Prenatal and postnatal cocaine exposure enhances the induction and expression of locomotor sensitization to cocaine in rats

Prenatal and postnatal exposure to cocaine can affect the development and function of the central nervous system in offspring. It also produces changes in cocaine-induced dopamine release and increases cocaine self-administration and cocaine-induced conditioned place preference. Further, prenatal cocaine exposure involves greater risk for development of a substance use disorder in adolescents. Therefore, the objective of this study was to determine the effect of prenatal and postnatal cocaine exposure on locomotor sensitization in rats. A group of pregnant female Wistar rats were administered daily from day GD0 to GD21 with cocaine (cocaine pre-exposure group) and another group pregnant female rats were administered daily with saline (saline pre-exposure group). During lactation (PND0 to PND21) pregnant rats also received cocaine administration or saline, respectively. Of the litters resulting of the cocaine pre-exposed and saline pre-exposed pregnant female groups, only the male rats were used for the recording of the locomotor activity induced by different doses of cocaine (1, 5, 10, 20 and 40 mg/Kg/day) during the induction and expression of locomotor sensitization at different postnatal ages (30, 60, 90 and 120 days), representative of adolescence and adult ages. The study found that prenatal and postnatal cocaine exposure enhanced locomotor activity and locomotor sensitization, and such increase was dose- and age-dependent. This suggests that prenatal and postnatal cocaine exposure can result in increased vulnerability to cocaine abuse in young and adult humans.     

Prenatal cocaine exposure and school-age intelligence

Assessments of the possible consequences of prenatal exposure to cocaine have been limited by lack of control for socio-demographic confounders and lack of follow-up into the school years. We evaluated intelligence at ages 6–9 years in 88 children from a cohort of 280 born between September 1, 1985 and August 31, 1986 and identified at birth as cocaine-exposed, and in a group of unexposed (n=96) births of comparable gender and birthweight. IQ scores did not differ between children with and without prenatal exposure to cocaine (mean 82.9 vs. 82.4, difference=0.5 points, 95% CI-3.1, 4.1); results were unchanged with adjustment for child height, head circumference and prior residence in a shelter or on the street, and for caregiver IQ and home environment (mean difference=2.2 points, 95% CI-1.5, 5.8).     

Prenatal cocaine: maternal toxicity, fetal effects and locomotor activity in rat offspring

Either 30 or 60 mg/kg of cocaine hydrochloride (COC) was administered by gastric intubation to gravid rats during the last two weeks of gestation. A pair-fed control group was administered the vehicle alone and allowed to eat and drink only the amount consumed by the 60 mg/kg group on the same gestation days. A nontreated control group was left undisturbed during pregnancy. All treated and control litters were fostered at birth to untreated dams. None of the treated dams died nor were any gross signs of cocaine toxicity observed. Among the COC-60 dams, there was a reduction in food and water intake at the beginning of treatment; whereas water intake returned to control levels, food intake remained approximately 12% below that of the controls. Compared to the nontreated dams, both COC-treated and pair-fed dams gained significantly less body weight from conception to term. Cocaine had no effect on offspring mortality, birthweight or rate of postnatal growth. Measurement of the ontogeny of motor activity during the first month of life revealed a similar activity pattern for all the groups except for the COC-60 group which showed heightened activity on Days 20 and 23. These findings are discussed in relation to other animal and clinical reports of prenatal cocaine exposure.     

Gestational ethanol and nicotine exposure: effects on maternal behavior, oxytocin, and offspring ethanol intake in the rat

Alcohol consumption and smoking during pregnancy is common, despite the known adverse effects of these drugs on fetal development. Though studies on the effects of each drug separately are published, little is known about the effect of concurrent use of alcohol and nicotine in humans or in preclinical models. In this report, we examined the impact of continuous gestational exposure to both ethanol via liquid diet and nicotine via an osmotic minipump on maternal behavior, offspring ethanol intake, and oxytocin levels in a rat model. Dams were tested for the onset of maternal behavior with litters of unexposed surrogate pups and then killed to examine oxytocin levels within specific brain regions. Drug-exposed offspring reared by surrogate dams were tested for ethanol intake at either adolescence or adulthood, and oxytocin levels were measured in relevant brain regions after behavioral tests. Dams exhibited minor deficits in maternal care, which were associated with lower oxytocin levels in both the ventral tegmental and medial preoptic areas compared to control dams. Prenatal exposure altered sex-specific ethanol intake, with differential effects at adolescence and adulthood. Oxytocin system changes were also apparent in the ventral tegmental and medial preoptic regions of drug-exposed adolescent and adult offspring. These results suggest that dam treatment with ethanol and nicotine can somewhat negatively affect the early rearing environment, and that prenatal exposure to both of these drugs results in drinking behavior differing from what would be expected from either drug alone. Oxytocin's possible involvement in the mediation of these effects is highlighted.     

Phencyclidine during pregnancy in the rat: effects on locomotor activity in the offspring

Either 5 or 10 mg/kg of phencyclidine hydrochloride (PCP) was administered by gastric intubation to gravid rats during the last two weeks of gestation. Intubation controls received the vehicle and all offspring were fostered to untreated controls at birth. PCP produced a decrement in maternal weight gain and a small but nonsignificant reduction in birth weight that was no longer evident at weaning. There were no maternal deaths nor were resorptions or stillbirths increased by PCP exposure. Offspring were tested for differences in locomotor activity from birth to weaning at 30 days of age and during adulthood. No behavioral differences were found among the preweanling or adult offspring. Results are compared with other prenatal studies of PCP toxicity and teratogenicity.     

A fostering study of the effects of prenatal cocaine exposure: I. Maternal behaviors

The effect of rearing condition and prenatal exposure to cocaine on maternal behaviors was examined. Sprague-Dawley dams were given SC injections of 40 mg/kg/3cc cocaine HCl (C40) or saline (LC) daily from gestational days 8–20. Maternal behavior was assessed in treated dams rearing their biological pups (LC/LC; C40/C40), treated dams rearing untreated pups (LC/FOS; C40/FOS), and foster dams rearing treated pups (FOS/LC; FOS/C40). All dams were monitored for home cage behavior (time eating, drinking,and with pups) for 2 h during both the light and dark cycle on postnatal day 4 (P4), pup retrieval on P5–P9, and maternal aggression to a female intruder (latency to the first attack, number of attacks, boxing, pins, intruder time spent submissive and motionless) on P10. No differences were observed in nest behavior or in tests of pup retrieval among the six groups. Dams rearing their biological litter (LC/LC and C40/C40) were significantly quicker to initiate the first attack when compared to all other groups. This increased aggression was maintained throughout the test session in the C40/C40 dams who made significantly more intruder attacks than all other groups, with the intruder spending significantly more time in a submissive posture (lying on back). In contrast, LC/LC dams did not exhibit an increased number of attacks during the test, apparently responding to an increased freezing in their intruders with a reduction in aggressive behavior. Taken together these findings suggest that prior cocaine exposure results in alterations in maternal aggression that is evident when these dams rear their own pups.     

Effects of perinatal exposure to bisphenol A on the behavior of offspring in F344 rats

The objective of this investigation is to evaluate whether perinatal maternal exposure to bisphenol A (BPA) at 4, 40, and 400 mg/kg per day affects the behavior of offspring in F344 rats. Perinatal BPA exposure inhibited the body weight increases of male and female offspring in a dose-dependent manner, which continued after weaning. Spontaneous activity analyses revealed that BPA elongated immobile time during the dark phase in female offspring. At 4 weeks of age, male offspring exposed to BPA at 40 and 400 mg/kg per day performed avoidance responses significantly higher in the shuttlebox avoidance test. At 8 weeks of age, however, male offspring only at 4 mg/kg per day showed significantly lower responses. In the open-field behavior test at 8 weeks of age, male offspring exposed to BPA only at 4 mg/kg per day showed a higher percent of grooming than the control male offspring. In conclusion, perinatal exposure to BPA caused the behavioral alterations in the offspring.     

Prenatal cocaine exposure in the Long-Evans rat: II. Dose-dependent effects on offspring behavior

Pregnant Long-Evans rats were injected daily with 40, 60, 80 or 100 mg/kg cocaine HCl (SC, 2% solution) from gestational days 7-20 (sperm positive = day 0). Daily doses were split with half given between 9:00-10:00 a.m. and half between 3:00-4:00 p.m. An ad lib-fed group as well as nutritional control groups that were pair-fed to the 80 and 100 mg/kg cocaine dams were also evaluated (N = 11-18 litters/group). The negative geotactic reaction of the offspring, evaluated from day 2-14 (birth = day 0), showed no group differences. Spontaneous alternation behavior in a T-maze showed no evidence of perseveration in any group on either day 21 or day 80. Most cocaine-treated offspring showed an altered preference in turning right versus left on day 21. Activity monitor behavior showed that the cocaine-treated and pair-fed offspring were hypoactive on day 20. Some degree of hypoactivity was still evident on day 49, but absent on day 80. The passive avoidance behavior of day 19 offspring showed no group differences in acquisition of task learning. The 100 mg/kg cocaine offspring did show significantly poorer retention of task learning 48 hr later. On day 80, no group differences were seen in passive avoidance behavior. Acquisition of an active avoidance behavior on day 80 was significantly poorer in the 100 mg/kg cocaine group.     

Psychopharmacological responsiveness to the dopamine agonist quinpirole in normal weanlings and in weanling offspring exposed gestationally to cocaine

The behavioral responsiveness to challenge doses of the D₂ agonist quinpirole was examined in 21-day-old normal offspring (experiment 1) as well as offspring exposed gestationally to cocaine (experiment 2). In both experiments weanling rats received a subcutaneous injection of 0 (0.9% saline), 0.04, 0.08, 0.5, or 1.0 mg/kg/3 cc of the D₂ agonist quinpirole and were placed in a divided glass testing apparatus containing either a dish of wet mash plus a food pellet or wood block (experiment 1) or both a food pellet and a wood block (experiment 2). Behaviors were recorded for 5 min via time-sampling at 30 and 60 min post-injection. In experiment 1 the three highest doses of quinpirole increased the amount of forward locomotion, rearing, sniffing and probing, as well as increasing directed oral movements at both the wood block and food pellet; in general these findings are reminiscent of those reported previously in adult animals. In experiment 2, cocaine-exposed weanlings exhibited an increased sensitivity to the stimulating effects of a low dose of the D₂ agonist for forward locomotion and rearing as well as an increase in the overall incidence of sniffing behavior and chewing on food pellets. These data provide psychopharmacological evidence that the increase in striatal D₂ binding previously observed in weanling offspring exposed gestationally to cocaine (Scalzo et al. 1990) may be associated with an increased behavioral sensitivity to the D₂ agonist quinpirole.     

Conditioned locomotor stimulant effects of cocaine in rats do not result from interference with habituation

RATIONALE: Classical conditioning has been proposed to account for the hyperactivity observed in drug-free rats when placed in an environment previously paired with cocaine administration. However, an alternative explanation is that hyperactivity results from an inability of rats to habituate to the environment under the influence of cocaine. OBJECTIVES: In this study, preconditioning exposure to the test environment was increased from one session (standard procedure) to seven (modified procedure) to test the "antihabituation" hypothesis. METHODS: After preconditioning exposure, six conditioning sessions took place over a 10-day to 13-day period. Paired rats received 10 mg/kg cocaine i.p. prior to activity sessions and saline i.p. upon return to the colony room. Unpaired rats received saline prior to and cocaine after activity sessions. Time-off rats were withheld from the activity boxes, but were subject to all other procedures during conditioning. On the test day, all rats received saline prior to activity sessions. RESULTS: In the standard procedure, paired rats exhibited significantly greater activity than unpaired rats on the test day, consistent with previous reports. In the modified procedure, mean activity (all rats) decreased between the first and last preconditioning sessions. Still, the paired group exhibited greater activity than the unpaired group on the test day, suggesting that a conditioned stimulant effect developed in habituated rats. Activity in the time-off group did not significantly differ from the unpaired group demonstrating the habituation had not dissipated over this time period. CONCLUSIONS: These results support the conclusion that hyperactivity observed on the test day was not a result of antihabituation effects of cocaine.     

Interactions between ethanol and cocaine,amphetamine, or MDMA in the rat: thermoregulatory and locomotor effects

Rationale (±)-3,4-methylenedioxymethamphetamine (MDMA, ecstasy) is often taken recreationally with ethanol (EtOH). In rats, EtOH may potentiate MDMA-induced hyperactivity, but attenuate hyperthermia. Objective Experiment 1 compared the interactions between EtOH (1.5 g/kg) and MDMA (6.6 mg/kg) with EtOH + cocaine (COCA; 10 mg/kg) and EtOH + amphetamine (AMPH; 1 mg/kg) on locomotor activity and thermoregulation. Experiment 2 used a weaker dose of MDMA (3.3 mg/kg) and larger doses of COCA (20 mg/kg) and AMPH (2 mg/kg). Materials and methods Drug treatments were administered on four occasions (2, 5, and 2 days apart, respectively; experiment 1) or two (2 days apart; experiment 2). Results All psychostimulants increased activity, and EtOH markedly increased the effect of MDMA. AMPH alone-related hyperactivity showed modest sensitization across treatment days, while MDMA + EtOH activity showed marked sensitization. AMPH, COCA, and MDMA induced hyperthermia of comparable amplitude (+1 to +1.5°C). Co-treatment with EtOH and AMPH (1 mg/kg) or COCA (10 mg/kg) produced hypothermia greater than that produced by EtOH alone. Conversely, EtOH attenuated MDMA-related hyperthermia, an effect increasing across treatment days. These results demonstrate that the interaction between MDMA and EtOH may be different from the interaction between EtOH and AMPH or COCA. Conclusion Because of potential health-related consequences of such polydrug misuse, it is worth identifying the mechanisms underlying these interactions, especially between EtOH and MDMA. Given the different affinity profiles of the three drugs for serotonin, dopamine, and norepinephrine transporters, our results appear compatible with the possibility of an important role of serotonin in at least the EtOH-induced potentiation of MDMA-induced hyperlocomotion.     

Prenatal and postnatal cocaine exposure predict teen cocaine use

Preclinical studies have identified alterations in cocaine and alcohol self-administration and behavioral responses to pharmacological challenges in adolescent offspring following prenatal exposure. To date, no published human studies have evaluated the relation between prenatal cocaine exposure and postnatal adolescent cocaine use. Human studies of prenatal cocaine-exposed children have also noted an increase in behaviors previously associated with substance use/abuse in teens and young adults, specifically childhood and teen externalizing behaviors, impulsivity, and attention problems. Despite these findings, human research has not addressed prior prenatal exposure as a potential predictor of teen drug use behavior. The purpose of this study was to evaluate the relations between prenatal cocaine exposure and teen cocaine use in a prospective longitudinal cohort (n = 316) that permitted extensive control for child, parent and community risk factors. Logistic regression analyses and Structural Equation Modeling revealed that both prenatal exposure and postnatal parent/caregiver cocaine use were uniquely related to teen use of cocaine at age 14 years. Teen cocaine use was also directly predicted by teen community violence exposure and caregiver negativity, and was indirectly related to teen community drug exposure. These data provide further evidence of the importance of prenatal exposure, family and community factors in the intergenerational transmission of teen/young adult substance abuse/use.     

Prenatal cocaine exposure potentiates paroxetine-induced desensitization of 5-HT2A receptor function in adult male rat offspring

This study investigated the ability of prenatal exposure to cocaine to alter serotonin(2A) (5-HT(2A)) receptor function and paroxetine-induced desensitization of 5-HT(2A) receptor function in rat offspring. Following exposure to saline or (-)cocaine (15 mg/kg, s.c., b.i.d.), during gestational days 13-20, adult male offspring were treated with either saline or paroxetine (10 mg/kg/day, i.p. 14 days). Eighteen hours post-treatment, changes in the stimulation of oxytocin, adrenocorticotropic hormone (ACTH) and corticosterone by (-)4-iodo-2,5-dimethoxyphenylisopropylamine (DOI, 0.5 or 2.0 mg/kg, s.c.) and in 5-HT(2A) receptor densities were determined. Prenatal cocaine exposure did not alter 5-HT(2A) receptor-mediated neuroendocrine responses or 5-HT(2A) receptor densities. In contrast, paroxetine treatment reduced cortical 5-HT(2A) receptors (18-25%) and desensitized 5-HT(2A) receptor-mediated oxytocin responses in both offspring groups. Furthermore, in cocaine offspring, paroxetine produced an inhibition of 5-HT(2A) receptor-mediated increase in plasma ACTH levels and a greater attenuation of the oxytocin responses to (-)DOI. Paroxetine-induced reductions in body weight gain (-8.8%) were comparable in both offspring groups. These data, demonstrating that prenatal exposure to cocaine potentiates paroxetine-induced desensitization of 5-HT(2A) receptor function, may be clinically relevant with respect to treating mood disorders in adults exposed in utero to cocaine.     

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.     

Potentiation of the behavioral and convulsant effects of cocaine by chronic administration in the rat

The effect of chronic administration on the behavioral response to cocaine was studied in male Sprague-Dawley rats. In experiment 1 five groups of rats received daily intraperitoneal injections of either saline, 20 mg/kg, or 40 mg/kg cocaine hydrochloride for 10 days, or of higher doses of cocaine until either one or three convulsions occured. Following this initial treatment, all animals were left untreated for seven days, and then sensitivity to cocaine was assessed in all animals by a test injection series (daily injections of increasing doses of cocaine). Animals which had received 40 mg/kg cocaine during the initial treatment exhibited a greater behavioral response (stereotyped behavior) to cocaine during the test injection series than did animals treated with saline; both the 40 mg/kg and one — convulsion treatments during the initial stage of the experiment resulted in greater sensitivity to the convulsant effect of cocaine during the test injection series. In experiment 2 animals were injected intraperitoneally with either saline or 40 mg/kg cocaine for 10 days and then tested with a series of daily cocaine injections of increasing dosage after remaining untreated for 4, 8, 16 or 32 days. The results indicated that the initial treatment with 40 mg/kg cocaine augmented both the behavioral and convulsant effects of cocaine during the subsequent test injection series. The sensitization to the convulsant effect of cocaine was significant at all intervals after initial treatment except 16 days, while the duration of sensitization to the behavioral effects of cocaine could not be determined due to apparent age-related changes in the response of control animals to cocaine. The sensitization which was observed was attributed to the effects of cocaine per se rather than to convulsions produced by the drug.     

The effect of prenatal cocaine exposure on neurobehavioral outcome: a meta-analysis

A meta-analysis was performed of the research published from 1985 to 1998 examining the effect of in utero exposure to cocaine on infant neuobehavioral outcome. The initial search for articles to include in the meta-analysis identified 18 studies with potentially meta-analytic variables. Of the studies originally retrieved, 13 failed to meet all of the inclusion criteria and were excluded from the meta-analysis. A total of 14 meta-analyses were performed comparing cocaine-exposed infants to nonexposed infants on NBAS cluster scales at birth and at 3–4 weeks of age. While the meta-analytic combination of studies produced a large enough sample size to drive statistical significance in a small majority of the tests of difference between the cocaine-exposed and nonexposed infants both at birth and soon after, the magnitude of all effects was small. The largest reliable differences appeared for the motor performance and abnormal reflexes clusters. Both also demonstrated a slight trend for increasing standard differences from birth to measures obtained at 3–4 weeks. The orientation and autonomic regulation clusters produced small, significant effects at both time periods, but the trend was for reduced effect sizes over time. All other effects appear truly negligible.     

Cocaine binding sites in fetal rat brain: implications for prenatal cocaine action

Binding of [³H]cocaine to membrane preparations from whole fetal rat brain was studied. High-affinity binding (10 nM cocaine) was detected as early as gestational day (GD) 15 and steadily increased across subsequent development. Saturation studies comparing [³H]cocaine binding at GD20 and adulthood yielded similar K_D values, and LIGAND analyses favored a two-site model if an extended range of [³H]cocaine concentrations was used. Various monoamine uptake inhibitors displaced labeled cocaine with potencies consistent with the idea that [³H]cocaine labels the dopamine (DA), serotonin (5-HT), and possibly also the norepinephrine (NE) transporters in whole fetal brain preparations. Synaptosomal DA uptake was well developed by GD20, as was the potency of cocaine to inhibit such uptake. The results indicate that functional, monoamine transporter related cocaine binding sites are present in the fetal rat brain. Such sites are likely to play an important role in mediating the direct interactions of prenatally-administered cocaine with developing monoaminergic systems in both animals and humans.Some of these data were published in preliminary form in: Meyer JS (1992) Prenatal neurochemistry of cocaine. Ann NY Acad Sci 654:487–488     

Fetal brain damage in the rat following prenatal exposure to cocaine

The aim of this study was to identify fetal brain damage induced by 1) prenatal cocaine exposure or 2) physical procedures causing temporary constriction or occlusion of the uterine vessels in pregnant rats. Brains were examined from rat fetuses killed 48 hours after the dam was given one or more intraperitoneal doses of cocaine (50–70 mg/kg) on day 16 of gestation. Only brains from fetuses with hemorrhage in the extremities were examined, as this indicated they had undergone a circulatory disturbance. Four of the 10 brains examined showed bilateral necrosis and cavitation in the cerebral cortex. There were also hemorrhage and ectopic outgrowths in the corpus striatum, bilateral cavitation in the brainstem and vacuolization in the lens of the eye. A similar type and distribution of damage was seen in rat fetal brains from dams treated by temporary occlusion of the uterine vessels or direct handling of the pregnant uterus on day 16 of gestation and examined 48 hours later. It is proposed that the procedures act through the common mechanism of constriction/occlusion of the uterine vessels. The damage to the fetuses appears to be due to hemorrhage from the fetal vessels and ischemia. These findings are discussed in relation to cocaine use during human pregnancy.     

Cocaine-like discriminative stimulus effects of novel cocaine and 3-phenyltropane analogs in the rat

RATIONALE: Cocaine dependence is a major health concern and there are no effective pharmacotherapies currently available. Although cocaine is an indirect DA agonist that binds to all three monoamine transporters, there is much evidence implicating a greater role for the dopamine (DAT) than norepinephrine (NET) and serotonin (SERT) transporters in the behavioral effects of cocaine. As such, several groups have developed compounds that exhibit high affinity and selectivity for the DAT. OBJECTIVE: The present investigation examined the cocaine-like discriminative stimulus effects in rats of novel cocaine analogs (RTI 12, 13, 15) and 3-phenyltropane analogs (RTI 111, 112, 113, 114, 117 120, 121, 123, 134 and 152) of which several exhibit high affinity (e.g., <7 nM) and selectivity for the DAT. RESULTS: During dose-effect testing all drugs produced 75-100% cocaine-lever responding. Analyses indicated that the potency of the compounds to produce cocaine-like discriminative stimulus effects was correlated with their affinity for the DAT and the NET but not SERT. Due to the extremely large concentrations (e.g., 10,000-31,024 nM) needed to occupy the NET in vitro, it is doubtful if the doses administered had meaningful NET activity. The selectivity at the DAT, relative to the other transporters, was not indicative of the potency with which these drugs substituted for cocaine. CONCLUSIONS: The cocaine-like discriminative stimulus of the RTI compounds tested appear to be mediated by the DAT, however the extent to which the NET is involved remains unclear. Additionally, several of the RTI compounds had properties consistent with those thought desirable in a pharmacotherapeutic for cocaine dependence.     

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.