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.     

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.     

Effects of AMPA receptor antagonists on dopamine-mediated behaviors in mice

 Current data indicate that dopaminergic and glutamatergic neurotransmitter systems interact. The role of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) glutamate receptor subtypes in modulating dopamine neurotransmission, however, remains unclear. The noncompetitive AMPA antagonists, GYKI 52466 (5–40 mg/kg) and LY300164 (1–6 mg/ kg), and the competitive AMPA antagonists, LY326325 (5–80 mg/kg) and NBQX (10–80 mg/kg), were compared to the dopamine antagonist, haloperidol (0.03– 1.0 mg/kg), for their ability to inhibit dopamine-mediated behaviors after IP administration in mice. The behavioral paradigms included amphetamine- or dizocilpine-induced hyperactivity, amphetamine-induced stereotyped sniffing, and apomorphine-induced climbing and stereotyped sniffing. All four AMPA antagonists and haloperidol attenuated amphetamine- and dizocilpine-induced hyperactivity and decreased spontaneous locomotion. Haloperidol and GYKI 52466 were more potent against amphetamine than against dizocilpine. In contrast, LY326325 was more potent against dizocilpine than against amphetamine. The hyperactivity decreases by LY300164 and NBQX were most likely due to non-specific effects on motor behavior. The AMPA antagonists and haloperidol also attenuated amphetamine- induced stereotypy. Unlike haloperidol, however, GYKI 52466, LY300164, and NBQX failed to attenuate apomorphine-induced climbing and stereotyped sniffing. LY326325, on the other hand, attenuated apomorphine-induced stereotypy, but not climbing. These results indicate that AMPA receptor antagonists can attenuate the behavioral effects of drugs, such as amphetamine and dizocilpine, that increase dopamine neurotransmission. However, the behavioral effects of the direct dopamine agonist apomorphine are not consistently attenuated by AMPA antagonists. The competitive AMPA receptor antagonist LY326325 appears to have a profile distinct from both haloperidol and the other AMPA antagonists tested. Received: 23 December 1996/Final version: 8 September 1997     

Cocaine-induced behavioral sensitization in preweanling and adult rats: effects of a single drug–environment pairing

Rationale Adult rats typically exhibit more robust behavioral sensitization than do preweanling rats. A possible explanation for this age-dependent difference is that environmental context may have relatively less impact on the psychostimulant-induced behaviors of preweanling rats. Objective The purpose of this study was to assess the importance of environmental context for the development of cocaine-induced sensitization in preweanling and adult rats. Materials and methods On postnatal day (PD) 19 or PD 79, rats in the context-dependent condition were injected with 30 mg/kg cocaine immediately before being placed in a novel test chamber for 30 min. The same rats were then injected with saline 30 min after being returned to the home cage. Rats in the context-independent condition were injected with saline before being placed in the novel chamber and cocaine in the home age. Control rats were injected with saline at both time points. One day later, adult and preweanling rats were challenged with saline or 10 mg/kg cocaine (experiment 1), or preweanling rats were challenged with 5, 20, or 30 mg/kg cocaine (experiment 2). After being injected, rats were placed in the test chamber, and behavior was measured for 60 min. Results Adult rats showed context-dependent locomotor sensitization and conditioned activity, with females exhibiting more locomotor activity than males. Preweanling rats did not exhibit conditioned activity, but they showed robust context-dependent and context-independent sensitization when challenged with 10–30 mg/kg cocaine. Conclusions Context did not influence the expression of behavioral sensitization in preweanling rats, suggesting that deficits in associative or memory processes may be responsible for age-dependent differences in behavioral sensitization and conditioned activity.     

Carbamazepine retards the development of cocaine-kindled seizures but not sensitization to cocaine-induced hyperactivity

The effects of chronic carbamazepine on cocaine-kindled seizures and behavioral sensitization were examined in this study. Rats were fed a diet containing carbamazepine or no drug and then repeatedly administered cocaine (40 and 50 mg/kg intraperitoneally [IP] [117.6 and 147.0 mumol/kg, respectively]). Carbamazepine markedly decreased the development of cocaine-kindled seizures and their associated lethality, but did not affect the development of sensitization of behavioral stereotypies. Carbamazepine consistently decreased the peak stereotypy ratings at the 40 mg/kg but not 50 mg/kg dose. In a 2-day sensitization paradigm chronic carbamazepine did not affect acute cocaine-induced hyperactivity (day 1; 40 mg/kg), nor did it affect sensitization to a low dose challenge of cocaine (day 2; 10 mg/kg [29.4 mumol/kg]). Sensitization of stereotypy and locomotor activity are thought to be related to the psychomotor stimulant properties of cocaine, while seizures may be associated with cocaine's local anesthetic effects. Our data suggest that carbamazepine is inhibiting mechanisms associated with local anesthetic kindling and only minimally affecting the psychomotor stimulant effects of cocaine.     

Development of behavioral sensitization to the cocaine-like fungicide triadimefon is prevented by AMPA, NMDa, DA D1 but not DA D2 receptor antagonists.

Triadimefon (TDF) is a triazole fungicide that blocks the reuptake of dopamine (DA) and leads to increased locomotor activity levels in mice and rats, effects similar to those of indirect DA agonists such as cocaine. We recently found in mice that intermittent TDF administration led to robust locomotor sensitization, a phenomenon reflecting neuronal plasticity, following challenge with the same TDF dose after a 2-week withdrawal period. The current study sought to determine whether antagonists to DA D1-like receptors (SCH 23390; SCH), DA D2-like receptors (remoxipride; Rem), ionotropic glutamate n-methyl-d-aspartate (NMDA) receptors (CPP), or ionotropic glutamate alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (NBQX) could prevent the development of TDF behavioral sensitization, therefore indicating their mechanistic involvement in TDF sensitization. Mice were treated with either vehicle, SCH (0.015 mg/kg), remoxipride (Rem, 0.3 mg/kg), CPP (2.5 mg/kg) or NBQX (10.0 mg/kg), followed 30 min later by vehicle or 75 mg/kg TDF (TDF), twice a week for 7 weeks, with locomotor activity measured post-dosing once a week. After a 2-week withdrawal period, mice were challenged with 75 mg/kg TDF or vehicle, to test for the presence of behavioral sensitization. Pretreatment with SCH, CPP, or NBQX, but not Rem, blocked the development of behavioral sensitization to TDF specifically for vertical activity. Antagonists that blocked TDF vertical sensitization also attenuated the increase in extracellular DA turnover (homovanillic acid [HVA]/DA) normally associated with this behavioral response. Therefore, DA D1, NMDA and AMPA receptors appear to be necessary for the development of behavioral sensitization to TDF. As such, TDF may be considered an environmental risk factor for behavioral dysfunctions linked to glutamatergic and dopaminergic systems.     

Gestational exposure to nicotine and monoamine oxidase inhibitors influences cocaine-induced locomotion in adolescent rats

Rationale Many pregnant women continue to smoke, despite a strong association between maternal smoking and neurobehavioral deficits in the offspring. Although gestational nicotine (GN) treatment in rodents is used as the primary animal model of maternal smoking, tobacco smoke contains more than 4,000 constituents, including monoamine oxidase inhibitors (MAOIs). Objectives The aim of this study was to determine whether there are interactions between the effects of gestational exposure to nicotine and MAOIs on cocaine-induced locomotor sensitization in adolescent rats. Materials and methods Pregnant rats were implanted on day 4 of gestation with osmotic minipumps delivering saline, nicotine (3 mg/kg per day), the MAOIs clorgyline and deprenyl (1 and 0.25 mg/kg per day, respectively), or nicotine/clorgyline/deprenyl (GMN). Adolescent female offspring were tested for cocaine-induced locomotor sensitization. Animals were treated with saline or cocaine (5 or 15 mg/kg, intraperitoneally) daily from postnatal (P) days 32–36 and challenged with cocaine (15 mg/kg) on P51 (day 20). Results Group differences were observed in chronic but not acute effects of cocaine. Whereas gestational MAOI treatment, with or without nicotine, increased ambulatory response to cocaine on day 5, the opposite was found for vertical activity. Different adaptive responses were observed on cocaine challenge day. GNM animals exhibited enhanced locomotor activity in the cocaine-associated environment before cocaine challenge on day 20. In contrast, only GN animals exhibited significant locomotor sensitization to the cocaine challenge. Conclusions Gestational nicotine and MAOIs both influence brain development. Such interactions may sensitize adolescents to drug abuse and should be considered in animal models of maternal smoking.     

Enhanced morphine- and cocaine-induced behavioral sensitization in alcohol-preferring AA rats

Locomotor stimulation and behavioral sensitization induced by acute and repeated treatment with alcohol, cocaine or morphine were studied in the alcohol-preferring AA (Alko, Alcohol), alcohol-avoiding ANA (Alko, Non-Alcohol) rats and non-selected Wistar rats. Daily treatment with alcohol (ethanol, 0.4 or 1.0 g/kg, IP) for 6 days had no effect on locomotor activity either in the AA or ANA rats. Acute cocaine (5, 10 or 20 mg/kg, IP) produced a locomotor stimulation in the animals of all lines studied, and there was no difference in this effect between the AA and ANA rats. During a 4-day repeated cocaine treatment, the AA rats became sensitized with the 10 mg/kg dose, while the ANA rats did not show any sensitization with this dose. With the 20 mg/kg cocaine dose, in addition to locomotor stimulation, the rats of all lines studied showed stereotyped behavior, which response was enhanced during repeated treatment. Morphine-induced locomotor stimulation was larger in the AA rats than in the ANA or Wistar rats both with 1.0 and 3.0 mg/kg doses and only the AA rats were sensitized during 4-day treatment with the 1 mg/kg dose. With the 3.0 mg/kg morphine dose, only the AA rats showed a weak sensitization evident only during the initial 30 min after morphine injection. As the drug-induced behavioral sensitization is an important factor in the development of drug addiction, it is possible that mechanisms underlying the enhanced susceptibility of the AA rats to morphine- and cocaine-induced sensitization contribute to the high intake of alcohol and other abused drugs by these animals. Received: 3 April 1998/Final version: 7 September 1998     

Experiential constraints on the development of tolerance to amphetamine hypophagia following sensitization of stereotypy: instrumental contingencies regulate the expression of sensitization

 In previous research, sensitization of stereotypy induced by injections of 2.5 mg/kg amphetamine did not interfere with subsequent tolerance development to the hypophagic effect of 2 mg/kg. This study examined the effect of a higher sensitizing dose. Rats given intermittent injections of 5 mg/kg amphetamine and then challenged with various doses of amphetamine showed focused head scanning at 2 mg/kg and oral stereotypy at 4 mg/kg. In contrast, saline controls showed diffuse sniffing and head scanning at 2 and 4 mg/kg. Subgroups from each condition were then given daily injections of either amphetamine (2 mg/kg) or saline and access to milk for 30 min. Dose-response tests revealed that both drugged groups learned to suppress stereotypy in order to feed at 2 mg/kg, but only the non-sensitized group could do so at 4 mg/kg. These results demonstrate that (1) rats learn to suppress only those stereotyped movements that they experience in the context of feeding and (2) instrumental contingencies can influence the expression of behavioral sensitization. Received: 18 December 1997 / Final version: 3 June 1998     

Nicotinic receptors differentially modulate the induction and expression of behavioral sensitization to methylphenidate in rats

Rationale  Nicotinic acetylcholine receptors (nAChRs) regulate sensitization to stimulant drugs such as d-amphetamine and cocaine. Objectives  The current study determined if nAChRs modulate the induction and/or expression of behavioral sensitization to high methylphenidate doses. Methods  In experiment 1, rats received saline or mecamylamine (3 mg/kg, sc), followed by saline or methylphenidate (5.6 or 10 mg/kg, sc) during 10 daily sessions; the effect of methylphenidate (1–17 mg/kg, sc) alone was determined 14 days later. In experiment 2, rats received saline or dihydro-β-erythroidine (DHβE; 3 mg/kg, sc), followed by saline or 5.6 mg/kg of methylphenidate. In experiment 3, rats received saline or methylphenidate (5.6 or 10 mg/kg, sc) alone for 10 days; the effect of acute mecamylamine (3 mg/kg, sc) on the response to methylphenidate (1–17 mg/kg, sc) was determined 14 days later. Locomotor activity, sniffing, rearing, grooming, and stereotypy ratings were dependent measures. Results  Methylphenidate produced dose-dependent increases in locomotor activity, sniffing, and stereotypy on day 1 and these effects were enhanced on day 10, indicative of sensitization. Mecamylamine attenuated methylphenidate-induced stereotypy only on day 1, but reduced locomotor activity, sniffing, rearing, and stereotypy on day 10 and during the methylphenidate challenge phase; similar results were obtained with DHβE. However, acute mecamylamine did not alter the effects of the methylphenidate challenge following the induction of sensitization to methylphenidate alone. Conclusions  Although nAChRs do not appear to regulate the expression of methylphenidate-induced behavioral sensitization, inhibition of high-affinity β2 subunit nAChRs attenuates the induction of behavioral sensitization to high doses of methylphenidate. The asterisk (*) found in the body denotes possible inclusion of additional nAChR subunits.     

Age-related differences in amphetamine sensitization: Effects of prior drug or stress history on stimulant sensitization in juvenile and adult rats

Repeated intermittent exposure to stimulants progressively increases a drug's effect, with stressors capable of producing cross-sensitization to stimulants. Studies examining such sensitization during development are few, however, with results mixed. In Experiment 1, juvenile (P22) and adult (P64) female Sprague-Dawley rats were administered (daily for 4 days) 1.5 mg/kg or 3.0 mg/kg amphetamine (1.5A and 3.0A groups), or saline (SAL group). In a second experiment, rats were exposed to either repeated restraint (60 min/day for 4 days; RS group) or were left non-manipulated in the home cage (NM group). Animals from both experiments were then challenged with 1.5 mg/kg of amphetamine and sensitization assessed via locomotion and stereotypy after a 2-day and 3-wk washout period. When compared to SAL animals, 3.0A juveniles and adults exhibited evidence of locomotor sensitization 2 days post-drug exposure, but this sensitization did not persist to the 3-week challenge. Compared to NM animals, RS animals showed stress-induced locomotor sensitization both 2 days and 3 weeks post-stress exposure, regardless of age. These results demonstrate that repeated drug/stress exposures prior to stimulant challenge are sufficient to induce behavioral sensitization among both juveniles and adults, with these effects particularly long-lasting following repeated stressor exposure.     

On the role of noradrenaline in psychostimulant-induced psychomotor activity and sensitization

Rationale Psychostimulant drugs exert their behavioral effects primarily through enhancement of monoaminergic neurotransmission. Augmented dopamine activity is thought to play a critical role in the psychomotor stimulant effects of amphetamine and cocaine, as well as in the development of long-term behavioral sensitization evoked by repeated exposure to amphetamine. However, despite the fact that brain dopamine and noradrenaline systems are closely interconnected, the extent to which noradrenergic transmission contributes to these behavioral effects of psychostimulants is a relatively unexplored issue. Objectives By inhibiting noradrenergic neurotransmission with the α₂-adrenoceptor agonist clonidine, the α₁-antagonist prazosin and the β-antagonist propranolol, we investigated the involvement of noradrenaline neurotransmission in the psychomotor stimulant and long-term sensitizing effects of d-amphetamine and cocaine in rats. Methods Clonidine (0.003–0.1 mg/kg), prazosin (0.1–3.0 mg/kg) and propranolol (1.0–3.0 mg/kg) were administered prior to d-amphetamine (1.0 mg/kg), cocaine (15 mg/kg) or apomorphine (1.0 mg/kg) and psychomotor activity was measured. In separate studies, clonidine (0.03 mg/kg), prazosin (1.0 mg/kg) or propranolol (3.0 mg/kg) were co-administered with d-amphetamine (2.5 mg/kg) or cocaine (30 mg/kg) for 5 days, and locomotor sensitization was assessed 3 weeks post-treatment. Results The psychomotor stimulant effect of d-amphetamine, but not that of cocaine or apomorphine, was dose-dependently inhibited by clonidine and prazosin, and enhanced by propranolol. Clonidine, prazosin, and propranolol did not influence the induction of sensitization by amphetamine or cocaine. Conclusions Enhancement of synaptic noradrenaline concentrations contributes to the psychomotor stimulant effect of d-amphetamine, but not cocaine or apomorphine. In addition, noradrenergic neurotransmission is not critically involved in the induction of psychostimulant sensitization.     

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.     

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.     

Evidence for a role of endogenous neurotensin in the initiation of amphetamine sensitization

This study was aimed at testing the hypothesis that endogenous neurotensin plays a role in the initiation of sensitization to the locomotor activating effect of amphetamine. During an initial training phase, different groups of male rats were injected on four occasions (every second day: Days 1, 3, 5 and 7) with one of three doses (40, 80 or 160 microg/kg, ip) of the neurotensin antagonist, SR-48692, or its vehicle, followed 30 min later by amphetamine (1.5 mg/kg, ip), or saline. Ambulatory, non-ambulatory, and vertical movements were measured for 2 h in photocell cages immediately following the second injection. One week after the training phase, sensitivity to amphetamine (0.75 mg/kg, ip) was tested in all the rats (sensitization test). The results show that SR-48692, when given alone, produced levels of locomotor activity that were not statistically different from control. At the low dose, it potentiated amphetamine-induced ambulatory and non-ambulatory movements, an effect observed on Day 7 but not on Day 1. On the day of the sensitization test, rats pre-exposed to amphetamine alone displayed stronger ambulatory and non-ambulatory movements than vehicle pre-exposed rats, a sensitization effect that was attenuated and prevented by SR-48692 at 80 and 160 microg/kg, respectively. The present results demonstrate that activation of neurotensin receptors by endogenous neurotensin is required for the initiation of amphetamine sensitization. They provide additional evidence that an increase in central neurotensinergic neurotransmission may lead to a lasting increased sensitivity to psychostimulant drugs.     

Individual differences in initial low-dose cocaine-induced locomotor activity and locomotor sensitization in adult outbred female Sprague-Dawley rats

Sex and individual differences are important considerations when studying cocaine responsiveness. We have previously shown that male Sprague-Dawley (S-D) rats can be classified as low or high cocaine responders (LCRs or HCRs, respectively) based on their locomotor activity following a single dose of cocaine (10 mg/kg, i.p.). Further, this distinction was found to predict dopamine transporter function, cocaine-induced locomotor sensitization, cocaine conditioned place preference and motivation to self-administer cocaine. Here we investigated whether or not individual differences in cocaine-induced locomotor activity and locomotor sensitization exist in female S-D rats. Female rats exhibited a broad range of locomotor activation following either a 5 or 10 mg/kg cocaine injection, allowing for classification as LCRs or HCRs. When administered over 7 days, both doses induced locomotor sensitization in female LCRs/HCRs. However, the magnitude of effects produced by 5 mg/kg cocaine in female LCRs/HCRs was more comparable to that produced by 10 mg/kg in male LCRs/HCRs, both of which, interestingly, developed sensitization in this study. These findings suggest that female S-D rats, like male S-D rats, can be classified as LCRs/HCRs and highlight the importance of accounting for dose when studying sex and individual differences to the effects of cocaine.     

Sensitization and individual differences to IP amphetamine, cocaine, or caffeine following repeated intracranial amphetamine infusions.

Rats that have a high locomotor response to novelty (HR) sensitize more readily to IP-administered amphetamine than rats with a low locomotor response (LR) to novelty. This experiment compared sensitization in HR and LR rats following amphetamine (3.0 micrograms/side for 5 days) infused bilaterally into either the nucleus accumbens (NACC), ventral tegmental area (VTA), or the medial frontal cortex (MFC). The subsequent locomotor response to IP-administered d-amphetamine sulfate (1 mg/kg), cocaine HCl (15 mg/kg), and caffeine benzoate (20 mg/kg) was also examined. No differences were observed between HR and LR rats following amphetamine infusion into either the MFC, NACC, or VTA. However, HR rats showed greater locomotor activity compared to LR rats following either IP amphetamine, cocaine, or caffeine for subjects cannulated in the NACC, MFC, or the VTA. Repeated infusions of amphetamine into the VTA increased the locomotor response to both IP amphetamine and cocaine, but not to IP caffeine, while repeated infusions of amphetamine into the NACC or MFC had no effect on locomotor response to any drug subsequently administered IP. The results support previous findings that changes induced by intra-VTA infusions, but not intra-NACC or MFC infusions, of amphetamine induce sensitization to IP-administered amphetamine and cocaine. Findings from the present experiment indicate the ability of the dopamine cell body region, but not the dopamine terminal fields, to produce locomotor sensitization to amphetamine and cocaine. The results from the present experiment also indicate the lack of localization to one of studied regions of individual differences.(ABSTRACT TRUNCATED AT 250 WORDS)     

Individual differences in cocaine-induced locomotor activity in male Sprague–Dawley rats and their acquisition of and motivation to self-administer cocaine

Rationale  Factors that increase an individual’s susceptibility to cocaine dependence remain largely unknown. We have previously shown that adult outbred male Sprague–Dawley rats can be classified as either low or high cocaine responders (LCRs or HCRs, respectively) based on their locomotor activity following the administration of a single dose of cocaine (10 mg/kg, i.p.). Furthermore, LCR/HCR classification predicts dopamine transporter function/inhibition, cocaine-induced locomotor sensitization, and cocaine-conditioned place preference. Objectives  The present study assessed LCR/HCR classification and the development of locomotor sensitization on the latency to acquire cocaine self-administration and motivation to self-administer cocaine. Results  LCRs and HCRs did not differ in their latency to acquire low-dose cocaine self-administration (0.25 mg/kg/infusion over 12 s, fixed ratio 1 schedule of reinforcement). In a follow-up experiment, repeated experimenter-administered injections of cocaine (10 mg/kg, i.p.) resulted in locomotor sensitization for LCRs, but not HCRs; nonetheless, all rats exhibited decreased latency to acquire cocaine self-administration compared to the first experiment. Repeated cocaine preexposure and LCR/HCR classification predicted break point when rats responded for cocaine under a progressive ratio schedule of reinforcement (0.25, 0.5, and 1.0 mg/kg/infusion; multiple exposure>single exposure, LCR>HCR), but there was no interaction between these variables. Conclusions  Although LCR/HCR classification did not predict the rate of acquisition of cocaine self-administration under these conditions, LCR rats demonstrated greater responding for cocaine after acquisition (PR). Thus, these findings demonstrate the relevance of using the LCR/HCR model when studying susceptibility to cocaine dependence.     

Does locomotor response to novelty in rats predict susceptibility to develop sensitization to cocaine and PHNO?

It has been suggested that the locomotor response of rats to novelty is positively correlated with motor stimulant effects of acute injections with psychomotor stimulants, and liability to self-administer these drugs. In addition, response to novelty appears to be inversely correlated with an individual's susceptibility to develop behavioural sensitization (an increase in the behavioural response to a given dose of stimulant after repeated treatments). To test some of these putative relationships, 96 rats were allocated to one of two subgroups based on a median split of locomotor responses to novelty. Animals then received 10 successive injections of either vehicle, cocaine (10 mg/kg), or the direct D2 agonist, (+)-4-propyl-9-hydroxynaphthoxazine (PHNO: 15 microg/kg), and locomotor activity was monitored. Conditioning tests and additional sensitization and cross-sensitization tests were conducted. Results showed that locomotor responses to novelty are not significantly correlated with locomotor effects of either acute injection with cocaine or PHNO, or rate of development of behavioural sensitization to these drugs. However, locomotor responses to novelty did predict level of locomotor and stereotypy responses to cocaine, and to a lessor extent to PHNO. Cocaine-treated, but not PHNO-treated, rats exhibited drug-conditioned-like effects. Cross-sensitization between cocaine and PHNO was not observed, indicating independent mechanisms for sensitization. It is concluded that the locomotor response to novelty can predict level of locomotion and stereotypy produced by cocaine and PHNO, but does not predict the degree or rate of behavioural sensitization to either of these drugs.