Changes in behavioural contingencies produce a loss of tolerance to amphetamine hypophagia in rats despite continued feeding tests while drugged

Rats administered amphetamine prior to access to milk in bottles develop tolerance to the hypophagic effect of the drug by learning to suppress stereotyped behaviours that interfere with feeding. When tolerant rats are later allowed to drink milk from a bottle in an unintoxicated state, tolerance is lost, even when drug exposure is held constant by administration of the drug after the test. In the present experiment, we show that tolerance can also be lost in the face of continued administration of amphetamine prior to milk tests, as a result of changes in the contingencies of reinforcement that govern the suppression of stereotypy. Rats were injected with 2 mg/kg amphetamine and given access to milk in bottles for 16 trials. Tolerance to the hypophagic effect was confirmed by dose-response tests in which milk was available in bottles. The rats were then injected with 2 mg/kg amphetamine prior to intraoral milk infusions for 21 trials. This method of feeding did not require the suppression of stereotypy to obtain milk. Subsequent dose-response tests in which milk was again presented in bottles revealed that tolerance was lost, even though intoxicated feedings were never interrupted. These results demonstrate that the contingencies of reinforcement governing the suppression of stereotypy determine whether tolerance is retained or lost.     

Experiential constraints on the development of tolerance to amphetamine hypophagia following sensitization of stereotypy: instrumental contingencies regulate the expression of sensitization

 In previous research, sensitization of stereotypy induced by injections of 2.5 mg/kg amphetamine did not interfere with subsequent tolerance development to the hypophagic effect of 2 mg/kg. This study examined the effect of a higher sensitizing dose. Rats given intermittent injections of 5 mg/kg amphetamine and then challenged with various doses of amphetamine showed focused head scanning at 2 mg/kg and oral stereotypy at 4 mg/kg. In contrast, saline controls showed diffuse sniffing and head scanning at 2 and 4 mg/kg. Subgroups from each condition were then given daily injections of either amphetamine (2 mg/kg) or saline and access to milk for 30 min. Dose-response tests revealed that both drugged groups learned to suppress stereotypy in order to feed at 2 mg/kg, but only the non-sensitized group could do so at 4 mg/kg. These results demonstrate that (1) rats learn to suppress only those stereotyped movements that they experience in the context of feeding and (2) instrumental contingencies can influence the expression of behavioral sensitization. Received: 18 December 1997 / Final version: 3 June 1998     

Long-term retention of tolerance to amphetamine hypophagia following cessation of drug injections and feeding tests.

According to the instrumental learning model, tolerance to amphetamine hypophagia involves learning to suppress stereotyped movements that interfere with feeding. If both drug injections and feeding tests are then suspended, learning should be retained and no loss of tolerance should occur. However, previous studies have only assessed the retention of tolerance for 3-4 weeks. In the present study, retention intervals of 4-31 weeks were used. Rats were given daily injections of amphetamine (2 mg/kg) and access to milk for 30 min until tolerance developed to drug-induced hypophagia. Yoked controls were injected with saline. Both before and after this phase, dose-response (DR) tests were conducted. Drug injections and feeding tests were then suspended. At 4, 10, 18, and 31 weeks, both groups were injected with 2 mg/kg amphetamine and given access to milk for 30 min to assess the retention of tolerance. A final DR determination was then conducted. Most (88%) rats retained tolerance to 2 mg/kg amphetamine for 31 weeks. However, DR tests revealed that tolerance was not retained at 4 mg/kg. The results demonstrate that learned tolerance to amphetamine can be retained over long intervals when both drug injections and feeding tests are suspended.     

Prenatal amphetamine exposure alters behavioral reactivity to amphetamine in rats

In utero exposure to psychostimulants produces neurobehavioral alterations in the offspring of laboratory animals. Most amphetamine-related behavioral changes have been related to changes in the monoamine transmission levels, where monoamines may act as developmental regulatory substances for maturation of neuronal population. This study investigates the effect of prenatal-amphetamine exposure on the offspring's behavioral responses under amphetamine conditioning settings. Pregnant female rats were injected (subcutaneous) with amphetamine or saline during the pregnancy [gestation day (GD) 8 until parturition day]. The prenatal amphetamine exposure resulted in significantly decreased birth weights. The offspring from the saline group displayed a significantly lower number of stereotyped behaviors across the four challenge doses of amphetamine injections. Offspring from the amphetamine-treated prenatal group displayed significantly increased average startle amplitude compared to the controlled offspring. Moreover, offspring from amphetamine-treated prenatal group showed significantly less inhibition for the prepulse startle trials compared to those of the offspring from saline group. These results, taken together, indicate that the prenatally exposed rats displayed a significantly different profile of behavioral reactivity upon amphetamine challenges.     

Acute tolerance to amphetamine in rats

Two groups of rats were given amphetamine intravenously at 5-min intervals (5 or 10 mg/kg/h) for 8h. Two control groups received saline infusions. On the second day a test dose of 10 mg/kg amphetamine was given to all groups. Body temperature, food intake, and motor behavior were registered every 30 or 60 min. The results showed the development of acute tolerance to the hyperthermic effect within 3–5 h. Tolerance was still visible on the 2nd day. There was also tolerance to the anorectic effect, which was evident on the 2nd day. One element of stereotyped behavior (swaying) also decreased during the amphetamine infusions.     

Effects of acute and chronic cocaine on milk intake, body weight, and activity in bottle- and cannula-fed rats

The effects of cocaine on the milk intake, body weight and activity of bottle- and cannula-fed rats was compared under both acute and chronic dosing conditions. Bottle-fed rats were initially more hypophagic than cannula-fed rats when given acute injections of cocaine (4-40mg/kg). Following chronic injections of the drug (16mg/kg), bottle-fed rats developed tolerance, as shown by a rightward shift in the dose-response function for milk intake. Such tolerance was accompanied by a decrease in drug-induced motor activity. In contrast, cannula-fed rats showed marked sensitization of stereotyped movements. Bottle -fed rats showed marked sensitization of stereotyped movements. However, weight loss per se was not a determining factor in tolerance development, because cannula-fed rats given chronic injections of 32mg/kg cocaine lost even more weight, but did not become tolerant. These results suggest that, at moderate doses, cocaine suppresses feeding primarily by inducing behaviors that are incompatible with the appetitive phase of feeding, and that tolerance involves learning to inhibit such responses in order to feed.     

The discriminative control of operant behavior by intravenous administration of drugs in rats

Rats were trained to discriminate the stimulus properties of amphetamine and saline. Food reinforcer was given after lever pressing following intravenous amphetamine infusions but not following saline infusions. Subsequent tests under extinction conditions showed that rats pressed a lever at a high rate following infusions of amphetamine, methamphetamine and cocaine, but at a low rate following saline, ethanol, epinephrine or sodium pentobarbital. Similar procedures indicated that rats could also discriminate between ethanol and saline. These findings confirm earlier results indicating that intravenously administered drug can act as discriminative stimuli in controlling operant behavior.     

十五肽BPC 157减弱慢性苯丙胺诱导的行为障碍

AIM: To investigate the effect of pentadecapeptide BPC 157 on chronic exposure to amphetamine in rats, particularly the changes commonly referred in chronic amphetamine studies as tolerance ( lesser grade of stereotyped behavior, without increased excitability) and reverse tolerance (ie, prominent stereotyped behavior and heightened startle response upon late amphetamine challenges). METHODS: After initial application (initial single dose-regimen), amphetamine (10 mg/kg, ip) was given once daily till d 5 ( continuous administration-regimen), and thereafter on d 8, 16, and 46 (intermittent administration regimen). For stereotyped behavior and heightened startle response the observation period was 120 min after amphetamine application, and each animal was observed for 10 s in 5 min intervals. Pentadecapeptide BPC 157 (10 μg/kg or 10 ng/kg, ip) or saline (5.0 mL/kg, ip) were given only at the beginning of the experiment, simultaneously with the initial dose of amphetamine. RESULTS: In relation to applied     

Time course of the development of the enhanced behavioral and biochemical responses to amphetamine after pretreatment with amphetamine

These experiments were designed to examine the time course of development of the enhanced stereotyped behavioral response to amphetamine after withdrawal from chronic pretreatment with amphetamine and to determine whether this time course correlates with that of the enhancement in the amphetamine-induced stimulation of the release of dopamine (DA) from striatal slices. Rats were pretreated with amphetamine (5 mg/kg, i.p.) or saline, twice daily for 5 consecutive days. At 3, 15 and 30 days after withdrawal of the drug the stereotyped behavioral response and the release of endogenous DA from slices of striatum in response to a challenge dose of amphetamine were measured. At all 3 times tested, the stereotyped behavioral response to the challenge dose of amphetamine was enhanced in the rats pretreated with amphetamine, with the greatest degree of enhancement seen at 15 and 30 days after withdrawal of the drug. At these times, the responses were associated with a significant attenuation in the stimulation of locomotor activity produced by the challenge dose of amphetamine, which was probably related to the enhanced stereotyped behavioral response. Amphetamine stimulated the release of endogenous DA from slices of striatum in rats pretreated with saline and amphetamine. However, the release of endogenous DA from slices of rats pretreated with amphetamine was significantly greater than that of saline-pretreated rats at 15 and 30 days after withdrawal of the drug, but not at 3 days after withdrawal. Thus, pretreatment with amphetamine resulted in enhanced behavioral and biochemical responses to amphetamine which increased over time after withdrawal of the drug.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacologic control of pemoline induced self-injurious behavior in rats

Administration of oral Pemoline produces long lasting amphetamine-type stereotyped behavior and persistent self-biting behavior in rats. The effects of haloperidol, pimozide, diazepam, and serotonin depletion by pretreatment with p-chlorophenylalanine (PCPA) or chronic pretreatment with p-chloroamphetamine (PCA) on abnormal behavior produced by pemoline were studied. Diazepam consistently increased the duration of stereotyped behavior. It also reduced licking/biting and self-biting but the latter effects were not consistent. Pretreatment with PCA had negligible effects on stereotyped behavior. Pretreatment with PCPA dramatically increased locomotion and rearing without affecting the other components of stereotypy--stereotyped head movements, licking/biting, and self-biting. Haloperidol (0.2 and 0.3 mg/kg) produced a dose related normalization of pemoline induced behaviors, including elimination of self-biting. Pimozide (0.5, 0.8 and 1.3 mg/kg) had little or no effect on behaviors such as locomotions, rears, licking/biting, or stereotyped head movements but eliminated self-biting at 1.3 mg/kg. These data suggest that pemoline, like amphetamine, produces stereotyped behavior through central dopaminergic mechanisms. Dopaminergic mechanisms also appear to be involved in pemoline induced self-biting. pemoline is apparently pharmacologically and behaviorally very similar to amphetamine. Pemoline may provide a useful animal model for syndromes characterized by self-injurious behavior and other repetitive behaviors.     

Effect of cortisone,aldosterone and nialamide on “amphetamine stereotypies” and brain methamphetamine levels of adrenalectomized rats

Cortisone, aldosterone or nialamide was administered to adrenalectomized or sham-operated rats for 7 days, and methamphetamine was injected 24 hrs after the last injection of these compounds. Stereotyped head movement and licking activity were scored 5 min, 30 min and 60 min after methamphetamine injection and, in parallel brain methamphetamine levels in similarly treated rats were measured 5 min, 30 min and 60 min after the methamphetamine injection.Adrenalectomy depressed stereotyped head movements but enhanced the brain amphetamine accumulation. Nialamide but not the hormones further increased the amphetamine accumulation in adrenalectomized rats. No drugs had any effect on the amphetamine-induced head movement suppressed by adrenalectomy.     

Effect of pretreatment with amphetamine on the interaction between amphetamine and dopamine neurons in the nucleus accumbens

The present study was designed to examine the effect of pretreatment with amphetamine on the ability of amphetamine to release dopamine from slices of the nucleus accumbens and striatum and to stimulate locomotor activity or stereotyped behavior, after direct injection into either the nucleus accumbens or the striatum. Rats were injected twice daily for 5 days with either amphetamine (5 mg/kg, i.p.) or saline. At 33 days after this pretreatment, the release of endogenous dopamine from both regions of the brain in vitro by amphetamine and the changes in behavioral responses to the direct injection of amphetamine into either region were examined. Amphetamine at both 1 and 10 microM stimulated the release of endogenous dopamine from slices prepared from both of the brain areas. The release of dopamine by amphetamine was increased in rats pretreated with amphetamine. Consistent with its ability to stimulate endogenous release of dopamine, amphetamine, when injected into the nucleus accumbens, stimulated locomotor activity, while stereotyped behavior was enhanced when amphetamine was injected into the striatum. However, the locomotor activity and stereotyped behavioral responses to small doses of amphetamine (5, 10 or 25 micrograms) were not significantly greater in amphetamine-pretreated rats, compared to saline-pretreated animals. A greater stimulation of both responses in amphetamine-pretreated rats was only observed when a large dose (50 micrograms) of amphetamine was administered into either the nucleus accumbens or striatum.(ABSTRACT TRUNCATED AT 250 WORDS)     

A sensitizing regimen of amphetamine impairs visual attention in the 5-choice serial reaction time test: reversal by a D1 receptor agonist injected into the medial prefrontal cortex.

Exposure to repeated, intermittent, escalating doses of amphetamine in rats disrupts information processing in several tasks. Some of these deficits, notably impaired attentional set shifting, may reflect altered prefrontal cortex function. This study examined the effects of repeated treatment with amphetamine on performance in the 5-choice serial reaction time test. This test measures sustained visual attention, a behavior that is known to require the prefrontal cortex. Rats were trained to respond to a brief light stimulus presented randomly in one of five spatial locations, with 100 trials per session. Once performance had stabilized rats were treated with escalating doses of amphetamine (three injections per week for 5 weeks at 1-5 mg/kg per week); testing was continued on nondrug days, and for several weeks of withdrawal. During the amphetamine-treatment and withdrawal phases accuracy of responding was unaffected, but errors of omission increased. Lengthening the stimulus duration abolished this effect. Reducing the stimulus duration also reduced response accuracy and this effect was more marked in amphetamine-treated rats. Both reduced accuracy, and increased omissions, seen in amphetamine-treated rats were reversed by injecting the D1 receptor agonist SKF38393 into the medial prefrontal cortex. This treatment also prevented the decline in accuracy in control animals that resulted from reducing the stimulus duration. These results, indicating that exposure to amphetamine induces a long-lasting deficit in visual attention, add to a growing list of deficits suggesting that amphetamine-sensitized state may model the cognitive deficit state in schizophrenia. The reversal of these deficits by a D1 receptor agonist provides further evidence that prefrontal D1 dopamine receptors are involved in cognition, and may be a potential target for treatment of impaired cognition in schizophrenia.     

A novel procedure for dissociating the anatomical bases of the behavioral effects of amphetamine

A novel operative procedure is described in which the same cannula may be used to administer drugs either to the caudate nucleus (CN) or to the nucleus accumbens (NAcc) of the rat. Microinjections of amphetamine (10 or 20 micrograms) into the CN produced a reliable and robust stereotyped response; when administered to the NAcc of the same animal the higher dose increased locomotor activity. The stereotypy following peripheral administration of amphetamine (5 mg/kg) was antagonised by infusions of haloperidol (30 micrograms) into the CN but not into the NAcc. Conversely, the locomotor activity following a lower dose of amphetamine (1 mg/kg) was antagonised by infusions of haloperidol (5 micrograms) into the NAcc but not into the CN. The results confirm earlier reports that different anatomical structures mediate the behavioral effects of low and high doses of amphetamine.     

Some central effects of opioid antagonists. Part I

This study concerned the influence of opioid antagonists: naloxone, naltrexone and diprenorphine on amphetamine hyperactivity in mice and rats, apomorphine hyperactivity in rats, amphetamine and apomorphine stereotypy in rats, and stereotyped gnawing induced by methylphenidate in mice. Naloxone, naltrexone and, in higher doses, diprenorphine attenuated the amphetamine hyperactivity in rats. In mice in the same test all antagonists at some doses produced attenuation. However they did not affect the apomorphine hyperactivity in rats. Both naloxone and naltrexone attenuated amphetamine and apomorphine stereotypy, while the effect of diprenorphine was different: it slightly attenuated the amphetamine stereotypy, but slightly potentiated the stereotypy induced by apomorphine. The influence of various antagonists on methylphenidate-induced stereotyped gnawing varied: naloxone had no effect, while naltrexone and diprenorphine showed a tendency to potentiate the response. The results suggest that naloxone and naltrexone show some actions resembling hose of antipsychotics, but of a mechanism different to that characteristic of typical neuroleptics.     

Stereotyped behavior elicited by amphetamine in the rat: Influences of the testes

Castrating male rats in adulthood increased the duration of stereotyped behavior in response to 5 mg/kg injections of d-amphetamine sulfate; exogenous treatment with testosterone propionate (TP) reversed this effect. Ovariectomy in adulthood had no effect on stereotypy, but TP injections reduced stereotyped responding by ovariectomized females. Thus testosterone exerts comparable effects on stereotypy elicited by amphetamine in both sexes. Males castrated at 1, 6 or 10 days of age but not males castrated in adulthood displayed levels of stereotyped behavior comparable to those of ovariectomized females when all animals were given TP in adulthood. Control experiments indicated that age of castration rather than time since castration was the critical factor, implying that secretions of the testes early in life exert effects on systems that regulate the responses of adults to amphetamine.     

Amphetamine: effects on defensive flight or avoidance in the rat

Treatment with a moderately high dose of amphetamine caused rats to retreat from a stimulus they would normally approach and explore (mechanical robot or live white rabbit). While saline-treated rats spent approximately equal amounts of time in the area of the apparatus near the stimulus, amphetamine-treated rats spent a high percentage of trial time in the area of the apparatus farthest from the stimulus. The drug effects were dose related (range: 1.75, 3.5 and 7.0 mg/kg) with higher avoidance time at higher doses, and significant linear trends accounting for much of the variance. The highest dose of amphetamine elicited response stereotypy. However, control conditions ruled out the possibility that the present results could be explained by competing motor responses of stereotypy or increased activity. Thus, apart from its actions on motor behavior, amphetamine treatment resulted in rats avoiding or retreating from an otherwise neutral stimulus.     

The effects of psychotropic drugs on exploratory and stereotyped behaviour of rats studied on a hole-board

Exploratory and stereotyped behaviour of Male Wistar rats was studied on a hole-board. The two forms of behaviour were differentiated according to the pattern of hole-dipping activity. Increasing doses of dl-amphetamine stimulated both forms of behaviour with stereotyped behaviour becoming predominant particularly at the higher dose levels. At the highest dose of amphetamine used (16 mg/kg) a gradual transition from exploratory to stereotyped behaviour was observed with time. As the drug wore off this transition was reversed. Haloperidol at a dosage of 0.1 and 0.05 mg/kg blocked the response to a high dose of amphetamine whereas a lower dose (0.02 mg/kg) blocked the stereotyped response to amphetamine while some exploratory behaviour still took place. Apomorphine inhibited hole-dipping but at lower doses another form of exploratory behaviour was induced, this behaviour becoming stereotyped as the dose was increased.It is concluded that there is a close relationship between exploratory and stereotyped behaviours. Monoamine systems appear to play a significant role in the regulation of both forms of behaviour.     

Acquisition of IV amphetamine and cocaine self-administration in rats as a function of dose

The effect of dose on the acquisition of IV amphetamine and cocaine self-administration was examined. Three unit doses of amphetamine (0.03, 0.06 and 0.12 mg/kg) and three unit doses of cocaine (0.05, 0.2 and 0.8 mg/kg) were tested in separate groups of ten (amphetamine) or 13 (cocaine) rats. Autoshaping methods were used to train rats to press a lever that resulted in drug infusion under a fixed-ratio (FR) 1 schedule. A daily 6-h autoshaping component non-contingently delivered 60 infusions according to a 60-s random time schedule with ten infusions delivered during the first half of each h. Each day autoshaping sessions were followed by a 6-h self-administration session. The criterion for acquisition was a 5-day period during which a daily mean of 100, 50 or 25 infusions for the three amphetamine doses and 400, 100 or 25 infusions were earned during the 6-h self-administration period for the three cocaine doses, respectively. As dose increased, more rats per group acquired drug self-administration and the mean number of days to meet the acquisition criterion decreased. The percentage of rats acquiring amphetamine self-administration increased with dose and ranged from 80 to 100%. Only one rat at the lowest cocaine dose met the acquisition criterion, but 100 percent of the rats at the two higher doses acquired. During the last 2 days of acquisition, mean infusions decreased and mean drug intake (mg/kg) increased as dose increased. On the last day of acquisition, the time course of infusions during the 6-h self-administration component was characterized by a steady rate of infusions per hour, and number of infusions was inversely related to dose. These findings indicate that the initial available dose of a drug is an important determinant of the rate and probability that successful acquisition will occur.     

Mazindol and amphetamine as inhibitors of the uptake and releasers of 3H-dopamine by rat striatal synaptosomes

Summary The effects of mazindol, amphetamine and fentluramine on uptake and release of ³H-DA by synaptosomes were studied in different systems.In in vitro incubations of ³H-DA with synaptosomes isolated from the caudate nucleus of the rat, mazindol inhibited the uptake of the radioactivity more potently than did amphetamine.When the synaptosomes were isolated from the caudate nuclei of rats treated in vivo with either mazindol or amphetamine, the uptake of ³H-DA during in vitro incubation was lower with synaptosomes of amphetamine-treated rats than with those of mazindol-treated rats.When synaptosomes of untreated rats were prelabelled with ³H-DA and incubated in the presence of amphetamine or of mazindol, amphetamine caused a greater releaseoof radioactivity than did mazindol.Fenfluramine was without activity in all these systems.In spite of the quantitative differences, both amphetamine and mazindol appear to have similar effects on uptake and release of dopamine, and this may account for their analogous pharmacological profile.Supported by C.N.R. grant N. 75.00620.04.115.2380