Self-administered cocaine causes long-lasting increases in impulsive choice in a delay discounting task.

Cocaine use is associated with high levels of impulsive choice (preference for immediate over delayed rewards), but it is not clear whether cocaine use causes elevated impulsive choice, or whether elevated impulsive choice is solely a predisposing factor for cocaine use. This study examined the effects of prior cocaine self-administration on rats performing a delay discounting task commonly used to measure impulsive choice. Male Long-Evans rats were implanted with intravenous catheters, and following recovery, were trained to self-administer 30 mg/kg/day cocaine HCl (approx. 0.5 mg/kg/infusion) for 14 consecutive days (a control group received yoked intravenous saline infusions). Following three weeks of withdrawal, all rats were food-restricted and began training on the delay discounting task in standard operant chambers. On each trial, rats were given a choice between two levers. A press on one lever delivered a small food reward immediately, and a press on the other delivered a large food reward after a variable delay period. Rats that self-administered cocaine displayed greater impulsive choice (enhanced preference for the small immediate over the large delayed reward, as reflected by shorter indifference points) compared to controls, but were no different from controls on a "probabilistic discounting" task in which they chose between small certain and large uncertain rewards. These data suggest that self-administered cocaine can cause lasting elevations in impulsive choice, and that the high levels of impulsive choice observed in human cocaine users may be due in part to long-term effects of cocaine on brain function.

Prenatal lead exposure enhances methamphetamine sensitization in rats.

Adult female rats were exposed to lead-free sodium acetate via gavage [0 mg (vehicle control)] or to 16 mg lead as lead acetate for 30 days prior to breeding. Following confirmation of breeding, the female animals continued to be exposed to their respective doses throughout gestation and lactation. When weaned, 16 control and 16 lead-exposed offspring were placed on regular water and food (lead-exposure was discontinued) until postnatal day (PND) 70. At this time, one-half of the control animals and one-half of the lead-treatment animals received intraperitoneal (i.p.) injections of the vehicle (saline) for 10 successive days and the remaining animals in each exposure conditions received daily injections of 1.0 mg/kg (+)-methamphetamine (METH) for 10 days (N=8/group). Locomotion in automated chambers was monitored daily for 45 min post-injection. Subsequently, during dose-effect testing, all animals received consecutive daily i.p. injections of 0, 1.0, 2.0, and then 4.0 mg/kg METH. The results of the experiment showed that both control and lead-exposed animals exhibited heightened locomotor activity (i.e. behavioral sensitization) to the repeated administration of 1.0 mg/kg METH. More importantly, animals developmentally (perinatally) exposed to lead showed more rapid sensitization than did their control counterparts. These data indicate that early lead exposure increases sensitivity to the locomotor-stimulating effects of METH. In contrast, identically exposed lead animals exhibit diminished METH dose-effect responding when tested in an intravenous (i.v.) self-administration paradigm [Rocha A., Valles R., Bratton G.R., Nation J.R. Developmental lead exposure alters methamphetamine self-administration in the male rat: acquisition and reinstatement. Drug Alcohol Depend 2008a;95:23-29, Rocha A., Valles R., Hart N., Bratton G.R., Nation J.R. Developmental lead exposure attenuates methamphetamine dose-effect self-administration performance and progressive ratio responding in the male rat. Pharmacol Biochem Behav 2008b;89:508-514].

Developmental lead exposure attenuates methamphetamine dose-effect self-administration performance and progressive ratio responding in the male rat.

Perinatal (gestation/lactation) lead exposure modifies the reinforcement efficacy of various psychoactive drugs (e.g., cocaine, opiates) across the phases of initial selection, use, and abuse [Nation J.R., Cardon A.L., Heard H.M., Valles R., Bratton G.R. Perinatal lead exposure and relapse to drug-seeking behavior in the rat: a cocaine reinstatement study. Psychopharmacol 2003;168: 236-243.; Nation J.R., Smith K.R., Bratton G.R. Early developmental lead exposure increases sensitivity to cocaine in a self-administration paradigm. Pharmacol Biochem Behave 2004; 77: 127-13; Rocha A., Valles R., Cardon A.L., Bratton G.R., Nation J.R. Enhanced acquisition of cocaine self-administration in rats developmentally exposed to lead. Neuropsychopharmacol 2005; 30: 2058-2064.]. However, changes in sensitivity to methamphetamine across the phases of drug abuse have not been examined in animals perinatally exposed to lead. Because the mainstream popularity of methamphetamine in the United States is increasing and lead exposure continues to be widespread, an examination of this drug and how it may be modified by perinatal exposure to lead is warranted. The studies reported here examined the effects of perinatal lead exposure on adult self-administration of intravenous (i.v.) methamphetamine across the maintenance phase of drug addiction. Experiment 1 examined dose-effect patterns in control and lead-exposed animals. Experiment 2 evaluated control and lead-exposed animals in a progressive ratio task. Female rats were administered a 16-mg lead or a control solution for 30 days prior to breeding with non-exposed males. Exposure continued through pregnancy and lactation and was discontinued at weaning (postnatal day [PND] 21). Animals born to control or lead-exposed dams received indwelling jugular catheters as adults (PND 70) and subsequently were randomly assigned to one of the two studies, using only one male rat per litter for each study. The data showed a general attenuation of the reinforcement efficacy of methamphetamine in animals perinatally exposed to lead, as compared to control animals.

Lobeline attenuates progressive ratio breakpoint scores for intracranial self-stimulation in rats.

The alkaloid lobeline inhibits the function of vesicular monoamine and dopamine transporters and diminishes the behavioral and neurochemical effects of nicotine and amphetamines. In the present study, we examined the interaction of systemic administration of lobeline on breakpoint scores on a progressive ratio (PR) schedule of intracranial self-stimulation (ICSS) of the medial forebrain bundle (MFB). Rats were run in two 30 min sessions, separated by a 10 min timeout period. At the end of the first session, each rat was injected with either 0, 0.5, 1.0 or 2.0 mg/kg (i.p.) lobeline. Positive controls known to suppress and to augment ICSS responding included the adrenergic antagonist prazosin (0, 0.5 and 2.0 mg/kg, i.p.) and the psychostimulant cocaine (0, 1.25, and 5.0 mg/kg, i.p.). Analyses of changes in average PR breakpoint scores between the 2 sessions revealed that lobeline significantly suppressed PR scores at doses of 0.5, 1.0 and 2.0 mg/kg, as did 0.5 mg/kg and 2.0 mg/kg prazosin. These changes are unlikely to reflect motoric effects of these drugs inasmuch as neither lobeline nor prazosin alter locomotion at these doses. In contrast, PR breakpoint scores were significantly increased at 5.0 mg/kg cocaine, a dose that is sufficient to elevate locomotion in the rat. These results are consistent with the view that lobeline modulates brain reinforcement processes.

Developmental lead exposure alters methamphetamine self-administration in the male rat: acquisition and reinstatement.

The rate of acquisition of drug self-administration and the return to drug seeking are important elements of the overall drug profile, and are essential factors in understanding risks associated with drug abuse. Experiment 1 examined the effects of perinatal (gestation/lactation) lead exposure on adult rates of acquisition of intravenous (i.v.) methamphetamine self-administration. Experiment 2 investigated the effects of perinatal lead exposure on drug-maintained responding in a reinstatement (relapse) paradigm. In Experiment 1, female rats were gavaged daily with 0 or 16 mg lead for 30 days prior to breeding with nonexposed males. Lead exposure continued through gestation and lactation and was discontinued at weaning (postnatal day [PND] 21). Male rats born to control or lead-exposed dams were tested daily as adults in an acquisition paradigm that incorporated both Pavlovian and operant components. An initial 3-h autoshaping period preceded a 3-h self-administration period. For 35 daily training sessions i.v. methamphetamine infusions [inf] (0.02 mg/kg) were paired with the extension and retraction of a lever (autoshaping), while inf occurred during self-administration only when a lever press was executed (FR-1). In Experiment 2 animals developmentally exposed to lead were trained on an FR-2 to self-administer methamphetamine (0.04 mg/kg/inf) and then placed on an extinction schedule prior to receiving intraperitoneal (i.p.) priming injections of saline, 0.50, 1.00, or 1.50 mg/kg methamphetamine. The findings from Experiment 1 showed that acquisition was delayed in rats born to lead-exposed dams gavaged daily with 16 mg lead throughout gestation and lactation when a 0.02-mg/kg/inf of methamphetamine served as the reinforcement outcome. Additional data from Experiment 2 indicated priming cues (injections of methamphetamine [i.p.]) administered after extinction were less likely to occasion a return to drug seeking (relapse) in the 16-mg group relative to the 0-mg control group. These results suggest perinatal lead exposure alters patterns of methamphetamine self-administration during the adult cycle.

Differential impact of cocaine on meal patterns in female and male rats.

Female rats, relative to males, exhibit greater behavioral activation to cocaine and other psychostimulants, but the effect of sex and the estrous cycle in modulating the hypophagic action of cocaine has not been evaluated. Meal patterns were recorded in automated food hoppers during the first 3 h of the dark phase in adult female and male rats after administration of ascending cocaine doses (0, 7.5, and 15 mg/kg cocaine, i.p.) on successive trials. Cocaine produced a greater suppression of feeding as well as a reduction in meal number over a 3 h test period in female rats during estrus, relative to that noted during diestrus. In contrast, during the 180 min test period, male rats showed minimal hypophagic responses to 7.5 or 15 mg/kg cocaine. These results extend the range of behavioral perturbations induced by cocaine that are modulated by sex and by the estrous cycle and are consistent with the notion that estradiol may modulate the neurochemical actions of cocaine.

Impairment of acquisition of cocaine self-administration in rats maintained on a high-fat diet.

Variations in dietary constituents such as carbohydrate are known to alter psychostimulant function in brain. Relatively few studies have examined the reinforcing effects of psychostimulants in subjects maintained on high-fat diets. The present experiment compared the rate of acquisition of an operant response for intravenous (i.v.) cocaine infusions (0.2 mg/kg) in rats fed either a chow-pellet diet or a 35.9% (by weight) high-fat diet for 45 days prior to cocaine self-administration testing. Rats maintained on a high-fat diet for 45 days exhibited diminished acquisition of cocaine self-administration, and this effect was not a function of dietary-induced obesity. The results suggest that prolonged exposure to a high-fat diet diminishes the efficacy of cocaine reinforcement.

The effects of concurrent administration of +/-3,4-methylenedioxymethamphetamine and cocaine on conditioned place preference in the adult male rat.

Conditioned place preference (CPP), a commonly used model for studying the role of contextual cues in drug reward and drug seeking, was employed to explore possible behavioral interactions between (+/-)3,4-methylenedioxymethamphetamine (MDMA; "ecstasy") and cocaine. On each of four occasions, adult male rats received one of three doses of MDMA (0 mg/kg, 5 mg/kg, 10 mg/kg; administered subcutaneously [s.c.]) combined with one of three doses of cocaine (0 mg/kg, 2.5 mg/kg, 5 mg/kg; administered intraperitoneally [i.p.]), and were then tested in a CPP paradigm. The results showed MDMA-induced CPP at a unit dose of 5 mg/kg, but at the 10 mg/kg dose there was a return to baseline (control) performance levels. For cocaine alone, CPP increased in a linear fashion as the drug dose was increased. Concurrent administration resulted in antagonism of each drug, but there was evidence that this pattern was reversible at higher doses of the respective drugs. These data are instructive insofar as they suggest that the behavioral and neurochemical effects of MDMA and cocaine presented in isolation are dramatically altered when the two drugs are presented in combination.

The effects of acquisition training schedule on extinction and reinstatement of cocaine self-administration in male rats.

Partial reinforcement is known to increase resistance to extinction (Rn) relative to training with continuous reinforcement. This phenomenon, referred to as the partial reinforcement extinction effect, is one of the most robust in learning and conditioning studies. Experiment 1 investigated manipulations known to affect the partial reinforcement extinction effect and determined their possible relevance for drug use patterns. Male rats received intravenous cocaine self-administration training under partial reinforcement (FR-10) training or continuous reinforcement (FR-1) conditions with either a low (0.25 mg/kg infusion) or a high cocaine dose (1.00 mg/kg infusion). Animals were placed on an extinction (recurrent nonreward) schedule for 10 days (1-hr sessions) prior to being tested for cue-induced reinstatement (single 2-hr session). Experiment 2 involved acquisition of cocaine self-administration under FR-1 conditions of short training (15 days) or extended training (30 days) with a low dose (0.25 mg/kg infusion) or a medium dose (0.50 mg/kg infusion) of cocaine reward prior to extinction or reinstatement. Experiment 1 showed that rats trained with FR-10-high dose outcomes exhibited greater Rn than the remaining groups. Additionally, FR-10-high dose and FR-10-low dose rats were more likely to return to active drug seeking during the reinstatement test. In Experiment 2, rats trained under FR-1-medium dose conditions were more persistent during extinction following short acquisition training than comparable rats experiencing extended acquisition training. The reinstatement test was conducted following extinction, in which it was observed that overtraining under FR-1-medium dose reward schedules resulted in a decrease in the tendency to return to active drug seeking.

The effects of the GABAA antagonist bicuculline on cocaine self-administration in rats exposed to lead during gestation/lactation.

The present investigation examined the effects of perinatal lead exposure on cocaine self-administration following a GABAA antagonist pretreatment. Female rats were exposed to either 0 or 16 mg lead daily for 30 days prior to breeding with unexposed males. Beginning on postnatal day (PND) 75, control (N=10) and lead-exposed (N=8) animals were trained to self-administer 0.50 mg/kg cocaine intravenously (IV). After stable responding was established, animals were tested at 0.03 and 0.06 mg/kg cocaine delivered intravenously (IV), combined with intraperitoneal (IP) administration of either saline, 0.50, 1.00 or 2.00 mg/kg bicuculline (a GABAA antagonist). The results showed that control animals increased self-administration responding at a cocaine dose of 0.06 mg/kg as bicuculline dose increased. Lead-exposed animals exhibited an opposite pattern, i.e., a decrease in active (cocaine) lever responding occurred as the bicuculline dose was increased. Results at the 0.03 mg/kg cocaine dose failed to show group separation, or significant changes consequent to the bicuculline pretreatment. The data suggest that GABA antagonism results in increased reward potency of a low dose of cocaine and further, that this effect is differentially expressed in animals exposed to perinatal lead.

Enhanced acquisition of cocaine self-administration in rats developmentally exposed to lead.

The rate of acquisition of drug self-administration may serve as a predictor of later drug-taking behavior, possibly influencing the vulnerability to use drugs. The present study examined the effects of perinatal (gestation/lactation) lead exposure on adult rates of acquisition of intravenous cocaine self-administration using an automated procedure that included both Pavlovian and operant components. For Experiment 1, female rats were gavaged daily with 0 or 16 mg lead for 30 days prior to breeding with nonexposed males. Metal administration continued through pregnancy and lactation and was discontinued at weaning (postnatal day (PND) 21). Animals born to control or lead-exposed dams subsequently were tested daily as adults in a preparation where sessions included an initial 3-h autoshaping period followed by a 3-h self-administration period where 0.20 mg/kg cocaine was delivered contingently. During autoshaping, intravenous cocaine infusions were paired with the extension and retraction of a lever, while infusions occurred during self-administration only when a lever press was executed (FR-1). The criterion for acquisition was a 2-day period during which a mean of 50 infusions/session occurred during self-administration. Animals were given 35 days to reach criterion. In Experiment 1, accelerated rates of acquisition of cocaine self-administration were evident for lead-exposed animals relative to controls. Overall, the number of self-administered cocaine infusions per session was significantly higher for lead-exposed rats as compared to control rats. Experiment 2 replicated Experiment 1 except that a higher dose of cocaine (0.80 mg/kg) was employed as the reinforcer, and 30 infusions/session was the set criterion. At the higher cocaine dose (Experiment 2), acquisition rates for control and lead-exposed animals were not markedly different, and significantly different infusion rates were not observed.

Neurotoxicants, Micronutrients, and Social Environments: Individual and Combined Effects on Children's Development.

-Systematic research evaluating the separate and interacting impacts of neurotoxicants, micronutrients, and social environments on children's cognition and behavior has only recently been initiated. Years of extensive human epidemiologic and animal experimental research document the deleterious impact of lead and other metals on the nervous system. However, discrepancies among human studies and between animal and human studies underscore the importance of variations in child nutrition as well as social and behavioral aspects of children's environments that mitigate or exacerbate the effects of neurotoxicants. In this monograph, we review existing research on the impact of neurotoxic metals, nutrients, and social environments and interactions across the three domains. We examine the literature on lead, mercury, manganese, and cadmium in terms of dispersal, epidemiology, experimental animal studies, effects of social environments, and effects of nutrition. Research documenting the negative impact of lead on cognition and behavior influenced reductions by the Center for Disease Control in child lead-screening guidelines from 30 micrograms per deciliter (µg/dL) in 1975 to 25 µg/dL in 1985 and to 10 µg/dL in 1991. A further reduction is currently being considered. Experimental animal research documents lead's alteration of glutamate-neurotransmitter (particularly N-methyl-D-aspartate) activity vital to learning and memory. In addition, lead induces changes in cholinergic and dopaminergic activity. Elevated lead concentrations in the blood are more common among children living in poverty and there is some evidence that socioeconomic status influences associations between lead and child outcomes. Micronutrients that influence the effects of lead include iron and zinc. Research documenting the negative impact of mercury on children (as well as adults) has resulted in a reference dose (RfD) of 0.1 microgram per kilogram of body weight per day (µg/kg/day). In animal studies, mercury interferes with glutamatergic, cholinergic, and dopaminergic activity. Although evidence for interactions of mercury with children's social contexts is minimal, researchers are examining interactions of mercury with several nutrients. Research on the effects of cadmium and manganese on child cognition and behavior is just beginning. Experimental animal research links cadmium to learning deficits, manganese to behaviors characteristic of Parkinson's disease, and both to altered dopaminergic functioning. We close our review with a discussion of policy implications, and we recommend interdisciplinary research that will enable us to bridge gaps within and across domains.

Augmentation of cocaine hyperactivity in rats by systemic ghrelin.

The feeding-relevant pathway by which food deprivation (FD) augments cocaine action is unknown. Systemic administration of the 28 amino acid acylated peptide ghrelin (1-10 nmol) increases food intake in rats and circulating levels of rat ghrelin are up-regulated by FD. The present experiment examined the impact of ghrelin or vehicle pretreatment on the locomotion and stereotypy induced by systemic cocaine hydrochloride. Male Sprague-Dawley rats were pretreated at -60 min with 0 or 5 nmol rat ghrelin (IP) and then injected (IP) at time 0 with 0, 2.5, 5.0, or 10.0 mg/kg cocaine. Locomotor activity was monitored over a 45-min post-cocaine period. Rats received the same ghrelin dose, but a different cocaine dose (in random order) on each of the four drug trials, with each drug trial separated by at least 2 days. Administration of 5 nmol ghrelin-0 mg/kg cocaine slightly increased locomotion relative to that of 0 nmol ghrelin-0 mg/kg cocaine. Cocaine increased locomotion as a function of dose in the 0 nmol ghrelin group, but the effect of cocaine was even greater when preceded by 5 nmol ghrelin. These results indicate that acute injection of ghrelin, at a feeding-relevant dose, augments the acute effects of cocaine on locomotion in rats.

Exposure to cadmium during gestation and lactation decreases cocaine self-administration in rats.

This investigation examined the effects of perinatal cadmium exposure on subsequent self-administration of cocaine during the adult cycle. Female Sprague-Dawley rats were gavaged daily with 0.0 (14% sucrose solution, w/v) or 5.0 mg cadmium chloride (dissolved in 14% sucrose solution, w/v) for 30 days prior to breeding with non-exposed males. Dams continued to experience cadmium exposure through gestation and until pups were weaned at postnatal day (PND) 21. On PND 70, offspring were anesthetized and chronic indwelling jugular catheters were implanted. Following recovery, test subjects were trained in operant chambers to self-administer 0.500 mg/kg infusion (inf) intravenous cocaine on a fixed-ratio (FR) 2 schedule of reinforcement. Following acquisition, self-administration rates were tested for saline, 0.030, 0.060, 0.125, 0.250, and 0.500 mg/kg inf cocaine. Rats exposed developmentally to cadmium self-administered significantly less than controls at saline, 0.030, and 0.060 mg/kg inf cocaine. These data indicate that early-life cadmium exposure, a common exposure vector of which is the use of tobacco products, may affect cocaine sensitivity.

Self-administration of heroin in rats: effects of low-level lead exposure during gestation and lactation.

RATIONALE: Developmental lead exposure has been found to produce differential patterns of drug self-administration in adult animals. OBJECTIVES: The present study examined the effects of perinatal (gestation/lactation) lead exposure on adult patterns of heroin self-administration. METHODS: Female rats were gavaged daily with 0 mg or 16 mg lead for 30 days prior to breeding with non-exposed males. Metal administration continued through pregnancy and lactation and was discontinued at weaning [postnatal day 21 (PND 21)]. Animals born to control or lead-exposed dams received indwelling jugular catheters as adults and were randomly assigned to one of two studies. In experiment 1, animals were tested on a FR-2 schedule in an effort to examine differential sensitivity to heroin in an intravenous self-administration paradigm. Seven doses of heroin were selected ranging from 0.56 microg/kg to 36 microg/kg per infusion. In experiment 2, littermates were tested on a progressive ratio (PR) schedule in order to more explicitly determine the nature of the change in sensitivity to the drug. RESULTS: In experiment 1, lead-exposed animals responded for heroin at significantly lower rates across most doses as evidenced by a downward shift in the inverted-U dose-effect curve. Congruent with these findings, lead-exposed animals in experiment 2 exhibited a decrease in progressive ratio responding (lower breaking points) across all heroin doses, further suggesting that perinatal lead exposure attenuates opiate self-administration in adult animals by altering the rewarding efficacy of the drug. In experiment 2, it was determined further that lead-exposed animals had lower latencies to make the initial lever press for heroin. CONCLUSIONS: These results support previous literature suggesting that perinatal exposure to inorganic lead attenuates the effectiveness of opiates as a reinforcer when animals are tested in the adult life cycle.

Early developmental lead exposure increases sensitivity to cocaine in a self-administration paradigm.

The purpose of this investigation was to determine if lead exposure during pregnancy and nursing alters cocaine sensitivity later in the adult cycle, although lead exposure had been discontinued following early development. Female rats were exposed via gavage to 0 or 16 mg/kg lead daily for 30 days prior to breeding with nonexposed males. The respective daily exposure regimens continued throughout gestation and lactation (perinatal lead exposure). Lead exposure was discontinued on the day of weaning (postnatal day [PND] 21). Beginning on PND 70, male offspring were trained to self-administer cocaine HCl intravenously. Examination of a range of cocaine doses (0.030, 0.060, 0.125, 0.250, and 0.500 mg/kg/infusion) revealed that, as adults, animals exposed to lead during early development self-administered cocaine at significantly greater rates at a low dose of the drug. In addition, self-administration rates were lower among lead-exposed animals at higher doses of cocaine. These findings were observed in metal-exposed animals where blood and brain tissue levels had returned to the levels of controls. Collectively, these data suggest that early developmental lead exposure may increase sensitivity to cocaine later in the life cycle.

Developmental exposure to cadmium alters responsiveness to cocaine in the rat.

The purpose of the present report was to investigate the potential interactive relation between perinatal (gestation/lactation) cadmium exposure and changes in responsiveness to cocaine. In Experiment 1, adult female rats were exposed to a diet containing 50 ppm cadmium (as cadmium chloride) or a diet containing no added cadmium for 30 days prior to breeding with nonexposed males. The metal-exposure regimen continued throughout gestation, and for 15 days of lactation, at which time all animals were placed on standard rat chow diets containing no added cadmium for the remainder of the investigation. Atomic absorption assays confirmed that cadmium concentrations were significantly elevated in metal-exposed dams, littermates, and test animals. Offspring were weaned on postnatal day (PND) 21 and commenced cocaine sensitization testing on PND 70. Testing operations for controls and animals perinatally exposed to cadmium consisted of 21 daily i.p. injections of vehicle (saline) or 10 mg/kg cocaine HCl, and subsequent recording of locomotor activity. Subsequently, across successive days, all animals received 0, 10, and 20 mg/kg cocaine challenges. The results showed that cocaine sensitization was attenuated in animals perinatally exposed to cadmium. A similar pattern of antagonism was observed in Experiment 2 where a higher dose of cocaine was required to produce conditioned place preference (CPP) in cadmium-exposed animals. The implications of these findings with respect to the interactive role of cadmium in the dynamics of cocaine use/abuse remain unclear.

Morphine conditioned place preference is attenuated by perinatal lead exposure.

The purpose of this investigation was to determine if perinatal lead exposure alters the conditioned reinforcing properties of morphine when offspring were tested as adults. Dams were gavaged daily with 0- (sodium acetate) or 16-mg lead (as lead acetate) for 30 days prior to breeding with nonexposed males. Administration continued through gestation and lactation and was discontinued at weaning (postnatal day [PND] 21). At PND 70 animals were tested in a conditioned place preference (CPP) preparation using 0.00, 0.60, 1.25, 2.50, or 5.00 mg/kg i.p. morphine as the unconditioned stimulus (US). Relative to controls, attenuation of CPP was evident in animals exposed to 16-mg lead at 1.25 and 2.50 mg/kg morphine. Analysis of blood lead concentration revealed that by the end of testing residue levels in metal-exposed animals had returned to control levels. However, data from littermates sacrificed well beyond the current testing period revealed that brain lead residues remained elevated in animals exposed to lead, even though the metal had gained clearance from blood. The present data suggest that early lead exposure may have an enduring impact on the reinforcing properties of morphine.

Perinatal lead exposure and relapse to drug-seeking behavior in the rat: a cocaine reinstatement study.

RATIONALE: Intravenous self-administration of cocaine at low doses is increased by chronic low-level exposure to lead during gestation and lactation (perinatal lead exposure). Insofar as drug potency is increased by early lead exposure, it must be considered that cocaine-seeking and relapse after periods of withdrawal similarly may be enhanced by perinatal lead exposure. OBJECTIVES: Employing an animal model, the present study examined the effects of lead exposure during gestation and lactation on cocaine-induced reinstatement of drug-seeking, when animals were tested as adults. METHODS: Adult female rats were gavaged once daily with 0 or 16 mg lead for 30 days prior to breeding with non-exposed males. This exposure regimen continued until offspring were weaned at postnatal day (PND) 21. At PND 120, male offspring were trained to self-administer cocaine intravenously (IV) [0.50 mg/kg cocaine per infusion on a fixed-ratio schedule where two lever presses resulted in drug delivery (FR-2 schedule)]. After steady-state responding was established, cocaine reinstatement responding was assessed for each group within an extinction paradigm. During the initial 1 h of reinstatement testing, the previous baseline contingencies were in place, i.e. animals operated under an FR-2 schedule for an infusion of 0.50 mg/kg cocaine. During the 2 h, 3 h, and 4 h of testing saline infusions were substituted for cocaine infusions. After responding extinguished during hour 4, reinstatement of responding was tested by administering an intraperitoneal (IP) priming injection of 0.00, 5.00, 10.00, or 20.00 mg/kg cocaine. Following these injections, lever responding for saline infusions was monitored during hour 5. RESULTS: The number of saline infusions self-administered during hour 5 increased in a dose-dependent fashion for both controls (group 0-mg) and lead-exposed (group 16-mg) animals. However, lead-exposed animals self-administered significantly more saline infusions than controls at the 5.00 mg/kg and 10.00 mg/kg doses. This apparent metal-related increase in sensitivity to cocaine was evident with blood lead in metal-exposed test animals returning to control levels. However, brain lead levels remained elevated in lead-exposed test animals, relative to controls. CONCLUSIONS: The results of this investigation suggest that low-level lead exposure during gestation and lactation increases sensitivity to the relapse phase of drug abuse. It is further apparent that this increased sensitivity to the reinstatement of drug-seeking behavior is long-lasting.

The effects of developmental cadmium exposure on morphine sensitization and challenge with selective D(1) and D(2) antagonists.

The purpose of this investigation was to determine the effects of developmental (perinatal) cadmium exposure on the development and expression of behavioral sensitization to morphine. Adult female rats were maintained ad libitum on diets containing 0, 25, or 50 ppm added cadmium (administered as cadmium chloride) for 30 days prior to breeding with nonexposed males. This exposure regimen continued throughout the gestational period and for 15 days postnatally during lactation, at which time regular rat chow was provided. On postnatal day (PND) 21, male pups from the respective litters were weaned and placed on an unadulterated food supply (no added cadmium) and tap water for the remainder of the study. Beginning on PND 70, animals from each exposure condition (0, 25, 50 ppm exposure conditions) received, for 21 consecutive days, either vehicle (distilled water) or 10 mg/kg morphine sulfate injections (ip) prior to being monitored for locomotor activity during 80-min test sessions. Following this 21-day period of morphine sensitization training, dose-effect profiles were determined for each exposure condition with successive daily challenges of 0, 10, and 20 mg/kg morphine. Subsequently, different doses of the D(1) antagonist SCH 23390 (0.01, 0.056, and 0.10 mg/kg) and the D(2) antagonist eticlopride (0.01 and 0.056 mg/kg) were presented prior to administration of the training dose of morphine (10 mg/kg). The results of the investigation revealed that developmental cadmium exposure attenuated the development/expression of morphine sensitization. Furthermore, it was found that the suppressive effects of the D(2) antagonist eticlopride were decreased by early cadmium exposure.