Developmental lead exposure alters the stimulatory properties of cocaine at PND 30 and PND 90 in the rat.

The aim of this study was to examine the effects of perinatal lead exposure on locomotor responding following acute and repeated cocaine challenges (sensitization). Adult female rats were gavaged daily with 0, 8, or 16 mg lead acetate for 30 days prior to breeding. This exposure regimen was maintained throughout gestation and lactation (perinatal exposure). On Day 21, male pups were weaned and lead exposure was discontinued for the remainder of the study. Beginning on postnatal day (PND) 30 or PND 90, and continuing for 14 successive days, separate groups of perinatally-exposed animals were presented with challenges of 10 mg/kg cocaine HCl (i.p.), and tested for locomotor responding. Following this testing period, dose-effect profiles were determined, with animals receiving daily injections of 0, 10, 20, and 40 mg/kg cocaine. The results indicated that both at PND 30 and PND 90 lead-exposed animals were less responsive to the initial administration of cocaine, but exhibited a supersensitivity to the stimulatory effects associated with repeated administration of cocaine, i.e., behavioral sensitization to cocaine was augmented by perinatal lead exposure. Analyses of blood lead levels following the completion of testing revealed that lead levels were below detectable limits for all animals (< 1 microg/dl). Collectively, these findings show that developmental lead contamination produces changes in cocaine sensitivity long after exposure has been discontinued and the toxicant has gained clearance from blood.     

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.     

Cocaine-induced behavioral sensitization in adolescent rats endures until adulthood: lack of association with GluR1 and NR1 glutamate receptor subunits and tyrosine hydroxylase

Exposure to repeated cocaine induces enduring behavioral sensitization, which has been implicated in the psychostimulant-induced craving and psychosis. Adaptations in dopamine and glutamate neurotransmission in the nucleus accumbens (NAc) and medial prefrontal cortex (mPFC) seem to mediate psychostimulant-induced behavioral sensitization. The abuse of drugs often begins during adolescence; however few studies have been devoted to study the effects of drugs of abuse at this age. The aim of our study was to examine whether repeated cocaine during adolescence could induce behavioral sensitization that endures into adulthood. Moreover, the protein levels of Tyrosine Hydroxylase (TH) and the glutamate receptor subunits GluR1 and NR1 in the NAc and mPFC were measured following the behavioral tests. Adolescent rats were treated with cocaine from postnatal day (PND) 30 to PND34 and behavioral sensitization was verified recording locomotor activity after cocaine challenge injection to adolescent (PND37) or adult (PND64 or 94) rats in separate groups at each time point. TH, GluR1, and NR1 protein levels were measured by Western blotting. Rats exposed to cocaine during adolescence expressed behavioral sensitization when tested on PND37 and PND64. In cocaine sensitized rats GluR1 protein was increased in the mPFC on PND37 but not in other ages. Thus, cocaine-induced behavioral sensitization during adolescence endures into early adulthood. However, cocaine pretreatment during adolescence induced a transient increase of GluR1 in the mPFC only when animals were challenged in the same age.     

Prenatal cocaine exposure: effects on locomotor activity in rat offspring

This study examines the developmental effects of prenatal exposure to cocaine in the rat, evaluated during the first month of life through open-field behavior. The offspring of Wistar dams that received 60 mg/kg of cocaine, from gestational day 8 to 22, were examined in the open-field during the second, third and fourth weeks of postnatal life in three consecutive 15-min daily sessions, starting on postnatal day (PND) 14, (PND 14–16), PND 21 (PND 21–23) and PND 28 (PND 28–30). Results show that prenatal exposure to cocaine increased total activity and rearing behavior on PND 22 and PND 29. Also, on PND 14, cocaine-exposed animals reared significantly more than control rats. There were no significant differences in the frequency of center and peripheral ambulation, nor in the defecation rate. The present results evidence alterations in the emotional behavior of rats prenatally exposed to cocaine. The delayed onset of exploration in the open-field observed in cocaine-exposed animals suggests that they take more time to become habituated to a novel and open environment.     

Repeated administration of methylphenidate in young,adolescent, and mature rats affects the response to cocaine later in adulthood

Rationale Previous studies have shown that the expression of behavioral sensitization to psychostimulants depends on the age and gender of the animal. Objective This study was conducted to determine the pattern of behavioral sensitization to repeated administration of methylphenidate (MPD) at three different developmental ages and to assess the response to a cocaine challenge in adulthood. Methods We gave five daily i.p. injections of 10 or 20 mg kg⁻¹ of MPD (10 MPD, 20 MPD) or saline to male and female rats beginning on postnatal days (PND) 21, 45, or 60. When all groups reached PND 90, rats were challenged with 10 mg kg⁻¹ cocaine. For both MPD administration and cocaine challenge, locomotion and stereotyped behaviors were assessed for 1 h. Results The 10 MPD dose produced increased locomotion over the other two treatments at all ages. Rats that received 20 MPD showed a decline in locomotion across days with an increase in the time spent in high intensity stereotypy by day 5. Animals treated with 10 MPD showed diverse behavioral responses with adolescents showing somewhat dampened stereotypy than the other two age groups. In response to cocaine, pretreatment with MPD at all ages enhanced the cocaine response and produced qualitatively different patterns of stereotyped behavior for each gender and pretreatment age group. Conclusion MPD produced clear age-specific sensitization of behavior in rats. Furthermore, exposure to MPD cross-sensitized with cocaine regardless of the age at which MPD exposure occurred with each pretreatment age group showing a unique pattern of responses.     

Repeated cocaine administration does not alter morphine-induced rotational behavior in nigrally denervated rats

Repeated administration of morphine to rats increases their sensitivity to behavioral effects of morphine as well as to those of psychomotor stimulants, such as cocaine and amphetamine. Conversely, stimulant-induced sensitization to behavioral effects of stimulants often results also in sensitization to behavioral effects of morphine. However, in nigrally lesioned rats, repeated injections of morphine produce sensitization to morphine-induced turning but not to turning induced by cocaine or amphetamine. The present study was performed to determine whether giving repeated cocaine injections to nigrally lesioned rats would produce cross-sensitization to morphine-induced turning. Daily injections of 10 mg/kg cocaine (i.p.) enhanced the turning response to cocaine by day 8, but not the turning response to 3.0 mg/kg morphine (s.c.). The response to morphine increased equally in both cocaine- and saline-treated animals after they had received morphine once. Dose-response curves for morphine (1.0-10 mg/kg) and for cocaine (3.0-30 mg/kg), determined during weeks 3 and 4, were the same in rats receiving daily injections of cocaine or daily injections of saline. Thus, although repeated exposure to cocaine or morphine resulted in sensitization to turning induced by each drug, respectively, there was no cross-sensitization between the two drugs. In contrast to other behaviors, rotational behavior does not seem to exhibit cross-sensitization between morphine and psychomotor stimulants.     

Estrous cyclicity and behavioral sensitization in female rats following repeated intravenous cocaine administration.

Repeated intermittent administration of cocaine is well known to produce behavioral sensitization in male animals. The present studies explored whether intact adult female rats maintained normal estrous patterns in response to repeated IV cocaine administration and whether behavioral sensitization occurred with this route of administration. Adult female Sprague-Dawley rats (N = 48) were surgically implanted with an intravenous access port. Animals received 3.0 mg/kg IV cocaine once/day for 14 days. Daily vaginal lavages indicated that female rats continued to cycle normally throughout the experiment. Estimates of statistical power for detecting alterations in estrous cycle length ranged from 0.61-0.95 for small (0.1) to large (0.4) effect sizes. Moreover, no cocaine-treated animals displayed persistent vaginal estrus or were acyclic and cocaine treatment did not decrease body weight. Immediately after the cocaine injection, animals were placed in IR photocell activity chambers for 60 min. Female rats displayed a significant 75% increase in locomotor activity across the 14-day time course of IV cocaine injections. These data indicate that 3.0 mg/kg of IV cocaine does not interfere with normal estrous cyclicity, and that behavioral sensitization occurs in female rats following repeated daily IV cocaine dosing. Collectively, these data suggest that the IV cocaine-dosing model may be particularly useful in exploring the gender-dependent effects of cocaine using intact female rats.     

Effects of osemozotan, ritanserin and azasetron on cocaine-induced behavioral sensitization in mice

Repeated intermittent administration of psychostimulants causes behavioral sensitization in rodents. Previous studies using serotonin (5-HT) receptor ligands show that the 5-HT system is involved in cocaine-induced behavioral sensitization in rats, but the role of the 5-HT system has not been studied in mice. The present study examined the effects of the 5-HT(1A) receptor agonist osemozotan, the 5-HT(2) receptor antagonist ritanserin and the 5-HT(3) receptor antagonist azasetron on cocaine-induced behavioral sensitization in male ddY mice. Repeated administration of cocaine for 7 days enhanced cocaine-induced locomotor activity, and this sensitization was observed even after withdrawal for 7-14 days. Cocaine-induced behavioral sensitization after a 7-day withdrawal was significantly reduced with the coadministration of osemozotan, ritanserin or azasetron with cocaine repeatedly for 7 days. A single injection of osemozotan or ritanserin before cocaine challenge also reduced repeated cocaine-induced behavioral sensitization. However, none of these ligands inhibited cocaine-induced behavioral sensitization, when each drug was administered for 7 days after repeated cocaine administration. These results suggest that the central 5-HT system plays a role in the development and expression, but not maintenance, of behavioral sensitization in cocaine-treated mice.     

Interactions between chronic haloperidol treatment and cocaine in rats: an animal model of intermittent cocaine use in neuroleptic treated populations

This experiment investigated the possibility that rats maintained on chronic haloperidol treatment would show increased behavioral responsiveness to cocaine, similar to that observed in human stimulant abusers who are chronically treated with neuroleptics. Thus, the effects on locomotion and stereotyped behavior of intermittent injections of cocaine were investigated in female rats receiving chronic haloperidol treatment. Daily injections of haloperidol (0.2 mg/kg, IP) or vehicle were administered for 6, 12 or 18 days prior to the start of testing with cocaine and were then continued throughout cocaine testing. All rats received four doses of cocaine (0.0, 3.0, 7.5, or 15.0 mg/kg, IP) in random order with an intervening vehicle day between successive drug days. The four dose sequence of cocaine was repeated a total of four times. Initial cocaine administration produced dose dependent increases in locomotion and stereotyped behavior. When the sequence of cocaine doses was repeated, differences among treatment groups emerged. Groups treated with haloperidol exhibited heightened locomotion in response to cocaine and with repeated injections, showed a higher rate of behavioral sensitization than control animals. These differences in the behavioral response to cocaine were maintained for at least 2 months following termination of daily haloperidol treatment. In order to examine the mechanisms underlying this heightened responsiveness to cocaine, apomorphine-induced locomotion (dose range, 0–250 µg/kg, SC) was determined. Regardless of dose, rats treated with haloperidol showed different temporal patterns of locomotion in response to apomorphine suggesting that the increased response to cocaine was related to changes in dopaminergic receptor sensitivity.     

Reversal of methamphetamine-induced behavioral sensitization by repeated administration of a dopamine D1 receptor agonist

Repeated intermittent administration of methamphetamine (MAP) produces an enduring hypersensitivity to the motor stimulant effect of MAP, termed behavioral sensitization. Dopamine plays a critical role in the development and expression of behavioral sensitization. Here, we investigated whether a dopamine D₁ receptor agonist could reverse behavioral sensitization to MAP. Administration of MAP (1.0 mg/kg, i.p.) to rats once every 3 days for a total of 5 times (days 1–13) induced the enhancement of locomotor activity after MAP challenge (0.5 mg/kg, i.p.) on day 20, verifying the development of behavioral sensitization. The MAP-sensitized rats then received a dopamine D₁ agonist, R-(+)-SKF38393 (3.0 mg/kg, i.p.), once a day for 7 consecutive days (days 21–27). Behavioral analysis on days 30 and 41 revealed that the enhanced locomotor activity was reversed by repeated R-(+)-SKF38393 administration. Moreover, repeated R-(+)-SKF38393 administration reversed the increased dopamine release in the striatum after MAP challenge on day 41. Thus, repeated administration of the dopamine D₁ receptor agonist induces the reversal of established behavioral sensitization to MAP and of increased dopamine release in the striatum, lasting for at least 2 weeks. Dopamine D₁ receptor agonists may be useful therapeutic agents for the treatment of psychostimulant addiction.     

Behavioral and neurochemical responses to cocaine in periadolescent and adult rats.

Although recreational drug use by human adolescents is a well-known and long-standing problem, relatively little is known regarding differences in behavioral and physiological responses to abused substances in adolescent vs adult animals. The present study compared effects of the psychomotor stimulant, cocaine, in periadolescent (postnatal days 37-52) and adult (postnatal days 75-90) male Wistar rats. Locomotion and motor stereotypy were recorded after acute and repeated cocaine injections (0, 10, or 20 mg/kg cocaine, intraperitoneal (i.p.), four injections spaced 5 days apart). Spontaneous acquisition of intravenous (i.v.) cocaine self-administration was investigated in two dose groups ( approximately 0.37 or 0.74 mg/kg/infusion) over 14 days. Dopamine levels in the nucleus accumbens were recorded under basal conditions (no net flux method) and after cocaine administration ( approximately 0.37, 0.74, and 2.92 mg/kg/i.v. infusion or 20 mg/kg i.p.) using in vivo microdialysis. The locomotor data are in partial agreement with previous reports of hyposensitivity to acute cocaine in periadolescent vs adult rats; periadolescents were less active overall than adults. Moreover, adult rats exhibited significant locomotor sensitization after repeated injection of 10 mg/kg cocaine, whereas periadolescents required the high dose of 20 mg/kg cocaine to demonstrate sensitization. Neither age group showed sensitization of motor stereotypies. No age-related difference was observed in acquisition of cocaine self-administration, or in basal or cocaine-stimulated nucleus accumbens dopamine. These experiments imply a developmental dissociation between the motor activating and reinforcing effects of cocaine. Similarities in dopamine levels across age groups suggest that age-specific motor responses to cocaine are not mediated by dopamine in the nucleus accumbens.     

Long-term blockade of the expression of cocaine sensitization by ondansetron, a 5-HT(3) receptor antagonist

Intermittent cocaine administration induces sensitization (reverse tolerance) to its behavioral effects. The mechanism(s) mediating sensitization is not clear, however, previous research has implicated 5-HT(3) receptors in the expression of sensitization. The present experiment evaluated the ability of the 5-HT(3) receptor antagonist, ondansetron, administered during withdrawal from chronic intermittent cocaine administration, to block the expression of sensitization. Rats were pretreated for 14 days by daily subcutaneous injections of either 40 mg/kg cocaine or 0.9% saline. During the first 5 days of withdrawal from this pretreatment regimen, all rats received a daily subcutaneous injection of 0-1.0 mg/kg ondansetron. On days 7, 14 or 28 of withdrawal from the cocaine pretreatment, the rats received a 15.0-mg/kg cocaine challenge. Ambulatory behavior was automatically recorded for 60 min. Ondansetron had no significant effect on the subsequent behavioral response to cocaine in the saline control subjects. In contrast, daily injections of ondansetron blocked the expression of sensitization at all withdrawal times. We thus report that it is possible to permanently block the expression of sensitization once it has developed by administering a 5-HT(3) receptor antagonist.     

Effects of early postnatal sibling deprivation on anxiety and vulnerability to cocaine in offspring rats

RATIONALE: Early-life experience has long-term consequences on affective behavior and drug abuse in adults. While many manipulations used to study these consequences alter mother-infant interactions, the effects of sibling interactions are less well characterized. OBJECTIVES: To examine the long-term effects of early postnatal sibling deprivation (EPSD) on anxiety-like behavior, sucrose preference and behavioral responses to cocaine in adult rats. MATERIALS AND METHODS: After EPSD manipulation, in which litters were culled to one pup on postnatal day 1 (PN1) or 7 (PN7), the dams' maternal behavior was observed. After the pups reached adulthood, we tested their behavioral responses in the elevated plus maze and sucrose consumption, and to cocaine conditioned place preference and cocaine sensitization. RESULTS: The pups with EPSD on PN1 received more maternal licking/grooming during the first postnatal week. EPSD on PN1 but not PN7 enhanced locomotor activity in the open field test and exploration of open arms in the elevated plus maze in both female and male offspring. While EPSD had no effect on sucrose intake in adult rats, it decreased vulnerability to cocaine sensitization and cocaine conditioned place preference in male but not female rats. CONCLUSION: Our findings that early postnatal sibling deprivation influences maternal licking/grooming behavior, as well as anxiety-like behavior and vulnerability to drugs in pups that have grown to adulthood, suggests that both sibling interaction and maternal behavior, play critical roles in individual development.     

Differential effects of adult and perinatal lead exposure on morphine-induced locomotor activity in rats

The effects of adult and perinatal lead treatment on the development of locomotor sensitization produced with repeated morphine administration was investigated. In Experiment 1, adult male rats received a diet containing 250 ppm lead acetate or a control diet for 43 days. Animals then received 10 mg/kg morphine sulfate or water vehicle (ip) and locomotor activity was monitored for 14 consecutive days. While both control and lead-exposed animals demonstrated a locomotor sensitization to morphine, the magnitude of the increased locomotor response was reduced in lead-treated animals. Subsequent analysis of blood-lead in the adult lead-exposed animals indicated residue levels ranging between 20 and 30 microg/dl. In Experiment 2, adult female rats were treated daily with 0, 8, or 16 mg lead via gavage for 30 days before breeding with non-exposed males. Lead exposure in dams continued through gestation and until pups were weaned at postnatal day (PND) 21. At PND 60, male offspring received morphine or vehicle challenges identical to those described in Experiment 1. Animals perinatally exposed to dams receiving 16 mg lead daily demonstrated an enhanced behavioral response to morphine relative to control animals. Analysis of offspring blood indicated lead levels below detectable limits (<1 microg/dl) for all animals. The results suggest exposure to lead at environmentally relevant levels produces long-lasting changes in drug-induced behavior, and the developmental period in which lead exposure occurs is a significant contributor to the manifestation of these effects.     

Differential behavioral and neuroendocrine effects of repeated nicotine in adolescent and adult rats

Despite the high prevalence of tobacco abuse among adolescents, the neurobiology of nicotine addiction has been studied mainly in adult animals. Repeated administration of this drug to adult rats induces behavioral sensitization. Nicotine activates the HPA axis in adult rats as measured by drug-induced increases in ACTH and corticosterone. Both behavioral sensitization and corticosterone are implicated in drug addiction. We examined the expression of behavioral sensitization induced by nicotine as well as the changes in corticosterone levels after repeated injections of nicotine in adolescent and adult animals. Adolescent and adult rats received subcutaneous (s.c.) injections of saline or 0.4 mg/kg of nicotine once daily for 7 days. Three days after the last injection animals were challenged with saline or nicotine (0.4 mg/kg; s.c.). Nicotine-induced locomotion was recorded in an activity cage. Trunk blood samples were collected in a subset of adolescent and adult rats and plasma corticosterone levels were determined by radioimmunoassay. Adult, but not adolescent, rats expressed behavioral sensitization. Pretreatment with nicotine abolished corticosterone-activating effect of this drug only in adult animals, indicating the development of tolerance at this age. Our results provide evidence that adolescent rats exposed to repeated nicotine display behavioral and neuroendocrine adaptations distinct from that observed in adult animals.     

Behavioral responses during the initial exposures to a low dose of cocaine in late preweanling and adult rats

Human drug experimentation begins during late childhood and early adolescence, a critical time in physical and CNS development, when the immature CNS is vulnerable to the long-term effects of psychoactive drugs. Few preclinical animal studies have investigated responses to such drugs in a developmental stage equivalent to late childhood of humans. We used a rodent model to examine behavioral responses of female Sprague-Dawley late preweanling and adult rats during acute and repeated exposures to a low dose of cocaine. Results show that after cocaine injection, preweanling rats (18-21 days old) have locomotor responses that differ from adults, but after postnatal day 22, the responses are indistinguishable from adults even though rats are still not weaned. Before day 22, locomotor effects of cocaine differ from those in adults in three ways: preweanlings are active for a longer time after cocaine injection at day 18; preweanling activity peaks more rapidly after subcutaneous administration; and after only three injections of cocaine, a tolerance-like pattern is seen in preweanlings whereas an emerging pattern of sensitization to cocaine is seen in adults. The behavioral patterns of this age group offer a preclinical model of the early effects of drugs of abuse.     

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.     

Differential effects of 7-OH-DPAT on the development of behavioral sensitization to apomorphine and cocaine

The primary objective of this study was to determine whether concurrent treatments with a low dose of the dopamine D(3)-preferring receptor agonist 7-OH-DPAT would attenuate the development of behavioral sensitization to the indirect dopamine receptor agonist, cocaine, or the direct dopamine receptor agonist, apomorphine. In two experiments, male Wistar rats (250-350 g) were given seven daily injections of 7-OH-DPAT (0.05 mg/kg sc) or vehicle in combination with either cocaine (15 mg/kg ip), apomorphine (1.0 mg/kg sc), or vehicle. After the injections, the rats were tested for activity in photocell arenas for 40 min, and three measures of motor behavior (distance traveled, rearing, and stereotypy) were recorded at 10-min intervals. A total of 24 h after the last preexposure session, all rats were given a challenge injection of either cocaine (10.0 mg/kg ip, Experiment 1) or apomorphine (1.0 mg/kg sc, Experiment 2) and tested for activity. Major findings were as follows: (a) 7-OH-DPAT treatments alone suppressed all measures of locomotor activity and did not affect subsequent behavioral sensitivity to either cocaine or apomorphine; (b) cocaine treatments acutely increased all measures of activity, and repeated treatments produced behavioral sensitization to the horizontal locomotor-activating effects of cocaine; (c) apomorphine treatments alone increased horizontal activity and stereotypy but completely abolished rearing behavior; (d) like cocaine, repeated treatments with apomorphine induced behavioral sensitization; (e) concurrent treatments of 7-OH-DPAT with cocaine acutely attenuated cocaine-induced increases in motor behavior but enhanced the development of behavioral sensitization to cocaine; and (f) concurrent 7-OH-DPAT treatments did not significantly affect either the acute or chronic effects of apomorphine. It is evident from these results that concurrent treatment with 7-OH-DPAT does not block the development of behavioral sensitization to either cocaine or apomorphine. Moreover, the differential acute and chronic effects of 7-OH-DPAT on cocaine- and apomorphine-induced hyperactivity appear to be mediated by dopamine autoreceptor stimulation.     

Implication of the nucleus accumbens shell, but not core, in the acute and sensitizing effects of cocaine in rats

Expression of cocaine-evoked motor behaviors appears to be dependent on dopamine neurotransmission particularly in the target area of the mesolimbic system, i.e. the nucleus accumbens (NAc). To test potential anatomical component of the locomotor effects of cocaine and expression of its behavioral sensitization, male Wistar rats were implanted with bilateral cannulae aimed at the two subregions of the NAc (the shell or the core) and then intracranially injected with cocaine (locomotor activity) or injected with cocaine given either systemically or intracranially following the repeated (5 days) systemic drug administration (sensitization). Sensitization was measured at early (5-day) and late (21-day) withdrawal periods. Acute administration of intra-NAc shell cocaine (6.73-50 microg/side) in a dose-dependent manner increased locomotor activity in rats; significant hyperactivation was observed after 25 and 50 microg/side of cocaine. Intra-NAc core injection of cocaine (12.5-50 microg/side) did not change rats' locomotor activity. After 5- or 21-day withdrawal, behavioral sensitization (ca. 2 times higher locomotor activity than that after acute drug administration) was observed when cocaine was injected either systemically (10 mg/kg) or intra-NAc shell (12.5-25 microg/side) in animals repeatedly treated with cocaine (10 mg/kg). No difference was observed in the response to the challenge with intra-NAc core cocaine (12.5-25 micorg/side) in rats treated repeatedly with cocaine at either withdrawal period. The above findings show the differential regulation of motor responses to cocaine within the subregions of the NAc. They also indicate a preferential effect for the NAc shell in expression of the acute and sensitizing effects of cocaine in rats.     

Age-specific behavioral responses to psychostimulants in mice

This study investigated the influence of age on the behavioral responses elicited by psychostimulants in male CD-1 mice. Behavioral activity including locomotion and stereotypy was measured following acute or repeated administration of cocaine, methylphenidate, amphetamine or saline to postweanling (24 days old), periadolescent (33 days old) and adult (60 days old) mice. Postweanling mice exhibited less total and ambulatory activity than periadolescent mice following a single acute injection of cocaine (20 or 30 and 30 mg/kg, respectively). Further, postweanling mice showed less total activity than both periadolescent and adult mice at a dose of 10 mg/kg methylphenidate. Less stereotypy was also seen in postweanling mice when compared to adolescent mice after 30 mg/kg amphetamine. Seven daily injections of cocaine resulted in a heightened behavioral response on day 7 as compared to day 1, indicative of behavioral sensitization in adult and periadolescent, but not postweanling mice. Repeated methylphenidate resulted in increased total activity in adult, but not periadolescent or postweanling mice. None of the animals were sensitized to the behavioral activating effects of amphetamine. The magnitude of behavioral response and the development of sensitization were dependent upon the age of the animal and the agent tested.