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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
Biol Psychiatry. Author manuscript; available in PMC 2009 January 15.
Published in final edited form as:
PMCID: PMC2173697
NIHMSID: NIHMS31057

Prenatal Exposure to Cocaine Increases the Rewarding Potency of Cocaine and Selective Dopaminergic Agonists in Adult Mice

Abstract

Background

Substance abuse during pregnancy results in persistent affective and behavioral deficits in drug-exposed children, and increased rates of substance abuse have been observed in young adults prenatally exposed to drugs of abuse. Animal models of prenatal cocaine exposure have yielded differing results depending on the behavioral method used to assess drug potency.

Methods

The effects of cocaine, the dopamine D1 agonists SKF-81297 and SKF-82958, and the D2 agonist quinpirole on intracranial self-stimulation were measured in adult Swiss-Webster mice exposed to cocaine in utero (40 mg/kg/day) and vehicle controls using the curve-shift method of brain stimulation-reward (BSR) threshold determination.

Results

The reward-potentiating effects of cocaine (0.3-30 mg/kg i.p.) and SKF-82958, but not SKF-81297, on BSR were increased in adult male but not female mice following prenatal cocaine exposure. Quinpirole exerted biphasic effects on BSR, both elevating (0.1-0.3 mg/kg i.p.) and lowering (1.0-10 mg/kg i.p.) reward thresholds. Both effects of quinpirole were also enhanced in adult male mice following prenatal cocaine exposure.

Conclusions

Prenatal cocaine exposure results in increased reward-potentiating potency of cocaine on BSR in adult mice in a sexually-dimorphic manner. This augmented rewarding effect of cocaine is also associated with increased sensitivity to both D1- and D2-selective agonists.

Keywords: In utero, gestation, psychostimulant, intracranial self-stimulation, ICSS, brain stimulation-reward, BSR

INTRODUCTION

Prenatal exposure to drugs of abuse, both legal and illicit, affects over 800,000 infants, or approximately 20% of all live-births, each year in the United States [1]. An estimated 45,000 infants each year are exposed to cocaine at least once during gestation, and the cost in special educational expenses alone for these children is estimated to exceed $350 million annually [2]. Longitudinal clinical follow-up of cocaine-exposed infants has demonstrated that these children have persistent deficits in multiple developmental domains [3-5], as well as abnormalities of both attention and affect [6-8] suggesting persistent dysfunction of limbic forebrain systems implicated in control of motivation and reward. As addiction is increasingly conceptualized as a developmental disorder, one emerging question is whether drug exposure during vulnerable developmental periods, such as gestation and adolescence, can increase the liability for addictive behaviors later in life. Prenatal exposure to alcohol [9, 10] or tobacco [11-13] have been shown to be associated with an increased risk of alcohol or nicotine abuse, respectively, in adolescents and young adults. Similar investigations of the rate of adolescent or adult drug abuse in cocaine-exposed children have not yet been published. While these clinical studies demonstrate associations and not causal mechanisms, they are sufficiently concerning to prompt further translational study.

While many studies of gestational exposure to drugs of abuse have demonstrated changes in spontaneous exploratory behavior in animal models, pre-clinical investigations of alterations in the rewarding potency of drugs of abuse following gestational exposure (reviewed in [14]) are much less common. Operant or instrumental behavioral methods such as drug self-administration [15, 16] and intracranial self-stimulation [17, 18] are useful in studying the reinforcing effects of drugs of abuse in animal models. Investigations employing operant behavioral measures of reward in adult animals following prenatal exposure to cocaine or other drugs of abuse are comparatively limited; however, increased intravenous self-administration of cocaine following gestational cocaine exposure [19, 20] and increased potentiation of rewarding electrical self-stimulation by cocaine following neonatal cocaine exposure [21] have been demonstrated. Conversely, chronic non-contingent cocaine administration to adult animals exposed to cocaine in utero results in less locomotor sensitization [22-24] and impaired development of conditioned place-preference [25]. Therefore, an apparent dissociation exists between the effects of prenatal cocaine exposure on the subsequent potency of cocaine in adulthood using operant methods compared to classical methods. We explored this distinction further using a different operant behavioral method, intracranial self-stimulation (ICSS), in a series of experiments investigating the potency of cocaine and selective dopamine receptor agonists to potentiate brain stimulation-reward (BSR) in adult mice that were exposed to cocaine in utero. Preliminary results of these studies have been presented in abstract form [26].

MATERIALS AND METHODS

Animal care and handling

All animal procedures were carried out according to the NIH Guide to the Care and Use of Laboratory Animals, and were approved by the Subcommittee on Research Animal Care at Massachusetts General Hospital.

In utero cocaine exposure

Mice were exposed to cocaine in utero as previously described [27]. Adult timed-pregnant white Swiss-Webster dams (Taconic Labs) were allowed access to food and water ad libitum and housed on a 12-hour (7:00AM light–7:00 PM dark) cycle. Two pregnant dams of comparable weight were identified on embryonic day 6 (E6) as an experimental pair: one to receive cocaine (40 mg/kg/day, COC40) and one to receive saline (SAL). On E7 all pregnant dams were given free access to liquid chow (BioServ, #F1259SP), and consumption was recorded daily from E7 through term (E18-19). All dams were weighed and received twice-daily (7:00 AM and 7:00 PM) injections from E7 until parturition: COC40 dams received 20 mg/kg of cocaine HCl dissolved in sterile normal saline and SAL dams received an equivalent volume of sterile saline. All injections were subcutaneous and injection sites were rotated with each administration. Our previous studies demonstrated that this cocaine regimen produces maternal serum cocaine concentrations that are similar to those measured in human cocaine addicts [27]. At birth (postnatal day zero, P0) each litter was fostered to an untreated surrogate black Swiss-Webster dam that had given birth within the preceding 24-72 hours. Pups were weaned and group-housed (4 per cage) by gender on P21. For each prenatal treatment group, only one animal of each gender per litter was used for experiments to avoid oversampling bias, or “litter effects” [28].

Intracranial Self-Stimulation (ICSS)

Male and female mice at least P50 or weighing >25g were anesthetized (ketamine/xylazine 120/18 mg/kg i.p.; Sigma) and stereotaxically implanted with an insulated monopolar stainless steel electrode (0.1mm diameter, Plastics One) to the right median forebrain bundle in the lateral hypothalamus using coordinates derived from Paxinos and Franklin (1996): bregma -2.0mm (anterior/posterior), sagital -0.8mm (medial/lateral) and depth -4.5mm (dorsal/ventral) [29]. A stainless steel screw (electrical ground) and the electrode assembly were secured to the skull with dental cement. After recovery animals were allowed access to food and water ad libitum.

One week after implantation mice were trained on a continuous (FR-1) schedule of reinforcement for brain stimulation-reward (BSR) in a 16 × 14 × 13 cm operant chamber with a wheel manipulandum and a house light (MedAssociates). Each quarter-turn of the wheel earned a 500 msec train of unipolar cathodal square-wave current at a frequency of 158Hz (pulse width = 100μsec). Each quarter-turn delivered one stimulus train, and activated the house light for 500 msec; subsequent responses during the 500 msec did not earn additional stimulation. Optimal stimulus intensity to sustain reliable responding (≥40 responses/min) was determined for animals individually during training, and varied between -90 and -220μA: current intensity was kept constant for each animal for all experiments.

Mice were then presented a series of training stimulus frequencies in descending order from 158Hz to 19Hz in discrete 0.05 log10 increments (i.e., log10{112Hz}=2.05; log10{100Hz}=2.00, etc.). At each frequency, five non-contingent priming stimuli were followed by 50 sec ad libitum access to intracranial self-stimulation (ICSS) on an FR-1 schedule during which responses were measured. A 5 sec time-out period followed each trial frequency during which responses earned no additional stimulation. Mice were trained to complete four series of 15 trial frequencies (i.e., one hour daily). After training, the range of frequencies was adjusted for each mouse such that only the highest 4-6 frequencies would sustain responding. For each series of 15 stimulus frequencies, the rate of operant responding for BSR was plotted (i.e., the rate-frequency curve). BSR threshold (θ0) was defined as the X-intercept of the least-squares regression line through frequencies that sustained responding at 20, 30, 40, 50 and 60% of the maximal response rate in each series, and was calculated automatically by custom-designed software (courtesy of W.A.C.) at the end of each experiment. This method of reward threshold determination is less sensitive to changes in response rate than other calculations, e.g., the frequency sustaining ½ -maximal response, or EF50 [30]. Drug testing began in each animal when its mean BSR threshold varied <10% over three consecutive days.

For each test, three series were acquired before and four after injection with saline vehicle or drug. The first series served as a warm-up and was discarded; θ0 and maximum rate from the second and third rate-frequency curves were averaged and used as baselines for each animal daily. All drugs were dissolved in sterile normal saline and administered by intraperitoneal injection. BSR thresholds and maximal response rates were measured for four 15-minute series following drug or vehicle injections and expressed as percent changes from baseline. Following initial cocaine dose-response determinations, mice received all doses of the selective dopamine D1-like agonists SKF-81297 and SKF-82958 and the selective dopamine D2-like agonist quinpirole in random order, and received only one dose of one drug on any day. Our prior work has shown that the BSR-potentiating effects of cocaine and SKF-82958 do not sensitize with repeated administration [31]. Animals were tested with drug and vehicle on alternating days to ensure stability of baseline BSR thresholds.

Histology

After ICSS experiments mice were deeply anesthetized with sodium pentobarbital (120 mg/kg) and perfused intracardially with 4% paraformaldehyde in 0.1 M phosphate-buffered saline (PBS; pH=7.4). Brains were cryoprotected in sucrose (30% in PBS) and frozen in crushed dry ice; 50 μm coronal sections were stained with cresyl violet for Nissl and photographed under low-power (5X) light microscopy for confirmation of electrode placements.

RESULTS

ICSS electrode tip positions are shown in Figure 1. No significant effects of gender (F(1,44)=0.05, P=0.82) or prenatal treatment (F(1,44)=0.11, P=0.75) were observed on baseline brain stimulation-reward (BSR) thresholds (θ0), determined as the total charge delivery in Coulombs (μA × μsec) at the stabilized baseline threshold prior to saline determinations (Table 1), indicating that prenatal cocaine exposure does not alter responding for BSR, and that ICSS does not differ between males and females.

Figure 1
Intracranial self-stimulation electrode placements in the medial forebrain bundle of adult Swiss-Webster mice at the level of the lateral hypothalamus. Locations of electrode tips are plotted on templates from the standard mouse stereotaxic atlas [29 ...
Table 1
Mean ICSS Thresholds (θ0) in Coulombs (C)

The effects of cocaine on BSR thresholds (θ0) are shown in Figures 2 and and33 and on maximal operant response rate in Figure 4. Significant main effects of cocaine dose (F(5,95)=213.79, P<0.001), time after injection (F(3,95)=62.08, P<0.001) and gender (F(1,95)=13.31, P<0.001) were observed. While main effects of prenatal treatment were not evident, there was a significant interaction between cocaine dose and prenatal treatment (F(5,95)=3.04, P=0.010), indicating a difference in the cocaine dose-response relationship between SAL and COC40 mice; and between dose and gender (F(5,95)=4.18, P<0.001) indicating a difference in the cocaine dose-response relationship between male and female mice. Significant lowering of θ0 (Tukey’s P<0.05) compared to vehicle was observed for 60 minutes following 30 mg/kg cocaine in both SAL and COC40 males; however, following 10 mg/kg cocaine significant changes were observed in the first 15 minutes in SAL males but the entire 60 minute test in COC40 males (Figure 2). COC40 but not SAL males also showed a significant lowering of threshold following 3.0 mg/kg cocaine. Figure 3 demonstrates that in each 15 minute pass after cocaine injection the dose-response curve is shifted to the left in COC40 males relative to SAL males with no apparent change in maximum cocaine effect. No significant differences in the effects of cocaine were observed between prenatal groups in female mice. While main effects of cocaine dose (F(5,95)=7.87, P<0.001) and time after injection (F(3,95)=42.58, P<0.001) were observed on maximal response rates, Tukey’s post-hoc analyses showed no significant differences from vehicle at any cocaine dose tested within any group (Figure 4).

Figure 2
Changes in intracranial self-stimulation (ICSS) thresholds (θ0) following acute administration of cocaine or saline vehicle. Values at each time point are plotted as the mean percentage of the average of 30 minutes of pre-injection reward thresholds ...
Figure 3
Dose-response curve for effects of cocaine on intracranial self-stimulation (ICSS) thresholds (θ0). Each dose-response curve represents one 15-minute post-injection epoch. Values at each time point are plotted as the mean percentage of the average ...
Figure 4
Changes in maximum rate of operant response following acute administration of cocaine or saline vehicle. Values at each time point are plotted as mean percentages of the average of 30 minutes of pre-injection maximum response rates ± S.E.M.; ...

To determine the pharmacological specificity of the enhanced reward-potentiating effect of cocaine in male COC40 mice, ICSS experiments were performed using the D1-like agonists SKF-81297 and SKF-82958, and the D2-like agonist quinpirole. The effects of SKF-81297 are shown in Figure 5. Significant main effects of dose (F(5,95)=9.64, P<0.001) and time (F(3,95)=4.00, P<0.01), but neither prenatal treatment nor gender, nor interactions of prenatal treatment and dose were observed on θ0. Neither 0.1 nor 0.3 mg/kg SKF-81297 produced significant changes during the 60 minute test session in any group (data not shown). At doses higher than 0.3 mg/kg the effects of SKF-81297 were highly variable. Simple pairwise comparisons showed significant (P<0.05) effects at multiple time points, particularly after 30 minutes post-injection; however, due to variability of responses, post-hoc Tukey’s tests showed significant effects of SKF-81297 compared to vehicle only in COC40 males at 10 mg/kg and only between 30 and 45 minutes post-injection (Figure 5). No significant difference in thresholds were observed in female mice at any time point following injection, and no significant effect of SKF-81297 on maximal response rate was observed in any prenatal treatment group (data not shown).

Figure 5
Changes in ICSS thresholds (θ0) following acute administration of the D1-agonist SKF-81297 or saline vehicle. Values at each time point are plotted as a percentage of the average of 30 minutes of pre-injection reward thresholds ± S.E.M. ...

The effects of SKF-82958 are shown in Figure 6. Significant main effects of dose (F(3,95)=24.04, P<0.001) and prenatal treatment (F(3,95)=5.42, P=0.02) but neither gender nor time on θ0 were observed; significant interactions among the four variables were also not observed. SKF-82958 was the only drug tested that did not show a significant effect of time after injection; data were therefore collapsed across the entire 60 minute post-injection test (Figure 6). In pilot studies from our laboratory, SKF-82958 doses above 1.0 mg/kg resulted in behavioral activation sufficient to damage to the electrode headstage and were therefore not subsequently administered; however, consistent with our previous findings [31], there was no significant effect of SKF-82958 dose on maximal operant response rate (data not shown).

Figure 6
Changes in ICSS thresholds (θ0) over 60 minutes following acute administration of the D1-agonist SKF-82958 or saline vehicle. Values at each dose are plotted as a percentage of the average of 30 minutes of pre-injection reward thresholds ± ...

The D2-like agonist quinpirole showed a markedly different response profile than either cocaine or the D1-like agonists on both θ0 and maximal response rate, as shown in Figures 7 and and8.8. In males and females of both prenatal treatment groups, lower doses (0.1-0.3 mg/kg) and higher doses at early time points after injection (0-15 min.) decreased the value of BSR, shown in Figure 7 as increases (>100% of baseline) in θ0. At higher doses (1.0-10mg/kg), particularly at later time points (16-60 min.), lowering of θ0 was observed. Significant main effects of dose (F(5,95)=57.92, P<0.001) and time (F(3,95)=54.71, P<0.001) and a significant interaction between dose and prenatal treatment (F(5,95)=5.75, P<0.001) were observed on θ0, indicating differences in the quinpirole dose-response relationship between SAL and COC40 mice. COC40 males showed significantly greater potentiation of BSR by quinpirole at doses above 0.3 mg/kg than SAL males. In addition to its biphasic dose-response relationship on θ0, quinpirole was the only drug tested that resulted in clear dose-dependent changes in the maximal response rate (Figure 8). Significant main effects of dose (F(5,95)=121.67, P<0.001), time (F(3,95)=3.33, P<0.02) and prenatal treatment (F(3,95)=6.52, P<0.02) on maximal response rates were observed, with COC40 males being the least sensitive of the four groups to the rate-suppressing effects of quinpirole at doses lower than 3.0 mg/kg.

Figure 7
Changes in ICSS thresholds (θ0) following acute administration of the D2-agonist quinpirole or saline vehicle. Each dose-response curve represents one 15-minute post-injection epoch. Values at each dose are plotted as a percentage of the average ...
Figure 8
Changes in maximum rate of operant response following acute administration of quinpirole or saline vehicle. Each dose-response curve represents one 15-minute post-injection epoch. Values at each dose are plotted as a percentage of the average of 30 minutes ...

DISCUSSION

Most preclinical investigations of consequences of prenatal exposure to drugs of abuse have employed passive behavioral methods, particularly open-field exploration or locomotor behavior. The relatively fewer studies examining appetitive behavior using either instrumental or classical conditioning methods have shown subtle but reproducible and consistent effects of gestational exposure to drugs of abuse (reviewed in [14]). Most investigations of operant behavior following such exposures have demonstrated increased potency of drug reinforcers [19-21, 32, 33], while most investigations of classical conditioning have demonstrated decreased association of behavior with specific drug-paired environments [25, 34, 35]. We sought to clarify this distinction in a well-characterized mouse model of prenatal cocaine exposure using intracranial self-stimulation (ICSS), a robust method of examining the function of neural circuitry mediating motivation and reward in the mammalian brain [17, 18, 36]. Unlike the other operant behavioral method primarily used to assess the rewarding potency of drugs of abuse, intravenous drug self-administration, ICSS bypasses the peripheral nervous system entirely, and as such the perception of brain stimulation-reward (BSR), and the processing of motor behaviors to obtain it, occur largely in the absence of sensory input [18]. It is therefore thought that ICSS involves a more selectively distributed set of cortical and subcortical brain circuits specific to motivated behavior than other behavioral methods.

We found that the potency of cocaine to lower BSR threshold was greater in male but not female mice exposed to cocaine in utero. One of the limitations of ICSS is that each data point, defined as one response at a given drug dose, is collected over a time interval in which a range of stimulation frequencies is tested, in our case 15 minutes. Therefore, four data points corresponding to four 15-minute epochs are generated after each drug injection. The dose-response curve to cocaine is shifted to the left in COC 40 males compared to SAL males in each 15-minute epoch after acute cocaine administration, indicating an increase in the potency of cocaine to potentiate the value of BSR. That this effect is not due to changes in cocaine pharmacokinetics is supported by 1. an increase in potency at early time points (0-15 minutes) after administration at which impaired metabolism would be unlikely to produce significant changes in effect, as well as later time points; and 2. previous studies showing no effect of prenatal cocaine exposure on the distribution of cocaine and its primary metabolite, benzoylecgonine, in the adult brain [34] or of neonatal cocaine exposure on adult plasma cocaine levels [21]. We conclude from these data that prenatal cocaine exposure results in an increased rewarding potency of cocaine in adult animals measured by lowering of BSR threshold, and that this effect is sexually dimorphic, preferentially affecting cocaine-exposed male offspring. The gender effect we observe is consistent with prior observations that male offspring are typically more affected than females by prenatal cocaine exposure [37], suggesting that drug exposure may affect interactions between sex hormones and early brain development.

It is generally accepted that dopamine release from VTA projections to the limbic forebrain is necessary for the rewarding effects of ICSS [38-41]. Dopamine acts at two classes of receptors, D1-like (D1 and D5) and D2-like (D2, D3 and D4). We explored the pharmacological specificity of the increased potency of cocaine using the D1-like agonists SKF-81297 (Ki =1.90 nM at D1 vs. SCH-23390; >1000 nM at D2 vs. nemonapride) and SKF-82958 (Ki =4.56 nM at D1; 264 nM at D2 [42]) and the D2-like agonist quinpirole (Ki =48 nM at D2 vs. spiperone; >1000 nM at D1 vs. SCH-23390 [43]).

While most investigators agree that BSR threshold is elevated by systemic administration of the selective D1 antagonist SCH-23390, findings are inconsistent among the few studies that have examined the effect of systemically-administered D1 agonists on ICSS. Reports have shown decreased ICSS following SKF-38393 administration in a reward-summation procedure [44] and increased BSR threshold following SKF-81297 administration using a rate-independent method [45]; while others have shown decreased BSR threshold with SKF-38393 [46] and A-77636 [47] using the curve-shift method that we employ. We previously demonstrated in Swiss-Webster mice that systemic administration of SKF-82958 lowers BSR threshold in a dose-dependent manner [31]. The effect size we observe to both D1-like agonists is small, consistent with our previous data and with prior reports in mice. Given the wide variability in effect on ICSS we observe, it is not possible to statistically differentiate prenatally cocaine-exposed mice from controls on the basis of our SKF-81297 data. However, despite a small effect size, cocaine-exposed adult male mice demonstrate greater sensitivity to the threshold-lowering effect of SKF-82958 than controls, while females show no difference in the reward-potentiating effect of this D1-like agonist. We conclude that it is possible that increased sensitivity to D1 receptor-mediated effects may account in part for the increase in cocaine potency we observe in adult male mice following prenatal cocaine exposure.

Most investigators agree that agonists acting at dopamine D2-receptors potentiate the rewarding value of ICSS in rats [46-48]. However, one study [49] demonstrated similar increases in reward threshold using quinpirole at doses in the same range as those at which we also observe elevations in BSR threshold, although that study did not test doses higher than 0.066 mg/kg. Apomorphine, an agonist with similar affinity for D2 and D1 receptors [50, 51], also increases BSR threshold at low doses (0.01-0.1 mg/kg) and decreases threshold at higher doses (0.3-1.0 mg/kg) [52]. We observe clear increases in BSR threshold following low doses of quinpirole (0.1-0.3 mg/kg) and decreases in threshold at higher doses (1.0-10 mg/kg). We conclude from our biphasic dose-response data that it is likely that the D2-selective agonist quinpirole acts to suppress dopamine release from presynaptic terminals at low doses and to increase postsynaptic signaling at higher doses, consistent with the known pharmacology of D2-mediated actions in the nAc [53, 54]. We observe enhanced potency of quinpirole to both increase threshold at low doses and decrease threshold at higher doses in cocaine-exposed male but not female mice, and conclude from these data that it is possible that increased D2 receptor sensitivity may also account in part for the increased potency of cocaine we observe in adult male mice following prenatal cocaine exposure.

The efficacies of SKF-82958 and SKF-81297 to stimulate adenylyl cyclase through the D1 receptor are similar [55, 56]. However, it has also been shown that SKF-82958 possesses significantly more affinity for D2 receptors than other relatively D1-selective agonists [42]. While the locomotor-stimulating effects of systemically-administered SKF-82958 and SKF-81297 are similar [57-59] the potency of SKF-81297 is significantly less than that of SKF-82958 to produce conditioned place preference in rats [58, 60]. Systemically-administered SKF-82958 but not SKF-81297 decreases mesencephalic dopaminergic neuronal firing in the rat, and this inhibition is blocked by D2 (haloperidol, eticlopride) but not D1 (SCH-23390) antagonists [61]. Taken together, these studies suggest that SKF-82958 may be a partial agonist at D2 receptors as well as a full agonist at D1 receptors. It is therefore possible that the increased potency of SKF-82958 to lower ICSS threshold that we observe may reflect adaptations at the D2 receptor or its signal transduction systems rather than changes in D1 signaling in males following gestational cocaine exposure. Investigation of the effects of D1 (e.g., SCH-23390) and D2 antagonists (e.g., eticlopride) on ICSS threshold, which are known to possess greater relative selectivity than available agonists, are currently addressing this question.

One of the most persistent criticisms of the curve-shift ICSS method is that the behavior measured is rate-dependent [17], and therefore changes in reward threshold cannot be reliably determined for drugs that may interfere with motoric performance of the operant response. In this study we demonstrate that administration of a drug that decreases the rate of operant response in a dose-dependent manner, the dopamine D2-selective agonist quinpirole, results in biphasic effects on BSR threshold in the same dose range in which we observe decreased maximum rates of operant response. While quinpirole is known to have different behavioral effects in rats and mice, this dissociation of pharmacological effects on BSR threshold and rate of responding indicates that the two measures are experimentally separable in mice, and supports the validity of rate-dependent ICSS methods.

In summary, convergent preclinical findings from several different lines of behavioral investigation of the rewarding properties of drugs of abuse suggests that early developmental exposure to cocaine increases the rewarding potency of cocaine in operant procedures, such as ICSS and drug self-administration, and decreases the rewarding potency of cocaine in procedures employing non-contingent administration and classical conditioning, such as locomotor sensitization and conditioned place-preference. Our current findings suggest that adaptations in dopamine D2 and possibly D1 receptor signaling may account in part for the changes we observe in the rewarding potency of cocaine in adult male mice following prenatal cocaine exposure. These changes in the function of brain reward circuitry persist into adulthood, and may be relevant to the vulnerability of adults to drug-seeking and drug-consuming behaviors following exposure to drugs of abuse occurring in prenatal life or during other critical developmental periods. We hope that these preclinical findings will facilitate the design of future clinical studies on later liability for drug-abusing behavior, and the development of early therapeutic intervention, in drug-exposed children.

Acknowledgments

The authors are grateful to Dr. Josephine Johns for her helpful comments in the preparation of this manuscript. This work was supported by grants from the National Institute on Drug Abuse DA015429 (CJM); DA012736 (WAC); DA000354 (BEK); DA008648 (BEK), and an award from the William Randolph Hearst Fund for Pre- and Perinatal Research at the Harvard Medical School (CJM).

Footnotes

FINANCIAL DISCLOSURES The authors have no conflict of interest, financial or otherwise, related directly or indirectly to the work presented in this manuscript.

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