Stereoselective effects of methylphenidate on motor hyperactivity in juvenile rats induced by neonatal 6-hydroxydopamine lesioning

RATIONALE: The psychostimulant dl-threo-methylphenidate is commonly used to treat attention deficit-hyperactivity disorder (ADHD). Consistent with its effects in ADHD patients, racemic methylphenidate antagonizes behavioral hyperactivity in several animal models of ADHD, including juvenile rats with neonatal 6-hydroxydopamine (6-OHDA) lesions of forebrain dopamine projections. The enantiomers of methylphenidate differ markedly in stimulant potency but have not been compared in the 6-OHDA lesion model. OBJECTIVE: Locomotor-inhibiting effects of methylphenidate enantiomers were compared in 6-OHDA-lesioned rats to test the hypothesis that d-methylphenidate is more potent than dl- and l-methylphenidate. METHODS: Selective dopamine lesions were made using 6-OHDA (100 microg, intracisternal, IC) on postnatal day (PD) 5 after desipramine (25 mg/kg, SC) pretreatment to protect noradrenergic neurons. Effects of d-, l- and dl-threo-methylphenidate on locomotor activity of lesioned and sham control rats were quantified at PD 23-27. RESULTS: Lesioning yielded robust motor hyperactivity at PD 23-27. Both d- and dl-methylphenidate stimulated locomotor activity in intact rats, and inhibited activity in lesioned rats. l-Methylphenidate did not affect locomotor activity in either lesioned rats or controls. d-Methylphenidate (ED(50)=1.66 mg/kg) was 3.3 times more potent than dl-methylphenidate (ED(50)=5.45 mg/kg) in reducing locomotor hyperactivity in lesioned rats. In addition, pretreatment of lesioned rats with l-methylphenidate significantly reduced the motor inhibiting effects of d-methylphenidate. CONCLUSIONS: The more active enantiomer, as predicted, was d-methylphenidate, but the l-enantiomer interfered with its effects, suggesting that clinical potency of d-methylphenidate may be more than twice that of the racemate.     

Behavioural effects of methylphenidate in 6-hydroxydopamine-treated neonatal rats

Neonatal rats treated at 7 days of age with 6-hydroxydopamine show normal levels of activity during maturation, but less hyperactivity than normals do when additionally treated with methylphenidate hydrochloride between 14 and 22 days of age. Comparison of these results with those of other workers suggests that several experimental variables must be controlled precisely if reproducible results analogous to the disturbed behaviour of children with minimal brain dysfunction (MBD) are to be obtained.     

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 6-hydroxydopamine and 6-hydroxydopa on development of behavior

Rats treated at birth with 6-hydroxydopamine (6-OHDA) (60 microgram/g, IP) or 6-hydroxydopa (6-OHDOPA X2) (60 microgram/g, IP at birth and 48 hr later) exhibited increases in general activity throughout the initial 5 weeks after birth, with peak activity occurring around 20 days postnatally. Activity changes in the 6-OHDOPAx2 group appeared to be due to increased exploratory behavior (ambulation, climbing, rearing, sniffing), while the 6-OHDA changes appeared to be due to the increased self-directed behavior (eating, grooming, scratching). Despite these behavioral differences there was no obvious difference between treated groups in norepinephrine (NE) levels in the various brain regions, i.e., all treatments resulted in a reduction in neocortical and hippocampal NE and an elevation in cerebellar NE. These findings suggest that noradrenergic neurons may be altered to different degrees by each agent in more discrete brain regions than were tested, or that other neurotransmitter systems may be more selectively altered by either of the drug treatments. Because striatal dopamine was unaltered in any of the groups, however, there is reason to question a previously suggested link between minimal brain dysfunction (MBD) and dopamine depletion in the neonatal brain.     

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.     

Effects of dopamine D4 receptor-selective antagonists on motor hyperactivity in rats with neonatal 6-hydroxydopamine lesions

RATIONALE: Dopamine D4 receptor gene polymorphism has been repeatedly associated with attention deficit hyperactivity disorder (ADHD) and related personality traits. We recently reported that motor hyperactivity in an animal model of ADHD was dose-dependently reversed by CP-293,019, a D4 receptor-selective antagonist. However, behavioral effects of this agent may not be attributed exclusively to D4 receptor blockade, since it interacts with other sites including serotonin receptors. OBJECTIVES: To test further the hypothesis that D4 receptor blockade can reduce motor hyperactivity, behavioral effects of three chemically and pharmacologically dissimilar D4 antagonists were compared to that of ketanserin, a serotonin 5-HT(2A/2C) antagonist. METHODS: Selective dopamine lesions were made in male rats at postnatal day (PD) 5 with intracisternal 6-hydroxydopamine (100 microg) after desipramine pretreatment (25 mg/kg, SC) to protect noradrenergic neurons. Effects of D4 receptor-selective antagonists and ketanserin on lesion-induced motor hyperactivity were examined during the periadolescent period (postnatal days 23-26) with an infrared photobeam activity system. RESULTS: The D4 antagonists L-745,870 and U-101,958 dose-dependently inhibited motor hyperactivity in rats with neonatal lesions, whereas S-18126 lacked this effect at doses up to 30 mg/kg. None of these drugs affected motor behavior in sham control rats. In contrast, ketanserin produced apparent sedative effects in both lesioned and intact control rats without normalizing hyperactivity. CONCLUSIONS: Motor hyperactivity in this ADHD model was selectively antagonized by three of four dopamine D4 receptor antagonists evaluated, encouraging clinical assessment of D4 antagonists in patients with ADHD.     

The acquisition of responding with conditioned reinforcement: Effects of pipradrol,methylphenidate, d-amphetamine,and nomifensine

The effects of pipradrol (5–15 mg/kg), methylphenidate (5–15 mg/kg), d-amphetamine (0.5–3.0 mg/kg), and nomifensine (5–15 mg/kg) on the acquisition of responding with conditioned reinforcement (CR) were examined. In preliminary training (phase 1), a panel-push was required for water-deprived rats to obtain access to a water-dipper. The presentation of the dipper occurred at variable intervals, independently of responding, and was preceded by a light stimulus. In phase 2, no water was available and presentation of light and empty dipper (CR) was contingent upon pressing one of two levers present (CR lever), according to a variable-ratio 2 schedule. Pressing the other lever had no effect (NCR lever). In Experiment I, pipradrol produced a dose-dependent increase in responding on the CR lever, but a dose-dependent decrease on the NCR lever. Methylphenidate and d-amphetamine produced inconsistent results, and nomifensine produced a general reduction in responding. The stimulation of responding by pipradrol transferred to the undrugged state, but previous experience with pipradrol outside the experimental setting did not increase responding during control sessions. Experiment II showed that the effects of repeated doses of pipradrol changed over sessions. Experiment III showed that 15 mg/kg pipradrol did not increase responding for the light and dipper stimuli when these had not previously been paired with water. The results suggest that pipradrol enhances the effects of conditioned reinforcers, and are discussed in terms of the other behavioral effects of psychomotor stimulant drugs.     

Effects ofd-amphetamine on spontaneous motor activity in pigeons

Animal activity monitors were used to measure spontaneous motor activity in pigeons.d-Amphetamine produced dose-dependent (0.56–5.6 mg/kg) increases in total activity counts while the highest dose (10.0 mg/kg) of drug increased activity counts less. Compared to the 24-h distribution of activity counts in the undrugged control conditions, the 5.6- and 10.0-mg/kg doses produced a change in the temporal pattern from a unimodal to a bimodal form. Increased spontaneous motor activity at low to moderate doses ofd-amphetamine, with smaller increases at the higher doses, has been observed with other species, indicating that the spontaneous motor activity of the pigeon is affected byd-amphetamine in a manner similar to that of other species.     

Effects of neonatal 6-hydroxydopamine treatment on catecholamine levels and behavior during development and adulthood

The effects of neonatal intraventricular 6-hydroxydopamine (6-OHDA) (50–400 g) treatment on catecholamine levels in various brain regions, and on motor activity, were investigated in rats during development and adulthood. At 30 days catecholamine levels were lower in the frontal cortex and ventral diencephalon: minor reductions were observed in midbrain and pontine regions. At 90 days the effects of 6-OHDA treatment were similar in frontal and rostral midbrain regions but in the pontine area norepinephrine levels were substantially elevated. Behavioral tests in a stabilimeter indicated 6-OHDA-treated rats were hyperactive during development, at 25 and 35 days of age, as well as in adulthood. However, 6-OHDA-treated rats did not differ from controls in habituation. These effects are interpreted as supporting the notion that low catecholamine levels in the forebrain alter activity during development and in adulthood.     

Intraventricular 6-hydroxydopamine in the newborn rat and locomotor responses to drugs in infancy: No support for the dopamine depletion model of minimal brain dysfunction

Bilateral intraventricular injections of 6-hydroxydopamine (6-OHDA) after desmethylimipramine (DMI) in rats 1 and 2 days of age, severely depleted brain dopamine (DA) particularly in the neostriatum, where levels in adulthood were about 7% of control. Compared to vehicle-injected controls these rats were hyperactive only at 15 and 20 days of age, and in adulthood were impaired in a two-way avoidance. Rats with similar 6-OHDA treatment but without DMI pretreatment showed severe depletion of brain norepinephrine (NE) as well as DA, and were behaviorally similar to the DA-depleted only rats. This behavioral syndrome is similar to that reported after intracisternal injection of 6-OHDA in 5-day-old rats, which has been argued as a model for minimal brain dysfunction (MBD). Contrary to expectation from this model, however, challenge doses of either d-amphetamine or methylphenidate did not reduce, but instead increased activity of these rats. The 6-OHDA treatments also did not alter the enhancement of locomotor activity by scopolamine, which was present at 30 days but not at 15 days.     

Effects of neonatal and adult 6-hydroxydopamine treatment on random-interval behavior

Rats were given intraventricular injections of 6-hydroxydopamine (6-HDA) or saline-ascorbate vehicle as neonates (3-days old) and as adults (49 and 51 days old). At 73 days of age, they were trained on a random interval 90-sec schedule of water reinforcement. The rats treated with 6-HDA as adults stabilized at response rates approximately twice those of vehicle-treated rats, while rats treated with 6-HDA as neonates showed response rates which were not significantly different from vehicle-treated rats. Both L-Dopa and apomorphine decreased response rates at all doses tested. There were no differences among the groups with respect to the effect of these drugs. Adult-treated rats showed greater response rate decreases following peripheral decarboxylase inhibition with Ro 4-4602. Catecholamine analyses revealed the rats treated with 6-HDA as neonates had greater depletions in the striatum and the remainder of telencephalon than adult-treated rats but an increase in brainstem norepinephrine. These findings suggest that age of treatment is an important determinant of the biochemical and behavioral effects of treatment with 6-HDA.     

Effects of apomorphine on appetitive conditioning in 6-hydroxydopamine treated rat pups

Rat pups were treated on postnatal day 5 either with the combination of desmethylimipramine (DMI) and 6-hydroxydopamine (6-OHDA) to produce depletion of brain dopamine, or with control injection of saline. Two days later they were presented a novel anise odor paired with intraoral baby formula, and on the next day were tested for preference for the novel odor. Before conditioning and testing, animals were treated with either apomorphine (0.05 mg/kg) or isotonic saline. Performance of the conditioned appetitive response was impaired in dopamine depleted animals. In DMI/6-OHDA treated pups, apomorphine administration prior to conditioning produced an improvement in performance, but drug treatment prior to testing had no effect. In normal pups, apomorphine administration either before conditioning or testing produced impaired performance at testing.     

Cholinergic modulation of an opposed effect of d-amphetamine and methylphenidate on the rearing response

Rats given d-amphetamine (1 mg/kg) engage in frequent, short-duration rearing responses, whereas rats given methylphenidate (1 mg/kg) make less frequent, long-duration responses. The effects on this behavior of mixing d-amphetamine or methylphenidate with scopolamine or physostigmine suggest that this opposed action on rearing response duration is related to cholinergic-catecholaminergic balance. The anticholinergic agent scopolamine produces changes in rearing response duration similar to those produced by d-amphetamine, while the cholinergic agent physostigmine lengthens response duration and further potentiates this effect of methylphenidate.     

Injection of 5-HT into the nucleus accumbens reduces the effects ofd-amphetamine on responding for conditioned reward

Injection ofd-amphetamine into the nucleus accumbens potentiates responding for stimuli paired with a primary reward. A previous study showed that this potentiating effect ofd-amphetamine on responding for conditioned reward (CR) was attenuated by peripherally injectedd-fenfluramine, a 5-hydroxytryptamine (5-HT) releaser and re-uptake inhibitor. The present experiments further examined the effects of manipulating 5-HT function within the nucleus accumbens on responding for CR, and on the potentiation of CR responding following intra-accumbens injection ofd-amphetamine. Water deprived rats were trained to associate a compound stimulus with water delivery during a conditioning phase. During a test phase water was not delivered, but the compound stimulus was delivered according to a random ratio 2 schedule following a response on one of two levers. Rats responded at a higher rate on the lever delivering this CR.d-Amphetamine (10 g) injected into the nucleus accumbens enhanced responding on the CR lever. Co-injections of 5-HT (5 and 10 g) into the nucleus accumbens abolished the response-potentiating effect ofd-amphetamine but were without effect on the base-line level of responding for CR. This reduction by 5-HT of the response potentiating effect ofd-amphetamine was prevented by prior treatment with the 5-HT receptor antagonist metergoline (1 mg/kg). Responding for water was not altered by 5-HT and so the effects of 5-HT on responding for CR cannot be due to a change in the motivation to seek the primary reward. Thus, elevating 5-HT activity within the nucleus accumbens antagonises the effects ofd-amphetamine on responding for CR within the nucleus accumbens. These results suggest that 5-HT within the nucleus accumbens may play an important role in mediating incentive motivation by modulating dopaminergic neurotransmission.     

6-Hydroxydopamine lesions of the nucleus accumbens,but not of the caudate nucleus,attenuate enhanced responding with reward-related stimuli produced by intra-accumbens d-amphetamine

Intra-accumbens d-amphetamine enhances responding for reward-related stimuli (conditioned reinforcers, CRs), whereas intra-caudate d-amphetamine has only weak and variable effects (Taylor and Robbins 1984). The present experiment further examined the involvement of the nucleus accumbens and the role of dopamine (DA) in this effect. Thirsty rats were trained to associate a flash of a light and movement of a dipper (CR) with water. After implantation of permanent guide cannulae aimed at the nucleus accumbens, they were assigned to one of four groups, receiving either bilateral 6-OHDA (4 mg/ml free base in 2 1 0.1% ascorbic acid/0.9% saline) or sham (vehicle) infusions into the nucleus accumbens or the caudate nucleus. In the test phase, two novel levers were available. Responding on one lever (CR lever) produced the light and dipper stimuli without water presentation, whereas responding on the other (NCR lever) had no effect. All four groups received four counterbalanced intra-accumbens infusions of d-amphetamine (3, 10, 20 g/2 l) or vehicle. On the 5th test day, subjects were pretreated subcutaneously with apomorphine (0.1 mg/kg). Intra-accumbens d-amphetamine in both sham-lesioned groups produced a dose-dependent increase in responding on the CR lever, but no significant change on the NCR lever. No selective increases in responding on either lever were found in animals with 6-OHDA-induced depletion of DA (>80%) in the nucleus accumbens following intra-accumbens d-amphetamine; however, in subjects with DA depletion of the posterior caudate nucleus (>80%), increases in responding on the CR lever were observed to be similar in magnitude to those of both the sham-lesioned groups. Following systemic administration of apomorphine, only rats in the nucleus-accumbens-lesioned group continued to respond, preferring the CR lever, thus suggesting the involvement of DA receptors in these effects. These results indicate that enhanced responding for CR following administration of psychomotor stimulant drugs is critically dependent on dopaminergic activation of the nucleus accumbens, rather than the caudate nucleus.     

Effects of triadimefon on a multiple schedule of fixed-interval performance: Comparison with methylphenidate, d-amphetamine and chlorpromazine

Triadimefon is a fungicide that has recently been shown to increase motor activity and rates of schedule-controlled responding. These findings indicate that triadimefon resembles psychomotor stimulants and in this respect is a unique pesticide. The present experiment was designed to evaluate triadimefon's effects on performance maintained by a multiple schedule of reinforcement and to compare triadimefon to known psychomotor stimulants. Four rats were trained to perform under a mult FI 1-min FI 5-min schedule of milk reinforcement. They then received a series of dosages of triadimefon (10–170 mg/kg, IP) and of methylphenidate (1–17.3 mg/kg, IP) in a counterbalanced order. Triadimefon increased response rates in both the FI 1-min and FI 5-min components. Methylphenidate did not consistently alter response rates in either component. Temporal patterns of responding were disrupted much more in the FI 5-min component than in the FI 1-min component by both triadimefon and methylphenidate. Performances were then evaluated following a series of dosages of d-amphetamine (0.3–3.0 mg/kg, IP) and chlorpromazine (0.5–2.0 mg/kg, IP). Response rates were increased d-amphetamine in the FI 1-min component but not in the FI 5-min component. Like triadimefon and methylphenidate, d-amphetamine produced a greater disruption of response patterning in FI 5-min than in FI 1-min. Only chlorpromazine decreased response rates in both components. Chlorpromazine also disrupted FI 5-min response patterning, but left FI 1-min patterning intact. Although triadimefon did not closely resemble any of the comparison drugs, it had opposite effects on response rates from chlorpromazine in both components of the schedule and resembled d-amphetamine in its effects on FI 1-min response rates. The rate-increasing effects frequently obtained with psychomotor stimulants were more evident for triadimefon than for either methylphenidate or d-amphetamine.     

Dopaminergic agonists differentially affect open-field activity of rats with A10 lesions

Dopaminergic systems appear to exert considerable control over locomotor activity. Although dopamine neurons are located in relatively close proximity within the mesencephalon, their axons project to more diffuse areas, perhaps reflecting some underlying heterogeneity in their function. The purpose of this study was to determine whether dopamine agonists differentially affect activity by acting upon distinct dopamine systems. Bilateral radio-frequency lesions of area A10 in rats failed to affect spontaneous open-field behavior over a 1-month postoperative period. When injected with 1 mg/kg of apomorphine, however, experimental rats more than doubled their activity as compared to the response of sham-operated controls. In contrast, no difference between the two groups of animals was observed in terms of increased activity following 3 mg/kg of either d-amphetamine or methylphenidate. These results are consistent with previous work indicating the involvement of ventromedial mesencephalic dopamine somata in the control of locomotor activity. The data suggest, however, that systems in addition to the dopaminergic mesolimbic projection are responsible, in part, for the hyperactivity elicited by d-amphetamine or methylphenidate.     

Bilateral intra-accumbens self-administration ofd-amphetamine: Antagonism with intra-accumbens SCH-23390 and sulpiride

The efficacy ofd-amphetamine to support a selective bilateral intra-accumbens self-administration response was examined. Bilateral intra-accumbens infusions ofd-amphetamine were made contingent upon the acquisition of a lever-pressing response. Two identical levers were available within the operant chamber. Depression of the drug lever resulted in the intra-accumbens delivery of 1 µgd-amphetamine; responses upon the second, control lever were recorded but had no programmed consequences. Animals were not primed with non-contingent infusions ofd-amphetamine at any time during these experiments. Nonetheless, animals readily acquired a selective response upon the drug lever. Removal of thed-amphetamine moiety from the infusate resulted in a large decline in responding, and the abolition of the selectivity of the response for the drug lever. Adulteration of the infusate with either the D₁ dopamine receptor antagonist SCH-23390 or the D₂ dopamine receptor antagonist sulpiride enhanced the rate of response selectively upon the drug lever. Reductions in the dose ofd-amphetamine also increased the rate of response. The effect of co-adulteration of the infusate with both SCH-23390 and sulpiride together was purely additive. The implications of these data for the methodology of intracranial drug self-administration, and the relationship between D₁ and D₂ dopamine receptors within the nucleus accumbens are discussed.     

Unilateral neonatal intracerebroventricular 6-hydroxydopamine administration in rats: II. Effects on extracellular monoamine,acetylcholine and adenosine levels monitored with in vivo microdialysis

6-hydroxydopamine (6-OHDA, 100 µg in 5 µl) was injected into the right ventricle of 3-day-old Sprague-Dawley rats in order to produce a unilateral dopamine (DA) lesion. At adult stage, the rats were implanted with microdialysis probes into the left and right striata. On the injected side, basal extracellular levels of DA were reduced by >65%, as compared to the contralateral side or to the levels found in vehicle-injected rats. Extracellular 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were reduced by >95%, while acetylcholine (ACh) was decreased by >50%.d-Amphetamine (2 mg/kg SC) produced a 10-fold increase in extracellular DA levels in the striatum contralateral to the 6-OHDA-injected side, while on the ipsilateral side, DA levels were not affected byd-amphetamine.d-Amphetamine produced an increase (>2 fold) in extracellular ACh levels, on both ipsilateral and contralateral sides. Choline and adenosine levels were unaffected by any of the experimental conditions. Thus, neonatal unilateral ICV administration of 6-OHDA produced an ipsilateral decrease in striatal extracellular DA, DOPAC and HVA levels, compared to the contralateral side. A reduction of extracellular ACh levels was also observed on the 6-OHDA-injected side. The DA releasing effect ofd-amphetamine was abolished on the 6-OHDA-injected side, but not that on ACh levels, indicating that striatal DA and AChd-amphetamine-induced release are produced by independent mechanisms in the meonatally unilateral 6-OHDA-treated animals. As a whole the present study gives evidence showing that neonatal unilateral ICV treatment with 6-OHDA produces a predominantly unilateral lesion of the mesencephalic DA systems.     

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.