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.     

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.     

Importance of environmental context for one- and three-trial cocaine-induced behavioral sensitization in preweanling rats

Rationale

Preweanling rats, unlike adults, exhibit context-independent behavioral sensitization after a single pretreatment injection of cocaine.

Objective

The purpose of this study was to examine environmental factors modulating one- and three-trial sensitization in preweanling rats.

Methods

For preweanling rats, drug pretreatments occurred on postnatal day (PD) 17–PD 19 (experiment 1) or PD 19 (experiment 2). One set of rats was injected with cocaine (30 mg/kg) and placed in anesthesia (“small”), operant conditioning (“large”), or activity chambers for 30 min. Rats were returned to the home cage and injected with saline. Additional groups of rats were injected with saline and placed in small, large, or activity chambers for 30 min and then injected with cocaine after being returned to the home cage. Control groups were injected with saline at both time points. In separate experiments, rats were pretreated with cocaine or saline and restricted to the home cage. On PD 20, all rats were injected with cocaine (20 mg/kg) and placed in activity chambers where locomotor activity was assessed for 60 min. For comparison purposes, sensitization was also assessed in adult rats.

Results

Adult male and female rats exhibited only context-dependent sensitization, whereas preweanling rats showed context-independent sensitization in a variety of conditions (e.g., when pretreated with cocaine in various novel chambers or the home cage).

Conclusions

These results suggest that nonassociative mechanisms underlying behavioral sensitization are functionally mature in preweanling rats, but associative processes modulating the strength of the sensitized response do not function in an adult-like manner during the preweanling period.     

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.     

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.     

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.     

Kappa opioid-mediated behavioral sensitization in the preweanling rat: relationship to Fos immunoreactivity

 When given acutely, drugs that stimulate kappa opioid receptors (e.g., U-50,488) enhance the locomotor activity of preweanling rats and induce regional increases in Fos immunoreactivity (IR). In contrast, the effects of chronic treatment with kappa opioid agonists are unknown. The purpose of the present study was two-fold: first, to determine whether repeated treatment with a kappa opioid agonist would sensitize the locomotor activity of preweanling rats and, second, to determine whether changes in Fos IR correspond with the occurrence of locomotor sensitization. To test these hypotheses, rats were injected with U-50,488 (5 mg/kg, SC) or saline on either postnatal days (PD) 5–9 or PD 11–15. For rats pretreated on PD 5–9, a test day injection of U-50,488 or saline was given after either 1 or 7 abstinence days (i.e., at PD 11 or PD 17). For rats pretreated on PD 11–15, a test day injection of U-50,488 or saline was given after 1 abstinence day (i.e., at PD 17). In two additional experiments, the acute and chronic effects of U-50,488 treatment were assessed in adult rats. As expected, repeated treatment with U-50,488 produced locomotor sensitization at both PD 11 and PD 17, but only when the test day occurred 1, and not 7, days after cessation of drug pretreatment. Thus, the persistence of the sensitized response was very brief. Test day treatment with U-50,488 stimulated Fos IR in various brain regions of the preweanling rat, including the medial striatum, nucleus accumbens, lateral habenula, and septal area. Chronic treatment with U-50,488 depressed Fos expression in a number of brain regions (relative to acutely treated rats); however, these changes in Fos IR did not necessarily coincide with the occurrence of behavioral sensitization. Repeated treatment with U-50,488 did not produce locomotor sensitization in adult rats, so Fos IR was not assessed in this age group. Therefore, while acute treatment with U-50,488 both increased locomotor activity and stimulated Fos IR in preweanling rats, chronic U-50,488 treatment produced behavioral changes that did not correspond with Fos expression. Received: 6 August 1997 / Final version: 25 November 1997     

Higher locomotor response to cocaine in female (vs. male) rats selectively bred for high (HiS) and low (LoS) saccharin intake

Rats selectively bred for high saccharin consumption (HiS) self-administer more oral ethanol and i.v. cocaine than those selectively bred for low saccharin consumption (LoS). Male and female drug-seeking-prone (HiS) and -resistant (LoS) rats were used in the present experiment to test the prediction that cocaine-induced locomotor activity and sensitization varied with sex and their selective breeding status (HiS and LoS). All rats were intermittently exposed over 2 weeks to pairs of sequential saline and cocaine injections, separated by 45 min. The first 5 pairs of injections, each separated by 2-3 days (10-12 days total), were given to examine the development of cocaine-induced locomotor activity and the development of locomotor sensitization, which was determined by comparing the effects of cocaine injection 1 with injection 6 (given 2 weeks after the 5 pairs of intermittent injections). Results indicated that after the first injection pair (saline, cocaine) the HiS and LoS groups did not differ (saline vs. cocaine) in locomotor activity; however, after cocaine injection pairs 1, 5, and 6, HiS females were more active than HiS males and LoS females. There were also significant phenotype differences (HiS>LoS) in locomotor activity after cocaine injections 5 and 6. There was a weak sensitization effect in cocaine-induced locomotor activity in HiS females after cocaine injection 5 (compared to 1); however it was not present after injection 6 or in other groups. The lack of a strong sensitization effect under these temporal and dose conditions was inconsistent with previous reports. However, the results showing HiS>LoS and females>males on cocaine-induced activity measures are consistent with several measures of cocaine-seeking behavior (acquisition, maintenance, escalation, extinction, and reinstatement), and they suggest that cocaine-induced locomotor activity and sensitization are behavioral markers of drug-seeking phenotypes.     

Effects of environmental conditioning on the development of nicotine sensitization: behavioral and neurochemical analysis

We have investigated the effects of environmental conditioning on the induction of nicotine sensitization of locomotion, stereotypy and nucleus accumbens dopamine release. Sprague-Dawley rats, some of which had been previously implanted with a microdialysis guide cannula over the nucleus accumbens, were sensitized with 5 days of repeated nicotine (0.6 mg/kg per day, SC) or saline injections (1 ml/kg per day). During nicotine treatment the drug administration was either paired with the microdialysis/activity monitor testing chamber (conditioned) (n=6) or with the animal's home cage (unconditioned) (n=6) and after 60 min the animal was returned to home cage and received a second injection of saline 15 min later. A third group received saline in the testing apparatus followed by nicotine in the home cage (pseudo-conditioned) (n=6). In the guide cannulated animals, 2 mm microdialysis probes were inserted after completing day 5 of treatment and all animals were tested for their response to nicotine (0.6 mg/kg, SC) on day 6. Both locomotor activity and nucleus accumbens dopamine release showed a larger response subsequent to nicotine challenge in the nicotine versus saline pretreated animals in the conditioned group, but not in the unconditioned group. In the pseudo-conditioned group there was an increase in the stereotypy responses to nicotine, however the locomotor and dopamine release responses were not significantly enhanced. The results from the conditioned group were confirmed in animals which were tested for behavioral activation and dopamine release simultaneously (n=5). These findings indicate that nicotine sensitization of locomotor activity and nucleus accumbens dopamine release (using a 5-day pretreatment protocol) is dependent on conditioning the animal to the testing environment during nicotine pretreatment.     

Context-independent sensitization to the locomotor-activating effects of cocaine.

After repeated intermittent exposure to psychostimulants, an increase in the behavioral response to the drug is observed. The development of this sensitized response is greatly influenced by environmental cues. For example, when the pretreatments are administered in an environment distinct from the test, a sensitized response is often not observed. This finding has led some investigators to suggest that sensitization is completely context dependent. The present experiment established context-independent sensitization by administering pretreatments in an environment distinct from the test and measured the effects of pretreatment on potency and/or efficacy of subsequent cocaine administrations. Separate groups of rats received single or multiple daily injections of cocaine (10.0 mg/kg) or the saline vehicle in the home cage during a 5-day pretreatment phase. Ninety-six hours following the last of the pretreatment injections the locomotor-activating effects of cocaine (0.0, 5.0, 10.0, or 20.0 mg/kg) were measured. For control rats, a significant increase in motor activity was obtained following administration of the 20.0 mg/kg dose. Rats that received the cocaine pre-treatment became sensitized to cocaine's motor activating effects. For these rats, cocaine pretreatment produced a leftward shift in the dose-effect curve, consistent with an increased potency. The maximum locomotor response was not altered by pretreatment, suggesting that drug efficacy was not effected by preexposure. Thus, context-independent sensitization to cocaine reflects an increased potency, but not efficacy, of the drug.     

Time-dependent effects of repeated cocaine administration on dopamine transmission in the medial prefrontal cortex

The medial prefrontal cortex (mPFC) has been implicated in the development of behavioral sensitization, which is the progressive enhancement of locomotor activity that occurs with repeated administration of psychostimulants. Previous data suggest that mPFC dopamine (DA) transmission may be attenuated in cocaine-sensitized animals, but the onset and duration of this effect have not been investigated. After recovery from stereotaxic surgeries, animals were given four daily injections of saline (1 ml/kg, i.p.) or cocaine (15 mg/kg, i.p.) and were subsequently challenged with saline or cocaine after 1, 7 or 30 d of withdrawal, on which days in vivo microdialysis of the mPFC was conducted simultaneously with monitoring of locomotor activity. Compared to acutely administered controls, the results in cocaine-pretreated animals were as follows: 1d of withdrawal was associated with a significant attenuation in cocaine-induced locomotion and mPFC DA overflow; after 7d, behavioral sensitization was accompanied by a significant attenuation in cocaine-induced elevations in mPFC DA levels; 30 d of withdrawal led to the expression of sensitized behaviors paralleled by an augmentation in cocaine-induced mPFC DA. These data suggest that repeated cocaine produces temporally distinct behavioral effects associated with alterations in mPFC DA responsiveness to cocaine that may be involved in the development of behavioral sensitization.     

Evidence of cross-tolerance between behavioural effects of nicotine and cocaine in mice

Rationale. Studies have reported that chronic exposure to nicotine does not alter the effects of cocaine on locomotor activity, and vice versa. However, the apparent lack of effect of one drug on the behavioural response to the other may be due to an exclusive focus on locomotor activity as the target behaviour. Objective. To test whether repeated pretreatment with nicotine causes tolerance or sensitization to cocaine's effects on diverse behaviours: locomotion, rearing, grooming, and immobility. Similarly, the effects of repeated cocaine treatment on the acute response to nicotine were also tested. Methods. Mice were pretreated with 14 injections of nicotine (0.3 mg/kg), cocaine (5 mg/kg) or saline, the injections being given once daily, except for three breaks of two days each. Two days after the final pretreatment injection, mice were given a challenge injection of saline, cocaine (3 or 5 mg/kg) or nicotine (0.3 or 1 mg/kg), and observed in a large test cage for 40 min using a time-sampling procedure. Results. Repeated administration of either drug produced some tolerance to subsequent challenge with the same dose of the drug. Prior nicotine exposure significantly attenuated cocaine-induced decreases in grooming and increases in rearing, but did not significantly affect other behaviours. In contrast, prior cocaine exposure failed to alter nicotine's effects on any behaviour. Conclusions. Cross-tolerance between nicotine and cocaine (but not vice-versa) can be demonstrated if several behaviours are observed; measures of locomotor activity are less sensitive to the effect. The asymmetrical pattern of cross-tolerance may be due to differential inhibition of dopamine uptake by the two drugs. Electronic Publication     

Evidence for behavioral sensitization to cocaine in preweanling rat pups

While chronic intermittent administration of stimulants often induces behavioral sensitization in adulthood, stimulant sensitization has rarely been reported prior to weaning [around postnatal day (P) 21]. Consistent pairing of drug administration with the test context often facilitates sensitization in adults, yet young animals have been typically returned to the home cage immediately post-injection. To determine whether promoting context-dependent sensitization might facilitate expression of sensitization in preweanlings, Sprague-Dawley rats were injected daily from P14 to P20 with 0, 5, 15, or 30 mg/kg cocaine HC1 and placed for 30 min in either the experimental chamber or home cage. On P21 (test day), subjects were challenged with either 15 mg/kg cocaine or saline prior to placement in the experimental chamber. Significant sensitization of cocaine-induced stereotyped head movements was evident in animals given 15 or 30 mg/kg chronically in the experimental chamber, but not when these same doses were given in the home cage. Less consistent evidence for cocaine-induced sensitization was seen when examining locomotion, although trends for sensitization of this behavior were seen in animals chronically injected in either the test chamber or home cage. Thus, preweanlings can exhibit cocaine sensitization, particularly in terms of stereotypy, when tested shortly after the chronic exposure period, with expression of this sensitization being facilitated by pairing the chronic injections with the test context. Received: 19 November 1996/Final version: 10 December 1997     

Effects of dizocilpine [(+)-MK-801] on the expression of associative and non-associative sensitization to <Emphasis Type="SmallCaps">d</Emphasis>-amphetamine

Blockade of glutamate receptors of the NMDA type inhibits the sensitization to psychostimulant drugs, such as amphetamine, that occurs after repeated administration. Both associative (conditioning) and non-associative (pseudo-conditioning) mechanisms may contribute to sensitization phenomena. The aim of the present study was, thus, to determine which type of sensitization is influenced by blockade of NMDA-type receptors by examining the expression (manifestation) of sensitization. Locomotor activity was assessed and, in some experiments, extracellular dopamine in the nucleus accumbens was also assessed using in vivo microdialysis in non-anaesthetized, almost freely moving rats. Male albino Wistar rats of 225–250 g were given 1 mg/kg i.p. d-amphetamine every 2nd day for 7 days and with saline on the other days. Half the rats were exposed to d-amphetamine in the presence of conditioning stimuli (test cage, auditory and olfactory stimulus) and to saline in the home cage in absence of these stimuli, the other half were treated with saline and exposed to the conditioning stimuli and were placed into their home cages (without conditioning stimuli) after treatment with d-amphetamine. Ten days after the end of this treatment, both groups were exposed to the conditioning stimuli and half of each group were pretreated with dizocilpine [(+)-MK-801, 0.1 mg/kg i.p.], a blocker of NMDA receptors, 30 min before administration of 1 mg/kg d-amphetamine.(+)-MK-801 reduced the locomotor activity in rats sensitized associatively, but not in those sensitized non-associatively. It had no significant effect on spontaneous locomotor activity or that induced by acute administration of 1 mg/kg d-amphetamine. Similarly, (+)-MK-801 inhibited the increase in extracellular dopamine in the nucleus accumbens induced by the test dose of d-amphetamine in rats sensitized associatively but not non-associatively. The results suggest that the expression of both types of sensitization to d-amphetamine are dependent on glutamatergic NMDA mechanisms, although in different ways. Inhibition of sensitization, in particular of the associative type, might be of therapeutic value in drug dependence.     

Home cage observations following acute and repeated IV cocaine in intact and gonadectomized rats

The purpose of the present experiment was to examine the effects of acute and repeated intravenous (IV) cocaine on rat behavior in the home cage environment. An observational sampling method was used. Pair-housed, male, female, castrated (CAST), and ovariectomized (OVX) rats were administered daily IV cocaine injections (3.0 mg/kg/injection) in the home cage for 13 consecutive days, and observations occurred after the 1st and 13th injections. The incidence, i.e., occurrence or nonoccurrence of a behavior, was recorded according to a behavioral profile comprised of 11 behaviors. Data were analyzed as locomotor composite and orofacial composite scores. Behaviors not amenable for combination into a composite incidence score were evaluated independently (e.g., still behavior). Females exhibited more locomotor incidence scores than males following acute injection and more still behavior after repeated cocaine administration. Females exhibited more locomotor activity than OVX rats following acute, but not repeated, cocaine injection. There were no differences between the male and CAST rats on days 1 or 13. CAST rats exhibited more still behavior than OVX following only acute cocaine administration. This study indicates that IV cocaine-induced sex differences and the effects of gonadectomy can be measured in the home cage, and furthermore, describes a simple method to screen changes in cocaine-induced locomotor behaviors in the absence of automated equipment.     

Cocaine sensitization in the mouse using a cumulative dosing regime

Many rodent models of cocaine sensitization use intermittent high doses of cocaine pretreatment followed by testing with a single moderate cocaine dose. The aim of the present study was to investigate the rate and extent of sensitization to the locomotor-stimulant effects of cocaine using multiple cocaine doses (5-40 mg/kg). Eight groups of male Swiss-Webster mice were pretreated with either single doses of cocaine (40 mg/kg) or saline in the home cage, or multiple doses in the test environment, for 4 days. On the fifth day they were tested for locomotor activity, following a single dose of saline and cumulative doses of cocaine (5-40 mg/kg at 10-minute intervals). All eight groups of mice developed context-dependent sensitization to the locomotor stimulant effects of cocaine. Subsequent testing, at 10-day intervals, revealed that sensitization was maximal after five test sessions of cumulative cocaine dosing, regardless of the pretreatment regime. The main determinant of the rate at which sensitization occurred was the frequency of cumulative cocaine dosing. However, both the potency and efficacy of cocaine were altered by different pretreatments associated with exposure to the locomotor activity chambers. This robust context-dependent sensitization was long lasting, and not abolished by a 5-day extinction procedure involving cumulative saline dosing in the locomotor activity chambers. In conclusion, cumulative dosing and its inherent handling, in combination with cocaine, induced marked sensitization not produced by cocaine alone.     

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.     

Stress-induced cross-sensitization to cocaine: effect of adrenalectomy and corticosterone after short- and long-term withdrawal

 We have recently shown that adrenalectomy (ADX) in rats blocks the appearance of cocaine-induced sensitization when this behavioral response is tested at early withdrawal times (1–2 days), but not after later withdrawal from cocaine (12 days). To determine if a similar phenomenon occurred with stress-induced sensitization, male Sprague-Dawley rats were given a sham ADX, ADX surgery, or ADX plus SC implanted corticosterone (CORT) pellets (CORT 12.5% pellets or CORT 50% pellets). A fifth group was given ADX surgery, but CORT 50% pellets were implanted after repeated stress treatment. One week after surgery, each group was divided into two additional groups, naive and stress. Naive animals remained unhandled, while stress rats were given a variety of daily stressors administered twice per day for 6 consecutive days. One day after the last stress, rats were given a saline injection followed by a cocaine injection (15 mg/kg, IP) the next day, and locomotor activity was monitored (early withdrawal). Two weeks after the last stress, the locomotor responses to an additional saline and cocaine injection were monitored (late withdrawal). At early withdrawal, no significant sensitization occurred for horizontal activity, but cross-sensitization was demonstrated for vertical activity. At late withdrawal, sham controls showed a stress-induced elevation in horizontal activity, with only a trend toward increased vertical activity. Animals given ADX surgery or ADX and CORT 12.5% pellets did not demonstrate sensitization to repeated stress, while CORT 50% pellets in ADX rats restored the sensitized horizontal response to cocaine challenge at late withdrawal. In contrast, stress-pretreated rats which were given CORT 50% pellets during the 2-week withdrawal period after the stress showed a marked decrease in horizontal activity in response to cocaine challenge at late withdrawal. The results provide evidence for a necessary role for adrenal hormones in long term, but not short-term, stress-induced cross-sensitization. Together with our previous study on the role of CORT in cocaine-induced sensitization, the results indicate that CORT is not the common factor mediating the long-term sensitization to cocaine and stress. Received: 10 April 1997 / Final version: 19 August 1997     

Intra-accumbal Tat1–72 alters acute and sensitized responses to cocaine

The effects of Tat, an HIV-1 protein, on intravenous cocaine-induced locomotor activity were examined in ovariectomized rats. Animals were habituated to activity chambers, administered an IV baseline/saline injection, and 24 h later, received bilateral, intra-accumbal microinjections of Tat_1–72 (15 µg/µl) or vehicle. Twenty four hours later, rats received the first of 14 daily IV cocaine injections (3.0 mg/kg/inj, 1 /day) or saline. Locomotor activity was measured in automated chambers for 30 min following baseline and after the 1st and 14th cocaine injections. Observational time sampling following cocaine was also performed. Following acute cocaine/saline, Tat significantly increased cocaine-induced total activity over the 30-min session, with no significant effects for activity in the central compartment. Repeated cocaine injections produced behavioral sensitization with ∼ 2-fold higher levels of total activity, ∼ 3-fold higher levels of centrally directed activity, and increased locomotor scores via direct observations. Following repeated cocaine/saline, Tat altered the development of cocaine-induced behavioral sensitization for total activity with prior Tat exposure attenuating the development of cocaine-induced sensitization. Collectively, these data show that bilateral microinjection of Tat into the N Acc alters IV cocaine-induced behavior, suggesting that Tat produces behavioral changes by disrupting the mesocorticolimbic pathway.