Discrete opioid gene expression impairment in the human fetal brain associated with maternal marijuana use.

Fetal development is a period sensitive to environmental influences such as maternal drug use. The most commonly used illicit drug by pregnant women is marijuana. The present study investigated the effects of in utero marijuana exposure on expression levels of opioid-related genes in the human fetal forebrain in light of the strong interaction between the cannabinoid and opioid systems. The study group consisted of 42 midgestation fetuses from saline-induced voluntary abortions. The opioid peptide precursors (preprodynorphin and preproenkephalin (PENK)) and receptor (mu, kappa and delta) mRNA expression were assessed in distinct brain regions. The effect of prenatal cannabis exposure was analyzed by multiple regression controlling for confounding variables (maternal alcohol and cigarette use, fetal age, sex, growth measure and post-mortem interval). Prenatal cannabis exposure was significantly associated with increased mu receptor expression in the amygdala, reduced kappa receptor mRNA in mediodorsal thalamic nucleus and reduced preproenkephalin expression in the caudal putamen. Prenatal alcohol exposure primarily influenced the kappa receptor mRNA with reduced levels in the amygdala, claustrum, putamen and insula cortex. No significant effect of prenatal nicotine exposure could be discerned in the present study group. These results indicate that maternal cannabis and alcohol exposure during pregnancy differentially impair opioid-related genes in distinct brain circuits that may have long-term effects on cognitive and emotional behaviors.

Marijuana impairs growth in mid-gestation fetuses.

Marijuana (Cannabis sativa) is the most commonly used illicit drug by pregnant women, but information is limited about the effects of prenatal cannabis exposure on fetal development. The present study evaluated the influence of early maternal marijuana use on fetal growth. Women electing voluntary saline-induced abortions were recruited at a mid-gestational stage of pregnancy (weeks 17-22), and detailed drug use and medical histories were obtained. Toxicological assays (maternal urine and fetal meconium) were used in conjunction with the maternal report to assign groups. Subjects with documented cocaine and opiate use were excluded. Main developmental outcome variables were fetal weight, foot length, body length, and head circumference; ponderal index was also examined. Analyses were adjusted for maternal alcohol and cigarette use. Marijuana (n=44)- and nonmarijuana (n=95)-exposed fetuses had similar rates of growth with increased age. However, there was a 0.08-cm (95% CI -0.15 to -0.01) and 14.53-g (95% CI -28.21 to 0.86) significant reduction of foot length and body weight, respectively, for marijuana-exposed fetuses. Moreover, fetal foot length development was negatively correlated with the amount and frequency of marijuana use reported by the mothers. These findings provide evidence of a negative impact of prenatal marijuana exposure on the mid-gestational fetal growth even when adjusting for maternal use of other substances well known to impair fetal development.

Preferential limbic expression of the cannabinoid receptor mRNA in the human fetal brain.

The cannabinoid receptor one (CB1) is responsible for the effects of cannabis on motor and cognitive function in the CNS. There is to date very limited information about the CB1 gene expression in the human brain, in particular during fetal development. In the present study, in situ hybridization experiments were used to examine the microscopic and macroscopic organization of the CB1 mRNA expression in normal human fetal (approximately 20 weeks of development) and adult brains. The fetal brain showed a distinct heterogeneous pattern of the CB1 mRNA expression which was low to moderate in many brain areas. The most striking feature of the fetal brain was the intense expression in the hippocampal CA region and basal nuclear group of the amygdaloid complex. Many of the same brain areas that showed positive expression of the CB1 mRNA in the fetal brain also expressed the gene in the adult brain. However, aside from an intense expression in the hippocampus which resembled that in fetal brain, the adult brain showed very high expression throughout the cerebral cortex, caudate nucleus, putamen and cerebellar cortex. These results document a different pattern of the anatomical organization of the CB1 mRNA expression in the mid-gestation fetal and adult human brain. Overall, the high CB1 mRNA expression in the fetal hippocampus and amygdala indicates that these limbic structures might be most vulnerable to prenatal cannabis exposure.

AZT distribution in the fetal and postnatal rat central nervous system.

The distribution of 3'-azido-3'-deoxythymidine (AZT, zidovudine), an antiviral drug used in the treatment of human immunodeficiency virus, was investigated in gestation day-20 (G-20) fetuses and in postnatal day-20 (PND-20) rats. At both ages, a single dose of 150 mg/kg (1.78 mmol/kg) AZT was administered orally along with tracer amounts of 14C-AZT, and rats were randomly killed at 15, 30, 60, 120, or 240 min after dosing. The fetuses, brains, and spinal cords were processed for autoradiography. The peak concentrations of AZT in plasma of G-20 and PND-20 rats were 92.2 microg/mL (0.345 micromol/mL) and 56.6 microg/mL (0.21 micromol/mL) at 15 and 30 min after intubation, respectively. The peak concentration of fetal tissue occurred in the colon at 60 min and was 205.8 microg/g tissue. In the G-20 rats, the brain showed higher levels of AZT than spinal cord only at the 30-min sample time, whereas in the PND-20 rats, greater radioactivity was found in the spinal cord up to the 240-min sample time. This pattern of AZT distribution in the central nervous system may hypothetically be attributed to the postnatal development of an organic anion carrier system believed to be responsible for transporting AZT from the brain to the blood, resulting in relatively greater overall exposure of the spinal cord to AZT than observed in the brain.

Impairment of spatial learning following preweaning cocaine exposure in the adult rat.

The present investigation focuses on learning and working memory capabilities of adult male and female Sprague-Dawley rats that were exposed to either cocaine (50 mg/kg/day sc) or distilled water during infancy (postnatal days 11-20). Learning and memory were assessed at 4 months using the eight-arm radial maze. Training was carried out in three phases in order to separate procedural learning from spatial capacity. Once criterion (entering at least seven arms without repeating arms for four out of five trials) was achieved in the first training room (Room 1), testing was moved to a second room (Room 2) with unique visual cues and an identical maze. Upon reaching criterion in Room 2, animals were returned to Room 1 and examined again. Cocaine-pretreated rats were less accurate than vehicle-pretreated rats during the first 10 trials of training. During the first five trials in Room 2 cocaine-pretreated animals made more errors, and made errors earlier within trials, than the vehicle-pretreated animals. Upon return to Room 1, reliable Gender x Pretreatment interactions were found for errors and total arms entered. These data demonstrate that a brief period of postnatal cocaine exposure can impair spatial cognition in adulthood and tentatively suggest that females are more sensitive than males.

Behavioral responses to dopamine agonists in adult rats exposed to cocaine during the preweaning period.

In order to determine whether developmental cocaine exposure altered the functional responses of dopamine systems, the behavioral responses to selective D1 or D2/D3 agonists were examined and compared to rats treated during the same period with a selective inhibitor of the dopamine transporter, GBR 12909. Sprague-Dawley rats were administered cocaine or GBR 12909 at 25 or 50 mg/kg/day during postnatal days (PND) 11-20. At 60+ days of age, rats were administered a challenge drug (either SKF 82958, a full D1 agonist, at 1.0 or 10 mg/kg, or quinpirole, a D2/D3 agonist, at 0.08 or 0.5 mg/kg, or saline) and subjected to 1 h of behavioral assessment. The cocaine or GBR treatments produced significant effects in three behavioral categories: distance traveled, sniffing, and rearing. For distance traveled, preweaning treatments interacted with sex since in the males, all cocaine- and GBR-treated groups showed relatively flat patterns of locomotor activity across time blocks, while in the treated females, locomotor activity typically increased across the time blocks. For other behaviors, the treatments generally produced enhanced responses to the challenge drugs. These results suggest that intermittent inhibition of the dopamine transporter with either cocaine or GBR during PND 11-20 produces long-term alterations in the functional responses of dopaminergic systems but that the neural substrates for these effects depend upon the sex of the animal.

Sexual dimorphism in the brain metabolic response to prenatal cocaine exposure.

The effects of prenatal cocaine exposure on the metabolic function of major central neuronal systems in the periweanling rat are reported in this study. Pregnant Sprague--Dawley rats were administered cocaine at either 30 or 60 mg/kg or the vehicle from gestation day (G) 8 through 22 via daily gastric intubation. Since prenatal cocaine has been shown to alter behavior in weanling rats, brain functional activity was quantified using the deoxyglucose method in male and female 21-day-old offspring (one of each gender/litter). Cocaine's effects were most significant within the limbic system where a three-way interaction between cocaine treatment, sex and brain region was seen. Within the limbic system, two regions, the rostral accumbens and the diagonal band of Broca showed reductions in metabolic activity in the exposed male offspring compared to the control offspring while no changes were seen in females. At more caudal levels of the forebrain, the accumbens (at the level of 1.2 micro rostral to Bregma) and septum showed cocaine-induced reductions in metabolism which were not dependent upon the sex of the animal. Metabolism within the hypothalamus also tended to show a significant interaction between treatment, gender and brain region (P=0.06). Two regions, including the ventromedial nucleus and lateral hypothalamic area, were metabolically depressed in the males alone while three other regions; the dorsomedial, arcuate, and medial preoptic nuclei were also metabolically depressed in the treated groups collapsed across gender. There were no significant treatment or sex-related effects or interactions within the sensory and motor systems. Chronic prenatal cocaine exposure reduced metabolism significantly in a restricted portion of the forebrain, the mesocortical-limbic system, particularly in regions associated with the medial forebrain bundle. These reductions were seen primarily in males while some regions showed changes which were independent of the sex of the animal. These cocaine-induced effects resembled, to a great extent, those seen in similarly-treated males examined as adults. The data emphasize that cocaine use during a restricted period of early pregnancy depresses function within limbic and hypothalamic regions and that many of these effects are sexually dimorphic in nature.

Differential behavioral responses to chronic amphetamine in adult male and female rats exposed to postnatal cocaine treatment.

The impact of cocaine exposure during development on behavioral sensitization as measured by locomotor activity and stereotypy following repeated intermittent administration of amphetamine is examined. Male and female Sprague-Dawley rats were exposed to cocaine at 50 mg/kg/day during postnatal days (PND) 11-20 and, as adults (PND193-212), were administered seven daily injections of 2.0 mg/kg amphetamine. Both locomotor activity and stereotypic behavior were assessed following the first and seventh injections. Control males and females showed sensitized behavior following repeated amphetamine injections with females showing greater locomotion while males showed increased stereotypy. Male rats pretreated with cocaine failed to develop sensitized locomotor or stereotypic responses following repeated amphetamine injections consistent with dampened D(1) receptor activity. Females pretreated with cocaine did not show a sensitized locomotor response but did display sensitization of stereotypy following repeated amphetamine administration. Thus, it appears that postnatal cocaine treatment produces differential effects on the circuits mediating sensitization behavior in male and female rats.

Distribution of protein kinase Mzeta and the complete protein kinase C isoform family in rat brain.

Protein kinase C (PKC) is a multigene family of at least ten isoforms, nine of which are expressed in brain (alpha, betaI, betaII, gamma, delta, straightepsilon, eta, zeta, iota/lambda). Our previous studies have shown that many of these PKCs participate in synaptic plasticity in the CA1 region of the hippocampus. Multiple isoforms are transiently activated in the induction phase of long-term potentiation (LTP). In contrast, a single species, zeta, is persistently activated during the maintenance phase of LTP through the formation of an independent, constitutively active catalytic domain, protein kinase Mzeta (PKMzeta). In this study, we used immunoblot and immunocytochemical techniques with isoform-specific antisera to examine the distribution of the complete family of PKC isozymes and PKMzeta in rat brain. Each form of PKC showed a widespread distribution in the brain with a distinct regional pattern of high and low levels of expression. PKMzeta, the predominant form of PKM in brain, had high levels in hippocampus, frontal and occipital cortex, striatum, and hypothalamus. In the hippocampus, each isoform was expressed in a characteristic pattern, with zeta prominent in the CA1 stratum radiatum. These results suggest that the compartmentalization of PKC isoforms in neurons may contribute to their function, with the location of PKMzeta prominent in areas notable for long-term synaptic plasticity.

Neurobehavioral effects of perinatal AZT exposure in Sprague-Dawley weaning rats.

Because AZT (azidothymidine, zidovudine, ZDV) has become the standard of care for preventing HIV transmission during pregnancy, we conducted a study to assess the possible neurobehavioral effects of this drug, using a rat model. Each litter was randomly assigned to a treatment group: vehicle, AZT 50, 100, or 150 mg/kg, or no treatment. Treatments were administered once daily via gastric intubation, prenatally from gestation day (G) 19-22 and then postnatally from postnatal day (PND) 2-20, except the nontreated group, which was only weighed every 4 days. On PND21 each rat was given a single dose of amphetamine (0.25, 0.50, 0.75, or 1.0 mg/kg) or saline and placed in the Accuscan activity chamber for 1 h of data collection and video taping. Results show that all of the behaviors analyzed produced statistically significant main effects of perinatal treatment, challenge drug, and time block. For distance traveled, there was a significant three-way interaction between treatment, sex, and time block, an effect that was independent of the effects of handling and injecting the rats. That is, within the males, the AZT 150 group displayed the greatest amount of locomotion, while among the females, the AZT 50 group was the most active. Furthermore, the AZT 50 group showed significantly less margin time (wall hugging) and more grooming than the nontreated control group. However, handling contributed to these differences because they were not observed when the vehicle-intubated group was used as the control. Across all treatment groups, amphetamine increased locomotion, the duration of rearing, and sniffing, while it decreased wall hugging, grooming, and time spent quiet. Complex interactions between amphetamine dose and time block were also seen for each behavior. In summary, these data indicate that amphetamine, at the doses used in the current study, alters behavior in the rat at 21 days of age, and that perinatal AZT exposure alters behavior in a single domain, locomotion with the threshold for this effect depending on genders.

Cocaine decreases uteroplacental blood flow in the rat.

Although cocaine administration reduces blood flow to the fetus in the pregnant ewe, the effects of cocaine on uterine and placental blood flow in the pregnant rat have not been adequately documented. The current study tested the hypothesis that cocaine decreased uterine and placental blood flow in awake and freely moving pregnant rats 17 min following gastric intubation. Blood flow was determined using [14C]iodoantipyrine in pregnant Sprague-Dawley rats 1 day prior to parturition. On the day of the experiment, rats were intubated with either 60 mg/kg cocaine or the vehicle and 17 min later infused i.v. with 75 microCi [14C]iodoantipyrine. Ten arterial blood samples were taken over 1 min through a femoral arterial catheter placed on the previous day. At 1 min the animal was decapitated and the entire uterus rapidly removed and frozen. After processing for autoradiography, the amounts of radioactivity in the tissues were determined by computerized image analysis. The results show that cocaine reduced blood flow in the uterus by 27% and decreased blood flow in the placenta by 30%. While cocaine reduced the total amount of iodoantipyrine reaching the fetus, the distribution of tracer within the fetus did not appear to be altered by cocaine. Maternal blood pressure and heart rate decreased by 5% and 13% respectively (paired t-test), while maternal and fetal blood gases were not altered. These data indicate that acute cocaine administration reduces uteroplacental blood flow in the rat. The duration of this effect and whether these decreases are sufficient to produce neurobehavioral changes in the offspring remain to be determined.

Neurobehavioral effects of perinatal AZT exposure in Sprague-Dawley adult rats.

Since AZT (azidothymidine, zidovudine, ZDV) has become the standard of care for preventing human immunodeficiency virus transmission during pregnancy, we conducted a study to assess the possible long-term neurobehavioral effects of AZT, using a rat model. Each litter was randomly assigned to a treatment group: no treatment, vehicle or AZT 50, 100, or 150 mg/kg. Treatments were administered once daily via gastric intubation, prenatally from gestation day (G) 19-22 and then from postnatal day (PND) 2-20. Between PND 59-65, each rat was given a single dose of amphetamine (0.1, 0.5, 1.0, or 2.0 mg/kg) or saline and placed in the Accuscan activity chamber for 1 h of data collection and video taping. There was a significant interaction between perinatal treatment and amphetamine challenge drug for one behavioral category, distance traveled, which was due to differences in the nontreated control group compared to all treated groups. These data indicate that chronic AZT treatment at three dose levels during the perinatal period produces no lasting changes in response to amphetamine in the open field in the rat.

Behavioral sensitization to apomorphine in adult rats exposed to cocaine during the preweaning period: a preliminary study.

Sixty-day-old rats treated with cocaine (50 mg/kg SC) during postnatal days (PND) 11-20 received daily injections of apomorphine (2.0 mg/kg SC) for 10 consecutive days to examine the development of sensitization to a direct dopamine agonist. Behavior was monitored on days 1, 5, and 10, using a photobeam system, and on day 10 using the videotape assessments as well. Locomotor sensitization to apomorphine developed in the preweaning vehicle-treated males only. Neither the cocaine-treated males nor any females exhibited locomotor sensitization to repeated apomorphine injections at 2 mg/kg. There were no other treatment-related effects except for grooming, which showed an interaction between treatment and gender. Overall, every behavior analyzed showed significant apomorphine effects, except rearing. Margin time (wall hugging), grooming, and quiet were significantly decreased by apomorphine, while locomotion and the duration of sniffing were increased. In summary, these data indicate that with respect to locomotor activity, the development of sensitization to apomorphine at 2.0 mg/kg is prevented by preweaning cocaine administration in males. These data further suggest that developmental cocaine exposure produces long-term alterations in DA D1 receptor-mediated responses in male rats.

Chronic haloperidol alters dopamine receptors: effects of cocaine exposure during the preweaning period.

The effect of cocaine exposure during the preweaning period on the function of the central dopaminergic systems was determined in adult rats. The present study investigated the alterations in dopamine receptors in 93-day-old male and female rats treated with cocaine (50 mg kg(-1) day(-1)), 1-[2-[bis(4-fluorophenyl)methoxyl]-4-[3-phenylpropyl]piperazine (GBR 12909) (50 mg kg(-1) every other day) or water during postnatal days 11-20. Haloperidol (2 mg kg(-1) day) or saline was injected during postnatal days 76-90 and the rats were killed on postnatal day 93. Quantitative receptor autoradiography with [3H]R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-b enzazepine ([3H]SCH 23390) for the dopamine D1 receptor and [3H]raclopride for the dopamine D2 receptor was carried out. The results show that haloperidol increased [3H]raclopride binding in many forebrain regions. Preweaning cocaine treatment in males increased the area showing this effect. Males generally were more responsive to haloperidol than females. However, in GBR 12909-treated females, raclopride binding showed widespread increases following haloperidol injection. For SCH 23390 binding, most regions showed a significant interaction between haloperidol, sex and preweaning treatment group. This was due primarily to the GBR 12909-treated males, which showed elevated basal dopamine D1 receptor binding levels and a haloperidol-induced reduction in dopamine D1 receptor binding in most regions evaluated. These data suggest that inhibition of the dopamine transporter during ontogeny produces long-term alterations in dopamine receptor regulation but that selective inhibitors of the dopamine transporter produced greater effects than cocaine on both raclopride and SCH 23390 binding following chronic haloperidol injection.

Perinatal cocaine decreases the expression of prodynorphin mRNA in nucleus accumbens shell in the adult rat.

Preprodynorphin mRNA expression in the striatal-olfactory tubercle complex was studied in adult rats exposed to cocaine (50 mg/kg) during postnatal days (PnD) 11-20. While multiple regions of the striatum and olfactory tubercle were examined, alterations were only found in the nucleus accumbens. A 50% and 20% reduction in expression within the shell region was observed at 1.2 and 1.7 mm rostral to Bregma respectively. While the core regions at these levels were unaffected, the rostral accumbens showed a trend toward an increase in expression in the cocaine-treated rats. These findings, in combination with other behavioral and neurochemical data collected on similarly treated rats, suggest that perinatal cocaine produces a long-term dampening of function in a specific population of neurons within the mesolimbic system

Neurobehavioral and pregnancy effects of prenatal zidovudine exposure in Sprague-Dawley rats: preliminary findings.

In 1994, the Public Health Service made prenatal zidovudine (ZDV, AZT) the standard of care to prevent mother-to-child transmission of HIV. The current study was undertaken to determine if prenatal exposure to ZDV has an impact on pregnancy outcomes, birth anomalies, or offspring behavior in an animal model using Sprague-Dawley (SD) rats. Thirty-one virgin female SD rats were mated and randomly assigned to receive either ZDV at 150 mg/kg/day or vehicle via gastric intubation for 22 days starting on gestation day (G) 1. On G 22, teratologic examination of 12 litters showed no gross structural malformations. There were no significant differences between the groups for maternal food and water consumption or maternal weight gain across pregnancy. However, ZDV treatment significantly reduced litter size and increased birth weights for both male and female pups. One developmental milestone, pinna detachment, occurred significantly earlier in the ZDV-exposed male pups compared to the vehicle-intubated male controls. On day 21-22 of life, pups in each litter were injected with one of four doses of amphetamine and were observed for behavioral activity in a photobeam-based activity monitor for 1 h. Overall amphetamine increased activity and decreased thigmotaxis or wall-hugging behavior. ZDV treatment increased the locomotor response to amphetamine in females only and dampened the action of amphetamine to decrease thigmotaxis in both genders. Further studies are warranted to determine the threshold dose at which these changes occur, the duration of the effects, as well as the neurochemical system(s) responsible for the altered amphetamine responses.

Preweaning cocaine administration alters the adult response to quipazine: comparison with fluoxetine.

This study investigated whether exposure to cocaine during the preweaning period affects the behavioral response to administration of a challenge dose of quipazine, a relatively nonselective serotonin (5-HT) mixed agonist/antagonist, in adulthood. To determine whether selective inhibition of the 5-HT transporter during the preweaning period would produce a cocaine-like pattern of effects, another group of rats was given fluoxetine, a highly selective and potent inhibitor of the 5-HT transporter, and was tested along with the cocaine-treated rats. Male and female rats received 25 mg/kg cocaine HCl (82.5 mumol/kg), 25 mg/kg fluoxetine HCl (72.3 mumol/kg), or vehicle subcutaneous (s.c.) during postnatal days 11-20. Both treatments reduced weight gain during the injection period only. At 60 days of age, subjects were administered a single dose of quipazine (0, 0.4, or 1.0 mg/kg, s.c.) and placed in the Accuscan activity monitor for 1 h of behavioral recording. Overall, distance traveled, vertical activity, and time in the center of the chamber decreased during the initial time blocks of the session and vertical activity decreased with increasing doses of quipazine. Females in general showed greater overall activity levels than males as well as greater responsivity to quipazine. Preweaning cocaine exposure produced different effects in males and females. In males, cocaine enhanced the response to quipazine for vertical activity whereas it had no effect on quipazine-induced alterations on the other two behaviors. On the other hand, cocaine-treated females showed dampened dose-related quipazine responses across all behavioral measures. Fluoxetine administration produced a dampening of the quipazine effect for vertical activity and distance traveled in males and females. Therefore, these data indicate that cocaine administration during the preweaning period of development produced an increase in the effect of a serotonergic drug to alter vertical activity in males and a global dampening of the behavioral responses to that same drug in females. Preweaning fluoxetine treatment produced effects that resembled those produced by cocaine in females, a dampening of serotonergic responsivity, along with an overall decrease in locomotor activity. Because the majority of effects are seen during the initial portion of the behavioral session, a time of heightened activity in response to a novel environment, the data suggest that inhibition of the 5-HT transporter during the preweaning period alters serotonergic influences over novelty-induced activity but that brief periods of inhibition or other actions of cocaine, such as those at the catecholamine transporters, prevent this from happening, particularly in males.

Modification of acoustic startle reactivity by cocaine administration during the postnatal period: comparison with a specific serotonin reuptake inhibitor.

This study investigated whether exposure to cocaine during postnatal period affects the acoustic startle response (ASR) following administration of the serotonin (5-HT) agonists, 8-OH-DPAT and mCPP, in adulthood. To test the hypothesis that alterations in reactivity may be due to cocaine's effects at the 5-HT carrier, another group of rats was given fluoxetine, a specific 5-HT uptake inhibitor, during the same postnatal period and tested along with the cocaine-treated rats. Male and female rats received 25 mg/kg/day cocaine HCl, fluoxetine HCl, or vehicle SC during postnatal days 11-20. At 75 days of age, subjects were ASR tested for 30 min on 2 consecutive days. On the first test day, there was a significant effect of treatment and gender with post hoc analysis indicating that, overall, the males were more reactive than the females and that the fluoxetine-treated males showed a pattern of reactivity resembling sensitization. On the second test day, subjects received a dose of the 5-HT1A agonist 8-OH-DPAT, the 5-HT1B/2C agonist, mCPP, or saline prior to being placed in the startle chamber. Cocaine-exposed males showed an enhanced response to 8-OH-DPAT and a reduction in the depression produced by mCPP administration compared to their response to saline. Fluoxetine exposed males showed a significant increase in startle response following saline administration compared to the rats receiving vehicle during the postnatal period and 8-OH-DPAT produced an insignificant enhancement of that startle response. mCPP reduced startle in fluoxetine-treated males as it did in the postnatal vehicle-treated controls. In females, the postnatal cocaine and fluoxetine treatments did not alter the response to 8-OH-DPAT or mCPP compared to females receiving vehicle during the postnatal period. Together these data indicate that, in males, whereas postnatal cocaine alters the development of the 5-HT system as evidenced by an altered startle response to 5-HT agonists, cocaine does not produce the same alteration as that produced by the administration of a specific 5-HT uptake inhibitor during the same period of development.