Mouse locomotor activity: Effect of morphine,narcotic antagonists,and the interaction of morphine and narcotic antagonists

Morphine-induced locomotor activity in mice has been investigated but there appear to be only a small number of reports on the effects of narcotic antagonists on this increased activity. Also, it is well known that some narcotic antagonists can act as both morphine antagonists and analgesics in nociceptive assays, but there have been few demonstrations of this stimulant and antagonistic action with locomotor activity studies. In this study, six compounds (cyclazocine levallorphan, diprenorphine (M-5050), nalorphine, naloxone, and naltrexone) have been investigated in regard to their activity as antagonists of morphine-induced locomotor activity and in regard to their ability to stimulate locomotor activity themselves. All six compounds antagonized the effect of morphine, but only cyclazocine and levallorphan produced any significant stimulation of locomotor activity by themselves at the doses tested. This study indicates that changes in mouse locomotor activity can be used successfully to monitor the interaction between morphine and narcotic antagonists and that locomotor activity studies can also be used to study the stimulant (agonist) properties of narcotic antagonists.Supported in part by NIMH Contract No. HSM-42-72-167.The research was carried out with animals maintained in animal care facilities fully accredited by the American Association for Accreditation of Laboratory Animal Care.     

Effects of repeated DSIP and DSIP-P administration on the circadian locomotor activity of rats

Daily intravenous evening injections of 30 nmol/kg DSIP (Delta Sleep-Inducing Peptide) in rats adapted to a constant 24 hr light:dark cycle produced changes in the circadian locomotor behavior. After 3 days the normally high locomotor activity during the dark phase was reduced while during the light (sleeping) phase the animals became relatively more active. Similar, but more rapid and more marked changes were observed (with the same schedule of injections) after 0.1 nmol/kg DSIP-P (the analogue of DSIP phosphorylated at the serine in position 7). In fact the peptide and its analogue induced a relative reversal or shift of the circadian locomotor activity phases opposite to the persisting light:dark conditions (=Zeitgeber). This suggests that DSIP exerts rather complex “programming” effects on the circadian activities and has more than just a sleep-inducing activity.     

The effect of cyproheptadine on hunger,calorie intake and body weight in man

The appetite stimulating action and the weight gaining potential of one month's treatment with the antihistamine and antiserotonergic compound cyproheptadine (Periactin) 4 mg three times daily was compared to placebo in a double-blind crossover trial in sixteen thin but otherwise normal volunteers who wanted to gain weight. Subjects gained significantly more weight on cyproheptadine than on placebo. There was also a corresponding relative increase in subjective hunger ratings and food intake during the period on active drug. Drowsiness was the most frequent side effect observed. These findings are discussed in relation to a possible serotonergic feeding mechanism.     

Conditioning and place-specific sensitization of increases in activity induced by morphine in the VTA

The conditionability of increases in locomotor activity induced by morphine administration into the ventral tegmental area was studied in rats. Morphine produced a clear increase in locomotor activity that was reversed by the opiate receptor blocker, naloxone, and blocked by the neuroleptic, pimozide, suggesting the mediation of this effect by the ascending mesolimbic dopamine system. The increase in locomotor activity showed sensitization with repeated morphine administrations and this sensitization was found to be specific to the environment in which morphine was administered. Conditioning tests also revealed that, in the absence of morphine, increased locomotor activity was elicited by the administration environment. Pimozide blocked the development of the conditioned sensitization. These data demonstrate that a learned association developed between this excitatory action of morphine and the administration environment. These results have important implications for the role of conditioning factors in relapse to drug use and may provide an explanation for conditioning data obtained when morphine is administered systemically.     

Intraventricular injections of L-dopa: the effect on rat locomotor activity and body temperature

Intraventricular injections of microgram quantities of L-Dopa to unanesthetized rats stimulate locomotor activity and promote hypothermia. Locomotor stimulation is potentiated by nialamide pretreatment, and seems to be caused by the action of dopamine formed on the central dopamine receptor. The development of hypothermia is unaffected by nialamide and spiroperidol.     

Effects of nicotine on body weight and food consumption in rats

Recent human and animal studies have found that cigarette smoking or nicotine administration is accompanied by decreased consumption of sweet-tasting, high caloric foods. Cessation of smoking or nicotine is accompanied by increased consumption of these foods. Changes in consumption of these specific foods may partially account for the inverse relationship between smoking or nicotine and body weight. The present research was designed to determine whether consumption of nonsweet food is affected by nicotine and whether continuous access to only nonsweet foods attenuates the body weight changes associated with nicotine administration and cessation of nicotine administration. Alzet miniosmotic pumps were implanted SC to administer saline or three different concentrations of nicotine to male Sprague-Dawley albino rats for 2–3 weeks. Two studies on a total of 80 rats found an inverse dose-response relationship between nicotine administration and body weight without changes in bland food or water consumption. After cessation of nicotine administration, there were no differences in food consumption or body weight changes between groups. The effects of nicotine on body weight, both during and after drug administration, were attenuated in comparison to the results of studies that provided sweet-tasting foods.     

The effects of intraventricular 6-hydroxydopamine and 5,6-dihydroxytryptamine on morphine induced locomotor stimulation

Summary Morphine has a biphasic action on locomotor activity in rats but in mice it mainly causes hyperactivity. The effects of intraventricular 6-hydroxydopamine and 5,6-dihydroxytryptamine (5,6-DHT) on the time course and intensity of the locomotor stimulation were examined in the two species. Pretreatment with 6-OHDA or 5,6-DHT significantly reduced the peak locomotor response of grouped mice and depleted cerebral catecholamines (mostly noradrenaline) and 5-hydroxytryptamine respectively. Pretreatment of mice with 6-OHDA and a monoamine oxidase (MAO) inhibitor depleted dopamine more than 6-OHDA alone and restored the morphine-induced hyperactivity to near normal. d- Amphetamine caused a hyperactivity response similar to morphine in mice but, in contrast to morphine, the peak d-amphetamine locomotor response was not affected by either 6-OHDA or 5,6-DHT. However, in both cases the duration of the d-amphetamine response was shortened and pretreatment with 6-OHDA and the MAO inhibitor potentiated the peak locomotor response.The hyperactivity response produced by morphine in rats, which followed a period of reduced activity, was only slightly diminished by 6-OHDA and 5,6-DHT but was almost completely abolished by pretreatment with 6-OHDA and the MAO inhibitor.These results, which emphasize differences in the way morphine affects monoamine neurones in rats and mice, suggest that morphine relies on catecholamines and 5-hydroxytryptamine to increase motor activity in mice whereas in the rat dopamine and 5-hydroxytryptamine are probably most important in this respect.     

Effects of nicotine on body weight and food consumption in female rats

Women often report that they smoke cigarettes to avoid weight gains and that they relapse after abstaining from tobacco because of weight gains. Men also report these concerns but to a lesser extent. This gender difference may reflect sociological and cultural pressures about physical appearance, or it may reflect sex differences in the effects of nicotine. The present research was designed to examine the effects of nicotine administration and cessation of nicotine on body weight, food consumption, and water consumption. Alzet miniosmotic pumps were implanted SC to administer saline or three different concentrations of nicotine to female Sprague-Dawley rats for 17 days. This paradigm has been used in previous studies of nicotine and body weight in male rats. Animals were used as subjects to avoid cultural factors and cognitive concerns about body weight. Nicotine administration decreased normal body weight gains and cessation of nicotine was accompanied by significant increases in body weight compared to controls. In contrast to previous studies of male rats, the nicotine-related changes in body weight were accompanied by changes in bland food and water consumption. These findings indicate that females are more sensitive than males to the effects of nicotine on body weight and feeding during and after drug administration.     

Effects of nicotine on body weight in rats with access to “Junk” foods

The present experiment examined effects of nicotine on body weight of male and female rats when Oreo cookies, potato chips, laboratory chow, and water were available. Body weight and eating behavior were measured for 17-day periods before, during, and after nicotine or saline administration. There was an inverse relationship between nicotine and body weight. These effects were paralleled by changes in consumption of sweet foods. There were no effects of nicotine on salty or bland food consumption. Excessive gains in body weight after cessation of nicotine administration were greater for females than for males.     

A dissociation of the effects of d-amphetamine on locomotor activity and exploration in rats

A modified Berlyne Box was used to obtain independent measures of locomotor activity and exploration of novel stimuli in the same situation. 1.5 mg/kg of d-amphetamine was found to stimulate locomotor activity and decrease exploratory behaviour when compared with a control group. These behaviours were found to be compatible in undrugged animals when distributed over the 10 min trial. The results are discussed in terms of drug-induced response incompatibility rather than with recourse to motivational explanations.S.R.C. Scholar.     

Effects of antagonists upon locomotor stimulation induced by injection of dopamine and noradrenaline into the nucleus accumbens of nialamide-pretreated rats

The effects of injections of monoamines, alone and in combination with different antagonists, bilaterally into the nucleus accumbens of nialamide-pretreated rats were investigated.Dopamine was found to produce a stronger stimulation of locomotor activity than noradrenaline, whereas serotonin was effective only in a small number of animals, in which the duration of locomotor stimulation was shorter than after dopamine or noradrenaline. The effects of both dopamine and noradrenaline were completely antagonized by administration of a small dose of the dopamine antagonist haloperidol, administered bilaterally 15 min after the catecholamines. The -adrenergic antagonist phentolamine did not inhibit the effect of noradrenaline but, on the contrary, potentiated and considerably prolonged the duration of locomotor stimulation. Also, the effect of dopamine was potentiated and prolonged by phentolamine. Bilateral injection of phentolamine alone had no influence upon locomotor activity. The effect of noradrenaline was not clearly inhibited nor potentiated by the -adrenergic antagonist propranolol. It is suggested that the stimulation of locomotor activity induced by injection of noradrenaline into the nucleus accumbens of nialamide-pretreated rats is brought about via dopaminergic mechanisms.     

Effect of tetraethyl lead and restricted food intake on locomotor activity in the rat

The effect of tetraethyl lead (TEL) and restricted food intake on spontaneous locomotor activity in male albino rats was investigated. Forty animals were injected intraperitoneally with 4, 7, 10 or 13 mg/kg body weight of TEL in peanut oil, or a peanut oil placebo. Forty additional animals were food yoked to lead treated animals as a control procedure to hold food intake constant between lead treated and lead free animals. A comparison of pre- and posttreatment measures revealed significant decreases in food intake and increases in activity levels at dosages of 7, 10 and 13 mg/kg of TEL. In addition, food intake and activity were significantly correlated in both lead treated and yoked groups. The issue of factors associated with reduced food intake playing a role in observed activity level increases was raised.     

Effects of chronic phenylpropanolamine infusion and termination on body weight,food consumption and water consumption in rats

The present study determined the effect of chronic PPA infusion and withdrawal on weight regulation. Male Sprague-Dawley rats received PPA (0, 90 or 180 mg/kg) via miniosmotic pumps for 2 weeks. Body weight and food and water consumption were measured daily before, during, and for 2 weeks after PPA infusion. Additionally, body weight was measured once 6 weeks after the last day of drug administration. PPA infusion produced dose-dependent reductions in body weight and food consumption throughout drug administration. During the first week of PPA termination, food consumption returned to control levels; however, body weights of drug-treated animals remained below those of controls throughout the 6-week post-drug period. PPA depressed water intake during the first week of drug administration, but tolerance to this effect developed by the second week of administration. These results suggest chronic PPA infusion produces persistent appetite suppression and weight loss and that discontinuation of PPA does not result in hyperphagia or rapid weight gain. These findings may have clinical significance for the many individuals who wish to lose weight but have difficulty reducing intake without pharmacologic assistance.     

Effects of morphine on striatal dopamine metabolism: Possible mechanism of its opposite effect on locomotor activity in rats and mice

In rats, the catalepsy induced by analgesic doses of morphine was paralleled by a dose-dependent increase in the concentration of dopamine's (DA) metabolite, homovanillic acid (HVA) in the striatum. The effect of morphine on striatal HVA was supra-additive with the corresponding action of chlorpromazine (CPZ). It is concluded that in rats morphine induces catalepsy and a decrease in dopaminergic activity in the striatum by a mechanism different from that of other cataleptogenic agents, such as the neurologic CPZ. In mice, morphine induced an increased in locomotor activity (running); this effect was attenuated by bilateral lesions placed in the caudate nucleus. Pretreatment of mice with diethyldithiocarbamate (DDC), or d,l-α-methyl-p-tyrosine (αMT), inhibited the morphine-induced running activity. In αMT-treated mice 1-3,4-dihydroxyphenylalanine (l-dopa) restored the effectiveness of morphine whereas d,l-threo-3,4-dihydroxyphenylserine (dops) was ineffective. In contrast, in DDC-treated mice, dops and clonidine, but not 1-dopa, were effective in restoring morphine's effectiveness. Doses of morphine inducing running activity in mice produced a slight increase in striatal HVA level. It is concluded that in mice morphine produces locomotor hyperactivity by releasing DA from the presynaptic terminals in the striatum, thus increasing the dopaminergic activity in this structure. Norepinephrine has an important auxiliary function.     

The effect of p-chlorophenylalanine on the pethidine- or methadone-induced decrease in locomotor activity of rats.

Either pethidine HCl (50 mg/kg s.c.) or methadone HCl (8 mg/kg s.c.) produced a prominent decrease in locomotor activity of rats. Pretreatment of rats with p-chlorophenylalanine (p-CPA, 320 mg/kg i.p.) 48 h before the narcotic injection significantly antagonized the activity-decreasing effects of narcotics. When rats pretreated with p-CPA were given 5-hydroxytryptophan (75 mg/kg s.c.) 30 min before narcotic administration, the activity-decreasing response to narcotics was restored. Thus, a decrease in locomotor activity induced in rats by either pethidine or methadone is probably mediated by serotonergic mechanisms.     

The effect of d-amphetamine and amitriptyline administered to pregnant rats on the locomotor activity and neurotransmitters of the offspring

d-Amphetamine and amitriptyline (AT) were administered daily to female rats from day 7 of pregnancy until birth of the litters. Changes in the concentration of the biogenic amines, some of their metabolites, GABA, and the activities of glutamate decarboxylase, acetylcholinesterase (AChE), and choline acetyltransferase were determined in the whole brain of the offspring. The offspring of the amphetamine-treated rats showed a marked increase in serotonin concentration and that of its metabolite on postnatal day 1. Changes in the concentration of GABA were apparent on days 15 and 21 and were inversely correlated with changes in the activity of the synthesizing enzyme: Choline acetyltransferase and AChE activities were also increased at this time. Changes in neurotransmitter metabolism were not so evident in the offspring of rats treated with AT. The locomotor activity of the 8-, 15-, and 21-day offspring was also assessed. The offspring of the amphetamine-treated rats showed enhanced locomotor activity initially, but the activity decreased relative to the age-matched controls in the 21-day group. Offspring from the AT-treated group showed reduced locomotor activity.     

Influence of tetrahydrocannabinols (delta8-THC and delta9-THC) on body weight, food, and water intake in rats

Female Wistar rats, six to a group, were injected daily for a 23-day period with Δ⁸-THC (5.0 mg/kg), Δ⁹-THC (2.5 mg/kg) or vehicle. Body weight, food and water intake were recorded every second day. It was found that Δ⁸-THC caused a decrease of body weight, to a level maintained throughout the injection period, with only slight signs of recovery. Both drugs caused a marked decrease of water intake. Food intake was not significantly affected by the drugs. Factors in relation to the effects of THC on body weight, food and water intake are discussed.     

An assessment of the spontaneous activity of rats administered morphine,phencyclidine, or nicotine using automated and observational methods

The effects of morphine, phencyclidine, and nicotine on motor activity in rats were characterized using both observational and automated methods. Activity was scored observationally using a time-sampling method that tabulates discrete response categories (still, locomotion, rearing, sniffing, licking, gnawing, head down, swaying, grooming, falling). Behavior was assessed automatically using an activity monitor that records both the time and activity counts spent in large and small (less than 3 cm) movements, rearing, and resting. The following results using male Sprague-Dawley rats represent significant differences from saline-treated controls. Morphine (1–4 mg/kg SC) increased the incidence of locomotion, sniffing, swaying, and grooming depending on the time after drug injection. These changes corresponded to an increase in large and small movement counts and time as measured by the activity monitor. Phencyclidine (1.25–5 mg/kg SC) caused dose-related increases in the incidence of locomotion, sniffing, swaying, and falling, and induced greater large and small activity movement counts and time especially after the 5 mg/kg dose. Nicotine (0.033–0.33 mg/kg SC) decreased the incidence of rearing and increased the frequency of sniffing and grooming. These changes corresponded to a decrease of rearing activity and to a slight increase in small activity. The present data indicate that morphine, phencyclidine, and nicotine exert dose-related and time-related appearances of various categories of behavior in the rat, and that the data from the automated method complement the findings of the direct observational method.     

Differential effects of chronic naltrexone treatment on food intake patterns and body weight in rats depend on their food deprivation status

The aim of the present study was to assess the effect of chronic naltrexone treatment on daily patterns of food intake in food-deprived and free-feeding rats. In experiment 1, Wistar male rats had continuous access to food and water, while in experiment 2 they were deprived of food for 12 h/day. Animals in both experiments were studied as follows: a baseline period (7 days), followed by a treatment period (14 days) with either saline or naltrexone at 10 mg/kg/day. Finally, a post-treatment period (7 days) was assessed. Food and water consumption were measured every 2 h after the naltrexone or saline injection for 12 h and once more 12 h later. Experiment 1: Food intake was higher in the naltrexone group 10 h after injection. Total food intake and body weight gain were higher in the naltrexone group than in the saline group in the second week of treatment and in the post-treatment period. Experiment 2: The overeating observed in the saline group in the hours following the 12 h of the food deprivation period was suppressed by naltrexone, though total daily food intake was not affected. Body weight gain was initially reduced by naltrexone, but a rebound effect was observed during the post-treatment period in the naltrexone group. Naltrexone produced a differential effect on food intake and body weight that depended on the rats' food deprivation status. These results could be explained in terms of opioid receptor up-regulation that enhances the rewarding effects of food or by naltrexone-produced changes in palatability.