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.

Persistence training: a partial reinforcement procedure for reversing learned helplessness and depression.

This article examines the relative merits of either partial or continuous (total) success therapy as a device for reversing learned helplessness and depression in humans. College students experienced (a) no treatment followed by either abbreviated (20 trials) or extended (40 trials) continuous success therapy, (b) soluble problems followed by either abbreviated or extended continuous success therapy, (c) insoluble problems followed by either abbreviated or extended continuous success therapy, or (d) insoluble problems followed be either abbreviated or extended partial success therapy. Subsequently, subjects in all eight groups received 40 escape-extinction trials in which aversive tones were not controllable. The results of this experiment indicated that both continuous and partial success schedules were effective in reversing depressed responding (helplessness) induced by prior exposure to insoluble problems. However, only the partial success therapy schedules produced persistent escape responding in extinction. Also, across therapy procedures, extended therapy generated more response persistence in escape extinction than did abbreviated therapy. Theoretical implications of these results are discussed, and a compatible new treatment program, labeled persistence training, is introduced.

Brain stimulation reward following chronic lead exposure in rats.

Adult male rats were exposed to drinking water containing either 500 parts per million (ppm) lead acetate or an equal concentration of sodium acetate for 80 days. Bipolar electrodes were then implanted into the medial forebrain bundle (MFB), and rats were allowed to recover for 7 days. On Day 8 postsurgery, control and lead-treated rats were placed in an operant chamber and shaped to press a lever to receive 200-ms trains of current. Data from a range of current intensities and frequencies were recorded to obtain threshold values for each rat, defined as the stimulation needed to support half-maximal lever responding. Results indicated that chronic lead exposure attenuated the reinforcing effect of brain stimulation. Because of the large number of reward systems mediated by the MFB-nucleus accumbens pathway, these data suggest that a variety of motivational phenomena may be affected by contaminant exposure.

Dietary lead increases ethanol consumption in the rat.

Rats fed either a diet containing 500 ppm (parts per million) Pb (as lead acetate) or an unadulterated control diet for 50 days were offered a 15% ethanol (ETOH) solution in a nonchoice (one-bottle) test situation. The results from this test indicated that Pb-diet animals consumed greater amounts of the ETOH solution than did controls. In a subsequent choice (three-bottle, two-fluid) test situation offering a nonpreferred ETOH solution or tap water as alternatives, Pb-diet animals once again ingested greater amounts of the ETOH solution. These findings are discussed in terms of possible Pb-induced increases in emotionality and the potential stress-reduction properties of ETOH.

Effects of acute trimethyltin exposure on appetitive acquisition and extinction performance in the adult rat.

Adult male rats were given one intragastric infusion of either 7 mg/kg trimethyltin chloride (dose calculated as the base of trimethyltin [TMT]) or physiological saline. Twenty-one days after dosing, subjects from each condition were divided into two equal-sized groups and trained with either partial (PRF) or continuous (CRF) reinforcement in a straight alley maze. The acquisition phase of training, lasting 40 trials (4 trials/day), was followed by 20 trials of extinction training (4 trials/day). Analyses performed on total speed revealed that TMT-treated subjects performed at lower levels during acquisition than controls regardless of schedule condition. Also, the rate of resistance to extinction was significantly reduced for treated subjects compared with that of controls regardless of the training schedules used during acquisition. A partial reinforcement extinction effect was observed for both control and TMT-treated subjects, that is, independent of dose regimen; PRF training occasioned greater persistence during extinction than did CRF training. These findings are discussed in terms of their implications for contemporary empirical and theoretical issues relating to TMT-induced hippocampal lesions.

Effects of combined lead and cadmium exposure: changes in schedule-controlled responding and in dopamine, serotonin, and their metabolites.

Adult male rats were maintained on 1 of 4 ad-lib diets: Group Control-Diet received a normal laboratory diet that contained no added chemicals: Group Lead-Diet received a diet containing 500 ppm (parts per million) lead: Group Cadmium-Diet received a diet containing 100 ppm cadmium: and Group Lead-Cadmium-Diet received a diet containing both 500 ppm lead and 100 ppm cadmium. After 60 days of exposure to their respective diets, animals were placed on restricted diets (15 g/day) of the identical food received during the exposure period. Each animal was trained to lever press on a fixed-interval 1-min schedule for 21 sessions (1 session day). The results of schedule training showed that lead alone or cadmium alone was associated with increased lever pressing relative to control diet. However, when lead and cadmium were exposed jointly, performance was not significantly different from control performance. Similar attenuation of effects were observed for central neurotransmitter functions. Specifically disturbances in dopamine and serotonin turnover that were produced by lead alone were attenuated by the cotreatment of cadmium and lead. Possible accounts of the apparent antagonism between cadmium and lead are discussed.

Effects of cadmium on cocaine-induced changes in activity.

Adult male rats were exposed to a diet that contained 100 parts per million added cadmium or a control diet for 72 days before being tested in a Digiscan activity monitor. During the 1-hr test period, each animal's baseline activity levels were recorded for 20 min. Animals then received intraperitoneal injections of 0, 10, 20, or 40 mg/kg cocaine HCl, and their activity levels were recorded for the remaining 40 min of the test session. The results showed that the 10, 20, and 40 mg/kg doses of cocaine produced behavioral activation in the control-diet animals. For cadmium-treated animals, cocaine-induced behavioral changes at the 10 mg/kg dose were not observed, but increased activity was evident at the two higher doses.

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.

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.

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.

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.

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.

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.

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.

Attenuation of cocaine-induced elevation of nucleus accumbens dopamine in lead-exposed rats.

Fourteen adult male rats were placed on an ad lib watering regimen where they received water containing 500 ppm lead acetate (group lead) or an equivalent concentration of sodium acetate (group control) for 61 days. Subsequently, a microdialysis cannula was surgically implanted in the nucleus accumbens. Following recovery, the seven animals in group lead and the seven animals in group control were presented with a challenge of 10 mg/kg cocaine HCL (IP). Dopamine efflux was measured prior to and at 20, 40, and 60 min postinjection, using HPLC technology. The results of this experiment showed that cocaine caused a significantly greater increase in extracellular nucleus accumbens dopamine in control animals relative to lead-treated animals.

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.

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.

Ethanol consumption and free operant avoidance performance following exposure to dietary lead.

Rats were exposed ad libitum to a diet containing either 500 ppm lead (Group Lead-Diet) or a control diet with no added lead (Group Control-Diet). On Day 60 both groups were presented with a 15% ethanol solution (nonchoice test) in the home cage for five days prior to placement on a choice test that presented animals with a 10% ethanol solution and tap water. Concurrently with the choice test in the home cage, animals were placed in operant chambers for one hr (pre-avoidance) prior to a 30 min free operant avoidance session (avoidance) and remained there for one hr (post-avoidance) after training. Throughout avoidance training, the choice test was conducted in the chamber as well as the home cage. In addition to evidence of greater ethanol consumption by Group Lead-Diet rats, the results showed that these animals lever pressed more frequently, but not more efficiently, than Group Control-Diet animals.

Conditioned taste aversion in the adult rat induced by dietary ingestion of cadmium or cobalt.

The potential aversive qualities of dietary cadmium chloride (10, 100 mg/kg) or cobalt chloride (20, 100, 200 mg/kg) were evaluated in a conditioned saccharin aversion task. Male Long-Evans hooded rats (n = 42) were trained to drink tap water and ingest 10 grams of chow during daily 60 minute access tests. During the aversion-acquisition phase, a second bottle containing 0.1% sodium saccharin was introduced and the various metal-adulterated diets (10 grams, dose calculated as mg metal base/kg body weight) offered in place of plain chow. During extinction testing, all rats were fed the plain chow. Diets adulterated with cadmium (10 or 100 mg/kg) or cobalt (100, 200 mg/kg) induced marked conditioned saccharin aversions after 2-3 days of exposure and were found to be profoundly resistant to extinction. Both cadmium (100 mg/kg) and cobalt (100, 200 mg/kg) induced a corresponding suppression of intake of adulterated food and significant weight losses. The relation of these aversive effects to the influence of cadmium and cobalt on operant responding for food reward is discussed.

The effects of cadmium on ethanol self-administration using a sucrose-fading procedure.

Rats were exposed for 70 days to either a diet containing 100 ppm cadmium (Group Cadmium) or a control diet with no additives (Group Control). Subsequently, all animals were trained to lever press for a 20% sucrose solution. Across several phases, sucrose was faded out as the reinforcer and gradually replaced with a 10% ethanol solution. A subsequent operant choice (concurrent) test, during which pressing one lever resulted in a dipper presentation of ethanol and the other lever provided water, was followed by a single-lever test where sucrose was reinstated as the reinforcer. The results showed that although cadmium-treated rats lever pressed more than controls during the early phases of the sucrose-fading procedure, animals exposed to cadmium lever pressed at lower rats than controls for ethanol during the concurrent test. There were no group differences on the final sucrose test. The possibility that cadmium may alter sensitivity to ethanol is discussed.