6 mg/kg/day on days 8 through 13 of gestation. There were no significant differences in the relative weight of testes and epididymides between the group treated with FrdU at 6 mg/kg/day on days 8 through 13 of gestation and the control group. Absolute brain weight in the groups treated with FrdU on days 8 through 13 of gestation significantly decreased, while relative brain weight increased in the group treated at 6 mg/kg/day on days 8 through 13, and at 25 and 50 mg/kg/day on days 14 through 18 of gestation. Dilatation of the lateral and third ventricles was observed in all of the male offspring of dams treated with FrdU at 6 mg/kg/day on days 8 through 13 of gestation, when inspected at 12 and 17 weeks of age. In the subsequent study, ICR mice were treated intraperitoneally with FrdU at 6.25-100 mg/kg on day 12 of gestation, and the fetuses obtained 24 h after treatment. Histological observation was performed in the ventricular zone of telencephalon, and in the ependymal and mantle layers of diencephalon in the fetal brain. The incidence of pyknotic cells in these areas was increased linearly with increasing FrdU dose. From these results and our previous findings, we suggest that damage to the central nervous system, a substantial neuronal deficit, resulting from excessive cell death in the developing brain may lead to reproductive dysfunction after puberty.     

Effects of prenatal exposure to cocaine on conditional discrimination learning in adult rats.

Adult male rats that were gestationally exposed to cocaine and control offspring were trained on an instrumental conditioning task for assessment of the acquisition and reversal of an appetitive conditional discrimination based on olfactory cues. Offspring were derived from Sprague-Dawley dams that had received subcutaneous/ly (sc) injections of 40 mg/kg/3 cc cocaine hydrochloride (C40) daily on Gestational Days 8–20, pair-fed (PF) dams that were injected with saline, nutritional control dams (NC) that received saline injections, and nontreated control dams (LC). There were no differences among the prenatal treatment groups in acquisition of the barpress response or response rate throughout all phases of training. All prenatal treatment groups required approximately the same number of sessions to criterion on the initial odor discrimination. In contrast, adult C40 offspring required more sessions to acquire the reversal of the conditional discrimination than did animals from the other treatment groups (PF, NC, and LC). In addition, even at criterion performance for acquisition of the reversal discrimination, C40 animals exhibited lower accuracy on the 1st 10 responses and made significantly more errors before the 1st reward. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

U-69593, a kappa opioid receptor agonist, decreases cocaine-induced behavioral sensitization in female rats.

This study was designed to investigate if the kappa opioid system regulates the locomotor response to cocaine in the female rat and to determine if the effect is dependent on estradiol treatment. Adult rats were ovariectomized (OVX) and half received an estradiol (OVX-EB) implant. After a week, rats were injected for 5 consecutive days with vehicle or with the kappa opioid receptor (KOPr) agonist U-69593 (0.16, 0.32, and 0.64 mg/kg) 15 min prior to cocaine injection (15 mg/kg). Following a 7-day drug-free period, rats were challenged with cocaine (Day 13). The locomotor response to cocaine was measured on Days 1, 5, and 13. U-69593 (0.32 mg/kg) decreased cocaine-induced locomotor activity in drug-na?ve OVX rats and in those that received the OVX-EB implant. These results indicate that the acute effects of U-69593 are independent of estradiol treatment. Repeated exposure to U-69593 (0.32 mg/kg) prior to cocaine decreased the development of behavioral sensitization in OVX-EB-implanted rats. This decrease in cocaine-induced hyperlocomotion persisted after 1 week of cocaine withdrawal. These data indicate that the KOPr system participates in estradiol modulation of cocaine-induced behavioral sensitization in the female rat. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Cocaine sensitization can accelerate the onset of peak cocaine behavioral effects

The development of sensitization to the behavioral effects of cocaine occurs with repeated intermittent usage. In the present study rats were given five daily i.p. injections of cocaine (10 mg/kg) immediately prior to placement in an open-field environment for 20 min to induce cocaine sensitization. Control groups received saline injections or cocaine injections (10 mg/kg) 30 min after testing in the home cage. One week later the animals were given a challenge test with 10 mg/kg cocaine. The animals that had received cocaine in the test environment exhibited a more rapid onset of cocaine-induced behavioral effects than either animals previously treated with saline or animals that had received cocaine in the home cage. In a second experiment, the same sensitization protocol was followed except that during the interval between the end of the cocaine/saline treatments and the challenge test, the animals were given six daily 20-min saline tests to assess the contribution of differential habituation and/or Pavlovian conditioning to the sensitization effect. Neither habituation or Pavlovian conditioning altered the more rapid onset of cocaine stimulant effects induced by repeated cocaine treatments. It is suggested that the faster onset of cocaine effects is another way in which cocaine sensitization contributes to cocaine abuse liability.     

Demonstration of a carrier state for Cowdria ruminantium in wild ruminants from Africa

We recently conducted a study of the behavioral effects of combined cocaine and ethanol in genetically defined mice. Male and female C57BL/6 (B6) and DBA/2 (D2) were tested in an automated activity monitor on 2 consecutive days. On day 1, all animals received an IP injection of sterile saline and were placed into the activity monitor for 30 min. Behaviors measured were total distance traveled, stereotypy, nosepokes, and wall-seeking. On day 2, all animals were tested again for 15 min following injection of one of the following: saline, 10% v/v ethanol at 2.0 g kg(-1) or 2.0 g kg(-1) ethanol plus 5, 15, or 30 mg kg(-1) cocaine. Cocaine alone at the same doses was injected into separate groups of animals. For the B6 strain, the overall effect of ethanol was to reduce cocaine-induced locomotor stimulation; no consistent effect of ethanol on cocaine-induced locomotion was observed in D2 mice. Cocaine-induced inhibition of nosepokes in both strains and sexes was partially reversed by ethanol. Ethanol also partially reversed cocaine-elevated stereotypy in both strains and both sexes. In B6 mice, cocaine-increased wall seeking tended to be reversed by coadministration of ethanol, whereas no consistent pattern was observed in the D2s. Results from this study suggest that the several measures affected by cocaine (locomotor activity, stereotypy, exploration, thigmotaxis) were, in turn, differentially affected by concurrent treatment with ethanol. Furthermore, our results point to genetic-based differences in ethanol's effects on cocaine-related behaviors. We address the implications for combined ethanol and cocaine use in humans.     

Prenatal cocaine exposure induces deficits in Pavlovian conditioning and sensory preconditioning among infant rat pups.

Offspring derived from Sprague-Dawley dams that received daily sc injection of 40 mg/kg 3 cc–2 cocaine hydrochloride (C40) or saline (LC) from Gestational Days 8–20 were tested for first-order Pavlovian conditioning and sensory preconditioning at Postnatal Days 8 (P8), P12, and P21. Although C40 dams gained significantly less weight than LC dams, pup body weights did not differ between the 2 groups. Significant sensory preconditioning was obtained at P8 and P12 (but not at P21) in LC offspring, confirming previous reports (e.g., L. P. Spear et al; see record 1989-35900-001) of decline in performance in this task during ontogeny. In contrast, C40 offspring failed to exhibit sensory preconditioning at any test age. In addition, C40 pups tested at P8 did not display significant first-order conditioning. Taken together these results suggest a more general deficit in cognitive functioning rather than a delay in cognitive development in prenatally cocaine-exposed offspring. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Prenatal cocaine but not prenatal malnutrition affects foster mother-pup interactions in rats

The separate and combined effects of prenatal cocaine exposure and malnutrition on mother-pup interactions in rats were assessed daily from postnatal day 2 to day 21. Sprague-Dawley dams were fed a diet of low protein content (6% casein), an isocaloric diet of adequate protein content (25% casein, control), or a laboratory chow diet prior to mating and throughout pregnancy. Within each diet group, rats received either cocaine injections (30 mg/kg IP two times per week prior to mating and then 30 mg/kg SC daily from days 3 to 18 of pregnancy) or saline injections. Litters were fostered on the day of birth to control mothers (i.e., nondrug-exposed dams fed the control or chow diet). Foster mothers fed the 25% casein diet showed increased contact with cocaine-exposed pups compared with nondrug-exposed pups in the second postnatal week but lower levels as the pups approached weaning. Passive nursing was increased in dams caring for prenatally malnourished, cocaine-exposed pups compared with those caring for similar pups with no drug exposure. Chow-fed mothers did not differ in their behavior towards pups with or without prenatal cocaine treatment. Prenatal cocaine and malnutrition independently compromised birth weight and various reflexive milestones but the attainment of physical milestones was affected only by prenatal cocaine. There were no additive effects of the two prenatal insults on any measure of mother-pup interaction or pup development.     

Renal hemodynamic responses to dynamic exercise in rabbits

Cardiovascular hemodynamics, including renal blood flow, were measured in rabbits with one intact and one denervated kidney during various intensities of treadmill exercise. Within the first 10 s of exercise, there was rapid vasoconstriction in the innervated kidney associated with decreases in renal blood flow (range -10 to -17%). The vasoconstriction in the innervated kidney was evident at all workloads and was intensity dependent. There was no significant vasoconstriction or change in renal blood flow (range 0.5 to -3.1%) in the denervated kidney at the onset of exercise. However, a slowly developing vasoconstriction occurred in the denervated kidney as exercise progressed to 2 min at all workloads. Examination of responses to exercise performed under alpha-adrenergic blockade with phentolamine (5 mg/kg iv) revealed that the vasoconstriction in the innervated kidney at the onset of exercise and the delayed vasoconstriction in the denervated kidney were due primarily to activation of alpha-adrenergic receptors. In addition, a residual vasoconstriction was also present in the innervated kidney after alpha-adrenergic blockade, suggesting that, during exercise, activation of other renal vasoconstrictor mechanisms occurs which is dependent on the presence of renal nerves.     

The role of corticotropin-releasing factor and corticosterone in stress- and cocaine-induced relapse to cocaine seeking in rats

We have shown previously that footshock stress and priming injections of cocaine reinstate cocaine seeking in rats after prolonged drug-free periods (Erb et al., 1996). Here we examined the role of brain corticotropin-releasing factor (CRF) and the adrenal hormone corticosterone in stress- and cocaine-induced reinstatement of cocaine seeking in rats. The ability of footshock stress and priming injections of cocaine to induce relapse to cocaine seeking was studied after intracerebroventricular infusions of the CRF receptor antagonist D-Phe CRF12-41, after adrenalectomy, and after adrenalectomy with corticosterone replacement. Rats were allowed to self-administer cocaine (1.0 mg/kg/infusion, i.v) for 3 hr daily for 10-14 d and were then placed on an extinction schedule during which saline was substituted for cocaine. Tests for reinstatement were given after intermittent footshock (10 min; 0.5 mA) and after priming injections of saline and cocaine (20 mg/kg, i.p.). Footshock reinstated cocaine seeking in both intact animals and animals with corticosterone replacement but not in adrenalectomized animals. The CRF receptor antagonist D-Phe CRF12-41 blocked footshock-induced reinstatement at all doses tested in both intact animals and animals with corticosterone replacement. Reinstatement by priming injections of cocaine was only minimally attenuated by adrenalectomy and by pretreatment with D-Phe CRF12-41. These data suggest that brain CRF plays a critical role in stress-induced, but only a modulatory role in cocaine-induced, reinstatement of cocaine seeking. Furthermore, the data show that although reinstatement of cocaine seeking by footshock stress requires minimal, basal, levels of corticosterone, stress-induced increases in corticosterone do not play a role in this effect.