Ontogeny of behavioral sensitization to cocaine

The ontogeny of the behavioral effects of acute cocaine administration and behavioral sensitization to cocaine in rat pups was investigated. Acute behavior stimulating effects of cocaine were observed in pups as young as 7 postnatal days (PND) old, although they needed a higher dose of cocaine than adult rats to evoke the same motor effects. An adult dose-response curve pattern of stereotypy and locomotion to acute cocaine treatment was observed at PND 21, and of rearing at PND 28. Rats aged PND 7, 14, 21, 28, and 56 received repeated injections of saline or cocaine (15 mg/kg) twice a day for 5 consecutive days. After a 3-week period of abstinence, sensitization to a challenge dose of cocaine was assessed. Cocaine-induced stereotyped behavior was enhanced significantly only in rats in which cocaine pretreatment was initiated on PND 21, 28, and 56, but not earlier on PND 7 and 14. Adult female rats given repeated cocaine injections on PND 56–60 showed significantly greater sensitization than males, but no such sex difference was observed in pups given cocaine repeatedly on PND 21–25 or 28–32. These results show clearly that cocaine-induced behavioral sensitization in rats occurred only when subchronic cocaine administration was commenced on PND 21 or later.     

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.     

Locomotor activity and stereotypy in rats following repeated apomorphine treatments at 1-, 3-, or 7-day intervals

In two experiments, the effects of repeated intermittent administration of a relatively high dose of apomorphine (5 mg/kg) on locomotor activity and/or stereotypic behavior in rats was determined. In Experiment 1, male rats were given ten subcutaneous (SC) injections of apomorphine or vehicle and tested for locomotor activity and stereotypy. The first nine injection test sessions were given at 3-day intervals and the tenth injection test session was given 18 days following the ninth session. In Experiment 2, male rats were tested for locomotor activity following ten SC injections of apomorphine or vehicle with either a one- or seven-day interval between injections. Major findings were as follows: a) apomorphine produced progressively greater increases in locomotor activity with each succeeding injection (i.e., sensitization); b) sensitization to the locomotor activity stimulating effects of apomorphine developed with interinjection intervals of one, three, and seven days; c) the sensitization effect was maintained over the 18-day drug-free break; and d) the effect of apomorphine on stereotypic behavior did not significantly change with repeated injections. These findings indicate that even a single dose of apomorphine induces relatively long-lasting neurobiological changes. Moreover, these findings are consistent with the view that separate neural pathways mediate locomotor activity and stereotypy in rats.     

Chronic benzylpiperazine (BZP) exposure produces behavioral sensitization and cross-sensitization to methamphetamine (MA)

BACKGROUND: Like other psychostimulant drugs, acute exposure to benzylpiperazine (BZP) increases dopaminergic neurotransmission, producing hyperactivity and stereotypy. The consequences of repeated BZP exposure have not however been investigated. The effects of acute and repeated BZP and methamphetamine (MA) exposure on locomotor activity and stereotypy were measured in order to determine whether there was sensitization and cross-sensitization between these two psychostimulant drugs. METHODS: The effects of acute treatment with MA (0.0, 0.5, 1.0 and 2.0 mg/kg, intraperitoneal (IP)) or BZP (0.0, 5.0, 10.0, 20.0 and 40.0 mg/kg, IP) on locomotor activity and stereotypy were determined. Effects of repeated exposure were determined in other groups that received five daily injections of 2.0 mg/kg MA, 20.0 mg/kg BZP or vehicle. Following a 2-day withdrawal period, rats from each treatment group received either a low dose MA (0.5 mg/kg) or BZP (10.0 mg/kg). RESULTS: MA and BZP produced dose-dependent hyperactivity and stereotypy. Repeated MA and BZP resulted in a potentiated locomotor but not stereotypy response. Following the withdrawal period, MA pretreated rats exhibited a sensitized locomotor and stereotypy response to the low dose MA and a conditioned response to saline. BZP pretreated rats also demonstrated a sensitized locomotor response to the low dose of BZP and MA. CONCLUSIONS: The present findings indicate that repeated exposure to BZP results in sensitization and cross-sensitization to MA.     

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.     

Prenatal protein restriction increases sensitization to cocaine-induced stereotypy

The present study characterized the total amount of stereotyped behavior following acute and repeated administration of cocaine in male and female prenatally protein malnourished rats. Adult offspring of female Sprague-Dawley rats fed either a low (6% casein) or adequate (25% casein) protein diet 5 weeks prior to mating and throughout their pregnancy were studied. Once every 3 days (for a total of six injections), half the rats from each nutritional treatment group (repeated exposure) were injected with cocaine (30 mg/kg, i.p.) and their total amount of stereotypy (rearing, forepaw treading, compulsive sniffing and head bobbing) monitored. The remaining rats received five saline injections followed by a cocaine injection on the last injection day (acute exposure group) and their behavioral response was also measured. Despite being slightly less sensitive to cocaine following their first injection, by the sixth injection, prenatally protein malnourished animals in the repeated-exposure group exhibited significantly greater sensitization to the psychomotor stimulant effects of cocaine than well-nourished controls. In the acute exposure groups, however, prenatally malnourished males, but not females, exhibited significantly more stereotypy than well-nourished subjects following a single cocaine injection. These findings have implications for characterizing addiction potential in the previously malnourished rats, as well as providing additional information regarding factors which can influence sensitization.     

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.     

Ontogeny of the enhanced behavioral response to amphetamine in amphetamine-pretreated rats

Repeated administration of amphetamine to adult rats results in enhanced behavioral responses to subsequent amphetamine exposure. These experiments were designed to determine the earliest age at which behavioral sensitization to amphetamine could be detected. Rats from both sexes (n=6–8/group) at ages of 1, 7, 21 or 49 postnatal days (PNDs) were injected with eitherd-amphetamine sulfate (5 mg/kg) or saline, SC, twice daily for 5 consecutive days. Stereotyped behavior and locomotor activity responses to a challenge dose ofd-amphetamine (2.5 mg/kg), or saline, IP, were assessed for a total of 90 min, 15 days after the last dose of pretreatment. Amphetamine-induced stereotyped behavior was significantly enhanced only when amphetamine pretreatment was initiated at PND 49, but not at the earlier ages of PND 1, 7 or 21. There was no apparent sex difference in this effect. Correspondingly, amphetamine-induced locomotor activity was reduced in both sexes of the same age group (PND 49), but not in gropus pretreated earlier, when compared to the saline-pretreated rats. These results sugges that amphetamine sensitization may be a late-developing effect, one which occurs sometime after the 3rd week of postnatal life.     

Effects of the AMPA receptor antagonist NBQX on the development and expression of behavioral sensitization to cocaine and amphetamine

 We examined the effect of 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline (NBQX), an antagonist of the α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) subtype of glutamate receptor, on the development and expression of behavioral sensitization to amphetamine and cocaine in rats. A single injection of NBQX (12.5 mg/kg) administered 30 min prior to cocaine during the induction phase (days 1–5) prevented the development of cocaine sensitization, assessed by responsiveness to cocaine challenge on day 8. This NBQX regimen did not affect development of amphetamine sensitization. Two pretreatment injections of NBQX, one 20 min before and one 70 min after amphetamine on each day of the induction phase (days 1–6), did not affect sensitization of stereotypy but prevented sensitization of post-stereotypy ambulatory hyperactivity (both assessed by responsiveness to amphetamine challenge on day 8). The effect of NBQX on ambulatory sensitization was dose-dependent (attenuation with 12.5 mg/kg, complete prevention with 25 mg/kg). In contrast to its effects on development, NBQX (25 mg/kg) did not prevent expression of sensitization to cocaine or amphetamine. NBQX itself exerted no significant effects on locomotor activity in either drug-naive rats or rats that had received either NBQX or amphetamine repeatedly. These findings support a requirement for AMPA receptor stimulation in the development of locomotor sensitization to cocaine and amphetamine, but suggest a different mechanism for sensitization of amphetamine stereotypy. Received: 14 January 1997 / Final version: 24 June 1997     

Locomotor sensitization to quinpirole in rats: effects of drug abstinence and sex

RATIONALE: Behavioral sensitization, induced by the chronic administration of psychomotor stimulants, serves as an experimental model for the development of behavioral pathology. Although many factors are known to influence the sensitization produced by indirect dopamine agonists, such as cocaine and the amphetamines, less is known about factors that influence the behavioral sensitization produced by direct dopamine receptor agonists. OBJECTIVE: As the extent to which behavioral sensitization is expressed following the repeated administration of indirect dopamine agonists can depend upon a period of drug abstinence, the present study determined the effects of drug abstinence on the expression of locomotor sensitization to the D2/D3 receptor agonist, quinpirole (QNP). METHODS: Male and female rats were administered ten, twice weekly, injections of 0.5 mg/kg QNP or saline (SAL), and then received one of five QNP doses (0-1.0 mg/kg; n=7-10/dose) in two dose-response tests for locomotor sensitization, conducted at 3 and 15 days following the cessation of chronic treatment. RESULTS: The sensitized locomotor response of QNP-treated animals was similar on the 2 test days in both male and female subjects. Compared to males, female rats displayed greater locomotor responding to QNP, both during chronic treatment and on the dose-response tests for sensitization. CONCLUSIONS: QNP locomotor sensitization is (a) not influenced by 2 weeks of QNP abstinence and (b) can be influenced by the sex of the animal. It is suggested that direct and indirect dopamine agonists produce locomotor sensitization via distinct mechanisms that differ in sensitivity to the passage of time but are both influenced by sex-specific variables.     

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.     

Prenatal cocaine dampened behavioral responses to methylphenidate in male and female adolescent rats

Clinical and animal data point toward deficits in attention and arousal after prenatal cocaine exposure. Since methylphenidate (MPD) is widely used to treat attention disorders, we wanted to determine whether prenatal cocaine (PC) exposure affects the behavioral response to MPD in young rats of both sexes. Pregnant dams received 60 mg/kg of cocaine or vehicle from gestational days 8-22 by intragastric intubations. After delivery, litters were culled to 10 (5 males, 5 females) and fostered. On a single day between PND 41-44 locomotion was recorded in a Plexiglas box within an Accuscan activity monitor after receiving a single injection of 10 mg/kg intraperitoneally of MPD or saline. Rats were also videotaped for analysis of stereotyped behavior. Results showed that MPD administration enhanced locomotion compared to saline injected groups. PC exposure in male rats did not have any effect on the locomotor response to MPD compared to prenatal controls. However, PC-exposed males showed a lower amount of time spent in low intensity stereotypy compared to prenatal control males and both groups of females that received MPD. PC exposure in female rats that received MPD dampened the locomotor response compared to prenatal control females that also received MPD. In conclusion PC exposure dampens the behavioral response to MPD differentially in males and females with an apparent selectivity of locomotion in females and stereotyped behavior in males.     

Behavioral sensitization due to social defeat stress in mice: antagonism at mGluR5 and NMDA receptors

Rationale Repeated administration of psychostimulants progressively augments the behavioral response to and increases self-administration behavior of these drugs. Experience of repeated intermittent social defeat stress episodes also leads to a sensitized locomotor response following psychostimulant challenge. Both metabotropic and ionotropic glutamate receptors have been shown to be critical in the induction and expression of stimulant sensitization, but their role in sensitization due to social defeat stress remains unclear.Objective We evaluated the role of mGluR5 and NMDA glutamate receptors in the development of amphetamine-induced and social defeat stress-induced sensitization, using the non-competitive mGluR5 antagonist, MPEP, and the non-competitive NMDA antagonist, dizocilpine (MK-801).Methods In adult, male CFW mice, sensitization was induced by either ten daily injections of d-amphetamine (1 mg/kg) or ten daily brief episodes of social defeat. Mice were pretreated with MPEP (3 mg/kg or 10 mg/kg) or dizocilpine (0.1 mg/kg) prior to amphetamine injections. Mice subjected to social defeat were pretreated with MPEP (10 mg/kg) or dizocilpine (0.1 mg/kg). Ten days after induction, the expression of locomotor sensitization to amphetamine was determined.Results The induction of sensitization due to social defeat stress was prevented by MPEP, yet MPEP did not inhibit the development of behavioral sensitization to amphetamine. Confirming and extending earlier results, dizocilpine pretreatment blocked both amphetamine-induced and stress-induced sensitization.Conclusions These data indicate that behavioral sensitization to social defeat stress is dependent on mGluR5 receptors, whereas low-dose amphetamine sensitization may not be.     

Contribution of drug doses and conditioning periods to psychomotor stimulant sensitization

Rationale Repeated intermittent administration of psychostimulant drugs such as amphetamine and cocaine can cause sensitization (reverse tolerance) to the locomotor-stimulating actions in rats. Sensitization to the stimulant effects of these drugs might contribute to the development and maintenance of addictive behaviors (e.g. compulsive drug use).Objectives Studies were designed to systematically examine how testing conditions affect the development and expression of locomotor sensitization to cocaine and amphetamine.Methods Rats were treated once daily with intraperitoneal (i.p.) administration of amphetamine (0.5–2.0 mg/kg) or cocaine (5.0–20 mg/kg) and placed in activity chambers for 30, 60, or 120 min. All amphetamine-preexposed rats were challenged with 0.5 mg/kg amphetamine, and all cocaine-preexposed rats were challenged with 5.0 mg/kg cocaine for 120-minute activity tests 2 weeks after the final injection.Results Rats treated repeatedly with 2.0 mg/kg amphetamine and tested for 60 min in activity chambers or 20 mg/kg cocaine and tested for 30 min in activity chambers were most active in response to the drug challenge. These time points coincide with the maximal behavioral effects of each drug, as measured after the first injection. In contrast, rats treated with 2.0 mg/kg amphetamine and tested for 30 min or 20 mg/kg cocaine and tested for 120 min were least active in response to the drug challenge.Conclusions Repeated association of the peak behavioral effects of high doses of amphetamine or cocaine with the drug-paired environment produces maximal expression of sensitized locomotor responses. Certain testing conditions appear to disrupt sensitization to these same doses of the drugs.     

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.     

Prenatal and postnatal cocaine exposure enhances the induction and expression of locomotor sensitization to cocaine in rats

Prenatal and postnatal exposure to cocaine can affect the development and function of the central nervous system in offspring. It also produces changes in cocaine-induced dopamine release and increases cocaine self-administration and cocaine-induced conditioned place preference. Further, prenatal cocaine exposure involves greater risk for development of a substance use disorder in adolescents. Therefore, the objective of this study was to determine the effect of prenatal and postnatal cocaine exposure on locomotor sensitization in rats. A group of pregnant female Wistar rats were administered daily from day GD0 to GD21 with cocaine (cocaine pre-exposure group) and another group pregnant female rats were administered daily with saline (saline pre-exposure group). During lactation (PND0 to PND21) pregnant rats also received cocaine administration or saline, respectively. Of the litters resulting of the cocaine pre-exposed and saline pre-exposed pregnant female groups, only the male rats were used for the recording of the locomotor activity induced by different doses of cocaine (1, 5, 10, 20 and 40 mg/Kg/day) during the induction and expression of locomotor sensitization at different postnatal ages (30, 60, 90 and 120 days), representative of adolescence and adult ages. The study found that prenatal and postnatal cocaine exposure enhanced locomotor activity and locomotor sensitization, and such increase was dose- and age-dependent. This suggests that prenatal and postnatal cocaine exposure can result in increased vulnerability to cocaine abuse in young and adult humans.     

Sensitized activation of Fos and brain-derived neurotrophic factor in the medial prefrontal cortex and ventral tegmental area accompanies behavioral sensitization to amphetamine

Behavioral sensitization, or augmented locomotor response to successive drug exposures, results from neuroadaptive changes contributing to addiction. Both the medial prefrontal cortex (mPFC) and ventral tegmental area (VTA) influence behavioral sensitization and display increased immediate-early gene and BDNF expression after psychostimulant administration. Here we investigate whether mPFC neurons innervating the VTA exhibit altered Fos or BDNF expression during long-term sensitization to amphetamine. Male Sprague-Dawley rats underwent unilateral intra-VTA infusion of the retrograde tracer Fluorogold (FG), followed by 5 daily injections of either amphetamine (2.5 mg/kg, i.p.) or saline vehicle. Four weeks later, rats were challenged with amphetamine (1.0 mg/kg, i.p.) or saline (1.0 mL/kg, i.p.). Repeated amphetamine treatment produced locomotor sensitization upon drug challenge. Two hours later, rats were euthanized, and mPFC sections were double-immunolabeled for either Fos-FG or Fos-BDNF. Tissue from the VTA was also double-immunolabeled for Fos-BDNF. Amphetamine challenge increased Fos and BDNF expression in the mPFC regardless of prior drug experience, and further augmented mPFC BDNF expression in sensitized rats. Similarly, more Fos-FG and Fos-BDNF double-labeling was observed in the mPFC of sensitized rats compared to drug-naïve rats after amphetamine challenge. Repeated amphetamine treatment also increased VTA BDNF, while both acute and repeated amphetamine treatment increased Fos and Fos-BDNF co-labeling, an effect enhanced in sensitized rats. These findings point to a role of cortico-tegmental BDNF in long-term amphetamine sensitization.     

Medial septal lesions in rats enhance locomotor sensitization to amphetamine

Rationale: The mesolimbic dopamine (DA) system appears to play a major role in the locomotor activating and sensitizing effects of several addictive drugs. However, less is known about the neural structures that may modulate this system. Objective: We examined the effects of medial septal lesions on the locomotor activating and sensitizing effects of amphetamine in between-subjects (experiment 1) and within-subjects (experiment 2) experiments. Results: Repeated injections of 0.6 mg/kg (experiment 1) or 1.0 mg/kg (experiment 2) amphetamine over six sessions produced more locomotion in the lesioned rats than in the sham-operated controls. This repeated exposure to amphetamine subsequently increased the locomotor response to 0.2 mg/kg (experiment 2) and 0.4 mg/kg (both experiments) amphetamine in the lesioned rats, such that these sensitized, lesioned rats moved more in response to these doses than unsensitized, lesioned rats and sensitized controls did. Both experiments also indicated that this prior sensitization enhanced the locomotor response to 0.4 mg/kg amphetamine more in the lesioned rats than in the control rats when compared with the response produced by saline following sensitization or by the same dose of amphetamine prior to sensitization. In contrast, prior exposure to amphetamine decreased the locomotor response to 4.0 mg/kg amphetamine in the lesioned rats (experiment 1). Conclusions: Although medial septal lesions occasionally enhance locomotor responses to moderate doses of amphetamine prior to sensitization, a main effect of these lesions is to further enhance the effects of locomotor sensitization to amphetamine. Implications for drug addiction are discussed. Received: 26 August 1998 / Final version: 23 April 1999     

Effects of psychostimulant withdrawal on latent inhibition of conditioned active avoidance and prepulse inhibition of the acoustic startle response

RATIONALE: Chronic intermittent administration of amphetamine and cocaine can precipitate psychotic episodes in humans and produce persistent behavioral changes (i.e. increased locomotion, stereotypy) in the rat. The psychostimulant sensitization model of psychosis holds that the repeated administration of drugs such as amphetamine and cocaine induces long-lasting neuroadaptations and behavioral outcomes in animals that parallel aspects of the schizophrenic condition. OBJECTIVES: In the present study, we attempted to validate this model further by examining the effects of short-term withdrawal from repeated administration of cocaine and amphetamine on performance in two animal behavioral models of cognitive deficits found in schizophrenia: latent inhibition and prepulse inhibition. Reductions in both of these behavioral phenomena have been reported in schizophrenic patients and in acutely amphetamine-treated rats. METHODS: Animals were tested after 4 days of withdrawal from 5 days of daily systemic 20 mg/kg cocaine or 1.5 mg/kg amphetamine injections for either latent inhibition of two-way active avoidance acquisition or prepulse inhibition of an acoustic startle response. RESULTS: Our results indicate that, rather than reducing the expression of these behaviors, withdrawal from either cocaine or amphetamine enhanced the expression of latent inhibition of the active avoidance response while having no effect on prepulse inhibition of acoustic startle. CONCLUSIONS: These data indicate that although the sensitized response to amphetamine and cocaine administration may model some aspects of schizophrenic psychosis, behaviors exhibited by sensitized animals in the absence of an acute drug challenge are not consistent with models of the positive symptoms of schizophrenia.     

Importance of environmental context in the development of amphetamine- or apomorphine-induced stereotyped behavior after single and multiple doses

The present study was designed to determine whether single and repeated pretreatment regimens with amphetamine or apomorphine differ in the context-dependency of sensitization of stereotyped behavior. Male CF-1 mice that were pretreated with a single high dose of amphetamine (14 mg/kg intraperitoneally [IP]) or apomorphine (40 mg/kg subcutaneously [SC]) only became sensitized to a lower test dose of amphetamine (7 mg/kg IP) or apomorphine (3 mg/kg SC) when placed in an environment that was the same as the pretreatment environment. However, animals pretreated with 3 high doses (24-h apart) of amphetamine (14 mg/kg IP) or apomorphine (40 mg/kg SC) did demonstrate sensitization to a lower test dose of amphetamine (7 mg/kg IP) or apomorphine (3 mg/kg SC) when placed in an environment that was different from the pretreatment environment. Context-dependent sensitization, but not context-independent sensitization, was extinguished by pairing the test environment with saline injections instead of drug injections. In addition, it was determined that neither sensitization model could be related to pharmacokinetic factors. Therefore, the results indicate that repeated exposure to amphetamine or apomorphine overcomes the context-dependent component of sensitization of amphetamine- or apomorphine-induced stereotyped behavior.