Repeated neonatal maternal separation alters intravenous cocaine self-administration in adult rats

Behavioural responses to psychostimulant drugs can be profoundly affected by early environmental influences. The aim of this study was to describe the effects of repeated brief separations of rat pups from their dams during the early neonatal period on cocaine self-administration behaviour as adults. Lister hooded rats exposed to a repeated maternal separation procedure (REMS) showed altered acquisition and maintenance of cocaine self-administration as adults, the effects being dose and gender-dependent. Overall, the patterns of acquisition of self-administration across three doses of cocaine (0.05, 0.08 and 0.5 mg/injection) suggested a rightward shift in the acquisition dose-effect functions for the REMS animals relative to control animals. At 0.05 mg/injection, there was a retarded acquisition of cocaine self-administration in male and female neonatally separated rats. At 0.08 mg/injection there was a facilitated acquisition in female neonatally separated subjects. After establishment of stable self-administration of the training dose, in the same cohort of subjects, rightward and downward shifts in the cocaine self-administration dose-effect functions were determined for female and male REMS subjects, respectively, relative to their controls. The dose-effect function for both female groups was shifted to the left of that of the respective male groups, although the lighter body weights of the females meant that they administered a higher unit dose per unit body weight than the males. Whereas male REMS subjects tended to self-administer less cocaine than the controls at the dose eliciting maximal responding (0.03 mg/injection) and to make fewer lever responses overall at each dose tested, female REMS subjects self-administered significantly more cocaine than their respective controls at a dose of 0.03 mg/injection. There was no differential sensitivity to the rate-altering effects of the selective dopamine D2 receptor antagonist, eticlopride, or to the selective dopamine D1 receptor antagonist, SCH 23390. These data provide further evidence that altered early environment affects drug-taking behaviour in a developmentally specific and gender-specific manner, with the effects of neonatal separation contrasting with previously published data on the effects of post-weaning isolation rearing.     

Alterations in the reinforcing efficacy of cocaine in adult rats following prenatal exposure to cocaine.

Adult male rats gestationally exposed to cocaine and nonexposed control offspring were examined for differences in operant responding for cocaine and sucrose reinforcement. Offspring were derived from dams that had received subcutaneous injections of 40 mg/kg/3cc cocaine hydrochloride daily on gestational Days 8–20 and nontreated control dams. Although no prenatal treatment differences were seen when the animals lever pressed for sucrose pellets on a progressive-ratio (PR) schedule, adult offspring prenatally exposed to cocaine were observed to exhibit an enhanced rate of cocaine intravenous self-administration on a fixed-ratio 5 (FR-5) schedule along with a marked decrease in break point on the PR reinforcement schedule. These results suggest that the reinforcing efficacy of cocaine may be reduced in animals with a prenatal history of cocaine exposure. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

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

Partial reinforcement is known to increase resistance to extinction (Rn) relative to training with continuous reinforcement. This phenomenon, referred to as the partial reinforcement extinction effect, is one of the most robust in learning and conditioning studies. Experiment 1 investigated manipulations known to affect the partial reinforcement extinction effect and determined their possible relevance for drug use patterns. Male rats received intravenous cocaine self-administration training under partial reinforcement (FR-10) training or continuous reinforcement (FR-1) conditions with either a low (0.25 mg/kg infusion) or a high cocaine dose (1.00 mg/kg infusion). Animals were placed on an extinction (recurrent nonreward) schedule for 10 days (1-hr sessions) prior to being tested for cue-induced reinstatement (single 2-hr session). Experiment 2 involved acquisition of cocaine self-administration under FR-1 conditions of short training (15 days) or extended training (30 days) with a low dose (0.25 mg/kg infusion) or a medium dose (0.50 mg/kg infusion) of cocaine reward prior to extinction or reinstatement. Experiment 1 showed that rats trained with FR-10-high dose outcomes exhibited greater Rn than the remaining groups. Additionally, FR-10-high dose and FR-10-low dose rats were more likely to return to active drug seeking during the reinstatement test. In Experiment 2, rats trained under FR-1-medium dose conditions were more persistent during extinction following short acquisition training than comparable rats experiencing extended acquisition training. The reinstatement test was conducted following extinction, in which it was observed that overtraining under FR-1-medium dose reward schedules resulted in a decrease in the tendency to return to active drug seeking. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of prenatal exposure to cocaine on conditional discrimination learning in adult rats.

Adult male rats that were gestationally exposed to cocaine and control offspring were trained on an instrumental conditioning task for assessment of the acquisition and reversal of an appetitive conditional discrimination based on olfactory cues. Offspring were derived from Sprague-Dawley dams that had received subcutaneous/ly (sc) injections of 40 mg/kg/3 cc cocaine hydrochloride (C40) daily on Gestational Days 8–20, pair-fed (PF) dams that were injected with saline, nutritional control dams (NC) that received saline injections, and nontreated control dams (LC). There were no differences among the prenatal treatment groups in acquisition of the barpress response or response rate throughout all phases of training. All prenatal treatment groups required approximately the same number of sessions to criterion on the initial odor discrimination. In contrast, adult C40 offspring required more sessions to acquire the reversal of the conditional discrimination than did animals from the other treatment groups (PF, NC, and LC). In addition, even at criterion performance for acquisition of the reversal discrimination, C40 animals exhibited lower accuracy on the 1st 10 responses and made significantly more errors before the 1st reward. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of serotonergic manipulations on cocaine self-administration in rats

Rats were trained to self-administer cocaine (0.5 mg/kg/infusion) and were then pretreated with the 5-HT1A agonist 8-OH-DPAT (0.125, 0.25 or 0.5 mg/kg, SC). 8-OH-DPAT pretreatment produced a decrease in reinforced response rates. When the effect of 8-OH-DPAT (0.5 mg/kg, SC) on responding for a range of cocaine doses was assessed, the drug produced a decrease in response rates when lower doses of cocaine served as the reinforcer. Fluoxetine (10 mg/kg, IV), an indirect 5-HT agonist, also reduced reinforced response rates for a low dose infusion of cocaine. Rates of responding for infusions of higher cocaine doses were not affected by fluoxetine pretreatment during an FR1 schedule of reinforcement. When an FR10 schedule of reinforcement was imposed, reinforced response rates for infusions of higher doses of cocaine were also reduced. Thus, under conditions that produce high rates of responding (low dose infusion or high ratio requirements for an infusion) fluoxetine reduced responding. This effect may be due to the effects at the 5-HT1A receptor, since 8-OH-DPAT produced a similar effect on cocaine self-administration. Given that the effects of these 5-HT agonists are observed only when low doses of cocaine serve as the reinforcer or when task demands are high, it is possible that the suppression of responding reflects an effect that is not specific to the reinforcing impact of cocaine. An alternative explanation for these effects incorporates a concept of unit cost/cocaine infusion that allows for direct comparison across studies that employ different reinforcement schedules.     

Prenatal cocaine alters social competition of infant, adolescent, and adult rats

This series of experiments examined whether gestational cocaine exposure alters later social behavior exhibited during competition for biologically relevant stimuli. Rat offspring were derived from dams that received subcutaneous injections of 40 mg/kg/3cc cocaine HCl daily on gestational Days 8-20, pair-fed dams injected with saline, or nontreated control dams. Offspring competed with peers for access to a nipple in infancy, and to water in adolescence or adulthood. Prenatal cocaine exposure resulted in a decreased ability of cocaine-exposed infant rats to compete successfully for a nipple. Although adolescent and adult cocaine-exposed rats were no less successful than controls when competing for water, they exhibited a notable increase in aggression toward competitors during testing. Data provide evidence of alterations in social behavior and social competition as a result of prenatal cocaine exposure.     

Chronic pain alters drug self-administration: Implications for addiction and pain mechanisms.

This review article focuses on the impact that the presence of pain has on drug self-administration in rodents, and the potential for using self-administration to study both addiction and pain, as well as their interaction. The literature on the effects of noxious input to the brain on both spinal and supraspinal neuronal activity is reviewed as well as the evidence that human and rodent neurobiology is affected similarly by noxious stimulation. The convergence of peripheral input to somatosensory systems with limbic forebrain structures is briefly discussed in the context of how the activity of one system may influence activity within the other system. Finally, the literature on how pain influences drug-seeking behaviors in rodents is reviewed, with a final discussion of how these techniques might be able to contribute to the development of novel analgesic treatments that minimize addiction and tolerance. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Prenatal exposure to methylmercury alters locomotor activity of male but not female rats

In the present study the neurotoxic effects of a low dosage (0.5 mg/kg per day) of methylmercury (MeHg) on the developing nervous system were investigated. Pregnant rats were treated with MeHg from day 7 of pregnancy to day 7 of lactation. Locomotor activity (locomotion, rearing, and motility) and spatial learning ability were tested in the offspring at 6 months of age. The expression of tyrosine hydroxylase (TH) was examined by immunohistochemistry and in situ hybridization. A significant decrease in spontaneous motility and rearing was observed only in the MeHg-treated male rats. After administration of a low dose of d-amphetamine (0.5 mg/kg) no differences could be observed between control and MeHg-treated male rats, suggesting that changes in dopaminergic transmission were involved. However, no change in TH messenger RNA expression was observed. No changes in spatial learning acquisition or memory were shown in MeHg-treated rats. Taken together, these findings show that during development a very low dosage of MeHg exerts neurotoxic effects detectable in adulthood, and that susceptibility is gender-dependent.     

Dopamine release during cocaine self-administration in rats: effect of SCH23390

This experiment tested the hypotheses that: (1) self-administration of cocaine would produce an increase in dopamine (DA) oxidation current in the nucleus accumbens (n. acc.); and (2) a faster rate of cocaine intake in the presence of a D1 receptor antagonist would produce a greater increase in DA levels. Rats trained to self-administer cocaine under a fixed-ratio 2 schedule were implanted with stearate-modified graphite paste electrodes bilaterally in the n. acc. The effect of pretreatment with the D1 receptor antagonist, SCH23390, on the DA oxidation current associated with self-administration of cocaine (1 mg/inj.) or saline was investigated using chronoamperometry. Pretreatment with SCH23390 produced a 2-fold increase in the amount of cocaine intake. This in turn resulted in a 2-fold increase in the DA oxidation current recorded in the n. acc. Pretreatment with SCH23390 did not, however, produce any significant change in either the number of saline injections received or the DA oxidation current recorded during saline self-administration. These findings show that cocaine increases DA oxidation currents in the n. acc., and that both the rate of cocaine self-administration and the magnitude of these currents increase even further following SCH23390. The results also imply that the baseline rate of cocaine self-administration does not result in the occupation of all possible DA transporter sites.     

Chronic exposure of rats to hypoxic environment alters the mechanism of energy transfer in myocardium

We have investigated the effect of chronic exposure of rats to an hypoxic environment (10% O2; 3 weeks), on the first step of the intracellular energy transfer process in the myocardium, i.e. the transfer at mitochondrial level of high energy bonds from ATP to creatine. In the left ventricles from rats adapted to normobaric hypoxia, we observed, using the permeabilized fiber technique, that the stimulatory effect of creatine on the mitochondrial respiration in presence of a low ADP concentration (0.1 mM) was attenuated when compared to control. Furthermore, the creatine-induced decrease of the apparent K(m) for ADP of the mitochondrial respiration, which is observed in control, was significantly reduced. Both the basal and maximal respiratory rates of the fibers were unchanged by the hypoxic exposure of the rats. A significant decrease of the total creatine kinase activity from 755 to 630 IU/g wet weight (for control and hypoxic rats, respectively) was detected and was accompanied by a 25% decrease in mitochondrial isoform activity (mitoCK) and in the mitoCK/citrate synthase ratio. In the right ventricles, identical alterations in the effect of creatine on apparent K(m) for ADP were observed while we did not detect any changes in CK activity. The decrease in mitoCK activity and the fall in the reactivity of respiration to creatine could be interpreted as a mechanism for downregulating oxygen demand during chronic hypoxia. The consequences of such alterations on energy metabolism of cardiomyocytes under conditions of reduced oxygen supply are discussed.     

Behavioral sensitization is induced by intravenous self-administration of cocaine by rats

Salicylate-kodein is a widely used analgesic agent, particularly in outpatient practice. Salicylates have been incriminated in hepatic injury while kodein may induce biliary spasm. We report here a case of granulomatous hepatitis attributed to prolonged intake of this combination, which has never been reported previously to our knowledge.     

Early adversity alters attention and locomotion in adult Sprague-Dawley rats.

This study investigated the effects of prenatal stress and its interaction with artificial rearing (AR) on adult rat behavior. Pregnant dams underwent restraint stress from Gestational Day 10 to 21. After parturition, pups were raised by their mothers or in the AR paradigm, with or without stroking stimulation. In adulthood, rats were tested on prepulse inhibition (PPI), locomotor activity, elevated plus-maze, and spatial working memory. There were main effects and interactions of both prenatal stress and AR on activity. Additional stimulation reduced activity in nonstressed AR rats but increased activity in prenatally stressed AR rats. AR altered PPI and plus-maze behavior whereas additional stimulation partially reversed these effects. This study demonstrates that prenatal experiences can modulate the effects of postnatal treatments. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of adolescent nicotine exposure on opioid consumption and neuroendocrine response in adult male and female rats.

Effects of adolescent nicotine exposure on illicit drug consumption and neuroendocrine functioning were examined in adult rats. Nicotine (NIC; 2 doses) or saline (SAL) was administered via osmotic minipumps to 30 male and 30 female adolescent Wistar rats for 19 days. After NIC/SAL cessation, oral opioid consumption was assessed in the home cage for 4 weeks. Plasma corticosterone and ACTH were measured at the end of the experiment. Low-NIC male rats consumed more fentanyl than did high-NIC male rats; opioid consumption among adult female rats was not altered by NIC exposure. Females consumed more fentanyl than did males, regardless of NIC history. NIC exposure increased adult corticosterone and ACTH levels in a dose-dependent manner. Results suggest important effects of adolescent NIC exposure, including altered neuroendocrine status and opioid consumption. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Changes in cigarette smoking not observed following repeated cocaine self-administration.

Acute administration of some psychoactive drugs (e.g., cocaine, heroin, methadone, d-amphetamine) has been found to increase spontaneous cigarette smoking for 1-3 hr, but the effects of chronic drug administration have not been systematically studied. Computerized cigarette dispensers were used to study the effects of multiple daily cocaine administrations on cigarette smoking. Participants were 8 (5 male) cocaine-dependent cigarette smokers who resided on a closed clinical research ward and smoked an average of 16.7 cigarettes per day during the week prior to starting the study. During test sessions on Monday, Wednesday, and Friday of each week, participants could obtain either cocaine (25 mg iv) on 2 days or saline (1 ml iv) on the other day, 3 times per day at 2-hr intervals under double-blind conditions. The number of cigarettes dispensed during study days was analyzed in 2-hr increments. No significant cocaine effect was found. These findings fail to show a change in the number of cigarettes smoked after chronic cocaine self-administration over time intervals longer than 1-3 hr. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Maternal cocaine alters eupneic ventilation but not gasping of neonatal rats

Lithium administration was used in a patient with a clozapine-induced neutropenia and in another with complete agranulocytosis to assess whether lithium could stimulate neutrophil production. In both cases, following lithium administration, the neutrophil count was increased to the normal range within 6 days. In the patient who had presented a neutropenia, clozapine treatment was then reinstated in the presence of lithium and continued without the neutrophil count dropping into the yellow-alert range thereafter.     

Wheel-running behavior is altered following withdrawal from repeated cocaine in adult rats.

The residual effects on open-field habituation and self-generated wheel running following withdrawal from repeated cocaine (COC; 30 mg/kg for 7 days) were examined in adult male rats. Control subjects received equivolumetric injections of saline (SAL) and were either allowed to feed ad libitum or pair-fed matched (PF SAL) to COC subjects to control for the drug's potential anorexic effect. Following 10 days of withdrawal, all subjects were examined twice on each of the two assessment instruments. Results indicated that COC subjects over the two test sessions failed to increase their wheel-running rates and did not show the expected habituation in the open field. However, because both COC and PF SAL groups yielded similar effects in the open field, conclusions about cocaine's consequences on habituation could not be established independent of the drug's anorexic effect. These data provide evidence for the view that repeated cocaine impairs motivational processes responsible for engaging in self-generated naturally rewarding behaviors. Speculation concerning the neurobiobehavioral substrates for this effect is presented. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Estradiol replacement in gonadectomized male rats alters scopolamine-induced disruptions of nonspatial learning.

Recent evidence indicates that testosterone can modulate learning in males through an interaction with the cholinergic system. However, the mechanism for this interaction between testosterone and the cholinergic system on learning remains uncharacterized and may involve several of testosterone's active metabolites. In the present study, two of the active metabolites of testosterone, 5α-dihydrotestosterone and estradiol, were administered in combination with the muscarinic receptor antagonist scopolamine (0.1-1 mg/kg, i.p.) to adult gonadectomized male rats that were trained to respond under a multiple schedule of repeated acquisition and performance of response sequences. In the acquisition component, subjects acquired a different three-response sequence each session, whereas in the performance component they responded on the same three-response sequence each session. When scopolamine was administered, it produced greater rate-decreasing and error-increasing effects in gonadally intact subjects than in gonadectomized subjects, even though gonadectomy had little or no effect on these measures under control conditions. In gonadectomized rats receiving 5α-dihydrotestosterone replacement, the disruptions produced by scopolamine were also smaller than those produced in gonadally intact subjects. In contrast, gonadectomized rats receiving estradiol replacement were as sensitive, or more sensitive, to scopolamine-induced disruptions of response rate and accuracy than those under the gonadally intact condition. These results suggest that testosterone's interactive effects with the cholinergic system on learning in gonadectomized male rats may not be mediated directly via androgen receptors, but rather by estrogen receptors following the aromatization of testosterone to estradiol. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Long-term effects of early diazepam exposure on social differentiation in adult male rats subjected to the diving-for-food situation.

The present study was designed to investigate the consequences of a chronic diazepam (DZ) exposure (10 mg/kg/day) during the first 3 wks of life on social behavior of adult male rats measured in a situation of restricted access to food, the diving-for-food model. The treatment had no long-term effects on the acquisition of social roles related to feeding. However, DZ-exposed rats were less efficient than controls in carrying food from the feeder to the cage during the first session but were able to adapt and improve their performances during the second one. In the home cage, DZ-exposed rats were mom aggressive toward conspecifics than controls and compensated for their deficit of food by stealing it from the others. These results suggest that an early DZ exposure has long-term consequences on social behavior of rats, possibly reflecting a reduction of the level of emotionality. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Phentermine/fenfluramine decreases cocaine self-administration in rhesus monkeys

Dopaminergic agonists can decrease cocaine self-administration at doses that do not decrease food-maintained responding, a pre-clinical effect indicative of a potential treatment for human cocaine abuse. To assess whether similar effects could be obtained with medications currently used to treat substance abuse, phentermine and fenfluramine were given alone and in combination to rhesus monkeys responding under schedules of food and cocaine delivery. Phentermine decreased cocaine-maintained responding with no effect on food-maintained responding. Fenfluramine also selectively decreased cocaine-maintained responding, but only at the highest dose. Combining a lower dose of fenfluramine with phentermine selectively decreased cocaine-maintained responding, but not more than with phentermine alone. These results suggest that phentermine, as well as its combination with fenfluramine, may be useful in the treatment of cocaine abuse.     

Prenatal exposure to cocaine: effects on aggression in Sprague-Dawley rats

Social/aggressive behavior in adult rat offspring (beginning at postnatal Day 180) prenatally exposed to saline, cocaine, or amfonelic acid (AFA) was examined. Pregnant rats received injections of 15 mg/kg of cocaine, or 0.9% saline twice daily, s.c., or on 2 consecutive days at 4-day intervals, or 1.5 mg/kg amfonelic acid daily throughout gestational Days 1-20. Frequency, duration, and latency of 11 social/aggressive behaviors were recorded for two 15-min sessions during which a smaller male intruder replaced an ovariectomized female in the resident's home cage. Subjects received a s.c. saline injection before Session 1 and 2.0 mg/kg of gepirone, a 5HT1a partial agonist, prior to Session 2. Prenatal cocaine treatment resulted in alterations of aggressive behavior. Aggressive behavior was reduced by gepirone in all groups but to a lesser extent in the AFA group.