Motor activity induced by substance P in rats

The effects of intraventricular injections of various doses (20.00, 5.00, 1.25, 0.30 and 0.07 μg) of synthetic Substance P on motor activity in rats were investigated. Activity scores as determined by photocell counts recorded for a 15 min test period were significantly increased in animals injected with 0.30 and 1.25 μg/rat Substance P. The other doses examined did not affect activity. Doses in the range of 40–80 μg produced immobility, rigidity and barrel rotations. Hypersalivation as indicated by a wet fur following an episode of grooming was observed in several animals. Administration of Substance P, in a dose of 0.60 μg, in combination with or 30 min after injections of 2 mg/kg d-amphetamine and 1 mg/kg apomorphine did not potentiate or reduce the increased activity and stereotypy induced by these two drugs.     

An open field study of stereotyped locomotor activity in amphetamine-treated rats

It is said that amphetamine induces stereotypy and locomotion in rats; however, the present paper shows amphetamine-induced stereotyped locomotion by analyzing the route of locomotion in an open field. Details of the analysis are given, normal as well as stereotypic features are discerned, and the results are discussed in relation to contemporary views on locomotion and exploration and on the mechanisms of amphetamine effect.     

Dopaminergic mediation of the interoceptive cue produced by d-amphetamine in rats

After rats were trained to differentiate between the effects of d-amphetamine and saline in a state-dependent task, pretreatment with the tyrosine hydroxylase inhibitor, -methyl-p-tyrosine, significantly decreased amphetamine discrimination. Pretreatment with the dopamine--hydroxylase inhibitor, disulfiram, or with the tryptophan hydroxylase inhibitor, p-chloro-phenylalanine, was observed to have no effect on the rats' ability to discriminate d-amphetamine. Administration of haloperidol, a selective dopamine receptor blocker, completely abolished the amphetamine discrimination, whereas - and -adrenergic receptor blockade had no effect. Apomorphine, a dopamine receptor stimulant, produced amphetamine-like responses and this was, likewise, abolished by pretreatment with haloperidol. These data suggest that dopaminergic systems mediate the interoceptive cue produced by d-amphetamine in rats, and these results are discussed in relation to possible dopamine mediation of amphetamine psychosis and paranoid schizophrenia.Supported as an Americal Medical Association Education and Research Foundation Senior Research Fellow.     

Reduction of dopaminergic supersensitivity by a single dose of amphetamine

Summary Chronic administration of haloperidol in rats resulted in a supersensitivity to apomorphine-induced stereotypy. This behavioral supersensitivity was reduced by a single administration of d-amphetamine given 2 days after the termination of haloperidol injections. The reduction of haloperidol-induced supersensitivity by amphetamine lasted for at least 3 days after amphetamine injection.     

The effects of l-, d-, and parahydroxy-amphetamine on locomotor activity and wall climbing in rats of different ages

In the first experiment, 15, 17, 21, 36, 90, and 275-day-old rats were injected with either physiological saline, 0.5, 1.0, 4.0, 8.0, or 16.0 mg/kg of l-amphetamine. In Experiment 2, rats of these ages were injected with saline or comparable doses of d-amphetamine. Starting immediately after the injection, photo-cell crossings and wall climbing were recorded during 15-min intervals for a total of 4 hours. In general, photo-cell crossings in 15-day-old rats were increased more by low doses than higher doses. In 17 and 21-day-old rats, the peak in the dose response curve gradually shifted toward higher doses, until, at 36 days of age, low doses produced no significant change in photo-crossings and the highest doses produced the maximum increase. In the two oldest ages, the dose-response curves for photo-crossings were the typical inverted U function. In adults, d-amphetamine had a more potent action on photo-cell crossings than l-amphetamine. However, in other ages, l-amphetamine appeared to be slightly more potent than d-amphetamine or there were no potency differences between the two isomers. Low doses of both d- and l-amphetamine increased wall climbing in the three youngest ages but higher doses were without effect. In 36-day-old rats, wall climbing was slightly increased by 4.0 mg/kg of d-amphetamine but no dose of either isomer altered wall climbing in adults. Since amphetamine appears to produce behavioral changes by acting on catecholamines, the age-dependent behavioral effects of amphetamine may be due to maturation of central nervous system catecholaminergic neurons. However, involvement of other neurotransmitter systems can not be excluded. In Experiment 3, parahydroxy-amphetamine (1.0, 4.0, and 16.0 mg/kg) did not significantly alter photo-cell crossings or wall climbing in 15, 17, 21, 36, or 90-day-old rats. Because parahydroxy-amphetamine has only peripheral effects, it appears likely that central actions are responsible for the age-dependent behavioral effects of l- and d-amphetamine.     

Differential effects of the new antipsychotic risperidone on large and small motor movements in rats: a comparison with haloperidol

Risperidone, a new antipsychotic agent, was studied for its effects on spontaneous motor activity in rats in comparison with haloperidol. Motor activity was recorded via the optical scanning technique (horizontal and vertical activity) and via a recently developed technique based on the piezo-electric principle which, in contrast to optical scanning, is very sensitive to small, stationary movements (piezo activity). Risperidone and haloperidol at low doses depressed both vertical activity (ED₅₀s: 0.062 and 0.038 mg/kg, respectively) and horizontal activity (0.18 and 0.060 mg/kg, respectively). With increase of dose, motor activity decline was significantly faster with haloperidol than with risperidone. Moreover, haloperidol also rapidly depressed piezo activity (ED₅₀: 0.085 mg/kg) whereas risperidone depressed this component of motor behaviour at much higher doses only (ED₅₀: 2.80 mg/kg). Visual inspection did not reveal abnormal behavioural movements following the test compounds. Risperidone, therefore, preserves normal small movements over a much larger dose interval than haloperidol; this effect may be related to its relatively low cataleptogenic activity and potentially also to a reduced EPS liability. The present results further confirm that the piezo technique may complement the optical scanning method, and thereby enhance the information on the extent that test compounds modify behaviour.     

Effects of amphetamine and apomorphine on locomotor activity after kainic acid lesion of the nucleus accumbens septi in the rat

Kainic acid injections into the nucleus accumbens in rats induced severe loss of neuronal perikarya and the presence of gliosis in its vicinity, without affecting more distant areas. Spontaneous locomotor activity was elevated in the lesioned rats. After a low dose of d-amphetamine (1.5 mg/kg) no significant differences in locomotor activity were found between lesioned and sham-operated rats, while the increase in locomotor activity normally induced by a moderate dose of apomorphine (1 mg/kg) was blocked in lesioned rats. These results indicate that although dopamine receptors on the nucleus accumbens neurons are involved in the mechanisms mediating locomotor behaviour, the locomotor stimulant effect of d-amphetamine is not exclusively dependent on intra-accumbens dopaminergic activity.     

A comparison of the effects of amphetamine,apomorphine and white noise on response switching in the rat

The effects of d-amphetamine, apomorphine and white noise on response switching in the rat were examined using a schedule of reinforcement which resulted in the subjects displaying a range of different probabilities of switching. The procedure was analogous to the use of a fixed interval schedule of reinforcement for examining the ratedependent effects of drugs. d-Amphetamine (0.4–4.0 mg/kg) increased response switching in a manner dependent both upon the dose of drug and the baseline probability of switching. Apomorphine (0.01–0.3 mg/kg) increased switching in a manner which depended upon dose but which was independent of the baseline probability of switching. Neither drug increased response rate, although both drugs reduced response rate at the highest doses. In contrast, continuous white noise (85–105 dB) increased response rate without affecting switching. The results indicate that different activating stimuli may have qualitatively different effects on behaviour.     

Effects of chronically administered nicotine and saline on motor activity in rats

This study investigated the differential effects of chronically administered nicotine and saline on motor activity in the rat. Nicotine was administered via a subcutaneously implanted osmotic minipump to effect an 8 hour off, 16 hour on, flow. Subjects were 48 male and 48 female albino rats, each about 165 days old. Activity was monitored every hour for 192 consecutive hours. Results indicated that the female animals were more active than the males, and that animals receiving nicotine were significantly more active on the first two days of drug administration than control animals; however, by the fourth day there were no significant differences between the activity levels of animals that received nicotine and those of control animals.     

Sources of variation in locomotor activity and stereotypy in rats treated with d-amphetamine

Rats injected with doses of d-amphetamine 0–5.0 mg/kg were observed continuously in either an enclosed Y-maze or on an elevated Y-shaped platform. Patterns of increased walking and stereotypy were unaffected by the type of apparatus, but rearing remained totally suppressed at all dose levels on the elevated platform. In the second experiment, groups of rats where given single short tests in the enclosed Y-maze, which was novel to them. The stimulant actions of d-amphetamine on locomotion were obscured by high baseline levels of motor activity induced by the novel environment. Continuous measurements of habituated rats may provide a more sensitive means of evaluating stimulant actions of drugs in screening tests. The observed changes in patterns of onset and offset of increased locomotion and of stereotypy were consistent with the view that these types of behaviour are, to some extent, independently, mediated.     

Apomorphine-induced alterations in cortical EEG activity of rats

Summary EEG activity after activation of dopamine receptors of D-1 and/or D-2 type was studied by using telemetric recordings in rats. Apomorphine, a preferential D-2 agonist, produced a characteristic increase in the power of alpha-1 band (7.00–9.50 Hz) when given in doses mediating stereotypies (0.2 or 0.5 mg/kg s. c.). Low doses produced a general increase in the power of all of the bands except beta-2. In particular, delta activity was enhanced which seems to be in correspondence with the sedation observed after these doses (0.02 and 0.05 mg/kg). Haloperidol in a dose which is assumed to block both D-1 and D-2 receptors (0.1 mg/kg i. p.) completely antagonized the alpha-1 activation produced by apomorphine (0.5 mg/kg). A similar, although not complete inhibition of alpha-I activation was found after administration of a large dose of the selective D-1 antagonist SCH 23390 (0.2 mg/kg i. p.). The selective agonist at D-2 receptors quinpirole (1.0 mg/kg s. c.) produced a less pronounced activation of the power in the alpha-1 band than apomorphine.In general, there was found to be a good correlation between the activation of the alpha-1 activity and stereotyped behaviour. The results suggest that for the full expression of alpha-1 activation, a pronounced activation of D-2 receptors and at least a minimal activation of D-1 receptors, for instance by the endogenous dopamine, is necessary. Send offprint requests to K. Kuschinsky at the above address     

Enhancement of effects of dopaminergic agonists on neuronal activity in the caudate-putamen of the rat following long-term d-amphetamine administration

Amphetamine- and apomorphine-induced changes in the activity of neurons in the caudate-putamen of paralyzed, locally anesthetized rats were recorded in animals pretreated with 2.5 mg/kg d-amphetamine sulphate for 6, 18 or 36 days, or in animals pretreated with saline for 36 consecutive days. In saline-pretreated animals, 2.5 mg/kg d-amphetamine sulphate (IP) produced an initial, brief potentiation of neuronal firing that was followed by a marked depression of neuronal activity lasting for approximately 35 to 110 min after injection. In amphetamine-pretreated animals, this depression of neuronal activity to the same dose of the drug was markedly prolonged, especially in animals given 36 consecutive days of d-amphetamine pretreatment. A similar enhancement occured in response to 0.25 mg/kg apomorphine (IP) in animals pretreated with amphetamine for 36 days compared to saline-pretreated control animals. These results are discussed in relation to the known behavioral and biochemical effects of acute and long-term amphetamine administration.     

Effects of multiple pretreatment with apomorphine and amphetamine on amphetamine-induced locomotor activity and its inhibition by apomorphine

Mice were given a saline preinjection and habituation to the testing environment followed by injection of amphetamine (0.675–5.0 mg/kg IP) and apomorphine (AP, 15–80 g/kg SC) 15 min later. AP produced a dose-dependent inhibition of the amphetamine-induced locomotor activity. A dose of 40 g/kg AP increased approximately threefold the amphetamine dose required to induce the same increase in activity. Repeated administration of AP (30 mg/kg IP once daily for 14 days) resulted in an enhanced response (in the early portion of the time response) to amphetamine challenge, while the ability of subsequent microgram challenge doses of AP to reduce the response were unaffected. Similarly, repeated administration (twice-daily IP injections for 5 days) of amphetamine (5.0 mg/kg) resulted in an enhanced locomotor response to amphetamine challenge and no change in the ability of AP to inhibit the response. These results suggest that repeated administrations of dopamine agonists, although acting through different mechanisms (i.e., indirect versus direct), increase the initial release of neurotransmitter. However, the repeated administration of these agonists does not attenuate the ability of AP to inhibit the release of the neurotransmitter induced by amphetamine. The regulatory functions (i.e., presynaptic receptor control) of release appears to remain intact, but the level of neuronal activity has been increased.     

Effects of apomorphine and haloperidol on the acoustic startle response in rats

A series of 3 experiments tested the effects of 0.01, 0.04, 0.19, 0.75, 3.00, and 6.00 mg/kg apomorphine and 0.13, 0.25, and 0.50 haloperidol on the acoustic startle response in rats. Apomorphine markedly facilitated startle amplitude for about 40 min after injection and then depressed startle over the next 40 min. Both the early facilitory and later inhibitory effects were directly related to the dose. Haloperidol (0.5 mg/kg — given 30 min before) completely blocked both the early facilitory and the later depressant effect of apomorphine (3 mg/kg). Haloperidol alone had only a slight depressant effect on startle. The data support the conclusion that DA receptor stimulation enhances acoustic startle amplitude and indicate that a previous report failed to find an effect of apomorphine on startle because startle was only measured 40 min after injection.     

The effects of cimetidine on schedule-controlled responding and locomotor activity in rats

The effect of intraperitoneal injections of cimetidine, a selective histaminergic H₂-receptor blocking agent, on operant behavior and locomotor activity were examined in rats. Cimetidine (1–100 mg/kg) failed to show any significant effect on responding maintained under a fixed-ratio (FR) 30 fixed-interval (FI) 5-min schedule of food presentation. A higher dose of cimetidine (300 mg/kg) produced decreases in both FR and FI rates of responding. In contrast, 100 mg/kg of cimetidineincreased the response rate and decreased reinforcement rate in rats performing under a schedule requiring the temporal spacing of responses (DRL-10 sec). Cimetidine (10–300 mg/kg) did not induce significant changes in locomotor activity in the rat. These data suggest that cimetidine is more potent in altering the steady low rate of responding under a DRL schedule of food presentation, than responding maintained under a multiple FR FI schedule, and that cimitidine is even less potent in altering locomotor activity.     

The influence of haloperidol and amphetamine on two different noise-escape situations in rats

The learning process of two different noise-escape responses—lever pressing and jumping—was studied in the same rats using a shuttle box automatically transformable during the experimental sessions into two Skinner boxes. The effects of different doses of haloperidol and amphetamine were studied in rats overtrained in the two situations.The learning process was slower in the Skinner box than in the shuttle box. To reach the maximum response level in 50% of the rats 13 to 18 training sessions of 5 min were necessary in the shuttle box versus 31 to 36 in the Skinner box.Haloperidol prolonged the latency (T) and reduced the frequency (F and F) of both lever pressing (L) and jumping responses (J) to about the same extent at the same dose levels (lowest effective dose 0.04 mg/kg s.c.). At 0.005 mg/kg haloperidol slightly increased FL.At doses lower than 2.5 mg/kg, amphetamine decreased T in both the Skinner and the shuttle box and the ineffective responses (F) were increased up to 4 to 5 times their control values. The lowest effective dose was 0.16 mg/kg in the shuttle box (FJ) and 0.31 mg/kg in the Skinner box (FL). At 2.5 mg/kg amphetamine increased T and reduced F.     

Classical conditioning of amphetamine-induced lateralized and nonlateralized activity in rats

Amphetamine-induced lateralized activity (rotation) and nonlateralized activity (extra quarter turns) was classically conditioned in female rats using the test environment as the conditioned stimulus (CS) and 1.25 mg/kg d-amphetamine as the unconditioned stimulus. Conditioned lateralized activity extinguished more rapidly than nonlateralized activity. Also, d-amphetamine-induced nonlateralized activity was selectively decreased by a schedule of 50% partial reinforcement. These results indicate that the two d-amphetamine responses can be distinguished, that they are differentially affected by learning, and that a schedule of partial reinforcement can selectively attenuate one effect of a drug while leaving the other intact. In addition, haloperidol blocked conditioned lateralized activity; this suggests that the conditioned response may be, like the drug-induced response, mediated by dopamine.     

Amphetamine- and apomorphine-induced alteration of the behavior of rats submitted to a competitive situation in a straight runway

The influence of various doses of apomorphine and amphetamine on the behavior of rats submitted to a competitive situation for food in a straight runway was studied. Both drugs significantly increased the number of victories. Experiments performed to verify whether pretreatment with pimozide or chlorpromazine would antagonize this effect were not conclusive since the neuroleptics disrupted the competitive behavior of several animals and failed to block the increase of victories induced by apomorphine and amphetamine in the remaining rats. Larger doses of the neuroleptics could not be used because these stopped the animals competing. The possibility that apomorphine and amphetamine increased the number of victories by acting, respectively, through a direct effect on central dopamine receptors and by releasing dopamine from the storage sites, and the eventual role played by catecholamines on the competitive behavior studied are discussed.     

Role of dopaminergic neurotransmission in locomotor stimulation by dexamphetamine and ethanol

Locomotor activity and brain tyrosine hydroxylation rate in vivo, assessed as dopa formation following dopa-decarboxylase inhibition by NSD 1015, was studied in mice. Dexamphetamine 91 mg/kg IP) induced increases in locomotor activity even from the high control baseline activity during the first 5 min in a motility meter. Inhibition of catecholamine synthesis by -methyl-p-tyrosine (250 mg/kg) alone, given 30 min before test, reduced this high baseline locomotor activity, but such pretreatment did not affect the amphetamine-induced locomotor increase. The inhibition of synthesis itself was slightly attenuated by amphetamine. Low doses of apomorphine (0.1 and 0.2 mg/kg) markedly antagonized the initial locomotor increase by amphetamine but only incompletely antagonized the amphetamine-induced stimulation 15–30 min after the start of the recording. After reserpine pretreatment, apomorphine did not antagonize the amphetamine-induced locomotor stimulation. The data suggest that the release of transmitter causing behavioural stimulation by amphetamine is brought about via two independent mechanisms: facilitation of release from intact granular stores which is not critically dependent on continued catecholamine synthesis but is sensitive to receptor-mediated regulation, and facilitation of the release of newly synthesized transmitter, insensitive to such regulation. Results with ethanol suggest greater dependence on intact dopamine (DA) neurotransmission for the stimulatory effect of this drug. Dexamphetamine (4 mg/kg) caused a greater increase in striatal than in mesolimbic dopa formation, and apomorphine (0.2 mg/kg) only incompletely antagonized the effect in the former region. It is suggested that this difference reflects a relatively greater component of extrinsic feedback regulation of nigrostriatal neurones, the operation of which may contribute to a more pronounced increase in tyrosine hydroxylation, less sensitive to inhibition by apomorphine than that occurring in the mesolimbic nerve endings.     

Interaction of apomorphine and haloperidol: Effects on locomotion and other behaviour in the marmoset

The behavioural effects of increasing doses of apomorphine and haloperidol were observed in a group of six marmosets. Behaviour was classified quantitatively into categories: Locomotion, inactivity, checking (small head movements), social interaction and purposeful activities. Statistical analysis revealed that apomorphine had a stimulant effect on checking and locomotion which could be antagonized by haloperidol. Activities and social contact were severely reduced by both apomorphine and haloperidol. Inactivity was increased by the lowest dose of apomorphine in otherwise untreated animals. It is suggested that haloperidol antagonizes the stimulant effects of apomorphine but is synergistic to its suppressant effects, and that the low dose effect of apomorphine on inactivity is mediated by a mechanism which may be different from that acted upon by haloperidol.