Drug‐induced reinstatement of heroin‐ and cocaine‐seeking behaviour following long‐term extinction is associated with expression of behavioural sensitization

The present study was designed to evaluate the relationship between reinstatement of drug-seeking behaviour following long-term extinction of intravenous (i.v.) drug self-administration (an animal model for craving) and long-term behavioural sensitization. Rats were allowed to self-administer heroin (50 μg/kg per inj., 14 daily sessions), cocaine (500 μg/kg per inj., 10 daily sessions) or saline. Following a 3-week extinction period, reinstatement tests were performed to evaluate priming effects of amphetamine, cocaine and heroin on non-reinforced drug-seeking behaviour. In addition, the occurrence of long-term behavioural sensitization in rats with a history of heroin or cocaine self-administration was determined. Heroin-seeking behaviour was reinstated by heroin (0.25 mg/kg), amphetamine (1.0 mg/kg) and cocaine (10 mg/kg). In addition, animals with a history of heroin self-administration displayed locomotor sensitization to both heroin and amphetamine. Cocaine-seeking behaviour was reinstated by cocaine and amphetamine, but not by heroin. Interestingly, locomotor sensitization to amphetamine, but not heroin, was observed in animals with a history of cocaine self-administration. In other words, the induction of drug-seeking behaviour following a prolonged drug-free period was found to be associated with the expression of long-term behavioural sensitization. These data provide experimental evidence for a role of behavioural sensitization in the incentive motivation underlying drug-seeking behaviour. If drug hyperresponsiveness would indeed be a crucial factor in drug-induced craving in human addicts, pharmacological readjustment of the neuroadaptations underlying drug sensitization may prevent relapse to drug use long after detoxification.     

Subchronic cocaine treatment enhances cocaine-induced dopamine efflux, studied by in vivo intracerebral dialysis

Repeated administration of cocaine in animals results in behavioral sensitization. In order to investigate the neurochemical mechanism underlying such behavioral sensitization, we designed the following two experiments. In both experiments, rats were pretreated with cocaine (20 mg/kg i.p.) or saline, once daily for 14 consecutive days. Exp. 1: 7 days after withdrawal from the drug, the stereotyped behavioral response to a challenge of cocaine (20 mg/kg i.p.) was measured. Exp. 2: 7 days after withdrawal from the drug, we measured extracellular dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) after the challenge administration of cocaine using an in vivo intracerebral dialysis technique. The rats pretreated with cocaine (20 mg/kg i.p.) exhibited behavioral augmentation in response to a challenge of cocaine. The challenge administration of cocaine caused an increase in DA and a decrease in DOPAC. The DA level in the striatal perfusates of the cocaine-pretreated rats was significantly greater than that in the saline-pretreated rats. These results suggest that the increased extracellular DA concentration in the striatum plays an important role in the cocaine-induced behavioral sensitization.     

Reduced-5-hydroxytryptamine-dependent behavior in rats following chronic corticosterone treatment

The effect of chronic corticosterone treatment (50 mg/kg s.c. 2 x daily) for up to 4 days on behavioural responses to drugs affecting 5-hydroxytryptamine (5-HT) and dopamine (DA) systems was examined in rats 20 h after the last treatment, when placed in experimental cages, to which they had become habituated. Corticosterone- and vehicle-treated rats exhibited both comparable spontaneous behavior when given 0.9% NaCl i.p. and showed similar behavioural responses following amphetamine (3 mg/kg i.p.). However, responses to the 5-HT-releasing drug p-chloroamphetamine (PCA, 4 mg/kg i.p.) were altered with decreased head-weaving hind-limb abduction and forepaw treading. Postsynaptic changes appear to be involved as responses to the 5-HT agonist 5-methoxy-N,N-dimethyltryptamine (5-MeODMT, 5 mg/kg i.p.) (tremor, hind-limb abduction and forepaw treading) were also decreased. Hind brain and striatal concentration of 5-HT, DA and their metabolites were comparable in corticosterone and vehicle treated rats killed 20 h after the last treatment. Brain PCA levels determined 30 min after injection were also comparable in both groups. PCA induced behaviour was not altered 20 h after 1 day corticosterone treatment or 4 day after 1 day treatment and 5-MeODMT-induced behaviour was not altered 20 h after 14 days treatment with a lower dose of corticosterone (10 mg/kg s.c. x 2). Twenty h after 1 day corticosterone treatment (50 mg/kg s.c. x 2), rats placed in an open field for the first time showed significantly more activity and dropped fewer faecal pellets than controls.(ABSTRACT TRUNCATED AT 250 WORDS)     

Evidence for an involvement of muscarinic cholinergic systems in the induction but not expression of behavioral sensitization to cocaine

The present study was designed to determine whether the muscarinic cholinergic antagonist scopolamine can prevent the expression and induction of sensitization to the locomotor-activating effects of cocaine. Rats received one daily injection of cocaine (20 mg/kg i.p.) for 5 days. Two days after withdrawal of pretreatment, rats were pretreated with scopolamine (3.0 mg/kg s.c.) or its vehicle and challenged 15 min later with either saline or cocaine (20–30 mg/kg i.p.). In a second set of experiments, scopolamine (3.0 mg/kg s.c.) or its vehicle was given in combination with either saline or cocaine (20 mg/kg i.p.) for 5 days. Activity in response to saline and to cocaine (20 mg/kg i.p.) was assessed on day 7. The effects of acute administration of acopolamine (3.0 mg/kg s.c.) on cocaine-induced locomotor activity were also assessed. Acute administration of scopolamine increased both distance traveled and time spent in stereotypy. When scopolamine was administered 15 min prior to an acute injection of cocaine, a significant increase in the behavioral response to cocaine was seen. Daily injections of cocaine for 5 days produced sensitized behavioral responses to a subsequent cocaine challenge. Acute administration of scopolamine to animals preexposed and sensitized to cocaine did not disrupt the expression of sensitization to the locomotor and stereotypic effects of cocaine. In contrast, when scopolamine was given in combination with cocaine for 5 days, sensitization to the locomotor-activating effects of cocaine was prevented. These results suggest an important role of cholinergic muscarinic systems in mediating sensitization to the locomotor-activating effects of cocaine, which occurred after the repeated context-independent administration of this agent. In contrast, the enhanced stereotypic effects in response to the repeated administration of cocaine seem to be independent of alterations in muscarinic cholinergic transmission. (This article is a US Govemernment work and, as such, is in the public domain in the United States of America.) © 1996 Wiley-Liss, Inc.     

Effects of coadministration of cannabinoids and morphine on nociceptive behaviour, brain monoamines and HPA axis activity in a rat model of persistent pain

The antinociceptive effects of Delta9-tetrahydrocannabinol (Delta9-THC) have been widely described; however, its therapeutic potential may be limited by secondary effects. We investigated whether coadministration of low doses of cannabinoids or cannabinoids and morphine produced antinociception in the absence of side-effects. Effects of preadministration (i.p.) of Delta9-THC (1 or 2.5 mg/kg), cannabidiol (5 mg/kg), morphine (2 mg/kg), Delta9-THC + morphine, Delta9-THC + cannabidiol or vehicle on formalin-evoked nociceptive behaviour were studied over 60 min. Trunk blood and brains were collected 60 min after formalin injection and assayed for corticosterone and tissue levels of monoamines and metabolites, respectively. Drug effects on locomotor activity, core body temperature and grooming were assessed. Delta9-THC reduced both phases of formalin-evoked nociceptive behaviour, enhanced the formalin-evoked corticosterone response and increased the 4-hydroxy-3-methoxyphenylglycol : noradrenaline ratio in the hypothalamus. Cannabidiol alone had no effect on these indices and did not modulate the effects of Delta9-THC. Morphine reduced both phases of formalin-evoked nociceptive behaviour. Coadministration of Delta9-THC and morphine reduced the second phase of formalin-evoked nociceptive behaviour to a greater extent than either drug alone, and increased levels of thalamic 5-hydroxytryptamine. While the antinociceptive effects of Delta9-THC and morphine alone occurred at doses devoid of effects on locomotor activity, coadministration of Delta9-THC and morphine inhibited locomotor activity. In conclusion, coadministration of a low dose of morphine, but not cannabidiol, with Delta9-THC, increased antinociception and 5-hydroxytryptamine levels in the thalamus in a model of persistent nociception. Nevertheless, these enhanced antinociceptive effects were associated with increased secondary effects on locomotor activity.     

Reduced 5-hydroxytryptamine-dependent behaviour in rats following chronic corticosterone treatment

The effect of chronic corticosterone treatment (50 mg/kg s.c. 2 × daily) for up to 4 days on behavioural responses to drugs affecting 5-hydroxytryptamine (5-HT) and dopamine (DA) systems was examined in rats 20 h after the last treatment, when placed in experimental cages, to which they had become habituated. Corticosterone- and vehicle-treated rats exhibited both comparable spontaneous behaviour when given 0.9% NaCl i.p. and showed similar behavioural responses following amphetamine (3 mg/kg i.p.). However, responses to the 5-HT-releasing drugp-chloroamphetamine (PCA, 4 mg/kg i.p.) were altered with decreased head-weaving hind-limb abduction and forepaw treading. Postsynaptic changes appear to be involved as responses to the 5-HT agonist 5-methoxy-N, N-dimethyltryptamine (5-MeODMT, 5 mg/kg i.p.) (tremor, hind-limb abduction and forepaw treading) were also decreased. Hind brain and striatal concentrations of 5-HT, DA and their metabolites were comparable in corticosterone and vehicle treated rats killed 20 h after the last treatment. Brain PCA levels determined 30 min after injection were also comparable in both groups. PCA induced behaviour was not altered 20 h after 1 day corticosterone treatment or 4 day after 1 day treatment and 5-MeODMT-induced behaviour was not altered 20 h after 14 days treatment with a lower dose of corticosterone (10 mg/kg s.c. × 2). Twenty h after 1 day corticosterone treatment (50 mg/kg s.c. × 2), rats placed in an open field for the first time showed significantly more activity and dropped fewer faecal pellets than controls. However 20 h after 4 days treatment, activity in the open field was significantly less than that of controls. These effects of corticosterone were strikingly different and largely opposite to those of repeated immobilisation stress. They thus suggest that stress-induced corticosterone release may oppose some of the behavioural consequences of stress.     

Altered cocaine-induced behavioral sensitization in adult mice exposed to cocaine in utero

Behavioral sensitization induced by psychostimulants is characterized by increased locomotion and stereotypy and may reflect aspects of neuronal adaptations underlying drug addiction in humans. To study the developmental contributions to addictive behaviors, we measured behavioral responses in adult offspring to a cocaine sensitization paradigm following prenatal cocaine exposure. Pregnant Swiss-Webster (SW) mice were injected twice daily from embryonic days 8 to 17 (E8-E17, inclusive) with cocaine (20 or 40 mg/kg/day; COC20 and COC40, respectively), or saline vehicle (SAL and SPF40) subcutaneously (s.c.). A nutritional control group of dams were 'pair-fed' with COC40 dams (SPF40). P120 male offspring from each prenatal treatment group were assigned to a behavioral sensitization group and injected with cocaine (15 mg/kg) or saline intraperitoneally (i.p.) every other day for seven doses. Locomotor activity and stereotypy were measured during habituation, cocaine initiation, and following a cocaine challenge 21 days after the last initiation injection. As expected, animals demonstrated significantly more locomotion and stereotypic behavior following acute and recurrent injection of cocaine compared to saline-injected animals. However, for each prenatal treatment group, cocaine-sensitized animals showed unique temporal profiles for the increase in locomotor sensitization and stereotypy over the course of the sensitization protocol. Two features that distinguished the altered behavioral progression of prenatally cocaine-exposed animals (COC40) from control (SAL) animals included blunted augmentation of locomotion and enhanced patterns of stereotypic behavior. These findings provide evidence that the behavioral activating effects of cocaine in adult animals are altered following exposure to cocaine in utero.     

Selective psychostimulant sensitization by food restriction: differential changes in accumbens shell and core dopamine

We have recently reported that behavioural sensitization to morphine, amphetamine, cocaine and nicotine is associated with an increased response of dialysate dopamine to the same drugs in the nucleus accumbens core and/or a reduced response in the shell. Prolonged exposure to stressful stimuli also induces behavioural sensitization to drugs of abuse. We therefore investigated the effect of different drugs of abuse on behaviour and on dopamine transmission in the nucleus accumbens shell and core of rats stressed by 1 week schedule of food restriction. Food-restricted rats (80% of their initial body weight) were implanted with microdialysis probes in the nucleus accumbens shell and core and challenged with cocaine (5 and 10 mg/kg i.p.), amphetamine (0.25 and 0.5 mg/kg s.c.), morphine (1 and 2 mg/kg s.c.), nicotine (0.2 and 0.4 mg/kg s.c.) and the changes in dialysate dopamine transmission were monitored together with the behaviour. Food restricted rats showed strong behavioural sensitization to cocaine and amphetamine but not to morphine or nicotine as compared to ad libitum fed controls. Behavioural sensitization to psychostimulants was associated with an increased response of dialysate dopamine in the core and with an unchanged or even reduced response in the shell. No significant differences were observed between controls and food-restricted animals in the ability of morphine and nicotine to stimulate dopamine transmission in the shell and core. The present results indicate that a sensitized dopamine response in the nucleus accumbens core is a general feature of the expression of behavioural sensitization.     

Valproate prevents the induction of sensitization to methylphenidate (ritalin) in rats

Repetitive exposure to methylphenidate (MPD) elicits sensitization to its locomotor effects. Drugs that affect the GABA system may modify adaptations to drug exposure. Therefore, we have examined the effect of sodium valproate, which enhances GABA function, on the development of sensitization to MPD using an automated, computerized animal activity monitoring system to record each rat's motor activities for 15 consecutive days. Rats were recorded before and after saline injection (Days 1-2) to provide baseline activity. Animals were then randomly assigned to the following three groups that received: (1) 2.5 mg/kg MPD (s.c.) for six consecutive days (Days 3-8), (2) a single dose of valproate (50 mg/kg; i.p.) 1 h prior to the first (Day 3) of six daily doses of MPD (2.5 mg/kg; s.c. ), or (3) five daily doses of valproate (50 mg/kg, i.p.) 1 h prior to MPD (2.5 mg/kg, s.c.) on Days 4-8. There was no drug treatment during the next 5 days (Days 9-13). All rats were then re-challenged with MPD (2.5 mg/kg, s.c.) on Day 14. Group 2 rats were also re-challenged with 50 mg/kg valproate followed by 2.5 mg/kg MPD 1 h later on Day 15. Administration of MPD alone produced a sensitized response. Multiple valproate injections prevented the induction of MPD-elicited sensitization in all four motor indices, while a single valproate injection prevented the induction of MPD-elicited sensitization in two of four motor indices studied. In conclusion, a single injection 50 mg/kg valproate given prior to any MPD treatment partially blocked the induction of MPD sensitization while repeated injections of valproate co-administered with MPD treatment completely prevented this effect.     

Determination of hemoglobin oxygen saturation in rat sciatic nerve by in vivo near infrared spectroscopy

Marijuana is a widely abused illicit drug known to cause significant cognitive impairments. Marijuana has been hypothesized to target neurons in the hippocampus because of the abundance of cannabinoid receptors present in this structure. While there is no clear evidence of neuropathology in vivo, suppression of brain mitogenesis, and ultimately neurogenesis, may provide a sensitive index of marijuana's more subtle effects on neural mechanisms subserving cognitive functions. We examined the effects of different doses and treatment regimens of Delta(9)-tetrahydrocannabinol (THC), the main active ingredient in marijuana, on cell proliferation in the dentate gyrus of adult male mice. Following drug treatment, the thymidine analog 5-bromo-2'-deoxyuridine (BrdU; 200 mg/kg, i.p.) was administered two hours prior to sacrifice to assess cell proliferation, the first step in neurogenesis. Administration of THC produced dose-dependent catalepsy and suppression of motor activity. The number of BrdU-labeled cells was not significantly changed from vehicle control levels following either acute (1, 3, 10, 30 mg/kg, i.p.), sequential (two injections of 10 or 30 mg/kg, i.p., separated by 5 h), or chronic escalating (20 to 80 mg/kg, p.o.; for 3 weeks) drug administration. Furthermore, acute administration of the potent synthetic cannabinoid receptor agonist R-(+)-WIN 55,212-2 (WIN; 5 mg/kg, i.p.) also had no significant effect on cell proliferation. These findings provide no evidence for an effect of THC on hippocampal cell proliferation, even at doses producing gross behavioral intoxication. Whether marijuana or THC affects neurogenesis remains to be explored.     

Chronic treatment with Delta-9-tetrahydrocannabinol alters the structure of neurons in the nucleus accumbens shell and medial prefrontal cortex of rats

The potential of repeated exposure to Delta(9)-tetrahydrocannabinol (Delta(9)-THC) to produce long-lasting changes in synaptic connections in a manner similar to other drugs of abuse was evaluated in Sprague-Dawley rats. For 12 days, rats received two i.p. injections per day (8 h apart) of vehicle, a low dose of Delta(9)-THC (0.5 mg/kg), or escalating doses of Delta(9)-THC (0.5-4.0 mg/kg). Thirty days later, they were evaluated for sensitized locomotor activity (during the night cycle) for 60 min on each of three trials. Using a within-groups design, rats were tested following an injection of vehicle, 0.5 mg/kg Delta(9)-THC or 2.0 mg/kg Delta(9)-THC. The rats showed no evidence of sensitized locomotor activity in any group. Twenty-four hours after the final sensitization test, their brains were removed and then processed for Golgi-Cox staining. Prior exposure to Delta(9)-THC (both the low dose and the escalating doses) increased the length of the dendrites as well as the number of dendritic branches in the shell of the nucleus accumbens and in the medial prefrontal cortex, but not in the hippocampus, striatum, orbital frontal cortex, parietal cortex, or occipital cortex. These results are similar to those evident in brains of rats sensitized to amphetamine, and support previous findings that cannabinoids promote DA activity in the mesolimbic DA system.     

Sensitization does not develop to cocaine-induced potentiation of the antinociceptive effect of morphine

Repeated intermittent cocaine administration produces a progressive increase (sensitization) in the motor stimulatory action of cocaine. Previous studies have shown that cocaine produces antinociception and also enhances the antinociceptive effect of opioid analgesics. The present study was designed to investigate if sensitization to these effects of cocaine develops. In the first part of the study, we determined if acute cocaine administration (3, 10, 30 mg/kg, intraperitoneal [i.p.]) increases the antinociceptive effect of morphine (5 mg/kg, subcutaneous [s.c.]) in rats using the hot plate test. Cocaine (30 mg/kg, i.p.), alone, produced a small but significant antinociceptive effect at 15 min after drug administration. When administered 15 min prior to morphine, cocaine dose-dependently enhanced the effect of morphine (5 mg/kg, s.c.) at the time (45 min post-cocaine) when cocaine by itself did not significantly change the hot plate latency. In the second part of the study, we examined if sensitization develops to cocaine-induced antinociception and its ability to increase the antinociceptive effect of morphine. Na?ve rats were injected with either saline or cocaine (30 mg/kg) once daily for 3 days and tested on the hot plate apparatus either 24 h or 1 wk after the last cocaine injection. Some of the rats from each group were also tested for motor stimulation induced by cocaine (5 mg/kg, i.p.) 24 h after the hot plate test to confirm that sensitization had occurred to the motor stimulatory action of the drug. Additional rats were treated with saline or cocaine for 3 days, but neither treated with morphine nor tested on the hot plate apparatus, and tested for behavioral sensitization to the motor stimulatory action of cocaine (5 mg/kg, i.p.) 24 h or 1 wk later. Sensitization developed to the motor stimulatory effect of cocaine in both groups, regardless of morphine treatment on the prior day. Sensitization also developed to the antinociceptive effect of cocaine 24 h but not 1 wk after the last cocaine injection. No sensitization was observed in the ability of cocaine to enhance the antinociceptive effect of morphine. Overall, our data suggest that while cocaine enhanced the antinociceptive effect of morphine, sensitization did not develop to this action of cocaine.     

Inhibition of nitric oxide synthase in the ventral tegmental area attenuates cocaine sensitization in rats

1. Male Sprague-Dawley rats were pretreated via bilateral infusion of the VTA with the selective neuronal nitric oxide synthase inhibitor, 7-nitroindazole (0, 8, or 40 ng/hemisphere), prior to each of 7 daily systemic cocaine (30 mg/kg, i.p.) or saline (1 ml/kg) treatments. 2. After a 7-day treatment withdrawal period, rats received a final systemic challenge with either cocaine (30 mg/kg, i.p.) or saline (1 ml/kg). 3. Locomotor and stereotypic activity were measured following the first and last treatments. 4. Daily cocaine treatment led to the development of sensitization to its stereotypic effects as revealed upon drug challenge. 5. The development of sensitization of cocaine-induced stereotypy was completely blocked by daily intra-VTA pretreatment with 7-nitroindazole. 6. In addition, attenuation of the locomotor effects of cocaine challenge was also observed in animals that received daily intra-VTA 7-nitroindazole (40 ng/hemisphere) infusions. 7. The results indicate that VTA nitric oxide is necessary for the development of sensitization of cocaine-induced stereotypic behavior, and that its repeated inhibition may produce lasting effects on the locomotor response to the drug.     

Behavioural sensitization to nicotine precedes the onset of nicotine-conditioned locomotor stimulation

Context-dependent behavioural sensitization to nicotine develops faster and is more robust than context-independent sensitization. However, some findings suggest that behavioural sensitization develops irrespective of context. In this study an attempt was made to dissociate the development of context-dependent nicotine sensitization from the onset of nicotine-conditioned locomotor stimulation. Seven days of daily nicotine administration (0.6 mg/kg, s.c.) paired with exposure to locomotor activity boxes produced stable and consistent behavioural sensitization, at which time no nicotine-induced conditioned locomotor stimulation could be demonstrated. However, after an additional two days of nicotine treatment, i.e. on day 9, nicotine-conditioned behavioural stimulation was observed. Our findings suggest that behavioural sensitization to nicotine appears to reach a plateau before induction of nicotine-conditioned locomotor stimulation.     

The effects of tifluadom and ketazocine on behaviour, dopamine turnover in the basal ganglia and local cerebral glucose utilization of rats

The purpose of the present study was to evaluate the interrelation between behavioural effects of kappa-opiates and cerebral neurochemical correlates in rats. Administration of the kappa-opiates tifluadom (2.5 mg/kg i.p.) or ketazocine (5 mg/kg i.p.) caused a marked initial decrease in locomotor activity lasting about 15-20 min, followed by an increase in locomotor activity at about 40 min after drug administration. At 15 min after i.p. injections of the same drugs 3,4-dihydroxyphenylacetic acid concentrations, measured by HPLC, were slightly increased in the nucleus accumbens, but unchanged in the striatum; dopamine concentrations were unchanged in both regions. The rates of glucose utilization, determined by quantitative [14C]2-deoxyglucose autoradiography, were mainly unchanged except for the nucleus accumbens, which showed an increased glucose utilization after both drugs given i.v. Tifluadom also decreased rates of glucose utilization in the caudate nucleus and parietal, sensorimotor, olfactory and frontal cortices. The above-mentioned effects on behaviour and local cerebral glucose utilization could be prevented by naloxone (3 mg/kg). The data suggest that changes in locomotor activity, neurotransmitter metabolism and neuronal activity in the nucleus accumbens are interrelated and that opiate-induced akinesia is mediated via the nucleus accumbens.     

Effects of guanethidine on sensitization to natural stimuli and self-mutilating behaviour in rats with a peripheral neuropathy.

In the present study we have used a recent rat model for neuropathic pain to investigate the effect of the sympatholytic drug guanethidine on changes in behavioural responses evoked by mechanical, heat and cold stimuli and on self-mutilating behaviour. After a unilateral peripheral mononeuropathy induced by ligatures around the right common sciatic nerve, the left side receiving just a sham wound, lesioned and non-operated control animals were treated with saline or guanethidine (30 mg/kg) for 4 consecutive days commencing 5 days before or 10 days after surgery. Behavioural parameters were followed for 4 weeks after drug treatment. Lesioned rats were found to be sensitized to the otherwise innocuous cold stimulus and showed decreased response thresholds to noxious heat and mechanical stimuli. Some lesioned animals self-mutilated. Treatment with guanethidine diminished heat and cold sensitization considerably, but had less effect on mechanical sensitization and, if administered before surgery, rather increased the severity of self-mutilating behaviour. While these results are in agreement with clinical observations on the prominence of sensitization to evoked stimuli, especially cold, and the effectiveness of guanethidine in sympathetically maintained neuropathic pain, they indicate that the mechanisms involved in sensitization to different stimuli and self mutilating behaviour differ.     

Sensitization to caffeine and cross-sensitization to amphetamine: influence of individual response to caffeine

The present study evaluated the ability of a subchronic intermittent administration of caffeine to induce a sensitized motor response and correlated the individual susceptibility of rats to acute caffeine to the development of sensitization. Moreover, individual susceptibility to caffeine and development of motor behaviour sensitization were correlated to the behavioural response obtained after a challenge with amphetamine. To this end, rats were subdivided in "low" and "high" responders according to their individual susceptibility to acute caffeine established on the basis of the motor activity observed after the first caffeine administration. "Low" and "high" responder rats were then repeatedly and intermittently treated with caffeine (15 mg/kg, i.p.), or vehicle, every other day for fourteen days. Three days after treatment discontinuation, behavioural activation induced by acute amphetamine (0.5 mg/kg, s.c.) was measured in vehicle- and caffeine-pretreated rats. Subchronic caffeine resulted in motor sensitization of a variable degree among rats and no difference were observed between "low" and "high" responders. Moreover, caffeine pretreatment potentiated the behavioural effects of amphetamine according to the degree of caffeine sensitization but not to individual susceptibility to acute caffeine. These results demonstrate that individual susceptibility to acute caffeine does not influence the modifications in caffeine motor effects produced by its subchronic administration and does not affect the enhancement of acute behavioural effects of amphetamine in caffeine-pretreated rats, rather sensitization to subchronic caffeine administration critically influences the behavioural effects of amphetamine.     

Behavioural consequences of withdrawal from three different administration schedules of amphetamine

Different administration schedules of amphetamine (AMPH) lead to different behavioural consequences, neurochemical changes and gene expression patterns in a variety of brain areas during drug withdrawal. However, direct comparisons of these different effects within the same experiment are rare in the literature. Accordingly, in this study, rats were tested in relevant behavioural paradigms during withdrawal from three different administration schedules of AMPH. The intermittent schedule (INT) consisted of one daily injection of 1.5 mg/kg AMPH for 6 days. The escalating administration schedule consisted of three daily injections for 6 days with increasing dosages from 1 to 5 mg/kg AMPH during the first five injections and 5 mg/kg for the following 13 injections (ESC-5). A second more severe escalating administration schedule (three injections per day for 3 days escalating from 1 to 9 mg/kg AMPH and a final 10 mg/kg AMPH injection on day 4, ESC-10) was also investigated. Control animals received saline injections according to the three administration schedules. Rats pretreated with AMPH according to the ESC-10 administration schedule exhibited a transient reduction of locomotor activity on day 1, but not day 5, of withdrawal, as well as a permanent disruption of prepulse inhibition (PPI) on days 4, 20, and 40 of withdrawal. There was no effect on anxiety measured by the elevated plus-maze on withdrawal day 2, and all the AMPH pretreated animals exhibited a similar magnitude of behavioural sensitization following an AMPH challenge irrespective of administration schedule on withdrawal day 42. These data suggest that, based on their persistent disruption of PPI, animals withdrawn from AMPH ESC-10 might model specific symptoms of schizophrenic patients.     

Litter has an effect on the behavioural changes caused by the administration of the nitric oxide synthase inhibitor NG-nitro-L-arginine and ethanol in mice

The aim of the work was to study the effects of litter and the nitric oxide synthase (NOS) inhibitor NG-nitro-L-arginine (L-NOARG) on the behaviour of mice after acute and chronic ethanol administration and withdrawal. Male outbred NIH/S mice, from 21 litters, were distributed among experimental groups and subjected to acute and chronic ethanol administration. After acute or chronic ethanol administration, the effects of L-NOARG on the behaviour of mice in the plus-maze test were studied. Acute ethanol (1 g/kg, i.p.), L-NOARG (20 and 40 mg/kg, i.p.) and their combination induced an anxiolytic effect. Furthermore, the values for the representatives of different litters tended to be either above or below the group mean, irrespective of the drug treatment. Chronic ethanol administration (23 days by inhalation) induced an anxiolytic effect and ethanol withdrawal induced an anxiogenic effect in the plus-maze. The administration of L-NOARG (20 mg/kg, i.p.) induced an anxiolytic effect in control mice and had no effect on ethanol-intoxicated mice, but attenuated the anxiogenic effect of ethanol withdrawal in the plus-maze. However, after chronic ethanol administration and withdrawal, litter had no effect on the behaviour of mice. If the litter is a significant determinant in the behaviour of outbred mice, then the use of information about the litter origin of animals could serve for the purposes of reduction. But only if this information is available from breeders.     

The effect of dopamine receptor blockade on the development of sensitization to the locomotor activating effects of amphetamine and morphine

The effect of dopamine (DA) receptor blockade on the development of sensitization to the locomotor activating effects of systemic amphetamine and intra-ventral tegmental area (intra-VTA) morphine was investigated. Rats were pretreated with the D-1 DA receptor antagonist, SCH-23390 (0.04 or 0.2 mg/kg, i.p.) or one of two D-2 DA receptor antagonists, pimozide (0.5 mg/kg, i.p.) and Ro 22-2586 (0.2 mg/kg, i.p.), prior to each of 5 exposures to the sensitizing drug. SCH-23390 blocked the development of sensitization to amphetamine but not to intra-VTA morphine. Pimozide had the opposite effect and Ro 22-2586 had no effect on the development of sensitization to either amphetamine or intra-VTA morphine. All 3 antagonists, at the doses tested, completely blocked the acute locomotor activating effects of these two drugs. Pretreatment in separate animals with low autoreceptor doses of sulpiride (25 mg/kg, i.p. with amphetamine and 10 mg/kg, i.p. with intra-VTA morphine) slightly potentiated the acute locomotor effect and produced a slight enhancement of the sensitized response to amphetamine and intra-VTA morphine. Pretreatment with a higher dose of sulpiride (50 mg/kg, i.p.) blocked the acute locomotor effect of intra-VTA morphine but had no effect on the development of sensitization to this drug. These results suggest that the mechanisms underlying the development of sensitization to the locomotor activating effects of amphetamine and intra-VTA morphine are different even though these may ultimately result in similar changes in the activity of mesencephalic DA neurons. Implications of these findings for the differential involvement of D-1 and D-2 DA receptors and for neural hypotheses of behavioral sensitization are discussed.