Effects of chlorpromazine and d-amphetamine on schedule-controlled and schedule-related behavior of rabbits

A lever-lifting response by Dutch Belted and New Zealand White rabbits was maintained in water-deprived animals by 0.25% saccharin solution and in food-deprived animals by food pellets under a multiple 3-min fixed-interval (FI) 30-response fixed-ratio (FR) schedule. Rabbits responding for the saccharin solution had food freely available during the session and in the home cage, whereas those responding for pellets had water continuously available during the session as well as in the home cage. Under nondrug conditions the FR and FI schedules controlled different rates and patterns of responding in the rabbit that were characteristic of those found with other species. In addition, eating or drinking occurred during the inital portion of the FI under the saccharin solution and initial food presentation schedules, respectively. Doses of d-amphetamine (0.1–10.0 mg/kg) increased responding under the FI and FR schedules of food delivery, but increased only FI responding maintained by the saccharin solution. Doses of 3.0–10.0 mg/kg d-amphetamine produced extremely high (300–800% of control) rates of stereotyped perseverative lever responding. Schedule-related eating or drinking were unaffected or decreased at doses of d-amphetamine that increased schedule-controlled responding. Chlorpromazine (0.03–0.3 mg/kg) increased FI responding maintained both by saccharin and food, whereas FR responding generally was unaffected at these dose levels; eating but not drinking was increased with chlorpromazine. Since the behavioral effects of drugs such as amphetamine and chlorpromazine differ somewhat in the rabbit from those found with other typically studied nonhuman mammals, further studies with the rabbit may yield useful information for comparative behavioral pharmacology.     

The effects of age and illumination on the dose-response curves for three stimulants

The dose-response relationships for three stimulants have been explored. These drugs have been shown to differ in potency and, with successive doubling of doses, have been found to have dose-response curves of differing slopes. In addition, the relationship between dose and activity level was not the same for younger and older rats. The relationship between dosage of both d-amphetamine and methylphenidate and locomotor activity was not the same in the light and the dark. The latter finding suggests a difference between these two stimulants and the third stimulant studied, caffeine, whose effects where unaltered by ambient illumination level.This work was supported by research grant (MH 22140) from the National Institute of Mental Health.     

Stereoselective effects of 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM) on schedule-controlled behavior

The effects of R(?)?, S(+) and R, S-1-2-5-dimethoxy-4-methylphenyl)-2-Aminopropane (DOM) were studied using rats responding under a fixed interval two-min schedule of food presentation. All three drugs decreased average rates of responding in a dose-related manner, with R-DOM being five to six times more potent than S-DOM but only about 1.2 times more potent than R,S-DOM. Relatively high doses of R,S-DOM and S-DOM increased the low response rates occurring at the beginning of the fixed interval and decreased the higher response rates occuring at the end of the interval (rate-dependent effects). These results are discussed in terms of the stereoselective metabolism of DOM and of the structural similarities between R-DOM and the behaviorally active isomer of LSD.     

Intruder-evoked aggression in isolated and nonisolated mice: Effects of psychomotor stimulants and l-Dopa

Adult male Swiss-Webster mice were housed either singly (isolated) or with a female (nonisolated). Aggressive behavior was evoked by introducing a group-housed male mouse (intruder) into the home cage of the isolated or nonisolated mouse (resident). d-Amphetamine, methamphetamine, methylphenidate, cocaine, and l-dopa decreased attack and threat behavior by resident mice, the isolates requiring 2–4 times higher drug doses for the antiaggressive effects than the nonisolates. d-Amphetamine, methamphetamine, and methylphenidate caused intruder mice to be more frequently attacked by their nontreated resident opponents, to escape more often, to assume the defensive upright posture less, and to move about more often. l-Dopa nonspecifically decreased all elements of agonistic and nonagonistic behavior, while the amphetamines and methylphenidate suppressed attacks, increased escapes, decreased upright postures, and increased nonagonistic locomotion. By contrast, cocaine's antiaggressive effects were remarkably specific, i.e., not accompanied by changes in other behavioral elements.     

Interactions of clonidine and naloxone on schedule-controlled behavior in opioid-naive mice

Schedule-controlled responding was maintained under a fixed-ratio schedule in mice. Administered alone, clonidine, morphine and naloxone produced dose-related decreases in rates of responding, with clonidine about 100 times more potent than morphine which was about ten times more potent than naloxone. Decreases in response rates produced by high doses of naloxone were antagonized by clonidine (0.003–0.1 mg/kg) in a dose-dependent manner; however, decreases in response rates produced by clonidine (0.3 mg/kg) were not antagonized by naloxone (1.0–100 mg/kg). Effects of high doses of naloxone (100 mg/kg) were not antagonized by morphine (1.0–100 mg/kg) whereas effects of morphine (17.0 mg/kg) were antagonized by naloxone (0.01–1.0 mg/kg). Thus, clonidine can reverse behavior-disrupting effects of naloxone in non-dependent subjects, indicating that at least some of the interactions of these two drugs are not specific to the opioid-dependent state.     

Effects of morphine alone and in combination with naloxone or d-amphetamine on shock-maintained behavior in the squirrel monkey

Key-pressing behavior in the squirrel monkey was maintained under an 8-min fixed-interval (FI) schedule of electric-shock delivery. The acute i.m. administration of morphine prior to a daily session decreased response rates at doses of 1.0–3.0 mg/kg but had little systematic effect on rate at doses of 0.03–0.3 mg/kg. When naloxone was administered concomitantly with morphine prior to a session, 0.01 mg/kg naloxone required a three-fold increase in the dose of morphine necessary to obtain decreased response rates, 0.1 mg/kg naloxone required a 30-fold increase in morphine, and 1.0 mg/kg required more than a 30-fold increase in morphine. Moreover, the administration of naloxone with morphine resulted in increased rates of responding at certain combinations of doses of the two drugs. The administration of d-amphetamine (0.03 or 0.1 mg/kg) alone increased mean response rates under the FI schedule; when combined with 0.03–0.3 mg/kg morphine the increases in responding were greater than obtained with d-amphetamine alone. The negative slope of the linear regression lines relating the effects of morphine to control rates of responding engendered under the FI schedule was decreased when morphine was combined with naloxone, but not with d-amphetamine. These results show that naloxone, but not d-amphetamine, can antagonize the response-rate decreasing effect of morphine when responding in the squirrel monkey is maintained by response-produced electric shock.     

Differential effects of methylphenidate and d-amphetamine on stereotyped behavior in the rat

Different equimolar doses of d-amphetamine and methylphenidate were compared for their potency in eliciting stereotyped behavior in rats. Although at lower doses d-amphetamine appeared more effective in causing stereotyped gnawing, repetitive body movements, and sniffing, at higher doses methylphenidate at certain times caused a greater incidence of gnawing than did d-amphetamine. Understanding these differences and comparing related biochemical correlates may lead to a better definition of mechanisms underlying psychostimulant effects.     

Self-administration of CNS stimulants by dog

Drug-naive dogs were trained to respond for intravenous infusions of either d-amphetamine, phenmetrazine, or methylphenidate until a stable response rate per 4-hr daily session was achieved. The magnitude of reinforcement (i.e., mg/kg/infusion) was then varied systematically across a wide range for each drug. An inverse relationship between unit dose and number of self-administered infusions per session was seen. Thus, total drug intake per session remained relatively constant and was independent of unit dose. Using a parallel line bioassay design, the relative potencies of d-amphetamine, phenmetrazine, and methylphenidate to maintain self-administration were estimated. By comparing the unit doses of d-amphetamine which yielded the same rate of self-administration it was found that 1 mg of phenmetrazine is equivalent to 0.1 mg of d-amphetamine. It was also determined that 1 mg of methylphenidate is equivalent to 0.75 mg of d-amphetamine. These data indicate the dog can be used to assess the reinforcing properties of psychomotor stimulants.     

Self-stimulation and amphetamine: Tolerance to d and l isomers and cross tolerance to cocaine and methylphenidate

The effects of the d and l isomers of amphetamine on self-stimulation responding were tested following acute and chronic administration. Tolerance and post-drug depression of responding occurred in tests with both isomers, indicating no role for p-hydroxynorephedrine (PHN) which is one of the metabolites of d-amphetamine. In the second experiment, d-amphetamine, methylphenidate and cocaine all produced quantitatively and qualitatively similar effects on self-stimulation responding following acute administration. Following chronic administration of d-amphetamine, animals showed tolerance to all three drugs, indicating cross-tolerance among them. These data are consistent with an hypothesis that tolerance and post-drug depression following chronic amphetamine treatment are the result of decreases in postsynaptic receptor sensitivity, which would lead to a decreased effectiveness of all three drugs, regardless of their pre-synaptic mechanisms.     

Antagonism of the behavioral effects of cocaine and d-amphetamine by prazosin

Key pecking by pigeons was maintained under a 30-response fixed-ratio schedule of food delivery; lever pressing by squirrel monkeys was maintained under a 3-min fixed-interval schedule of food delivery. Administered alone, d-amphetamine (0.1–3.0 mg/kg), cocaine (1.0–3.0 mg/kg) and bupropion (1.0–30 mg/kg) either did not affect or decreased fixed-ratio responding of pigeons, whereas d-amphetamine (0.056–0.3 mg/kg) either increased or decreased (0.56 mg/kg) responding of monkeys maintained under the fixed-interval schedule. Prazosin, a selective centrally-active alpha₁ antagonist, produced a dose-dependent reversal of the rate-decreasing effects of d-amphetamine and cocaine but not of bupropion on fixed-ratio responding in pigeons. Prazosin also reversed both the rate-increasing and rate-decreasing effects of d-amphetamine on fixed-interval responding of squirrel monkeys. In contrast, the non-selective alpha-antagonist phentolamine enhanced d-amphetamine-induced decreases in fixed-ratio responding. These findings suggest that the behavioral effects of d-amphetamine and cocaine are produced at least in part by activation of central alpha₁ receptors. Prazosin may be a useful tool for better understanding the mechanisms through which cocaine, amphetamine, and other abused stimulant drugs exert their potent behavioral effects.     

Effects of hypothalamic self-stimulation of drugs influencing dopaminergic neurotransmission injected into nucleus accumbens and corpus striatum of rats

The role of the nucleus accumbens septi (ACB) and corpus striatum (CPU) in self-stimulation were investigated by injecting directly or indirectly acting stimulant drugs or a dopamine-(DA-) receptor blocking agent into each site bilaterally. d-Amphetamine (68 nmol) facilitated hypothalamic self-stimulation when injected into either site. Apomorphine (40 nmol) depressed or facilitated responding, the direction and magnitude of this effect being contingent (C=0.52) on the effect of systemic injection (0.3 mg/kg i.p.), and correlated with the difference between the effects of d-and l-amphetamine (0.5 mg/kg i.p.) but not with injection site. Haloperidol (6.6 nmol) in either site depressed self-stimulation. Tyramine (730 nmol), an agent believed to cause noncontingent displacement of transmitter from catecholamine terminals, depressed self-stimulation when injected into CPU, but facilitated it when injected into ACB. The sitespecific effects found with tyramine but not with apomorphine may have been due to release by tyramine of transmitters other than DA.     

Unilateral neonatal intracerebroventricular 6-hydroxydopamine administration in rats: I. Effects on spontaneous and drug-induced rotational behaviour and on postmortem monoamine levels

6-Hydroxydopamine (6-OHDA; 100 µg in 5 µl) was injected into the right ventricle (intracerebroventricular, ICV) of 3-day old Sprague-Dawley rats in an attempt to produce a unilateral neonatal dopamine (DA) lesion. At adult stage, the rats were studied for spontaneous, handling- and drug-induced rotational behaviour. The 6-OHDA-treated rats showed hyperreactivity at handling, in the animal facility and in the experimental sets. This behaviour was not observed in vehicle-treated rats, and it did not decrease through the successive experiments. Apomorphine (0.05–1 mg/kg, SC) and caffeine (20 mg/kg SC) produced contralateral rotation in neonatal 6-OHDA, but not in vehicle-injected rats.d-Amphetamine (0.2–2 mg/kg, SC) produced strong, dose-dependent, ipsilateral rotation, while the serotonin (5-HT) releasing agent,p-chloroamphetamine (2 mg/kg, SC) produced a short-lasting and weak ipsilateral rotation in the 6-OHDA-treated rats. On the 6-OHDA-injected side, DA and metabolites levels were reduced by >70–90% in the striatum, the nucleus accumbens and the tuberculum olfactorium, while in the mesencephalon a 50% decrease was found. On the contralateral side, restricted decreases in DA and metabolites were observed. Noradrenaline (NA) levels were decreased bilaterally in the forebrain. In contrast, 5-HT and 5-hydroxyin-doleacetic acid (5-HIAA) levels were increased in the ipsilateral striatum (>180%), and tuberculum olfactorium (>120%). Thus, neonatal unilateral ICV 6-OHDA administration produced a significant unilateral decrease in tissue levels of DA and metabolites, which was most marked in the striatum. Changes in NA and 5-HT levels were also found in telencephalic and mesencephalic regions. The 6-OHDA lesion led to a lasting handling-related hyper-reactivity and, following stimulation with direct or indirect DA agonists, to rotational behaviour with a pattern similar to that observed in rats unilaterally lesioned at adult stage with 6-OHDA.     

Effects of acute and chronic interactions of diazepam and d-Amphetamine on punished behavior of rats

Drinking of water-deprived rats was punished by delivery of either 0.03 or 0.1 mA shocks through the drinking tube during the last 5 of 7-s tone components during a 15-min daily exposure to water. These sessions consisted of 66 alternating components marked by the presence or absence of a tone. Drinking was not punished during the 33 components without tones or during the first 2 s of each tone. The baseline number of shocks accepted by the rats at 0.1 mA was less than half that at 0.03 mA. Acute diazepam markedly increased shocks delivered from the baseline values for both shock intensities, while acute d-amphetamine either had no effect or decreased the number of shocks accepted. The combination of acute diazepam and d-amphetamine caused a decrease in shock rates as compared to diazepam alone. Daily treatment with the combination of 10 mg/kg diazepam and 1 mg/kg d-amphetamine caused a gradual increase in punished responding over 25 days under either shock intensity. Gross observation of these rats after daily treatments indicated the development of hyperreactivity and a pattern resembling stereotyped behavior. At the end of the chronic treatment with the drug combination the shock rates were significantly greater than those caused by diazepam alone. Nevertheless, neither the effect of diazepam nor that of d-amphetamine, when administered singly after the period of chronic treatment with the combination, differed significantly from initial effect of the respective drugs on punished responding.     

Joint effects of ethanol and caffeine on schedule-controlled responding in the pigeon

Interactions between ethanol and caffeine were studied in pigeons keypecking under a multiple fixed ratio 30 fixed interval 5-min schedule of food presentation. When ethanol was administered alone, rates of responding under both components of the multiple schedule were generally decreased in a dose-related manner. Caffeine alone either decreased or had no effect on rates of responding under both the fixed ratio and fixed interval components. When caffeine and ethanol were combined, doses of caffeine which did not decrease rates of responding when given alone attenuated the rate-decreasing effects of ethanol.     

Effects of d-amphetamine and ethanol alone and in combination on schedule-controlled responding of pigeons

Key pecking by pigeons was maintained under either a 5-min fixed-interval or a 30-response fixed-ratio schedule of food delivery. d-Amphetamine (0.1–1.0 mg/kg) either increased or did not affect overall rates of responding under the fixed-interval schedule; the lowest dose of ethanol (0.5 g/kg) did not affect or slightly decreased response rates, whereas higher doses (1.0–2.0 g/kg) substantially decreased rates. Combinations of low noneffective ethanol doses with most doses of d-amphetamine increased rates of responding under the fixed-interval schedule above those obtained with d-amphetamine alone; decreases produced by the higher doses of ethanol were attenuated by most doses of d-amphetamine. Doses of d-amphetamine (0.1–1.0 mg/kg) and ethanol (0.5–1.5 g/kg) alone generally had no effect on responding maintained under the fixed-ratio schedule; higher doses of these drugs decreased responding. The effects of dose combinations other than the highest ones generally differed little from those obtained with ethanol alone; the effects of high doses of each drug were antagonized by low to moderate doses of the other. Combinations of ethanol with d-amphetamine can result in higher rates of responding than are obtained with either drug alone. Further, effects of the drugs alone and in combination depend on the schedule under which behavior is maintained.     

Discriminative response control by d-amphetamine and related compounds in the rat

Rats were trained to discriminate between two levers utilizing drug-induced physiological states as discriminative stimuli. Drug injections were associated with reinforcement of response on one lever and saline was associated with reinforcement on the other lever. At equimolar doses, d- and l-amphetamine but not para-hydroxyamphetamine, functioned effectively as cues. Following training, stimulus generalization between these drugs was evaluated. Transfer of response control was observed between the d- and l-isomers, and between para-hydroxyamphetamine and saline in rats trained to utilize d- or l-amphetamine versus saline as cues. These findings suggest the importance of central pharmacological activity in this type of response control.This research was supported by National Institute of Mental Health Grant MH-19651.     

Effects of d-amphetamine on human aggressive behavior

Male research subjects were administered placebo and three doses of d-amphetamine (5, 10 and 20 mg/70 kg) in a laboratory situation which provided both aggressive and non-aggressive response options. The non-aggressive response was button pressing maintained by presentation of points exchangeable for money at the end of the session. The aggressive response was button pressing on a separate manipulanda which ostensibly subtracted points from a fictitious partner. Aggressive responding was elicited by subtracting points from the research subjects which was attributed to the fictitious partner. d-Amphetamine increased both aggressive and non-aggressive responding, particularly at 5 and 10 mg/70 kg. At the highest dose (20 mg/70 kg), aggressive responding decreased to levels similar to those observed during placebo sessions, while monetary reinforced responding remained elevated.     

Discriminative stimulus properties of psychomotor stimulants in the cat

Cats were trained to choose between two levers of an operant chamber using interoceptive cues provided by d-amphetamine or saline as the discriminative stimuli. Following training, stimulus generalization was observed to additional doses of d-amphetamine and cocaine, but not to morphine. Clozapine blocked the generalization of the drug discrimination response to d-amphetamine, but had no effect on generalization to cocaine. These data indicate that discriminative stimulus properties of psychomotor stimulants, previously described in rats, are similar in cats.     

Blockage of progesterone-induced release of luteinizing hormone and prolactin byd-amphetamine and fenfluramine in rats

Subcutaneous administration ofd-amphetamine at various doses (1.25, 2.5, and 5 mg/kg) decreased plasma luteinizing-hormone levels in ovariectomized rats primed with estradiol and injected with progesterone. In these animals prolactin levels decreased after injection of 0.6 and 1.25 mg/kg ofd-amphetamine. No significant hormone modifications were detected in ovariectomized and ovariectomized estradiol-primed rats after injection of 2.5 mg/kg ofd-amphetamine. Fenfluramine at doses of 25 mg/kg induced decreases of plasma LH and prolactin levels in ovariectomized estradiol-and progesterone-treated rats. A low dose of fenfluramine, 2.5 mg/kg, had no effect.It is concluded thatd-amphetamine and fenfluramine are able to alter the facilitatory actions of progesterone on luteinizing hormone and prolactin release in ovariectomized estradiol-primed rats.National Scientific Research Council of Argentina (CONICET) investigator     

5-Hydroxytryptamine involvement in the locomotor activity suppressant effects of amphetamine in the mouse

d-Amphetamine, in doses lower than required to increase motor activity, reduced mouse spontaneous locomotor activity when this was assessed using cages equipped with photocell units, using treadwheels, or the measurement of spontaneous climbing behaviour. Actue treatments with the serotonergic agonists quipazine and 5-hydroxy-dl-tryptophan also reduced wheel running activity, spontaneous locomotor activity assessed using photocell cages, and spontaneous climbing behaviour; fenfluramine caused a similar effect. Pretreatment with 5-hydroxy-dl-tryptophan enhanced the inhibitory effects of d-amphetamine. A 3-day treatment with fenfluramine, or lesions of the median raphe nucleus (but not the dorsal raphe nucleus) abolished the ability of d-amphetamine to reduce motor activity in the three test systems. It is concluded that low doses of d-amphetamine can reduce locomotor activity and that the effects may be mediated via an enhancement of the release of 5-hydroxytryptamine from the system arising in the median raphe nucleus.