Biomedical subjects

J R Nation

Publications and source records attributed to J R Nation.

At least 19 recordsLinked to original sources

PubMed2001

The effects of perinatal exposure to lead on the discriminative stimulus properties of cocaine and related drugs in rats.

RATIONALE: Developmental lead exposure may alter responsiveness to cocaine well into adulthood, and ultimately influence drug-use patterns. OBJECTIVES: The present study examined the effect of perinatal lead exposure on the discriminative stimulus properties of cocaine. METHODS: Female rats were treated with 0, 8, or 16 mg lead daily for 30 days before breeding with untreated males. This exposure regimen continued through gestation and until postnatal day (PND) 21, i.e., weaning. At PND 60 male pups were trained to discriminate between saline and cocaine (5 mg/kg) injections. After acquisition, a series of generalization/substitution tests were performed using a cumulative dosing procedure. RESULTS: Developmental lead exposure produced subsensitivity to SKF-82958 (D1-like dopamine receptor agonist), quinpirole (D2-like dopamine receptor agonist), and apomorphine (mixed D1-like/D2-like dopamine receptor agonist); but no differences were evident among lead-treatment groups on generalization/substitution tests with cocaine, d-amphetamine, or GBR-12909. Furthermore, when the kappa-opioid receptor agonist U69,593 was administered prior to cocaine (5 mg/kg), generalization to the cocaine stimulus decreased in control rats, but generalization in lead-exposed rats was not altered. Group differences were not evident in tolerance or recovery of tolerance to cocaine following repeated cocaine administration (60 mg/kg per day for 14 days). Furthermore, no differences were found across groups in concentrations of lead in brain, although pups exposed to 16 mg lead had slightly elevated blood lead concentrations (<7 microg/dl). CONCLUSIONS: These results further a growing research literature that suggests developmental lead exposure can produce long-lasting changes in drug responsiveness, even after exposure to the toxicant has been discontinued.

Animals↗

PubMed2001

Low-level lead exposure and intelligence in children.

Numerous prospective and cross-sectional studies of the relation between low-level lead exposure and cognitive functioning in children have suggested that intellectual and academic performance declines as lead burdens increase. Kaufman [Arch. Clin. Neuropsychol. (2001)] raises questions regarding interpretive issues along these lines, and therein challenges the wisdom of using the available lead/IQ data complex as an essential element of the decision-making process that leads to policy statements. In this article, we address some of the concerns expressed by Kaufman, and conclude that each of his five points are logically or statistically flawed, as is his overall strategy of critiquing individual studies after methodologically sound meta-analyses have been performed. Kaufman is perhaps correct that the findings from correlational research on low lead levels and IQ loss should be interpreted with caution, but the caution extends equally if not more greatly in the direction of previous research having underestimated the relationship between the two variables in question.

Comment↗

PubMed2000

Perinatal exposure to lead attenuates the conditioned reinforcing properties of cocaine in male rats.

The purpose of this study was to examine the effects of developmental lead exposure on drug responsiveness later in the life cycle. Adult female rats were gavaged daily with 0, 8, or 16 mg lead for 30 days before breeding with non-exposed males. The respective exposure regimens were maintained throughout gestation and lactation (perinatal exposure). In Experiment 1, at postnatal day (PND) 30 or 90, pups were trained with 0, 1.25, 2.5, or 5 mg/kg cocaine HCl (IP) in a biased conditioned place preference (CPP) procedure. At both PND 30 and 90, an attenuation in CPP was present in animals exposed to 8 or 16 mg lead relative to control rats. Using an identical lead-exposure regimen, a conditioned place aversion (CPA) procedure with 0, 10, 20, or 40 mg/kg lithium chloride (IP) was employed for Experiment 2. No significant differences were present among pups from each lead-exposure group conditioned and tested at PND 30 or 90, thus suggesting that an impairment of associative mechanisms was not solely responsible for the pattern of attenuation present in Experiment 1. Subsequent analyses of blood-lead in all experiments demonstrated concentrations below 5 microg/dl for all animals at PND 30 and below detectable limits (<1 microg/dl) at PND 90. The findings suggested attenuation in cocaine reinforcement with perinatal lead exposure even though the metal apparently had gained clearance from soft tissue.

Animals↗

PubMed2000

Differential effects of adult and perinatal lead exposure on morphine-induced locomotor activity in rats.

The effects of adult and perinatal lead treatment on the development of locomotor sensitization produced with repeated morphine administration was investigated. In Experiment 1, adult male rats received a diet containing 250 ppm lead acetate or a control diet for 43 days. Animals then received 10 mg/kg morphine sulfate or water vehicle (ip) and locomotor activity was monitored for 14 consecutive days. While both control and lead-exposed animals demonstrated a locomotor sensitization to morphine, the magnitude of the increased locomotor response was reduced in lead-treated animals. Subsequent analysis of blood-lead in the adult lead-exposed animals indicated residue levels ranging between 20 and 30 microg/dl. In Experiment 2, adult female rats were treated daily with 0, 8, or 16 mg lead via gavage for 30 days before breeding with non-exposed males. Lead exposure in dams continued through gestation and until pups were weaned at postnatal day (PND) 21. At PND 60, male offspring received morphine or vehicle challenges identical to those described in Experiment 1. Animals perinatally exposed to dams receiving 16 mg lead daily demonstrated an enhanced behavioral response to morphine relative to control animals. Analysis of offspring blood indicated lead levels below detectable limits (<1 microg/dl) for all animals. The results suggest exposure to lead at environmentally relevant levels produces long-lasting changes in drug-induced behavior, and the developmental period in which lead exposure occurs is a significant contributor to the manifestation of these effects.

Animals↗

PubMed2000

Developmental lead exposure alters the stimulatory properties of cocaine at PND 30 and PND 90 in the rat.

The aim of this study was to examine the effects of perinatal lead exposure on locomotor responding following acute and repeated cocaine challenges (sensitization). Adult female rats were gavaged daily with 0, 8, or 16 mg lead acetate for 30 days prior to breeding. This exposure regimen was maintained throughout gestation and lactation (perinatal exposure). On Day 21, male pups were weaned and lead exposure was discontinued for the remainder of the study. Beginning on postnatal day (PND) 30 or PND 90, and continuing for 14 successive days, separate groups of perinatally-exposed animals were presented with challenges of 10 mg/kg cocaine HCl (i.p.), and tested for locomotor responding. Following this testing period, dose-effect profiles were determined, with animals receiving daily injections of 0, 10, 20, and 40 mg/kg cocaine. The results indicated that both at PND 30 and PND 90 lead-exposed animals were less responsive to the initial administration of cocaine, but exhibited a supersensitivity to the stimulatory effects associated with repeated administration of cocaine, i.e., behavioral sensitization to cocaine was augmented by perinatal lead exposure. Analyses of blood lead levels following the completion of testing revealed that lead levels were below detectable limits for all animals (< 1 microg/dl). Collectively, these findings show that developmental lead contamination produces changes in cocaine sensitivity long after exposure has been discontinued and the toxicant has gained clearance from blood.

Animals↗

PubMed2000

Dietary cadmium exposure alters characteristics of training, substitution, and tolerance when morphine is used as a discriminative stimulus.

This study examined the possibility that cadmium, a toxicant in high concentration in all tobacco products, may alter the stimulus properties of morphine. Adult male rats were exposed to regular laboratory chow (Group Control) or chow containing 100 ppm added cadmium chloride (Group Cadmium). Following an initial 30 day exposure period, control and cadmium-exposed animals were trained to discriminate between i.p. injections of 3.00 mg/kg morphine sulfate and vehicle (distilled water) in a two-choice drug discrimination task. Subsequently, the morphine dose-effect generalization function (0.75-6.00 mg/kg) was determined for control and cadmium-exposed animals. Additional substitution tests were conducted with increasing doses of the high efficacy mu agonist fentanyl (0.0016-0.04 mg/kg), the intermediate efficacy mu agonist (-)-metazocine (0.60-5.00 mg/kg), and the kappa agonist (+/-)-bremazocine (0.03-0.12 mg/kg). Also, increasing doses of the selective mu antagonist naloxone (0.0008-0.50 mg/kg) were presented against the training dose of morphine (3.00 mg/kg) and 0.02 mg/kg fentanyl. Finally, training was discontinued, and control and cadmium-exposed animals were injected with 8.00 mg/kg morphine in the home cage every 12 hr for 2 weeks, prior to redetermining the morphine dose effect function. Following a 1 week recovery period where morphine injections were discontinued, a final determination of the morphine dose-effect function was made. The results of the investigation indicated that cadmium exposure, without affecting the rate-changing properties of the drugs, slowed initial acquisition of the morphine discrimination, decreased the potency of selective doses of naloxone with respect to antagonizing the stimulus effects of morphine and fentanyl, and blocked the development of tolerance to morphine. Morphine, fentanyl, and (-)-metazocine generalized (substituted) equally across both groups, while (+/-)-bremazocine failed to substitute for the morphine stimulus in either group. These findings add to the growing literature on the interaction between metal poisoning and drug selection/abuse.

Animals↗

PubMed1999

Sensitization of anorexia and locomotion induced by chronic administration of ephedrine in rats.

Repeated daily administration of the sympathomimetic agent ephedrine (EPH) leads to an augmentation (sensitization) of locomotor activity in rats. The present experiments examined the impact of repeated administration of the (-)- and (+)-EPH enantiomers on feeding in rats to assess whether the anorexic activity of EPH exhibits tolerance or sensitization during chronic exposure and whether the time course of these effects follows that observed in studies of locomotion. Adult male rats were injected once daily for 12 days with either vehicle or 5, 10 or 20 mg/kg (-)-EPH or with 10 or 20 mg/kg (+)-EPH. Horizontal locomotion and diet consumption were assessed for 60 min in an activity chamber. Suppression of feeding and the induction of locomotion were augmented over the first four days of administration of either 10 mg/kg or 20 mg/kg of the (-)-EPH enantiomer. In contrast, repeated administration of 20 mg/kg (+)-EPH resulted in augmentation of appetite suppression but not locomotion. These results confirm and extend the phenomenon of locomotor and feeding sensitization for ephedrine, but suggest that these effects may differ for the two enantiomers of ephedrine.

Animals↗

PubMed1999

Chronic cadmium exposure attenuates conditioned place preference produced by cocaine and other drugs.

Adult male rats were exposed ad lib for 40 days to 100 ppm dietary cadmium chloride (group cadmium) or an identical diet with no added cadmium (group control). Conditioned place preference (CPP) was conducted in a two-chamber apparatus in which all drugs were paired with the least-preferred side as determined by a pretest. In Experiment 1, animals received 0, 2.5, or 5 mg/kg cocaine HCl (IP) for 4 days and vehicle only for 4 days. Control animals showed a place preference for the drug side at 2.5 and 5 mg/kg, while the cadmium-exposed animals showed a preference at 5 mg/kg only. In Experiment 2, animals received 0, 5, or 10 mg/kg of the D1/D2 dopamine receptor agonist apomorphine HCl (SC) for 4 days and vehicle only for 4 days. Control animals showed a place preference at 5 and 10 mg/kg, while metal-exposed animals showed a preference at 10 mg/kg only. To determine the possible effects of alterations of learning mechanisms by cadmium, a conditioned place aversion (CPA) procedure was employed for Experiment 3. Animals received 0, 10, or 40 mg/kg lithium chloride (IP) for 4 days or vehicle only for 4 days. Control animals showed a significant place aversion at 40 mg/kg, while cadmium-exposed animals did not. These findings are discussed within a framework of possible metal-induced disturbance of neurochemical function and/or associative processing.

Animals↗

PubMed1999

The effects of cadmium contamination on the discriminative stimulus properties of cocaine and related drugs.

Rats were exposed to a diet containing 100 ppm cadmium chloride or a control diet. At 52 days of exposure, rats were trained to discriminate between saline and 5 mg/kg cocaine injections. After acquisition training, successive substitution tests were conducted using cocaine, the indirect dopamine agonist d-amphetamine, the mixed D1-D2 agonist apomorphine, SKF 38393 and SKF 82958 (both preferential D1 agonists), quinpirole (a preferential D2 agonist), GBR 12909 (a dopamine reuptake inhibitor), procaine (a local anesthetic), and morphine (an opiate). The results showed that cadmium-exposed rats were slower to acquire the saline-cocaine discrimination than controls. Moreover, cadmium contamination reduced substitution when apomorphine, SKF 82958, and GBR 12909 were presented during generalization testing. Also, cadmium exposure blocked tolerance to cocaine that was evident in control rats following 14 days of exposure to 60 mg/kg/day cocaine.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed1998

Effects of (-)-ephedrine on locomotion, feeding, and nucleus accumbens dopamine in rats.

The intent of the present study was to determine the effects of systemic injections of the sympathomimetic agent ephedrine (EPH) on extracellular dopamine (DA) levels within the rat nucleus accumbens (NAC) and to compare these effects with those of EPH on locomotion and on feeding. In experiment 1, adult male rats were prepared with an indwelling 3 mm microdialysis probe positioned within the NAC. The rats were injected (i.p.) with vehicle, 5, 10, or 20 mg/kg (-)-EPH with dialysates collected every 20 min for 100 min after drug injection. Systemic injections of 5, 10 or 20 mg/kg (-)-EPH significantly enhanced extracellular levels of NAC DA over baseline by 79%, 130%, and 400%. Systemic injection of 20 mg/kg EPH significantly reduced NAC levels of DOPAC and HVA by 37% and 31%. The effects of EPH on brain dopamine activity were stereospecific given that an additional group of rats injected with 20 mg/kg (+)-EPH exhibited smaller changes in NAC DA (< 25%), DOPAC (< 10%), and HVA levels (< 20%) than did rats injected with 20 mg/kg (-)-EPH. In experiment 2, adult male rats were injected (i.p.) with 0, 5, 10, or 20 mg/kg (-)-EPH prior to placement in automated activity chambers. Total distance traveled was significantly increased by 10 and 20 mg/kg (-)-EPH, but not by 5 mg/kg (-)-EPH. In experiment 3, adult male rats were injected (i.p.) with 0, 2.5, 5, or 10 mg/kg (-)-EPH or with 0, 2.5, 5, or 10 mg/kg (+)-EPH prior to a 30-min feeding test. Although each EPH enantiomer decreased feeding, (-)-EPH was more potent in feeding suppression than was (+)-EPH. The present results suggest that EPH may alter locomotion and feeding via an indirect action on brain dopamine activity.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1998

Repeated administration of ephedrine induces behavioral sensitization in rats.

Systemic injection of the sympathomimetic agent ephedrine (EPH) stimulates locomotion in drug-naive rats, an effect that may be dependent on the enantiomer of EPH employed [(-)-EPH or (+)-EPH]. The present experiments examined the effects of repeated EPH exposure on locomotion in rats to assess whether these treatments result in drug tolerance or sensitization. In experiment 1, adult male rats were injected once daily with 0, 10, 20, or 40 mg/kg (-)-EPH (IP) on each of 11 days. Locomotor activity was assessed for 60 min after drug injection. Acute exposure to (-)-EPH treatment increased locomotion for animals receiving 20 or 40 mg/kg, and this effect was augmented after 11 days of drug administration. A vehicle-only injection was given to all animals on day 12 to determine the influence of environmental cues on sensitization. On day 13, all rats were injected with 10 mg/kg cocaine HCl to assess whether repeated (-)-EPH exposure produced a cross-sensitization to cocaine (10 mg/kg, IP). Only rats treated repeatedly with 40 mg/kg (-)-EPH exhibited increases in cocaine-stimulated locomotion relative to saline-treated rats. In experiment 2, repeated exposure to (+)-EPH, 40 mg/kg, but not 20 mg/kg, increased activity and demonstrated the development of sensitization. Cross-sensitization to cocaine (10 mg/kg, IP) was not evident following treatment with either concentration of (+)-EPH. There was no evidence that contextual events alone played a role in the effects observed here.

Animals↗

PubMed1997

Chronic cadmium exposure attenuates the conditioned reinforcing properties of morphine and fentanyl.

Adult male rats were exposed ad libitum for 40 days to 100 ppm cadmium chloride through their diet, or an identical diet with no added cadmium. Conditioned place preference (CPP) was conducted in a 2-chamber apparatus in which all drugs were paired with the least-preferred side as determined on a pre-test. In Experiment 1. control and cadmium-exposed rats received 0, 0.6, 1.25, 2.5, or 5 mg/kg morphine sulfate (i.p.) for 4 days, and vehicle only for 4 days. Control animals showed a preference for the drug-paired side at 1.25, 2.5, and 5 mg/kg while the cadmium-exposed rats showed a preference at 5 mg/kg only. In Experiment 2, rats were implanted with cannulae into the lateral ventricles and 0, 2, 5 micrograms morphine sulfate was administered intracerebroventricularly (i.c.v.). An attenuation by cadmium again was observed, as control animals showed a place preference at 2 and 5 micrograms and cadmium-exposed animals showed preference at 5 micrograms only. In Experiment 3, increasing doses of the mu-opioid receptor agonist fentanyl (0, 0.0004, 0.004, and 0.04 mg/kg) were systemically administered (s.c.) and rats tested for CPP. While cadmium animals showed place preference only at 0.04 mg/kg, control animals showed preference at 0.0004, 0.004, and 0.04 mg/kg. These findings are discussed within the framework of metal-induced disturbance of neurochemical function and/or associative processing, and the implications that such disturbances may have for drug seeking and taking.

Animals↗

PubMed1997

Brain and plasma levels of cocaine and benzoylecgonine in lead-expose and cadmium-exposed rats following acute or chronic intraperitoneal administration of cocaine.

Previous investigations of metal/cocaine interactions have shown that chronic oral exposure to inorganic lead or cadmium attenuates the psychoactive effects of acute or repeated administration of cocaine. The purpose of this investigation was to assess the possibility that such interactive effects may derive from metal-induced disturbances in cocaine pharmacokinetics, i.e., delivery of cocaine to critical biologic sites may be disrupted by metal contamination. In this study, adult male rats were exposed to purified diets containing 250 ppm lead acetate (Group Lead), 100 ppm cadmium chloride (Group Cadmium), or unadulterated laboratory chow (Group Control); n = 48/exposure condition. Following ad libitum access to their respective diets in the home cage for 45 days, half the animals from each exposure regimen received single daily IP injections of 5, 10, or 20 mg/kg cocaine HCl for a period of 7 days (n = 8/group). The remaining half the animals received repeated daily injections of saline during this pretreatment phase. On the day following pretreatment, animals previously receiving cocaine injections were administered a single cocaine test challenge at a dose equal to that received in pretreatment. Similarly, saline pretreatment animals received either 5, 10, or 20 mg/kg cocaine. The results of this investigation did not reveal reliable evidence of metal-related differences in brain levels of cocaine. Plasma cocaine and benzoylecgonine (BE) levels also were essentially the same for control and metal-exposed animals. The failure to show that lead or cadmium alters the disposition of cocaine in brain or plasma underscores the need to pursue alternative accounts of metal/cocaine interactions.

Animals↗

PubMed1997

Chronic exposure to cadmium attenuates behavioral sensitization to morphine.

The purpose of this investigation was to assess the impact of dietary cadmium on morphine-induced changes in locomotor activity. Adult male rats were exposed ad libitum to an adulterated food supply containing 100 ppm added cadmium chloride, or an identical diet containing no added cadmium, for 45 days prior to testing for the locomotor activating effects of successive daily morphine administration (0, 5, 10, or 20 mg/kg per session) on locomotor activity. On day 1 of testing, increasing doses of morphine produced a dose-related suppression of activity, and this sedative effect was greater in control than in cadmium-exposed animals. Repeated morphine administration resulted in tolerance to the sedative effects of the drug, and a systematic elevation of locomotor activity over the 14-day testing period was observed, with the augmentation (sensitization) effect more pronounced in control than cadmium-exposed animals. There was no indication that conditioning (context) events played a role in the effects observed here.

Animals↗

PubMed1997

Effects of chronic lead exposure on cocaine-induced disturbance of fixed-interval behavior.

Chronic lead exposure has been shown to attenuate cocaine-induced increases in extracellular dopamine levels in the region of the nucleus accumbens, and antagonize the locomotor stimulating effects of the drug. The purpose of this study was to determine if similar lead-induced disturbances in the effects of cocaine include the impact of the drug on schedule-controlled responding. Adult male rats exposed ad libitum to water containing 500 ppm lead acetate (Group Lead), or a comparable concentration of sodium acetate (Group Control), were placed on a restricted diet (12-15 g food/day) prior to commencing fixed-interval (F1-5 min) schedule training on Day 33 of exposure. After 27 days of operant training, animals received a sequence of no injection, saline injection, and cocaine injection tests, repeating the sequence for 3, 10, 20 and 40 mg/kg cocaine HCl (i.p.). Local rates were determined for successive 30 s segments of the interval and the pattern of responding was compared under conditions of saline and cocaine injection. For both groups, cocaine increased responding, especially early in the interval. However, the rate enhancing effects of cocaine were less pronounced in lead-exposed animals than controls, at least at the 20 mg/kg dose. These data extend earlier findings and accent the need to examine further the interactive relations between the external chemical environment and drug sensitivity.

Animals↗

PubMed1997

(R)-methanandamide, but not anandamide, substitutes for delta 9-THC in a drug-discrimination procedure.

Fourteen male rats were trained to discriminate between injections of 2 mg/kg delta-9-tetrahydrocannabinol (delta 9-THC) and vehicle in a 2-lever operant drug-discrimination paradigm. Following training, substitution tests using a cumulative dosing procedure revealed that anandamide (0.5-16 mg/kg ip), the putative endogenous camabinoid receptor ligand, failed to generalize to the discriminative stimulus properties of the training dose of delta 9-THC. However, dose-dependent generalization to the delta 9-THC cue was observed following administration of both CP-55,940 (0.05-0.8 mg/kg ip), a synthetic cannabinoid, and (R)-methanandamide (0.5-8 mg/kg ip), a metabolically stable analog of anandamide. Collectively, these results demonstrate a cannabinoid-specific in vivo effect of an anandamide compound and suggest that the naturally occurring form of anandamide may be metabolized too rapidly to produce a cannabimimetic intercceptive state when administered peripherally.

Animals↗

PubMed1996

Chronic lead exposure attenuates sensitization to the locomotor-stimulating effects of cocaine.

Adult male rats were exposed to a water supply containing 500 ppm lead acetate (Lead Group), or a comparable concentration of sodium acetate (Control Group), for 30 days prior to commencing testing for behavioral sensitization to cocaine. Locomotor activity (total distance (cm) travelled) was monitored for animals in both exposure conditions across 14 daily 1 h test sessions. Across successive sessions, baseline activity was recorded for a 20-min baseline period, at which time half the animals from each exposure condition received an i.p. injection of saline or 10 mg/kg cocaine HCl. Post-injection locomotor responding was then monitored for 40 min prior to returning the animal to the home cage where the respective watering regimens remained intact. On the day following the completion of sensitization testing (day 15 of testing), animals in all groups received a saline injection, and on day 16 of testing all animals received a 10 mg/kg cocaine challenge. The results showed that repeated experience with cocaine augmented the stimulatory effects of the drug in both control and lead-exposed animals. However, this behavioral sensitization effect was slower to develop and less pronounced in lead-exposed animals. These data are discussed within the context of lead-related changes in sensitivity to cocaine.

Animals↗

PubMed1995

Cadmium exposure attenuates the initiation of behavioral sensitization to cocaine.

Employing a paired-watering procedure to control for differential fluid intake confounds, adult male rats were exposed in the home cage to water containing 100 ppm cadmium chloride, or a control solution containing no added cadmium chloride. On Day 61 of exposure to their respective watering regimens, half the animals from each condition received 12 repeated daily i.p. injections of 10 mg/kg cocaine-HCl, or saline. Locomotor activity (total distance traveled) was recorded in Digiscan Activity Monitors for a 20-min baseline period prior to each injection, and for a 40-min period post-injection. On Day 13 of testing, all animals received saline injections only in the test chambers, in an effort to evaluate the role of conditioned cues in the expression of cocaine sensitization. On Day 14-16 of testing, all animals received successive daily challenges of 10, 20, and 40 mg/kg cocaine in the test chamber. The results indicated that the initiation (development) of behavioral sensitization to 10 mg/kg cocaine was attenuated in cadmium-exposed rats. Moreover, the supersensitivity to higher doses of cocaine during dose-effect testing that was registered by control animals pretreated with cocaine, was not evident in cadmium-exposed pretreatment animals. These data suggests that environmental contaminants may alter drug responsiveness, and thereby may influence patterns of drug selection and use.

Animals↗