Cocaine-induced behavioral sensitization in the young rat

Rationale: Repeated psychostimulant treatment has been shown to sensitize the locomotor activity of young rats, but there is conflicting evidence suggesting that this sensitized response will persist across only a few drug abstinence days. Objective: The purpose of the present study was to determine whether: (a) young rats are capable of expressing a sensitized locomotor response after an extended drug abstinence period, and (b) the longevity of the sensitized response is critically affected by either the number of drug pretreatment days or environmental conditioning factors. Methods: Young rats were pretreated with saline or cocaine (15 mg/kg or 30 mg/kg, i.p.) for either five or ten consecutive days [i.e., on postnatal days (PD) 16–20 or PD 11–20]. After each daily injection, rats were placed in activity chambers, and locomotion was measured for 30 min. To assess environmental conditioning factors, some rats were injected with saline prior to being placed in the activity chambers and then injected with cocaine prior to being returned to the home cage. After one or seven abstinence days (i.e., on PD 22 or PD 28), rats received a challenge injection of saline or cocaine (15 mg/kg) in the activity chamber and locomotion was assessed. Results: Young rats exhibit cocaine-induced locomotor sensitization after either a short (1-day) or long (7-day) drug abstinence period. When a long abstinence period was used, locomotor sensitization was only apparent when cocaine pretreatment lasted for 10 days. Conditioning factors were also important for determining whether locomotor sensitization was expressed, because young rats pretreated with cocaine in the home cage did not show a sensitized locomotor response after seven abstinence days. Conclusions: Young rats are capable of showing cocaine-induced locomotor sensitization after an extended abstinence period. Both the number of drug pretreatment days and the environmental context in which cocaine was given (i.e., the activity chamber or home cage) influenced the longevity of cocaine-induced locomotor sensitization. Received: 30 August 1999 / Accepted: 21 December 1999     

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.     

The influence of environment on the induction of sensitization to the psychomotor activating effects of intravenous cocaine in rats is dose-dependent

 The acute psychomotor response and development of sensitization to amphetamine is attenuated if IP injections are given in the cage where a rat lives relative to when injections are given in a novel but physically identical test environment. Furthermore, when the environmental cues predicting IP injections are completely eliminated by using remotely activated IV injections in the home cage, 1.0 mg/kg amphetamine produces a very small acute response and no sensitization. The same treatments do produce sensitization if IV injections are signaled by placement of the rat in a novel test cage. The present experiment was designed to determine if there is a similar effect of environmental condition on the response to IV cocaine, and to what extent the effect may be dose-dependent. This was accomplished by comparing the psychomotor activating effects (rotational behavior) of repeated IV administrations of one of eight doses of cocaine (0.0, 0.3, 0.6, 1.2, 2.4, 3.6, 4.8, or 7.2 mg/kg) given in the home cage, with infusions of the same doses given in a novel test cage. There was no effect of environment on the acute psychomotor response to cocaine. There was, however, a significant effect of environment on the induction of sensitization. A higher dose of cocaine was required to induce sensitization when IV administrations were given in the home cage than when they were given in a physically identical but novel test environment. At high doses, however, cocaine induced sensitization regardless of environmental condition. The results suggest that the effect of this environmental manipulation is to shift the dose-effect curve for the induction of sensitization, and support the notion that the ability of psychostimulant drugs to induce sensitization can be modulated by the circumstances surrounding drug administration. Received: 19 August 1997 / Final version: 13 November 1997     

Behavioral sensitization to cocaine after a brief social defeat stress: c-fos expression in the PAG

The experiments explored the nature and time course of changes in behavior and Fos expression in the periaqueductal grey area (PAG) in response to an injection of cocaine that was given following a single episode of social defeat stress. Social defeat stress was defined as an intruder mouse’s response to an aggressive resident mouse. First, the intruder was briefly attacked, and secondly, it was threatened while protected by a perforated cage for 20 min. Plasma corticosterone levels rose after the beginning of the confrontation and remained elevated during the protected phase. In a first experiment, separate groups of intruder and control mice were challenged once with cocaine (20, 30, or 40 mg/kg) or saline. During tests for motor activity, behavioral measurements were obtained via (1) photobeam interruptions, (2) tracking of movements via image analysis, and (3) quantitative ethological analysis of postures and acts via videorecords. Several indices of ambulatory or horizontal forward locomotion confirmed the stimulant effects of cocaine. In a further experiment, separate groups of mice were challenged with 40 mg/kg cocaine at one time point, either during the social stress or 3, 5, 7 or 9 days thereafter. A cocaine challenge significantly increased locomotion 5 and 7 days after a brief social defeat stress, in excess of the level that is seen in non-stressed animals. Further experiments used immunohistochemical assays of sections through the caudal ventrolateral PAG and showed a significant increase in Fos-like immunoreactivity (Fos-LI) 1 h after the social stress experience or after cocaine. Importantly, concurrent administration of cocaine with social defeat stress produced inhibition of Fos expression throughout the PAG. A partial to complete recovery of cocaine-induced Fos expression was observed 5–7 days after social defeat stress. The results suggest that a single social stress episode is sufficient to engender a delayed sensitization of stimulant hyperactivity. The initial inhibition of Fos expression by concurrent social stress and cocaine may point to a relevant initiating event in the process of sensitization to stimulants. Received: 30 July 1997/Final version: 15 June 1998     

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.     

Cocaine, but not alcohol, reinstates cocaine-induced place preferences

Alcohol has been reported to modulate the reinforcing and aversive properties of cocaine. Given these effects, the present study examined whether this interaction could be extended to cocaine seeking using the conditioned place preference (CPP) procedure. Specifically, 31 drug-naive, male Sprague-Dawley rats were injected every other day (for 8 days) with either 20 mg/kg cocaine or vehicle in an alternating sequence prior to being restricted to a drug or vehicle side of a place preference chamber for 30 min. On Day 9, subjects were given 15-min access to the entire chamber to assess compartment preference. Animals then underwent extinction by pairing both compartments with vehicle for an additional 8 days. Extinction was assessed in the same manner as place conditioning. The animals were then given priming injections of vehicle, 15 mg/kg cocaine, 0.5 or 1.0 g/kg alcohol on the day following the extinction test. Pairing 20 mg/kg cocaine with a specific compartment resulted in a significant place preference. Breaking the relation between the compartment and the drug by pairing both compartments with vehicle extinguished this preference. Interestingly, only 15 mg/kg cocaine was able to reinstate the cocaine-induced place preference, suggesting that the ability to reinstate cocaine seeking may be drug specific.     

Phencyclidine-induced potentiation of brain stimulation reward: acute effects are not altered by repeated administration

Rats were given daily injections of bromocriptine (5.0 mg/kg IP) or vehicle either in the home cage or in a test box equipped with photocells to measure locomotion. The animals were then tested in the photocell boxes for their locomotor response to cocaine (10.0 mg/kg IP), heroin (0.5 mg/kg IP), or quinpirole (0.1 mg/kg IP). Repeated bromocriptine in the test box but not in the home cage caused progressive increases in sensitivity to the locomotor-stimulating effects of bromocriptine and increases in the subsequent sensitivity to quinpirole but caused only trivial signs of cross-sensitization to cocaine or heroin. Cross-sensitization to quinpirole was temporary; responsiveness to quinpirole decreased with further quinpirole injections. Lack of significant cross-sensitization between bromocriptine and either cocaine or heroin and lack of permanence of the cross-sensitization between bromocriptine and quinpirole raise questions as to the biological basis of psychomotor stimulant sensitization.     

Blockade of cocaine sensitization and tolerance by the co-administration of odansetron, a 5-HT3 receptor antagonist, and cocaine

The present experiment evaluated the ability of the 5-HT₃ antagonist, ondansetron, administered during chronic cocaine administration, to block the development of sensitization and tolerance induced by the intermittent or continuous administration of cocaine, respectively. Rats were pretreated with 40 mg/kg per day cocaine for 14 days by either SC injections or osmotic minipumps, or 0.9% saline, administered by SC injection. During this chronic (cocaine) treatment, all rats received a daily SC injection of 0–1.0 mg/kg ondansetron. The rats were then withdrawn from the pretreatment regimen for 7 days. On day 7 of withdrawal from the cocaine pretreatment all subjects received a 15.0 mg/kg IP cocaine challenge, and their behavior was then rated according to the modified Ellinwood and Balster scale for 60 min. The results indicated that daily injections of ondansetron had no consistent or significant effect on the subsequent behavioral response to cocaine in the saline control subjects. In contrast, daily injections of ondansetron with cocaine significantly blocked the development of sensitization with an inverted U-shape dose-response curve. In the continuous cocaine group ondansetron injections also attenuated the development of behavioral tolerance. The results therefore indicate that 5-HT₃ receptor stimulation during continuous and intermittent cocaine administration is an important link in the development of behavioral tolerance and sensitization. Received: 1 July 1996/Final version: 25 September 1996     

Scopolamine inhibits cocaine-conditioned but not unconditioned stimulant effects in mice

RATIONALE: In animal models, cocaine cues contribute to the development of conditioned responses to the psychomotor stimulating and rewarding effects of the drug. OBJECTIVES: In the present study we investigated the effect of scopolamine, known to impair learning and memory, on cocaine-induced conditioned and unconditioned responses in Swiss Webster mice. METHODS: In the first experiment, mice were treated with saline/saline, saline/cocaine (20 mg/kg), scopolamine (1.0 mg/kg)/cocaine, or scopolamine/saline for 5 days. The treatments were paired with the locomotor activity test cage twice, on days 1 and 5. This allowed to determine: (a) the induction and expression of place-dependent sensitization (PDS) to the psychomotor-stimulating effect of cocaine and (b) place-dependent hyperlocomotion (PDH; i.e., conditioning) as defined by the response to saline injection in the test cage. In the second experiment, all injections were delivered in animals' home cage in order to induce place-independent sensitization (PIS) to cocaine and to avoid the development of PDH. In the third experiment, the effect of scopolamine (1.0 mg/kg) on the acquisition of cocaine-induced conditioned place preference (CPP) was investigated. RESULTS: Data from the first experiment suggest that pretreatment with scopolamine had no specific effect on the induction and expression of cocaine-induced PIS. However, scopolamine blocked cocaine-induced PDH. Results from the second experiment confirmed that scopolamine had no effect on the induction of PIS to cocaine. Results from the third experiment showed that scopolamine completely blocked cocaine-induced CPP. CONCLUSIONS: The finding that scopolamine blocked the conditioned behaviors, PDH and CPP, that develop after exposure to cocaine supports the hypothesis that cocaine cue reactivity in the paradigms tested is associated with learning and memory.     

Behavioral and neurochemical components of nicotine sensitization following 15-day pretreatment: studies on contextual conditioning

The effects of contextual conditioning on the induction of nicotine sensitization of locomotor activity, stereotypy and nucleus accumbens dopamine release were studied using a 15-day pretreatment regimen. Six groups of Sprague-Dawley rats were employed to test for the effects of drug pretreatment, conditioning and novelty. Groups 1-4 were treated with daily nicotine (0.6 mg/kg, s.c.) or saline injections that were either paired with the test chamber or given in the home cage, followed by saline injections in the home cage. Group 5 received saline in the test chamber followed by nicotine in the home cage (unpaired). Group 6 was naive to handling and drug treatment. Pretreated animals were implanted with 2 mm microdialysis probes, via chronic guide cannulae, after completing the 15th day of treatment, and were tested for their response to nicotine (0.6 mg/kg, s.c) or saline on day 16. Naive animals were implanted with microdialysis probes and tested in a similar manner. Nicotine-stimulated locomotor activity was sensitized in the paired, unpaired and homecage pretreatment groups whereas nicotine-stimulated stereotypy was sensitized only in the paired pretreatment group. Nicotine-stimulated nucleus accumbens dopamine release was sensitized in the paired and unpaired pretreatment groups. Saline-stimulated nucleus accumbens dopamine release, but not locomotor activity or stereotypy, was also found in the nicotine-pretreated, paired group. These findings demonstrate the development of sensitization to nicotine-induced locomotor activity, stereotypy and nucleus accumbens dopamine release after a 15-day pretreatment regimen. Each of these responses to nicotine were differentially modulated by contextual conditioning. It is suggested that nicotine-stimulated dopamine release in sensitized animals represents the conditioned component of nicotine sensitization.     

Locomotor sensitization to quinpirole: environment-modulated increase in efficacy and context-dependent increase in potency

 This study examines whether behavioural sensitization to the dopamine agonist, quinpirole, reflects an increase in the drug’s potency and/or efficacy to induce locomotion, and how these parameters are influenced by environmental context. Three experiments were conducted in which animals received either chronic quinpirole (10×0.5 mg/kg, twice weekly) or saline injections in either the home cage environment, an alternate environment or the testing environment (activity monitors), followed by a dose-response test for the expression of sensitization in the activity monitors. Compared to the acute dose-response relationship, chronic quinpirole increased the maximum response. This increase in efficacy was significantly higher in animals treated with quinpirole in a non-home cage environment compared to those that received chronic treatment in the home cage. A leftward shift in the dose-effect function was observed only in animals with prior drug experience in the testing environment. Results indicate that locomotor sensitization to quinpirole reflects an environment-modulated increase in the drug’s efficacy, and an environment-dependent increase in drug potency. Efficacy and potency may be subject to sensitization by non-associational and associational mechanisms, respectively. Received: 11 April 1997 / Final version: 7 June 1997     

Persistence of one-trial cocaine-induced behavioral sensitization in young rats: regional differences in Fos immunoreactivity

Rationale  Unlike adult rats, young rats exhibit context-dependent and context-independent behavioral sensitization when assessed after a single pretreatment injection of cocaine. Objective  The purpose of this study was to determine whether: (1) the context-dependent and context-independent sensitization of young rats can be dissociated based on the persistence of the sensitized response and (2) the expression of behavioral sensitization is associated with region-specific increases in Fos immunoreactivity (Fos-IR). Materials and methods  On postnatal day (PD) 19, rats were injected with either saline or cocaine (30 mg/kg) in a novel test chamber or the home cage. After 1, 3, 5, 7, 14, or 61 abstinence days, rats were challenged with 20 mg/kg cocaine and locomotor activity was measured for 60 min. In a separate experiment, rats pretreated on PD 19 were challenged with cocaine (10–30 mg/kg) on PD 80. Results  The sensitized responding of young rats persisted for the same length of time (5 days) regardless of whether cocaine pretreatment occurred in a novel environment or the home cage. Behavioral sensitization did not reemerge in adulthood. When assessed after three abstinence days (i.e., on PD 22), acute treatment with cocaine increased Fos-IR in various brain regions, but sensitized responding was associated with elevated Fos expression in only the caudate–putamen (CP) and prefrontal cortex (PFC). Conclusions  Persistence of the sensitized response cannot be used to dissociate the one-trial context-dependent and context-independent sensitization of young rats. Fos data indicate that the CP and PFC may be involved in the mediation of short-term behavioral sensitization on PD 22.     

Locomotion,stereotypy, and dopamine D1 receptors after chronic "binge" cocaine in C57BL/6J and 129/J mice

We have shown that C57BL/6J and 129/J mice differ in their behavioral response to "binge" pattern cocaine (three daily injections of 15 mg/kg separated by 1 h). To determine if these differences persist during chronic binge cocaine administration, we examined the effects of 14-day binge pattern cocaine on home cage behavior. Since the dopamine D(1) receptor may be an important mediator of cocaine-induced locomotor activity, we examined binding to the dopamine D(1) receptor. Locomotor activity was increased by chronic binge cocaine in C57BL/6J (P<.0001) but not in 129/J mice. C57BL/6J mice developed tolerance to the locomotor-activating effects of cocaine. Stereotypic responses were greater in C57BL/6J than in 129/J mice (P=.03), with neither tolerance nor sensitization in either strain. Dopamine D(1) receptor binding in the nucleus accumbens and olfactory tubercle did not differ between strains and was not affected by chronic binge cocaine. In the caudate putamen, subregion specific strain differences in dopamine D(1) receptor binding were observed; chronic binge cocaine increased dopamine D(1) receptor binding in the caudal (P<.05), but not rostral caudate putamen. There was no correlation between locomotor activity or stereotypy and dopamine D(1) receptor density. Thus, with chronic binge cocaine administration, behavioral differences persist between the C57BL/6J and 129/J mice, and cocaine-induced locomotor activity is not correlated with changes in dopamine D(1) receptor binding.     

Blockade of the expression of sensitization and tolerance by ondansetron, a 5-HT3 receptor antagonist, administered during withdrawal from intermittent and continuous cocaine

 The present experiment evaluated the ability of the 5-HT₃ antagonist, ondansetron, administered during withdrawal from chronic cocaine administration, to block the expression of sensitization and tolerance induced by the intermittent or continuous administration of cocaine, respectively. Rats were pretreated with 40 mg/kg/per day cocaine for 14 days by either SC injections or osmotic minipumps, or 0.9% saline, administered via osmotic minipump. During the first 5 days of withdrawal from this pretreatment regimen, all rats received a daily SC injection of 0–1.0 mg/kg ondansetron. On day seven of with-drawal from the cocaine pretreatment (2 days after the final ondansetron injection) all subjects received a 15.0 mg/kg IP cocaine challenge. Their behavior was then rated according to the Ellinwood and Balster (1974) scale for 60 min. The results indicated that daily injections of ondansetron, on days 1–5 of withdrawal from the pretreatment regimen, had no significant effect on the subsequent behavioral response to cocaine in the saline control subjects. In contrast, daily injections of ondansetron, on days 1–5 of withdrawal from intermittent cocaine administration, significantly blocked the expression of sensitization. In the continuous cocaine group, ondansetron injections, on days 1–5 of withdrawal from continuous cocaine administration, also blocked the expression of behavioral tolerance. The results therefore indicate that changes in 5-HT₃ receptor function are associated with the expression of tolerance and sensitization, respectively. Received: 1 April 1997/Final version: 28 July 1997     

Mu-opioid receptors are not involved in acute cocaine-induced locomotor activity nor in development of cocaine-induced behavioral sensitization in mice.

Although mu-opioid receptors have been extensively investigated for their role in drug reinforcement, little is known about the contribution of these receptors to the acute and sensitized locomotor response to cocaine. In this study mu-opioid receptor involvement in acute cocaine-induced locomotor activity and in the development of cocaine-induced behavioral sensitization was evaluated using mu-opioid receptor knockout mice and chronic naltrexone (NTX) pretreatment as models. In addition, co-administration of the specific mu-opioid receptor antagonist CTOP with repeated saline or cocaine injections was used to establish the involvement of mu-opioid receptors in sensitization to the locomotor stimulant effects of cocaine. The acute locomotor response to cocaine (3, 10, 20, or 30 mg/kg i.p.) of mu-opioid receptor knockout or chronic NTX pretreated mice was not different from the cocaine response of their respective controls. With respect to cocaine-induced behavioral sensitization, induced by daily injections of 20 mg/kg cocaine for 11 subsequent days, mu-opioid receptor knockout mice developed behavioral sensitization to the locomotor stimulant effects of cocaine (challenge 10 mg/kg i.p.) comparable to wild-type littermates and the mu-opioid receptor antagonist CTOP did not affect cocaine-induced sensitization either. However, mice that were pretreated with NTX exhibited augmented cocaine-induced behavioral sensitization relative to placebo pretreated controls, which may be ascribed to increased delta-opioid receptor levels as has been described for chronic NTX pretreated mice. The present findings suggest that mu-opioid receptors are not required for the acute locomotor response to cocaine nor are they essential for the development of cocaine-induced behavioral sensitization.     

Context-specific enhancement of glutamate transmission by cocaine.

The repeated injection of cocaine causes an increase in the capacity of a subsequent acute injection to elevate extracellular glutamate levels in the nucleus accumbens, and the present study sought to determine if the elevation in extracellular glutamate is regulated by the pairing of environmental stimuli with drug administration. Three treatment groups were injected daily for seven days with saline or cocaine (15 mg/kg, ip); 1) injection of saline in the home cage, 2) injection of cocaine in the home cage (cocaine-unpaired), and 3) injection of cocaine in the test apparatus (cocaine-paired). Three weeks following the last daily injection dialysis probes were placed into the nucleus accumbens and all rats were injected with saline followed by cocaine. Basal levels of extracellular glutamate were significantly reduced in the cocaine-paired treatment group. Moreover, only in the cocaine-paired group did the cocaine injection elevate extracellular glutamate. Repeated administration of cocaine also produces an enduring increase in the motor stimulant response to an acute cocaine injection and it was previously found that administration of the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid and kainic acid glutamate receptor antagonist 6-cyano-7-nitroquinoxaline-2, 3-dione inhibited the sensitized, but not the acute motor, response to cocaine. In this study it was found that the motor stimulant response elicited by cocaine was blunted by pretreatment of the nucleus accumbens with 6-cyano-7-nitroquinoxaline-2,3-dione only in animals receiving daily cocaine injections in the paired environment. In contrast, the N-methyl-D-aspartate glutamate receptor antagonist R-(-)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid did not significantly affect cocaine-induced motor activity in any treatment group. These data support a hypothesis that environmental stimuli previously associated with daily cocaine administration can modulate glutamate transmission in the nucleus accumbens in a manner affecting cocaine-induced behavior.     

Injections of baclofen into the ventral medial prefrontal cortex block the initiation,but not the expression,of cocaine sensitization in rats

Rationale Increased excitatory output from the medial prefrontal cortex (mPFC) is thought to play a key role in the development of sensitization to cocaine. Gamma-aminobutyric acid (GABA) inhibits this excitatory output.Objectives The present studies were designed to determine the effects of intra-mPFC injections of the GABA_B agonist baclofen on cocaine-induced motor activity and on the development of sensitization to cocaine.Methods Rats received bilateral cannula implants above the ventral mPFC. Initial studies examined the dose–response effects of injection of baclofen (0.05–0.5 nmol/side) into the mPFC on the acute motor-stimulant response to cocaine (15 mg/kg, i.p.). Additional studies determined whether coadministration of intra-mPFC baclofen (0.5 nmol/side) and systemic cocaine (15 mg/kg, i.p.) could alter the initiation and/or expression of cocaine-induced behavioral sensitization.Results Intra-mPFC baclofen dose-dependently blocked cocaine-induced motor activity. In sensitization studies, intra-mPFC baclofen was able to prevent the initiation, but not the expression of cocaine-induced sensitization.Conclusions The data suggest that the ability of GABA to modulate excitatory output from the mPFC may be attenuated in animals sensitized to cocaine.     

Resistance of neuronal nitric oxide synthase-deficient mice to cocaine-induced locomotor sensitization

 In brain, nitric oxide (NO) is considered as a retrograde messenger involved in synaptic plasticity. The present study was undertaken to investigate whether mice lacking the neuronal nitric oxide synthase (nNOS) gene are protected from cocaine-induced behavioral sensitization. Mice were administered, IP, either saline or cocaine (15 mg/kg) for 5 days. Sensitization was determined as an increase in cocaine-induced locomotor activity on day 5 compared with day 1 and an amplified response of cocaine-experienced mice to a challenge cocaine injection given after a 10-day drug free period (e.g., on day 15). To investigate the development of a context-dependent locomotion (conditioning), the responses of cocaine- and saline-experienced mice to a saline injection were determined on day 17. Male homozygote nNOS(–/–) mice were sensitive to the acute effect of cocaine (15 mg/kg) on day 1; however, they developed neither a sensitized response to cocaine (on day 5 and 15) nor a conditioned locomotion. Female homozygote nNOS(–/–) mice neither were responsive to 15 mg/kg cocaine on day 1, 5 and 15, nor did they develop a conditioned locomotion. In contrast, the same cocaine regimen delivered to male and female heterozygote nNOS(+/–) mice, and wild type mice (B6 J/sv129, C57BL/6 and sv129) resulted in sensitization to cocaine-induced locomotor activity and context-dependent locomotion. Investigation of [³H]cocaine disposition in the striatum and frontal cortex of the mice revealed neither gender nor strain differences in the drug disposition. Also, no major difference in striatal dopaminergic markers between homozygote nNOS(–/–) and wild type mice was observed. The most significant distinction, however, was the finding that nNOS(–/–) mice are completely deficient in striatal nNOS binding sites. Taken together, our results suggest that the resistance of homozygote nNOS(–/–) mice to cocaine-induced behavioral sensitization is primarily due to the deletion of the nNOS gene. Considering the role of NO in synaptic plasticity, it is conceivable that reduced brain NOS activity blunts the processes that underlie the development of sensitization to cocaine. Received: 18 March 1998 / Final version: 9 May 1998     

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     

Ontogeny of methamphetamine-induced and cocaine-induced one-trial behavioral sensitization in preweanling and adolescent rats

The ontogenetic profile of psychostimulant-induced one-trial behavioral sensitization has not been determined. The purpose of this study was to systematically assess the ontogeny of methamphetamine-induced and cocaine-induced behavioral sensitization across the preweanling and adolescent periods. To this end, rats were injected with methamphetamine, cocaine, or saline in either an activity chamber or home cage during the preweanling [postnatal day (PD) 12, PD 16, or PD 20], preadolescent (PD 24), or adolescent (PD 34) periods. One day later, rats were challenged with the same psychostimulant and locomotion was measured in an activity chamber. The results showed that methamphetamine produced one-trial locomotor sensitization on PD 13 and PD 17; whereas, cocaine-induced behavioral sensitization was only evident on PD 21. The sensitized responding of preweanling rats was not influenced by environmental context. Interestingly, preadolescent and adolescent rats did not exhibit locomotor sensitization. The latter result is generally consistent with past studies showing that rats from the middle and late adolescent periods do not exhibit cocaine-induced one-trial behavioral sensitization. The present results show that methamphetamine, as well as cocaine, can produce one-trial context-independent behavioral sensitization during early ontogeny, but sensitized responding is only apparent within a narrow developmental window.