Sensitization to daily morphine injections in rats with unilateral lesions of the substantia nigra.

Morphine indirectly enhances dopaminergic activity in the nigrostriatal system, and repeated administration of morphine progressively increases the locomotor activity of rats. We used the rotational behavior model to determine if daily morphine produces an increase in turning and produces cross-sensitization to d-amphetamine and cocaine. Rats with unilateral nigrostriatal lesions received daily injections of saline or morphine (10 mg/kg). Repeated morphine administration produced a progressive increase in turning over 13 days. Next, a morphine dose-response curve (1.0-30 mg/kg) was determined. Both the saline and morphine-treated groups showed dose-dependent increases in turning, but, the peak effect in the morphine group was higher than that in the saline group, indicating sensitization to morphine. The morphine-treated group did not show cross-sensitization to either d-amphetamine (0.1-3 mg/kg) or cocaine (1.0-30 mg/kg); in fact, it showed less cocaine-induced turning than the saline group. Seventy-one days after saline or morphine injections began, the morphine group was still significantly more sensitive to turning induced by 10 mg/kg morphine than the saline group was (200 vs. 750). Therefore, repeated daily injections of morphine produce a progressive sensitization to turning induced by morphine in the absence of cross-sensitization to turning induced by psychomotor stimulants.     

皮质酮对吗啡条件性位置偏爱及条件性精神运动获得的影响

目的 :研究皮质酮作用下吗啡条件性位置偏爱 (CPP)及条件性精神运动的变化趋势及其可能机制 ,为探讨应激、环境线索诱发复吸的机制提供基础。方法 :32只♂SD大鼠分成 4组。训练 2d ,1次药物匹配训练 (吗啡 2mg·kg- 1 ,皮质酮 5mg·kg- 1 ,ip ,提前 2 0min注射 ) ,1次生理盐水训练。观察训练前后大鼠在伴药侧停留的时间 ,急性给药后的运动及条件性精神运动的变化。结果 :(1)吗啡组训练后在伴药侧停留的时间显著长于对照组 (P <0 0 1) ,皮质酮吗啡组、皮质酮组与对照组比较差异无显著性 (P >0 0 5 ) ;(2 )在 5 0、6 0min时皮质酮吗啡组的急性精神运动显著大于吗啡组和对照组 (P <0 0 1) ;(3)皮质酮吗啡组大鼠的条件性精神运动显著大于对照组、吗啡组 (P <0 0 1,P <0 0 5 )。结论 :5mg·kg- 1 的皮质酮显著抑制吗啡CPP的获得 ,但促进吗啡条件性精神运动的获得以及急性精神运动。CPP与条件性精神运动获得的机制可能存在差异     

Sex differences in locomotor activity after acute and chronic cocaine administration.

Adult, intact and gonadectomized male and female Wistar rats (n = 9) were exposed to an automated open field to assess the behavioral effects of acute cocaine administration (saline, 1.0 and 10.0 mg/kg subcutaneous). The subjects were exposed to the open field for 10 min, removed to be injected and returned to the open field for another 30 min. Three saline and two drug sessions were run in counterbalanced order. Locomotor activity in intact and castrated male rats and ovariectomized female rats decreased following injection, irrespective of the dose of cocaine. The locomotor activity of intact female rats was higher than that of any other group of subjects. It decreased during the session after saline and 1.0 mg/kg cocaine, but increased towards the end of the 30 min session after 10.0 mg/kg. Rearing measures paralleled the observations on locomotor activity. To determine the effects of chronic, home-cage, cocaine administration, five of the subjects in each group were injected with 10.0 mg/kg cocaine for 9 consecutive days. The remaining four subjects received saline injections. On day 10, all subjects were re-exposed to the open-field for 10 min, removed, injected with 10.0 mg/kg cocaine and returned to the open field for another 30 min. Chronic home cage cocaine administration produced an increase in cocaine's effects on locomotor activity and rearing in intact female rats only. However, behavioral sensitization was also observed in intact female rats who had been treated with saline for 9 consecutive days, suggesting that behavioral sensitization to cocaine in intact female rats may develop very rapidly and independent of environmental context.     

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     

Effects of serotonin (5-HT)6 receptor ligands on responding for cocaine reward and seeking in rats

The endogenous brain serotonin (5-HT) system is believed to have an important modulatory influence in mediating drug reward and seeking mechanisms. Data from preclinical behavioral studies have provided emerging evidence that 5-HT(6) receptors, among other 5-HT receptors, may play a significant role in the mechanisms of action of psychostimulant addicted drugs. The aim of the present study was to investigate whether the selective pharmacological blockade or activation of 5-HT(6) receptors altered the maintenance of cocaine self-administration, reinstatement of cocaine-seeking behavior following an extinction of cocaine self-administration or cocaine-evoked conditioned place preference in rats. We also evaluated the effects of 5-chloro-N-(4-methoxy-3-piperazin-1-ylphenyl)-3-methyl)-2-benzothiophene-sulfonamide (SB 271046, a 5-HT(6) receptor antagonist) or N-1-(6-chloroimidazo-[2,1-b]-[1,3]thiazole-5-sulfonyl)tryptamine (WAY 181187, a potent 5-HT(6) receptor agonist) on locomotor activity in rats. Our results indicate that SB 271046 (1-10 mg/kg) altered cocaine-maintained self-administration as well as cocaine-evoked reinstatement of cocaine seeking and expression of cocaine place preference in rats.We also demonstrate that pharmacological stimulation of 5-HT(6) receptors by WAY 181187 (3-30 mg/kg) attenuated the expression of cocaine conditioned place preference but not cocaine self-administration and reinstatement of cocaine seeking. WAY 181187 at the highest dose used (30 mg/kg) reduced basal locomotor activity. Despite current results, the precise function and therapeutic relevance of 5-HT(6) receptors need further clarification.     

Sex differences in cocaine-induced behavioral responses, pharmacokinetics, and monoamine levels

Female rats display a more robust behavioral response to acute cocaine administration than do male rats. However, a clear understanding of the biological mechanisms underlying these differences remains elusive. The present study investigated whether sexual dimorphisms in cocaine-induced motor behavior might be based on monoaminergic levels and/or cocaine pharmacokinetics. An acute injection of cocaine (5, 15, 20 or 30 mg/kg) or saline was administered to male and female rats, and behavioral activity was monitored for 3 h. Following acute cocaine or saline administration motor behavior varied according to dose and sex; overall, female rats displayed greater rearing counts and stereotypic scores, greater total locomotor counts at 15, 20, and 30 mg/kg of cocaine, and greater ambulatory counts at 20 and 30 mg/kg of cocaine than did male rats. Neurochemical determinations in post-mortem tissue showed that both male and female rats had increases in total dopamine (DA) in the caudate putamen (CPu) 15 min following cocaine administration. Additionally, male rats had a decrease in dihydroxyphenylacetic acid (DOPAC)/DA turnover. Female rats showed significant reductions in total levels of DA, DOPAC, HVA, serotonin (5-HT), 5-hydroxyindole acetic acid (5-HIAA), and DOPAC/DA turnover in the nucleus accumbens (NAc). Male rats displayed a reduction only in DOPAC/DA turnover and increases in 5-HT in the NAc following cocaine administration. Furthermore, sex differences in cocaine metabolism were observed where females had greater brain/blood levels of norcocaine and ecgonine methyl ester while male rats had higher blood levels of benzoylecgonine. These results suggest that sex differences in the behavioral responses to cocaine administration could be explained in part by intrinsic differences in both monoaminergic levels and metabolic processes.     

Effect of the mGluR5 antagonist 6-methyl-2-(phenylethynyl)pyridine (MPEP) on the acute locomotor stimulant properties of cocaine, <Emphasis Type="SmallCaps">d</Emphasis>-amphetamine,and the dopamine reuptake inhibitor GBR12909 in mice

Rationale Recent evidence suggests that, in addition to ascending monoaminergic systems, glutamate systems also play a role in psychostimulant-induced locomotor activity. The present study was conducted to examine the effects of the selective type-5 metabotropic glutamate receptor (mGluR5) antagonist 6-methyl-2-(phenylethynyl)pyridine (MPEP) on the acute locomotor stimulant effects of cocaine, d-amphetamine, and the dopamine reuptake inhibitor GBR12909.Methods Male DBA/2J mice were treated with saline or MPEP (1, 5, 20 or 30 mg/kg i.p.) 10 min prior to the administration of cocaine (15 mg/kg or 30 mg/kg i.p.), d-amphetamine (3 mg/kg or 5 mg/kg i.p.) or GBR12909 (10 mg/kg or 20 mg/kg i.p.). Locomotor activity was then monitored in an open-field environment for 30 min. The effects of MPEP alone (1, 5, 20 and 30 mg/kg i.p.) on locomotor activity were also examined.Results MPEP dose dependently inhibited the acute locomotor stimulant effects of cocaine, d-amphetamine, and the 10-mg/kg dose of GBR12909. However, MPEP had no effect on the locomotor stimulant effects of the higher (20 mg/kg) dose of GBR12909. When tested alone, MPEP increased locomotor activity at doses of 5 mg/kg and 20 mg/kg.Conclusions Our data suggest that mGluR5 receptors not only mediate spontaneous locomotor activity in DBA/2J mice but also the acute locomotor stimulant effects of cocaine, d-amphetamine and lower doses of GBR12909. However, the fact that MPEP did not attenuate the locomotor stimulant effects of the high (20 mg/kg) dose of GBR12909 suggests complex interactions between metabotropic glutamate receptors, dopamine transporters and possibly other monoamines in the regulation of psychostimulant-induced locomotor activity.     

Effects of GABAB receptor agonists on cocaine hyperlocomotor and sensitizing effects in rats

The present study was designed to find out whether pharmacological activation of GABA_B receptors played a role in cocaine sensitization. To this end, male Wistar rats were injected with baclofen or 3-aminopropyl(methyl)phosphinic acid (SKF 97541), the potent and selective GABA_B receptor agonists. The rats, which were repeatedly (for 5 days) administered with cocaine (10 mg/kg) and then challenged with cocaine (10 mg/kg) after 5-day withdrawal period, showed significantly higher locomotor hyperactivity in comparison with the effect observed in saline-pretreated and cocaine challenged rats. Baclofen (1.25, 2.5 and 5 mg/kg), administered for 5 days prior to cocaine, dose-dependently attenuated cocaine sensitization. When injected in the same treatment regimen, SKF 97541 (0.03 mg/kg) reduced the development of cocaine sensitization. To examine the effects of baclofen and SKF 97541 on the expression of cocaine sensitization, the drugs were given acutely before a challenge dose of cocaine (10 mg/kg) on day 10. Either baclofen (2.5 and 5 mg/kg) or SKF 97541 (0.1 mg/kg) decreased sensitization to cocaine. Our findings implicate a role of GABA_B receptors in locomotor responses to cocaine. More specifically, they show that stimulation of GABA_B receptors exerted inhibitory actions on acute locomotor responses to cocaine and on the expression of cocaine sensitization, what may offer a therapeutic potential of GABA_B receptor agonists in the treatment of cocaine dependence.     

Repeated social-defeat stress, cocaine or morphine

RATIONALE: Repeated social stress experiences engender "behavioral sensitization" and may also increase the potential for abuse of psychomotor stimulants, particularly cocaine use during "binges." OBJECTIVE: Experimental protocols were designed to induce behavioral sensitization through exposures to social-defeat stress or injections of cocaine or morphine. The impact of stress, cocaine or morphine sensitization on cocaine self-administration was assessed using several protocols. METHODS: Behavioral sensitization was induced in male Long-Evans rats by four social-defeat stress episodes, each separated by 72 h. Expression was assessed following a challenge of D-amphetamine (1.0 mg/kg) or cocaine (7.5 mg/kg or 10.0 mg/kg), 10-15 days after the last defeat. Sensitization to cocaine (15.0 mg/kg) or morphine (10.0 mg/kg) was induced via daily administrations for 10 days and later assessed by challenges with cocaine or morphine. Subsequently, i.v. self-administration of cocaine was analyzed for (i) rates of acquisition, (ii) sensitivity to various doses, (iii) "breaking points" during a progressive ratio schedule of cocaine reinforcement, and (iv) patterns of intake during a 24-h binge, in sensitized and control rats. RESULTS: Social-defeat stress, cocaine or morphine administrations increased the locomotor response to stimulant challenges. During 24-h cocaine self-administration binges, sensitization to social-defeat stress or to cocaine prolonged responding, resulting in more cocaine intake. In addition, cocaine sensitization increased the rate of acquisition to cocaine self-administration and the breaking point during a progressive ratio schedule. CONCLUSION: The process of sensitization to social-defeat stress or cocaine intensifies cocaine intake during a binge, supporting the hypothesis that sensitization may facilitate the transition to compulsive drug taking.     

Various GABA-mimetic drugs differently affect cocaine-evoked hyperlocomotion and sensitization

To substantiate the notion that cocaine behavioral effects may be influenced by gamma-aminobutyric acid (GABA) neurotransmission male Wistar rats were injected with gabapentin (a cyclic GABA analogue), tiagabine (a GABA reuptake inhibitor), or vigabatrin (a GABA transaminase inhibitor) before acute or repeated treatment with cocaine evoking either locomotor hyperactivation or sensitization. Gabapentin (1-30 mg/kg), tiagabine (2.5-10 mg/kg) or vigabatrin (75-250 mg/kg) attenuated the cocaine (10 mg/kg)-induced hyperactivation and in the highest doses they also decreased basal locomotor activation. Vigabatrin (75-250 mg/kg) dose-dependently reduced the development of cocaine sensitization in rats treated repeatedly (days 1-5) with cocaine (10 mg/kg) and then challenged with cocaine (10 mg/kg) following 5-day withdrawal; the remaining drugs were ineffective. When injected acutely with a cocaine challenge dose, gabapentin (3-10 mg/kg) or vigabatrin (150 mg/kg), but not tiagabine, significantly attenuated the expression of cocaine sensitization. The present results show that enhanced GABA-ergic neurotransmission exerted inhibitory actions on acute responses to cocaine, however, only in a case of vigabatrin the inhibition seems to be unrelated to the inhibitory effect of the drugs on basal locomotor activity. The finding that vigabatrin protected against the development and the expression of cocaine sensitization further supports its therapeutic potential in the treatment of cocaine dependence.     

Alterations in striatal acetylcholine overflow by cocaine,morphine, and MK-801: relationship to locomotor output

The activity of cholinergic interneurons in the striatum appears to be modulated by a variety of different systems including dopamine, opiate, and glutamate. The purpose of this study was to characterize the effects of drugs known to act on these three systems (i.e., cocaine, morphine, and MK-801) on striatal ACh overflow with microdialysis procedures, and to determine if alterations in ACh function induced by these agents are related to changes in locomotor activity. Cocaine was found to increase striatal ACh following intraperitoneal injections of 20 and 40 mg/kg, but not 10 mg/kg. The increases in locomotor activity induced by cocaine appeared to be dose dependent, while the effects on striatal ACh were not. Injections of 0.1 mg/kg MK-801 (a non-competitive NMDA receptor antagonist) produced dramatic increases in locomotor activity while decreasing striatal ACh overflow. A lower dose (0.03 mg/kg) of MK-801 failed to alter locomotor activity or striatal ACh. Morphine produced an apparent dose-dependent elevation in striatal ACh while only the lowest dose (5 mg/kg) increased locomotor activity. These appears to be no relationship between alterations in striatal ACh and locomotor output following systemic administration of these psychoactive agents.     

Inhibitory actions of mGlu4 receptor ligands on cocaine-, but not nicotine-, induced sensitizing and conditioning locomotor responses in rats

BackgroundMale Wistar rats were used to verify the hypothesis that metabotropic glutamate 4 (mGlu₄) receptor ligands may modulate the locomotor effects evoked by cocaine or nicotine.MethodsThe preferential mGlu₄ receptor orthosteric agonist (2S)-2-amino-4-[hydroxy[hydroxy(4-hydroxy-3-methoxy-5-nitrophenyl)methyl]phosphoryl]butanoic acid (LSP1-2111) and the mGlu₄ receptor positive allosteric modulator (+)-cis-N¹-(3,4-dichlorophenyl)cyclohexane-1,2-dicarboxamide (Lu AF21934) were used in the study. Rats were given repeated pairings of a test environment with cocaine (10 mg/kg), nicotine (0.4 mg/kg) or the respective vehicles for 5 days. On day 10, animals were challenged with cocaine (10 mg/kg, cocaine sensitization), nicotine (0.4 mg/kg, nicotine sensitization) or vehicle (conditioned hyperlocomotion) in experimental cages.ResultsGiven on day 10, LSP1-2111 (3 mg/kg) as well as Lu AF21934 (2.5–5 mg/kg) decreased the expression of cocaine sensitization. In another set of experiments, LSP1-2111 (3 mg/kg) and Lu AF21934 (5 mg/kg) administered on day 10 attenuated the conditioned hyperlocomotion in rats treated repeatedly with cocaine. Neither LSP1-2111 (1–3 mg/kg) nor Lu AF21934 (2.5–5 mg/kg) changed the expression of nicotine sensitization and conditioned hyperlocomotion in rats treated repeatedly with nicotine. None of the mGlu₄ receptor agonist/modulator altered the basal locomotor activity or acute hyperactivity to cocaine or nicotine.ConclusionsThe present data indicate that pharmacological stimulation of mGlu₄ receptors reduces the cocaine-induced expression of sensitization as well as conditioned hyperactivity. In contrast, mGlu₄ receptor activation seems to be devoid of any effect on the locomotor effects of nicotine.     

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.     

Prior morphine exposure enhances ibogaine antagonism of morphine-induced locomotor stimulation

Ibogaine is currently being investigated for its potential use as an anti-addictive agent. In the present study we sought to determine whether prior morphine exposure influences the ability of ibogaine to inhibit morphine-induced locomotor stimulation. Female Sprague-Dawley rats were pretreated once a day for 1–4 days with morphine (5, 10, 20 or 30 mg/kg, IP) or saline and then received ibogaine (40 mg/kg, IP) 5 h after the last morphine pretreatment dose. Compared to rats pretreated with saline, rats pretreated with morphine (10, 20 or 30 mg/kg, IP) before ibogaine (40 mg/kg, IP) showed a significant reduction in morphine-induced (5 mg/kg, IP) locomotor stimulation when tested 19 h after ibogaine administration. Furthermore, this effect was apparent over a range of ibogaine (5–60 mg/kg, IP) and morphine test (2.5–5 mg/kg, IP) dosages. Doses of ibogaine (5 and 10 mg/kg, IP) which alone were inactive inhibited morphine-induced locomotor activity when rats had been pretreated with morphine. These results, showing that morphine pre-exposure affects ibogaine activity, suggest that variable histories of opioid exposure might account for individual differences in the efficacy of ibogaine to inhibit opioid addiction.     

Hypothalamic peptide hormone,prolyl-leucyl-glycinamide and analog,inhibit tolerance to the analgesic and locomotor depressant but not to the locomotor stimulant effects of morphine in the mouse

The effects of prolyl-leucyl-glycinamide (melanotropin release inhibiting factor, MIF) and cyclo(Leu-Gly) on development of tolerance to the analgesic, locomotor stimulant and depressant effects of morphine were investigated in the mouse. Mice were made tolerant to morphine by subcutaneous implantation of a pellet (each pellet contained 75 mg of morphine free base) for three days. Both MIF and cyclo(Leu-Gly) inhibited the development of tolerance to the analgesic response to a challenge dose of morphine in peptide-treated as compared to vehicle-treated morphine-tolerant mice. Morphine in a small dose (10 mg/kg) depressed spontaneous motor activity, while, in a larger dose (80 mg/kg), increased the motor activity. Implantation of a morphine pellet resulted in the development of tolerance to both the locomotor depressant and stimulant effects of morphine. Administration of MIF or cyclo(Leu-Gly) during induction of tolerance in doses (2 mg/kg/day for 3 days) that inhibited the development of tolerance to morphine-induced analgesia and locomotor depressant activity, did not alter the development of tolerance to the locomotor stimulant effect. These studies indicate that the development of tolerance to the analgesic and locomotor depreressant effect of morphine may involve similar mechanisms, whereas, tolerance to the locomotor stimulant effect of morphine may be mediated via a different mechanism.     

Locomotor activity changes in female adolescent and adult rats during repeated treatment with a cannabinoid or club drug

Adolescents and young adults of both sexes are the primary consumers of "club" drugs; yet, most of the mechanistic preclinical research in this area has been performed in adult male rodents. The purpose of this study was to evaluate the acute and repeated effects of drugs that are commonly abused by adolescents in female adolescent and adult rats in a rodent model of behavioral sensitization. During two five-day periods separated by a two-day break, rats were injected daily with saline or with one of the following drugs: cocaine (7 or 15 mg/kg), ketamine (3 or 10 mg/kg), 3,4-methylenedioxymethamphetamine (MDMA) (3, 10, or 30 mg/kg), or Δ(9)-tetrahydrocannabinol (THC) (0.03, 0.1, 0.3 or 1 mg/kg) and their locomotor activity was measured. Cocaine increased activity across days in both age groups. Whereas ketamine produced progressive increases in activity with repeated administration in rats of both ages, MDMA increased, and then decreased, activity in the chronic dosing regimen in female adolescents only. Tolerance to the initial stimulatory effects of low doses of THC was observed at both ages. The results with THC are similar to those obtained for male rats tested under identical conditions in a previous study; however, in contrast with the present results in females, male adolescent rats in the previous study failed to develop behavioral sensitization to ketamine. Together, these results suggest that age and sex strongly influence the progressive adaptive changes that occur with repeated administration of some, but not all, of these commonly abused substances.     

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

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

Pre-exposure to the cannabinoid receptor agonist CP 55940 enhances morphine behavioral sensitization and alters morphine self-administration in Lewis rats

Three experiments examined the influence of pre-exposure to the cannabinoid receptor agonist CP 55940 ((-)-cis-3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-trans-4-(3-hydroxypropyl)cyclohexanol) on the sensitization of morphine-induced locomotor hyperactivity and self-administration in Lewis rats. In Experiment 1, rats received daily injections of vehicle or CP 55940 (0.1 mg/kg for 7 days then 0.2 mg/kg for a further 7 days). Four weeks later, the locomotor response to morphine (10 mg/kg s.c.) was tested once per day over a 3-h period for 14 consecutive days. Rats given morphine showed hypoactivity during the first hour following morphine but hyperactivity during the second and third hours. A progressive increase in hyperactivity to morphine was seen over the 14 days of administration, which was significantly greater in rats pre-treated with CP 55940. In Experiment 2, rats were given morphine (10 mg/kg) once a day for 14 days in combination with either vehicle, CP 55940 (0.1 mg/kg) or the cannabinoid CB(1) receptor antagonist SR 141716 (N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride) (3 mg/kg). Both CP 55940 and SR 141716 initially inhibited the hyperactive response to morphine, but these effects gradually wore off and by the end of 14 days, hyperactivity was similar in all morphine-treated groups. When tested 3 weeks later for their response to morphine (10 mg/kg) given alone, rats previously given the morphine/CP 55940 combination, but not the SR 141716/morphine combination, showed a greater locomotor stimulation than those previously exposed to morphine only. In Experiment 3, rats were pre-exposed to CP 55940 or vehicle for 14 days and were subsequently trained to self-administer morphine intravenously (1 mg/kg per lever press) for 14 days. Rats pre-exposed to CP 55940 self-administered a significantly greater number of morphine infusions than vehicle pre-exposed rats. However, both active and inactive ('dummy') lever presses were increased by cannabinoid pre-treatment. Overall, these results suggest that cannabinoid pre-exposure can lead to an exaggeration of morphine-induced hyperactivity and may alter the reinforcing effects of morphine in Lewis rats. The implications for 'gateway' theories of cannabinoid effects in humans are discussed.     

Effects of humoral modulators and naloxone on morphine-induced changes in the spontaneous locomotor activity of the rat

The s.c. administration of 20 mg/kg of morphine-HCl produced a decrease in the spontaneous locomotor activity (SLMA) of rats. The decrease in SLMA was significantly antagonized by p-chlorophenylalanine (p-CPA). When rats pretreated with p-CPA were given 5-hydroxytryptophan before morphine injection, the marked sedative response to morphine was restored, suggesting that the morphine-induced decrease in SLMA of rats may depend on the release of 5-hydroxytryptamine by morphine. By contrast, the s.c. administration of 5 mg/kg of morphine-HCl produced a significant increase in SLMA of rats. The magnitude of the increase was reduced by atropine, scopolamine or -methyl-p-tyrosine. It appears that both adrenergic and cholinergic mechanisms participate in the increase in SLMA of rats induced by morphine. Both the increase in SLMA produced by 5 mg/kg of morphine and the decrease in SLMA induced by 20 mg/kg of morphine were completely antagonized by the s.c. administration of naloxone-HCl, 0.0625 and 0.25 mg/kg, respectively. Thus, it appears that the receptor with which morphine interacts to produce stimulation is chemically identical with or very similar to the receptor with which morphine combines to induce depression. The former receptors, however, are likely to be located on different neurons from the latter.     

Stimulant activities of dimethocaine in mice: reinforcing and anxiogenic effects

The present study evaluated the effects of dimethocaine and procaine, esteratic local anesthetics, on locomotor activity, conditioned place preference and on the elevated plus-maze test of anxiety in mice, behavioral tests believed to be sensitive to cocaine action. Acute administration of dimethocaine (10–40 mg/kg, IP) significantly increased locomotor activity and time spent on the drug-paired side and reduced the relative number of entries and time spent on the open arms of the plus-maze in mice. Procaine (20–50 mg/kg, IP) failed to affect these responses. These data demonstrate the locomotor stimulant, reinforcing and anxiogenic actions of dimethocaine similar to those reported for cocaine in animals. In addition, these findings support a role for dopaminergic activity, rather than local anesthetic action, in the behavioral effects caused by dimethocaine.