Repeated pre-exposure to tobacco smoke potentiates subsequent locomotor responses to nicotine and tobacco smoke but not amphetamine in adult rats

These studies investigated if pre-exposure to tobacco smoke affects the locomotor response to tobacco smoke, nicotine, and amphetamine in adult rats. The rats were habituated to an open field for 3-4 days and then exposed to tobacco smoke for 2 h/day for 13-14 days. The effect of exposure to tobacco smoke on locomotor activity was investigated after 1, 7, and 14 days of smoke exposure and after one 2-hour exposure session that followed a 3-week off period. The effects of tobacco smoke on the locomotor responses to nicotine (0.04 and 0.4 mg/kg, base) and amphetamine (0.1 and 0.5 mg/kg) were investigated on day 14, one day after the last smoke exposure session. The locomotor response to tobacco smoke was increased after 7 and 14 days of smoke exposure and after one exposure session after the 3-week off-period. The acute administration of the high dose of nicotine (0.4 mg/kg) led to a brief period of hypoactivity that was followed by a period of hyperactivity. Pre-exposure to tobacco smoke attenuated the nicotine-induced hypoactivity and potentiated the nicotine-induced hyperactivity. The low dose of nicotine (0.04 mg/kg) did not affect locomotor activity in the control rats but increased the total distance traveled in the tobacco smoke exposed rats. Exposure to tobacco smoke did not affect the locomotor response to amphetamine. These findings indicate that exposure to tobacco smoke leads to tolerance to the depressant effects of nicotine and potentiates the stimulant effects of nicotine and tobacco smoke.     

Cadmium, lead, and thallium in mainstream tobacco smoke particulate.

The deliveries of cadmium, thallium, and lead in mainstream smoke particulate from cigarettes with different smoke delivery designs were determined by inductively coupled plasma-mass spectrometry in order to investigate their impact on the delivery of these known toxic compounds. Analyses showed that the levels of all three metals in smoke particulate were associated with their tar delivery category. After normalizing the metal concentrations to tar, there were no longer any statistically significant delivery differences between full-flavor, light or ultra-light cigarettes. When the concentrations were normalized to nicotine, the mean levels from the three delivery groups were much smaller than before normalization. But unlike the case using tar to normalize, in some of the cases, there were still some statistically significant differences in the nicotine-normalized results. These findings suggest that if smokers compensate for differences in nicotine intake, they receive exposures to toxic heavy metals from ultra-light, light and full-flavor cigarettes that are more similar than results would suggest from using the Federal Trade Commission method alone.     

Loss of locomotor sensitisation in response to morphine in D1 receptor deficient mice

Mice lacking D1 receptors were used to study the role of these receptors in morphine-induced antinociception and locomotor sensitisation. In the hot-plate test D1 receptor deficient (-/-) and wild-type (+/+) mice showed similar reaction times under basal conditions. A single injection of 1.25 mg/kg and 2.5 mg/kg morphine resulted in a stronger antinociceptive response in D1 receptor deficient mice than in wild-type animals. Tolerance to the analgesic effect did not develop in both groups of animals when 12.5 mg/kg morphine was chronically applied twice daily for 13 days. There was no change in basal locomotor activity between saline-injected wild-type and D1 receptor deficient mice. After chronic treatment wild-type mice showed a continuous increase in locomotor activity, indicating the development of sensitisation. In contrast, a subchronic administration of morphine did not change locomotor activity in mutant mice. The lack of the development of locomotor sensitisation in D1 deficient mice was associated with reduced levels of immunoreactive mu opioid receptors in dorsal striatal patches as compared to wild-type mice. In contrast, no change in the distribution of immunoreactive mu receptors could be detected in areas related to pain pathways such as the spinal cord. Taken together, these results suggest an involvement of D1 receptors in morphine-induced locomotor activity and analgesia.     

Repeated exposure to Delta(9)-tetrahydrocannabinol alters heroin-induced locomotor sensitisation and Fos-immunoreactivity

The present study examined the effect of chronic exposure to Δ⁹-tetrahydrocannabinol (THC) on heroin-induced locomotor sensitisation and Fos-immunoreactivity (Fos-IR). Adult male albino Wistar rats (n = 60) were injected intraperitoneally (i.p.) 21 times with vehicle, 0.05, 0.5, or 5.0 mg/kg THC (once every 48 h for 41 days). Locomotor activity was assessed for 180 min on pre-exposure days 1, 21, and 41. Following a 2-week washout period, rats were divided into five equal groups (n = 12) and injected subcutaneously (s.c.) with vehicle or heroin (0.5 mg/kg). Locomotor activity was recorded for 240 min. In drug-naïve rats, heroin significantly increased locomotor activity. THC pre-exposure further increased heroin-induced locomotion. After an interval of 2 weeks, rats pre-exposed to vehicle and 5.0 mg/kg THC in the first part of the experiment were randomly assigned to one of four treatment groups (n = 6) and injected s.c. with vehicle or 0.5 mg/kg heroin and perfused 2 h later. Fos-IR was examined in several brain regions. Acute heroin increased Fos-IR in drug-naïve rats in the caudate-putamen (CPu; central, medial and dorsomedial regions), nucleus accumbens (NAC; core and shell regions), bed nucleus of the stria terminalis (BNST), lateral septum, central nucleus of the amygdala (CEA), periaqueductal grey (PAG; dorsolateral, dorsomedial, and lateral), and the Edinger–Westphal nucleus. Pre-exposure to THC significantly increased heroin-induced Fos-IR in the dorsomedial CPu and the NAC (core). Conversely, THC pre-exposure reduced heroin-induced Fos-IR in the BNST, CEA, and the PAG (dorsolateral and lateral). The present study demonstrates that THC pre-exposure increases the locomotor stimulating effects of heroin and provides new evidence for the neural correlates that may underlie cannabinoid and opioid cross-sensitisation.     

Clonidine-induced locomotor hyperactivity in rats

Summary The -adrenergic agonist, clonidine, causes sedation in normal rats. The present study demonstrates that clonidine evokes strong locomotor stimulation in rats pretreated with 6-hydroxydopamine plus reserpine. Similar, but less intensive hyperactivity is observed in rats given clonidine after combined pretreatment with 6-hydroxydopamine plus p-chlorophenylalanine plus -methyl-p-tyrosine, or with reserpine plus low doses of yohimbine. The -adrenolytic drugs, phenoxybenzamine, phentolamine and aceperone, as well as high doses of yohimbine, antagonise the clonidine-induced locomotor stimulation; in contrast, the dopamine receptor blocking agents, pimozide and spiroperidol, exert no antagonistic effect. The results indicate that in the brain of normal animals, clonidine predominantly activates presynaptic -adrenoceptors on noradrenergic neurones and thereby induces sedation. After destruction of the noradrenergic fibres by 6-hydroxydopamine plus reserpine, activation of postsynaptic -adrenoceptors prevails so that hyperactivity results.This study was supported by Polish Academy of Sciences (10.4). Preliminary accounts were presented at the Pharmacology Meeting, Hannover, September 14–17, 1976 and at the 1 st Joint Symposium of Hungarian and Polish Pharmacological Societies, Zakopane, October, 13–15, 1976     

The 5-HT6 serotonin receptor antagonist SB-271046 attenuates the development and expression of nicotine-induced locomotor sensitisation in Wistar rats

5-HT₆ receptors are almost exclusively expressed in the central nervous system, particularly in areas relevant for addictive behaviour. Based on this, together with other data, this receptor may be a viable target for the control of drug abuse.The present study tested the ability of the 5-HT₆ receptor antagonist SB-271046 to attenuate the development and expression of nicotine-induced behavioural sensitisation.Rats were habituated to the test apparatus prior to experimentation (day 0) and locomotor activity recorded. On days 1 and 5, animals were placed in locomotor test apparatus and after 30 min injected with SB-271046 (1, 3, and 6 mg/kg, intraperitoneally IP) or vehicle. Thirty minutes later, nicotine (0.4 mg/kg, subcutaneously SC) or saline were administered and activity recorded for 60 min. On days 2, 3 and 4 treatments were performed in the home cage. After 17 days of withdrawal (day 23), a challenge test was performed with nicotine (0.4 mg/kg SC) or saline. In a separate experiment of similar design the effects of SB-271046 (1, 3, and 6 mg/kg IP) was tested for its ability to reduce the expression of behavioural sensitisation (day 23).SB-271046 dose dependently reduced the development and expression of nicotine sensitisation vs respective controls.In conclusion, the 5-HT₆ receptor antagonist SB-271046 reduced both the development and expression of nicotine sensitisation, suggesting that the 5-HT₆ receptor may be a viable target for the control of nicotine abuse. Further studies are warranted to substantiate this conclusion and further understand the role of 5-HT₆ receptors in addiction.     

Hyperuricemia and locomotor activity in developing rats

This research was motivated by the previous finding that serum uric acid levels correlate with symptoms of hyperactivity in normal children. We attempted, therefore, to investigate this relationship in an animal model. Dose and time relationships between allantoxanamide-induced heightened serum uric acid and locomotor activity were investigated. A dose- and time-dependent relationship was shown between serum uric acid levels and allantoxanamide. Those doses of allantoxanamide which elevated serum uric acid produced time-dependent changes in locomotor activity. In the first two hours following injection, activity increased relative to controls, in the next two-hour block activity decreased, only to rise again above control levels in the third two-hour period. The possible role of uric acid and allantoxanamide are discussed in relation to these complex changes in activity.     

Octopamine and locomotor activity of rats

Intracerebroventricular administration of P-octopamine (OA) had opposite effects on locomotor activity depending on whether or not the rats were subjected to uncontrollable electric shocks. In unshocked rats, OA produced a large decrease in locomotor activity, but when the rats were subjected to unsignalled and uncontrollable electric shocks, a significant increase in locomotor activity resulted. The latter effect was observed either when the shocks were applied during the measurement of locomotor activity or when they were applied the day before (conditioned suppression paradigm). These results support the hypothesis of a neuromodulation of central noradrenergic transmission by octopamine.     

Cocaine-induced locomotor activity in rats.

Rats were injected SC or IP with a dose of cocaine at 20 mg/kg twice daily or saline (2 ml/kg) for 15 consecutive doses. Horizontal (including ambulatory and repetitive activity) and ambulatory locomotor activities were assessed following the first (acute) and the 15th (chronic) injections. Total locomotor activity (area under curve, AUC) following the acute and the chronic administration of cocaine were comparable, regardless of the route of drug administration. However, the temporal patterns of activity were significantly different; the peak of locomotor activity occurred earlier (chronic vs. acute, 20 vs. 40 min after IP; 130 vs. 180 min after SC) following chronic cocaine administration. Furthermore, the peak activity was significantly higher (3-fold after IP and 50% after SC) in chronically than in acutely treated rats, providing evidence for sensitization. In contrast, activity in the late session (240-280 min after SC) was significantly lower following the chronic SC cocaine administration, providing evidence for desensitization. The absolute slope values of the ascending phase and the descending phase were significantly larger following chronic administration of cocaine than that following the acute dosing. The possibility of changes in locomotor activity with alteration of pharmacokinetics on chronic cocaine treatment is discussed.     

Differential effects of dopaminergic agents on locomotor sensitisation and on the reinstatement of cocaine-seeking and food-seeking behaviour

Rationale The dopaminergic pathways are involved in natural and drug reward related processes.Objectives To compare the respective involvement of the dopaminergic receptors D₁, D₂ and D₃ in natural-seeking versus drug-seeking behaviour and evaluate any concomitant expression of locomotor sensitisation.Methods In separate experiments, male Wistar rats were trained to self-administer cocaine (0.25 mg/infusion) or to press a lever to obtain food pellets. Following a prolonged period of extinction, reinstatement of lever responding was measured following non-contingent food delivery, cocaine (15 mg/kg), D₁-like (SKF 82958, 0.25 mg/kg), D₂-like (quinelorane, 0.25 mg/kg) and D₃-like (7-OHDPAT, 0.25 mg/kg) agonists. To demonstrate parallel expression of behavioural sensitisation, locomotor activity was recorded during the reinstatement sessions.Results Cocaine and quinelorane administrations reinstated cocaine-seeking behaviour and induced the expression of locomotor sensitisation, whereas SKF 82958 and 7-OHDPAT had either no effect or non-specific effects. In the food-seeking experiment, we found that quinelorane and 7-OHDPAT did not reinstate lever pressing. Cocaine increased responding on both active and inactive levers, whereas SKF 82958 had a more specific effect with higher responding on the previously food-associated lever.Conclusions Our results indicate that expression of locomotor sensitisation and reinstatement of cocaine-seeking but not food-seeking behaviours are in part supported by common dopaminergic substrates, among which the D₂ receptors play a crucial role.     

Methylphenidate potentiates morphine-induced antinociception, hyperthermia, and locomotor activity in young adult rats

The goal of this study was to determine if the exaggerated morphine-induced conditioned place preference (CPP) response seen in adult rats after preweanling methylphenidate exposure is unique to reward-mediated behaviors or is indicative of generalized changes in opioid-mediated behaviors. Rats were exposed to saline or methylphenidate (2.0 or 5.0 mg/kg) for 10 consecutive days starting on postnatal (PD) 11 with testing beginning on PD 60. In Experiment 1, morphine-induced (0, 2.5, 5.0 or 10.0 mg/kg) antinociception was assessed using the tail immersion and hot plate tasks. In Experiment 2, morphine-induced (0, 2.5, 5.0, or 10.0 mg/kg) hyperthermia and locomotor activity were measured. Morphine caused an increase in antinociception, with early methylphenidate (5.0 mg/kg) exposure potentiating the effects of 5.0 mg/kg morphine. Rectal temperatures were elevated after morphine, with the greatest increase occurring in male rats. Methylphenidate potentiated the hyperthermic effects of morphine (10.0 mg/kg) but only in males. Moderate doses (2.5 and 5.0 mg/kg) of morphine increased the locomotor activity of adult rats, while a higher dose (10.0 mg/kg) decreased locomotion. Interestingly, methylphenidate-pretreated females showed increased locomotor activity relative to controls. These results suggest that early methylphenidate exposure induces general changes in opioid system functioning that are not specific to reward-mediated behaviors.     

The dopaminergic stabilizer pridopidine decreases expression of l-DOPA-induced locomotor sensitisation in the rat unilateral 6-OHDA model

Treatment-limiting motor complications occur in patients with Parkinson's disease after chronic levodopa (l-DOPA) treatment, and represent an unmet medical need. We examined the motor and neurochemical effects of the dopaminergic stabilizer pridopidine (NeuroSearch A/S, Ballerup, Denmark) in the unilateral rodent 6-OHDA lesion model, which is often used to evaluate the potential of experimental compounds for such dopamine-related motor complications. In total, 72 rats were hemi-lesioned and allocated to receive twice-daily injections of either vehicle; 6.5 mg/kg l-DOPA; l-DOPA+25 μmol/kg pridopidine; or l-DOPA+25 μmol/kg (?)-OSU6162—a prototype dopaminergic stabilizer used previously in 6-OHDA hemi-lesion models. Animals were treated for 7, 14 or 21 days, and locomotor activity and ex vivo brain tissue neurochemistry analysed. In agreement with previous studies, l-DOPA sensitised the motor response, producing significantly more contralateral rotations than vehicle (P<0.05). Concomitant administration of pridopidine and l-DOPA significantly decreased the number of l-DOPA-induced contralateral rotations on day 7, 14 and 21 (P<0.05 versus l-DOPA alone), while still allowing a beneficial locomotor stimulant effect of l-DOPA. Concomitant pridopidine also reduced l-DOPA-induced rotation asymmetry (P<0.05 versus l-DOPA alone) and had no adverse effects on distance travelled. Brain neurochemistry was generally unaffected in all treatments groups. In conclusion, pridopidine shows potential for reducing motor complications of l-DOPA in Parkinson's disease and further testing is warranted.     

Differential anxiogenic,aversive, and locomotor effects of THC in adolescent and adult rats

Rationale Unpleasant side effects of drugs of abuse often limit their repeated use; however, such effects may be attenuated in adolescents compared to adults. Objectives We investigated whether the anxiogenic, aversive, or locomotor effects of delta-9-tetrahydrocannabinol (THC) differ between adolescent and adult rats. Methods We used the elevated plus maze (EPM) and light-dark tests of anxiety, the conditioned taste aversion and conditioned place aversion (CPA) tests of generalized aversion, and measures of stress hormone levels in serum to examine effects of THC in adolescent and adult rats. Locomotor activity was also recorded in the EPM, light-dark task, and CPA association sessions. Results In the EPM and light-dark tasks, THC was anxiogenic in both age groups, but the drug was more anxiogenic in adults than in adolescents. In the place and taste aversion tasks, THC was aversive in both ages, and at 1.25 and 5 mg/kg, was more aversive in adults than in adolescents. The locomotor response to THC, as measured in the anxiety tasks and CPA, affected adults more than adolescents. Multiple measures revealed a locomotor-decreasing effect in adults, whereas some measures suggested a small locomotor-increasing effect in adolescent rats. Conclusions These results suggest that THC can have greater anxiogenic, aversive, and locomotor-reducing effects in adult rats than in adolescent rats. These findings suggest an explanation for reduced marijuana use in adult humans compared to teenagers.     

Brain self-stimulation, locomotor activity and tissue concentrations of ethanol in male rats

These studies were aimed at correlating the effects of ethanol on operant behavior and on locomotor activity with its distribution in selected tissues in the body. One group of male rats was trained on a continuous reinforcement schedule for intracranial self-stimulation (ICSS) with electrodes in the lateral hypothalamus. Another group was studied in a locomotor activity apparatus, and both groups were given ethanol intraperitoneally over the dose-range 0.3-1.7 g/kg. Urine was collected 15 min and 60 min after ethanol administration and samples of blood, brain, heart, lung, liver, muscle and testis were obtained at both time points. Depressions of ICSS and of locomotor activity occurred, and these changes in behavior were correlated with increasing concentrations of ethanol in blood, urine and tissue. Thus, the disrupting effects of ethanol on behavior which occurred shortly after its acute administration were closely linked to its concentrations throughout the body.     

Effects of voluntary alcohol intake on nicotine-induced behavioural sensitisation in rats

Behavioural sensitisation has been suggested to play a role in the acquisition and maintenance of addictive behaviour. The aim of the present study was to assess nicotine-induced behavioural sensitisation in chronic voluntary alcohol drinking rats. Subjects had free access to alcohol/water or glucose/water solutions since weaning. Rats were pretreated after 2 months of voluntary alcohol drinking. Pretreatment consisted of once-daily intraperitoneal injection of nicotine (0.5 mg/kg) or saline administered for five consecutive days. The nicotine-induced behavioural sensitisation of locomotor activity was tested 3 weeks latter. Horizontal motor activity was monitored for 30 min and expressed as distance travelled (in centimetres). During all the experimental procedure, the animals were maintained under 1-h limited access to alcohol. In glucose-drinking animals, results indicated that nicotine induced locomotor activity sensitization: The locomotor effects of nicotine challenge in the nicotine-pretreated group of rats were significantly enhanced as compared with the saline-pretreated group (Duncan, P<.01). Instead, in the alcohol-drinking animals, no significant differences were observed between the nicotine- and saline-pretreated groups. Thus, chronic alcohol consumption at mild doses prevented the development and/or the long-term expression of the nicotine-induced sensitisation at the doses tested.     

LSD-induced alterations of locomotor patterns and exploration in rats

A free exploration test was used to examine the effects of LSD on investigatory responding and locomotor activity in a novel environment. Rats were injected with 20–30 g/kg LSD or saline prior to being placed in a home cage. After 10 min, a door was opened permitting entry into a larger holeboard chamber where crossovers, rearings, hole pokes, and routes of locomotion were monitored. When administered either 10 or 30 min prior to testing, LSD reduced the time spent in the holeboard chamber only during the first half of a 1-h session, resulting in a corresponding reduction in all holeboard activity measures. In the subsequent 30 min, LSD-treated rats maintained a steady level of responding, in contrast to the continual derement exhibited by controls. Despite their initial avoidance of the holeboard, LSD-treated rats made consistently longer hole pokes into floor holes and showed a more diversified pattern of locomotion than did controls throughout the 1-h session. Most striking was the failure of LSD-treated rats to establish the stereotyped excursion routes, characteristic of controls, from the home cage to various parts of the holeboard. It is suggested that LSD potentiates both neophobic (avoidance) and investigatory responses to a novel environment by retarding the rate of behavioral habituation.     

Effects of nicotine, caffeine, and their combination on locomotor activity in rats.

The interactive effect of caffeine and nicotine on spontaneous locomotor activity in a tunnel maze was determined in nicotine-naive and nicotine-tolerant rats. Rats were daily injected subcutaneously for 12 days with nicotine (0.4 mg/kg) to induce nicotine tolerance. Nicotine-naive rats were injected with saline. During the next two days, they were exposed to a tunnel maze for two 6-min trials. On the third day, locomotor activity was measured (30-min trial) in the tunnel maze 15 minutes after subcutaneous injection of saline, nicotine (0.2 mg/kg), caffeine (8 mg/kg), or nicotine (0.2 mg/kg) and caffeine (8 mg/kg) in combination. Acute exposure to nicotine decreased locomotor activity in nicotine-naive rats. This decrease was antagonized by simultaneous injection of caffeine. Chronic nicotine exposure induced the development of tolerance to the acute behavioral depressive effects of nicotine. In nicotine-tolerant rats, caffeine and nicotine in combination significantly increased locomotor activity above saline level, whereas given alone they had no significant stimulant effect. Neither chronic nicotine treatment nor acute drug treatments affected exploratory efficiency of rats.     

Alterations in beta-endorphin-induced locomotor activity in morphine-tolerant rats

Locomotor activity was monitored following administration of morphine or β-endorphin in rats pretreated for 9 days with either saline or morphine. Morphine pretreatment resulted in qualitatively similar alterations in the biphasic response patterns to morphine and β-endorphin. These results suggest that the same underlying mechanisms subserve the behavioral effects produced by opiates and opioid peptides.     

Sex-dependent changes in ketamine-induced locomotor activity and ketamine pharmacokinetics in preweanling,adolescent, and adult rats

Although ketamine has long been known to increase locomotor activity, only recently was it realized that this behavioral effect varies according to both sex and age. The purpose of the present study was threefold: first, to measure the locomotor activating effects of ketamine in male and female rats across early ontogeny and into adulthood; second, to assess ketamine and norketamine pharmacokinetics in the dorsal striatum and hippocampus of the same age groups; and, third, to use curvilinear regression to determine the relationship between locomotor activity and dorsal striatal concentrations of ketamine and norketamine. A high dose of ketamine (80 mg/kg, i.p.) was administered in order to examine the complete cycle of locomotor responsiveness across a 280-min testing session. In separate groups of rats, the dorsal striata and hippocampi were removed at 10 time points (0–360 min) after ketamine administration and samples were assayed for ketamine, norketamine, and dopamine using HPLC. In female rats, ketamine produced high levels of locomotor activity that varied only slightly among age groups. Male preweanling rats responded like females, but adolescent and adult male rats exhibited lesser amounts of ketamine-induced locomotor activity. Ketamine and norketamine pharmacokinetics, especially peak values and area under the curve, generally mirrored age- and sex-dependent differences in locomotor activity. Among male rats and younger female rats, dorsal striatal ketamine and norketamine levels accounted for a large proportion of the variance in locomotor activity. In adult female rats, however, an additional factor, perhaps involving other ketamine and norketamine metabolites, was influencing locomotor activity.     

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.