Tiospirone and the reinforcing effects of cocaine in the conditioned place preference paradigm in rats

Tiospirone (TSP) is an atypical antipsychotic drug. It has 5HT-2 antagonistic properties as well as affinity for D2, 5HT-1a, 5HT-6 and sigma receptors. Behavioural studies in our laboratory, which used a 24h free access to food and fluids paradigm, showed a decreased alcohol and increased food intake after twice-daily administration of TSP; the maximal effect was obtained at a dose of 0.48 mg kg(-1). This study used the conditioned place preference paradigm to determine the effect of TSP on the reinforcing properties of cocaine. Intraperitoneal administration of 5.0 mg kg(-1) cocaine, but not saline, increased the time rats spent in the drug-paired compartment of a three-compartment shuttle box by 104.9%. Two doses of TSP, 0.143 and 0.48 mgkg(-1), were tested subcutaneously 60 min before saline or cocaine administration during the conditioning phase only. A dose-response effect was observed with a significant reduction in the time rats spent in the cocaine-paired compartment on the drug-free test day produced by the dose of 0.48 mg kg(-1) (an increase of only 38.1% when post-conditioned times were compared with preconditioned times). These findings suggest that TSP reduces the reinforcing properties of cocaine exhibited in the conditioned place preference paradigm.     

Prenatal exposure to cocaine disrupts cocaine-induced conditioned place preference in rats.

Cocaine-induced conditioned place preference (CPP) was tested in adult offspring of Sprague-Dawley dams that had been injected subcutaneously with 40 mg/kg/3cc cocaine HCl (C40) daily from gestational days 8-20, pair-fed (PF) dams injected with saline, and nontreated control (LC) dams. C40 and PF dams gained significantly less weight than LC dams, although offspring body weights did not differ among the three prenatal treatment groups at birth or in adulthood. Significant place conditioning was obtained in LC and PF offspring when either 2.0 or 5.0 mg/kg of cocaine was paired with the designated place. In contrast, C40 offspring did not exhibit place conditioning at either training dose. Yet, all animals exposed to 5 mg/kg of cocaine during conditioning exhibited less activity during the test (when no cocaine was given) than controls given unpaired exposures to the apparatus and cocaine and C40 offspring did not differ from LC and PF offspring in this respect. Therefore, despite their lack of a conditioned place preference for cocaine, rats that had been exposed gestationally to cocaine nevertheless revealed an effect of cocaine during conditioning in one aspect of their test behavior. Possible explanations for the lack of cocaine-induced place preference in these animals include a learning deficit or a change in cocaine's effectiveness as a reward.     

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.     

Low and high locomotor responsiveness to cocaine predicts intravenous cocaine conditioned place preference in male Sprague-Dawley rats

Outbred, male Sprague-Dawley rats can be classified as either low or high cocaine responders (LCRs or HCRs, respectively) based on cocaine-induced locomotor activity in an open-field arena. This difference reflects cocaine's ability to inhibit the striatal dopamine transporter and predicts development of sensitization. To investigate the relationship between initial cocaine locomotor responsiveness and cocaine reward, here we first classified rats as either LCRs or HCRs in a conditioned place preference (CPP) apparatus. Subsequently, we conducted cocaine conditioning trials, twice-daily over 4 days with vehicle and cocaine (10 mg/kg, i.p. or 1 mg/kg, i.v.). When cocaine was administered by the i.p. route, similar to previous findings in the open-field, LCRs and HCRs were readily classified and locomotor sensitization developed in LCRs, but not HCRs. However, cocaine CPP was not observed. In contrast, when cocaine was administered by the i.v. route, the LCR/HCR classification not only predicted sensitization, but also CPP, with only LCR rats exhibiting sensitization and cocaine conditioning. Our findings show that the initial locomotor response to cocaine can predict CPP in male Sprague-Dawley rats under conditions when place conditioning develops, and that LCRs may be more prone to develop conditioning in the context of cocaine reward.     

Previous exposure to THC alters the reinforcing efficacy and anxiety-related effects of cocaine in rats.

The hypothesis that prior cannabis exposure increases the likelihood of becoming addicted to other drugs can be evaluated by giving rats a history of tetrahydrocannabinol (THC) exposure, then allowing them to self-administer other drugs. In Experiment 1, THC pre-exposure did not alter the acquisition of cocaine self-administration or the amount of cocaine taken under a fixed-ratio 1 (FR1) schedule, with one response required for each injection. Under a progressive-ratio schedule, with the response requirement increasing exponentially with each injection, cocaine-seeking was significantly reduced in THC-exposed rats, suggesting that the regimen of THC exposure used in the present study caused cocaine to be devalued as a reinforcer. In contrast, in an earlier study that used the same regimen, a history of THC exposure did not alter the value of heroin as a reinforcer under the progressive-ratio schedule, but it increased heroin self-administration under the FR1 schedule. Experiment 2 examined how this regimen of THC pre-exposure alters the locomotor effects of cocaine and heroin. THC pre-exposure produced cross-tolerance to the motor-depressant effects of heroin; this may explain the shortened post-injection pauses exhibited by THC-exposed rats under FR1 heroin self-administration. When given cocaine, THC-exposed rats exhibited normal increases in locomotion, but they avoided the center of the open field, suggesting that this THC pre-exposure regimen enhances the anxiogenic effects of cocaine. This enhanced anxiogenic effect-which was verified in Experiment 3 using another model of anxiety, the light-dark test-may explain the reduced reinforcing value of cocaine observed in THC-exposed rats in Experiment 1.     

Prenatal exposure to cocaine alters the development of conditioned place-preference to cocaine in adult mice

As addiction is increasingly formulated as a developmental disorder, identifying how early developmental exposures influence later responses to drugs of abuse is important to our understanding of substance abuse neurobiology. We have previously identified behavioral changes in adult mice following gestational exposure to cocaine that differ when assessed with methods employing contingent and non-contingent drug administration. We sought to clarify this distinction using a Pavlovian behavioral measure, conditioned place-preference. Adult mice exposed to cocaine in utero (40 or 20 mg/kg/day), vehicle and pair-fed controls were place-conditioned to either cocaine (5 mg/kg or 20 mg/kg, i.p.) or saline injections. The development of conditioned place-preference to cocaine was impaired in mice exposed to cocaine in utero, and was abolished by fetal malnutrition. A context-specific place-aversion to vehicle but not cocaine injection was observed in prenatally cocaine-exposed mice. Locomotor behavior did not differ among prenatal treatment groups. We conclude that early developmental exposure to cocaine may diminish the subsequent rewarding effects of cocaine in adulthood measured with classical conditioning techniques, and that this is not due to changes in locomotor behavior. Sensitivity to acute stress is also altered by prenatal cocaine exposure, consistent with earlier findings in this model.     

Prenatal exposure to cocaine alters the development of conditioned place-preference to cocaine in adult mice

As addiction is increasingly formulated as a developmental disorder, identifying how early developmental exposures influence later responses to drugs of abuse is important to our understanding of substance abuse neurobiology. We have previously identified behavioral changes in adult mice following gestational exposure to cocaine that differ when assessed with methods employing contingent and non-contingent drug administration. We sought to clarify this distinction using a Pavlovian behavioral measure, conditioned place-preference. Adult mice exposed to cocaine in utero (40 or 20 mg/kg/day), vehicle and pair-fed controls were place-conditioned to either cocaine (5 mg/kg or 20 mg/kg, i.p.) or saline injections. The development of conditioned place-preference to cocaine was impaired in mice exposed to cocaine in utero, and was abolished by fetal malnutrition. A context-specific place-aversion to vehicle but not cocaine injection was observed in prenatally cocaine-exposed mice. Locomotor behavior did not differ among prenatal treatment groups. We conclude that early developmental exposure to cocaine may diminish the subsequent rewarding effects of cocaine in adulthood measured with classical conditioning techniques, and that this is not due to changes in locomotor behavior. Sensitivity to acute stress is also altered by prenatal cocaine exposure, consistent with earlier findings in this model.     

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.     

Prenatal cocaine exposure attenuates cocaine-induced odor preference in infant rats.

In order to further examine whether prenatal cocaine exposure alters the later reward efficacy of cocaine, exposed offspring were tested for cocaine-induced odor preference early in life. Test offspring were derived from Sprague-Dawley dams that received daily SC injections of 40 mg/kg/3 cc cocaine hydrochloride (C40) from gestational day 8-20, nutritional control dams receiving daily SC saline injections (NC), and nontreated control dams (LC). At testing on postnatal day 8 (P8), both LC and NC offspring were observed to exhibit a preference for the odor that had been paired on P7 with 2.0, 5.0, or 10.0 mg/kg cocaine. In contrast, C40 offspring exhibited a significant odor preference only when the odor had been previously paired with 5.0 or 10.0 mg/kg cocaine. These results, combined with previous work from our laboratory showing that adult offspring exposed gestationally to cocaine did not exhibit a cocaine-induced conditioned place preference, provide evidence that offspring exposed prenatally to cocaine are less likely to develop a preference for stimuli associated with cocaine. Further studies are needed to determine whether these alterations in cocaine preference reflect a learning deficit, pharmacokinetics factors, or an attenuation in the rewarding properties of cocaine.     

Chronic cadmium exposure attenuates conditioned place preference produced by cocaine and other drugs.

Adult male rats were exposed ad lib for 40 days to 100 ppm dietary cadmium chloride (group cadmium) or an identical diet with no added cadmium (group control). Conditioned place preference (CPP) was conducted in a two-chamber apparatus in which all drugs were paired with the least-preferred side as determined by a pretest. In Experiment 1, animals received 0, 2.5, or 5 mg/kg cocaine HCl (IP) for 4 days and vehicle only for 4 days. Control animals showed a place preference for the drug side at 2.5 and 5 mg/kg, while the cadmium-exposed animals showed a preference at 5 mg/kg only. In Experiment 2, animals received 0, 5, or 10 mg/kg of the D1/D2 dopamine receptor agonist apomorphine HCl (SC) for 4 days and vehicle only for 4 days. Control animals showed a place preference at 5 and 10 mg/kg, while metal-exposed animals showed a preference at 10 mg/kg only. To determine the possible effects of alterations of learning mechanisms by cadmium, a conditioned place aversion (CPA) procedure was employed for Experiment 3. Animals received 0, 10, or 40 mg/kg lithium chloride (IP) for 4 days or vehicle only for 4 days. Control animals showed a significant place aversion at 40 mg/kg, while cadmium-exposed animals did not. These findings are discussed within a framework of possible metal-induced disturbance of neurochemical function and/or associative processing.     

Perinatal exposure of rats to Bisphenol A affects fertility of male offspring--an overview

Endocrine disruptors (ED) induce both functional and behavioral reproductive abnormalities. Bisphenol A (BPA) is a known ED that leaches from polycarbonate plastics, as such human exposure is common. Maternal BPA exposure has been shown to have negative effects on the fertility of male offspring. Pregnant rats exposed perinatally to environmentally relevant doses of BPA gave birth to offspring with significantly impaired spermatogenesis and fertility. Perinatal exposure had deleterious effects on the male germ line which manifested as impairments in the fertility of F(1) male offspring and subsequent F(2) and F(3) generations. This overview is an attempt to summarize the currently available data in the literature with regards to perinatal BPA exposure and male fertility.     

Perinatal exposure to the estrogenic pollutant bisphenol A affects behavior in male and female rats

Bisphenol A (BPA) is an environmental estrogen with potentially aversive effects on public health. In rats, we studied the effects of perinatal exposure to BPA on nonsocial behaviors partly influenced by gonadal hormones. BPA was administered orally to one group of mother rats at a concentration within the range of human exposure from 10 days before mating until the weaning of the pups. In a second group, BPA was given at a higher dosage during a critical period for brain organization, i.e., from day 14 of gestation until day 6 after birth. The offspring of the treated mothers were tested in the holeboard and the elevated plus-maze at 85 days of age. Various aspects of nonsocial behavior were affected by BPA, differently in males and females, confirming that exposure to a weak environmental estrogen in the period of sexual differentiation of the brain can influence adult behavior. However, contrary to our expectation, a clear masculinization of females was not observed. In general, the factor analysis indicated that in treated males both the motivation to explore and anxiety are reduced, while in females, motor activity and motivation to explore are depressed. Because there were no substantial differences between the two modalities of BPA administration, we suggest that the prolonged treatment with the low dosage compensates for the higher dosage given during a shorter steroid-sensitive period. This may be a cause of concern for public health, given the greater incidence of prolonged exposure of humans to low concentrations released into the environment.     

Active cocaine immunization attenuates the discriminative properties of cocaine

Anticocaine antibody, resulting from immunization with the cocaine-keyhole-limpet-hemocyanin (KLH) conjugate, weakened the ability of cocaine to act as a discriminative stimulus in rats. Subjects were given extensive training to discriminate 5.0 mg/kg of cocaine from saline prior to immunization. Several weeks following immunization with cocaine-KLH, subjects failed to reliably discriminate cocaine from saline. Nonimmunized control rats retained the ability to discriminate cocaine from saline throughout the experiment. These results further demonstrate that active immunization is effective in blunting cocaine effects. Immunized subjects were able to discriminate 20 mg/kg of cocaine, however, suggesting that anticocaine antibody may be overwhelmed by large cocaine doses.     

Individual differences in dopamine uptake in the dorsomedial striatum prior to cocaine exposure predict motivation for cocaine in male rats

A major theme of addiction research has focused on the neural substrates of individual differences in the risk for addiction; however, little is known about how vulnerable populations differ from those that are relatively protected. Here, we prospectively measured dopamine (DA) neurotransmission prior to cocaine exposure to predict the onset and course of cocaine use. Using in vivo voltammetry, we first generated baseline profiles of DA release and uptake in the dorsomedial striatum (DMS) and nucleus accumbens of drug-naïve male rats prior to exposing them to cocaine using conditioned place preference (CPP) or operant self-administration. We found that the innate rate of DA uptake in the DMS strongly predicted motivation for cocaine and drug-primed reinstatement, but not CPP, responding when “price” was low, or extinction. We then assessed the impact of baseline variations in DA uptake on cocaine potency in the DMS using ex vivo voltammetry in naïve rats and in rats with DA transporter (DAT) knockdown. DA uptake in the DMS of naïve rats predicted the neurochemical response to cocaine, such that rats with innately faster rates of DA uptake demonstrated higher cocaine potency at the DAT and rats with DAT knockdown displayed reduced potency compared to controls. Together, these data demonstrate that inherent variability in DA uptake in the DMS predicts the behavioral response to cocaine, potentially by altering the apparent potency of cocaine.Subject terms: Motivation, Addiction, Reward     

Corticotropin-releasing factor receptor blockade enhances conditioned aversive properties of cocaine in rats

The behavioral profile of corticotropin-releasing factor (CRF) in mediating anxiogenic-like and aversive responses to stressors may be particularly relevant for dependence and withdrawal in drug-experienced organisms. Moreover, stressful aspects of drug exposure in the drug naive organism may also induce CRF system activation. In the present studies, the dependence of aversive properties of cocaine on activation of endogenous CRF systems has been evaluated in rats using taste conditioning and runway self-administration paradigms. Systemic cocaine administration (20 mg/kg IP) produced a conditioned saccharin aversion which was dose-dependently potentiated by central administration of the CRF receptor antagonist, D-phe CRF (12–41). In addition, IV cocaine administration (0.75 mg/kg per injection IV) produced runway goal-box avoidance and conditioned place avoidance responses which were significantly accelerated by CRF antagonist treatment. In contrast, CRF receptor stimulation using CRF itself abolished cocaine-induced increases in goal latency in the runway paradigm. This generalized involvement of CRF systems in cocaine-related motivational/associative states is consistent with the comprehensive role of CRF in mediating emotional responses to non-drug stressors. Received: 3 June 1997/Final version: 28 August 1997     

Desmethylimipramine attenuates cocaine withdrawal in rats

Depression and anhedonia are two major symptoms of cocaine withdrawal in humans. Hence, pharmacological treatments effective in depression might also alleviate the symptoms of cocaine withdrawal. In the present study, the effects of acute and repeated administration of a tricyclic antidepressant, desmethylimipramine (DMI), were investigated in naive and cocaine-withdrawing rats. An animal model of cocaine withdrawal was used that employs the elevation in intracranial self-stimulation (ICSS) thresholds following the termination of prolonged periods of cocaine self-administration as a measure of an animal's anhedonic state. The influence of chronic DMI treatment on-adrenergic receptor binding and affinity was also correlated with the behavioral signs of cocaine withdrawal. Neither acute nor repeated DMI treatment influenced reward functions in rats that were not undergoing cocaine withdrawal. However, repeated DMI treatment significantly down-regulated-adrenergic receptors, and shortened the duration of the post-cocaine anhedonia (elevation in thresholds). Furthermore, the magnitude of the-adrenergic receptor down-regulation correlated significantly with the degree of effectiveness of DMI treatment in reversing the post-cocaine anhedonia. However, chronic DMI treatment did reduce the amount of cocaine self-administered by the animals. The reversal of the post-cocaine anhedonia in this animal model of cocaine withdrawal by chronic DMI treatment demonstrates the potential usefulness of the model in identifying new pharmacotherapies for cocaine withdrawal. In addition, the results indicate that tricyclic antidepressants may be able to ameliorate some of the symptoms of cocaine withdrawal.     

Perinatal choline supplementation attenuates behavioral alterations associated with neonatal alcohol exposure in rats

Children exposed to alcohol prenatally suffer from a variety of behavioral alterations, including hyperactivity and learning deficits. Given that women continue to drink alcohol during pregnancy, it is critical that effective interventions and treatments be identified. Previously, we reported that early postnatal choline supplementation can reduce the severity of learning deficits in rats exposed to alcohol prenatally. The present study examined whether choline supplementation can reduce the severity of behavioral alterations associated with alcohol exposure during the third trimester equivalent brain growth spurt. Male neonatal rats were assigned to one of three treatment groups. One group was exposed to alcohol (6.6 g/kg/day) from postnatal days (PD) 4-9 via an artificial rearing procedure. Artificially reared and normally reared control groups were included. One half of subjects from each treatment received daily subcutaneous injections of a choline chloride solution from PD 4-30, whereas the other half received saline vehicle injections. On PD 31-34, after choline treatment was complete, activity level was monitored and, on PD 40-42, subjects were tested on a serial spatial discrimination reversal learning task. Subjects exposed to alcohol were significantly hyperactive compared to controls. The severity of ethanol-induced hyperactivity was attenuated with choline treatment. In addition, subjects exposed to ethanol during the neonatal period committed a significantly greater number of perseverative-type errors on the reversal learning task compared to controls. Exposure to choline significantly reduced the number of ethanol-related errors. Importantly, these behavioral changes were not due to the acute effects of choline, but were related to long-lasting organizational effects of early choline supplementation. These data suggest that early dietary interventions may reduce the severity of fetal alcohol effects.     

Pretreatment with methylphenidate sensitizes rats to the reinforcing effects of cocaine

Repeated administration of cocaine produces sensitization to its locomotor-activating effects and increases the rate at which cocaine self-administration behavior is acquired. Methylphenidate is administered clinically on a daily basis, predominantly to children and adolescents, for the treatment of attention-deficit hyperactivity disorder (ADHD). It has been demonstrated previously that pretreatment with methylphenidate administered to periadolescent rats decreased the latency to acquisition of cocaine self-administration. Since methylphenidate is often also administered to adults with ADHD, the present study was conducted to determine the effects of prior administration of methylphenidate (5 or 20 mg/kg/day for 9 days) to adult rats on the rate of acquisition for cocaine self-administration (0.25 mg/kg/infusion). The higher dose of methylphenidate significantly decreased the latency for acquisition of this behavior, suggesting that the rats were sensitized to the reinforcing effects of cocaine after treatment with methylphenidate. These findings add to the growing body of evidence suggesting cross-sensitization between the behavioral effects of psychostimulants. Further, insofar as self-administration is a reliable measure of abuse liability, these data suggest that a short-duration pretreatment with a high dose of methylphenidate to adults increases vulnerability to cocaine abuse.     

Perinatal ethanol exposure alters met-enkephalin levels of male and female rats

This study used a rat model of Fetal Alcohol Syndrome to investigate whether combined prenatal and postnatal ethanol exposure affects met-enkephalin levels in the brains of male and female Long-Evans adult rats. Intragastric ethanol was administered to a group of rats (ET) from gestational day (GD) 1 through 22 and from postnatal day (PD) 2 through 10. The control groups consisted of a nontreated control group (NTC) and an intubated control group (IC) that received the intragastric intubation procedure but no exposure to ethanol. We measured met-enkephalin levels in the prefrontal cortex, nucleus accumbens, hypothalamus, central and basolateral nucleus of amygdala and ventral tegmental area. Met-enkephalin levels in the hypothalamus of male and female ET animals were significantly higher than those in either the NTC or IC animals. Met-enkephalin levels in the central nucleus of the amygdala of male and female ET animals were significantly lower than the levels in the NTC animals. Met-enkephalin levels in the nucleus accumbens of ET females were significantly greater than those in the IC females. These results demonstrate that the combination of prenatal and postnatal ethanol exposure affects basal met-enkephalin levels in specific regions in a sex-specific manner. These changes in met-enkephalin levels may explain how early ethanol exposure affects opioid-regulated behaviors such as social play, sexual behavior, and other social behaviors.     

Perinatal fenvalerate exposure: behavioral and endocrinology changes in male rats.

The effects of maternal exposure to fenvalerate during the prenatal and postnatal periods of sexual brain differentiation were studied in adult male offspring. Behavioral (open field, stereotyped, and sexual behaviors), physical (sexual maturation, body and organ weights), endocrine (testosterone levels), and neurochemical (striatal and hypothalamic monoamine and respective metabolite levels) data were assessed. The results showed that there was no change in the age of testis descent or testis weight, nor were there changes in monoamine levels or stereotyped behavior. However, there were significant reductions in ductus deferens and seminal vesicle weights and plasma testosterone concentrations. In addition, treated offspring showed decreased male sexual behavior and increased immobility in the open field. These results indicate that perinatal exposure to fenvalerate during the critical periods of male brain sexual differentiation has long-term effects on the reproductive physiology and behavior of male rats.