Nucleus accumbens dopamine depletions alter relative response allocation in a T-maze cost/benefit task

This experiment was conducted to study the role of nucleus accumbens dopamine in the performance of a novel T-maze cost/benefit procedure. Rats were trained on a T-maze task for food reinforcement. Under one of the test conditions, one arm of the maze contained a high reinforcement density (4 x 45 mg Bioserve pellets) and the other arm contained a low reinforcement density (2 x 45 mg pellets). A large vertical barrier (44 cm) was placed in the arm that contained the high density of food reinforcement. In the second test condition, a separate group of rats was trained in the same T-maze, in which there were 4 food pellets in the arm that was obstructed by the barrier, yet there were no food pellets in the unobstructed arm. After training rats received intra-accumbens of injections 6-hydroxydopamine or ascorbate vehicle. Nucleus accumbens dopamine depletions substantially decreased the number of selections of the obstructed arm with the high reinforcement density when the unobstructed arm also contained 2 food pellets. Dopamine-depleted rats in this condition showed increased selection of the no-barrier arm as well as decreased entry into the arm that contained the barrier. These effects persisted throughout the 3 weeks of post-surgical testing. Nevertheless, when the unobstructed arm contained no food pellets, and the only way to obtain food was to climb the barrier, rats with nucleus accumbens dopamine depletions showed only a modest effect on selections of the obstructed arm, which recovered by the second week of testing. Dopamine-depleted rats that were tested with food in the unobstructed arm showed significantly fewer barrier crossings than dopamine-depleted rats that were tested with no food in the unobstructed arm. Thus, the present findings are not consistent with the notion that nucleus accumbens dopamine depletion rendered the animals unable to climb the barrier, or set an absolute ceiling on the number of barrier crossings the animals could perform. Instead, the present results indicate that nucleus accumbens dopamine depletions affected the relative allocation of barrier climbing responses if alternative food sources were available.     

A simple slide-rule method for the assessment of renal tubular reaborption of phosphate in man

Twenty-five male Sprague-Dawley rats were trained in five two-lever operant chambers on a DRL-15 sec schedule of positive food reinforcement to discriminate 10 mg/kg cocaine from 1 ml/kg saline. Following acquistions of discrimination a counterbalanced design of extinction tests was performed before and after repeated administration of 20 mg/kg cocaine or saline (three times a day at five hr intervals for seven days). The extinction tests consisted of testing responses of animals following 1 ml/kg saline, 2.5 mg/kg cocaine, or 5 mg/kg cocaine. The results showed no significant difference in animals' level choice before and after repeated injection with saline. However, the percent cocaine lever choice with the two doses of cocaine was lower after repeated administration of cocaine than before the repeated injections. This indicates tolerance developed to the discriminative stimulus properties of cocaine.     

Fine structure of the pecten oculi of the barred owl (Strix varia)

Relapse prevention in abstinent cocaine addicts remains a major focus of drug addiction therapy. We used a rat model of cocaine addiction that focused on cocaine-seeking behavior elicited interoceptively and by conditioned stimuli. Each of 18 rats could self-administer a maximum of 20 intravenous cocaine injections (1.5 mg/kg) per session per day. To prevent initiation of responding by cocaine itself priming injections were never administered. Although cocaine was available beginning every session the rats displayed a self-imposed period of abstinence followed by a period of rapid consumption. The abstinence period was variable among rats but consistent for individual rats. In experiment 1 we studied the contribution of a CS+ (stimulus light and lever retraction) to the motivation to initiate and maintain a cocaine self-administration episode. We compared the number of responses the rats emitted to receive the first and subsequent injections of the day between a group responding on a fixed-ratio (FR) schedule (n = 6) and a group responding on a second-order (SO) schedule (n = 5) of reinforcement. For all rats the number of responses per injection was raised daily until a rat failed to consume more than four injections. The SO group was able to emit approximately four times as many responses as the FR group to obtain their first and subsequent injections. In experiment 2 (n = 7) responses during extinction were counted with and without the CS+. Responding was greater in the presence of the CS+ than in its absence. The present model demonstrates that the motivation to self-administer cocaine is variable and greatly enhanced by conditioned stimuli.     

L-DOPA exacerbates amphetamine-induced dopamine depletion

Administration of L-DOPA to Parkinson patients has been suggested to exacerbate "functional denervation" of the nigrostriatal system. Therefore, experiments were conducted to determine if L-DOPA combined with the DOPA decarboxylase inhibitor, Ro4-4602 (benserazide hydrochloride) would potentiate amphetamine-induced neurotoxicity. Mice received two injections of saline or benserazide + L-DOPA (25.0 or 100.0 mg/kg) interspersed with four injections of amphetamine (15.0 mg/kg) at 2-h intervals. Significant depletion of striatal dopamine, DOPAC, and HVA was evident 1 wk following amphetamine administered with or without 25.0 mg/kg L-DOPA + benserazide, whereas 100.0 mg/kg L-DOPA + benserazide potentiated amphetamine-induced depletion of striatal dopamine (17 vs 28% of control values). This enhanced toxicity may be consequent to increased dopamine turnover following L-DOPA (360 vs 231%), a situation akin to that observed in compromised dopaminergic nigrostriatal systems of parkinsonian patients. Furthermore, striatal 5-HT was not altered by amphetamine alone, whereas concurrent administration of L-DOPA/ benserazide depleted 5-HT to 82% of control values. No changes were evident in the frontal cortex following amphetamine with or without concurrent L-DOPA/benserazide; however, L-DOPA/benserazide administered alone reduced 5-HT and 5-HT turnover to 58% of control values.     

5-HT3 receptor modulation of behavior during withdrawal from continuous or intermittent cocaine

The present experiments examined alterations in 5-HT3 receptors during withdrawal from continuous or intermittent cocaine. Rats were pretreated with 40 mg/kg/day cocaine for 14 days by either SC injections or osmotic minipumps. The rats were then withdrawn from the pretreatment regimen for 7 days. In Experiment 1, rats received 0-16 mg/kg IP injections of ondansetron, a selective 5-HT3 receptor antagonist. In Experiment 2, the rats received 0-16 mg/kg IP ondansetron in combination with a 15 mg/kg IP injection of cocaine. In Experiment 3, the subjects received 0-16 mg/kg IP injections of ondansetron in combination with a 7.5 mg/kg IP injection of cocaine. Following these injections, the subjects' behavior was rated using the Ellinwood and Balster (18) rating scale. The results of Experiment 1 indicated that ondansetron had no effect on the behavior of the subjects, nor was there a differential effect of pretreatment regimen the effects of ondansetron. The results of Experiment 2 indicated that ondansetron had no effect on cocaine-induced locomotion in the saline control rats, but did have a slight, statistically significant, suppressive effect in the injection rats. In contrast, ondansetron had a robust facilitative effect on cocaine-induced locomotion in the continuous infusion rats. The results of Experiment 3 indicated that ondansetron had no effect on cocaine-induced locomotion in the saline control rats or the cocaine injection pretreatment subjects. In the continuous infusion subjects, ondansetron did have a slight, statistically significant, facilitative effect on cocaine-induced locomotion.(ABSTRACT TRUNCATED AT 250 WORDS)     

Role of experience in acquisition and loss of tolerance to the effect of delta-9-THC on spaced responding

Albino rats were given extensive training in spaced responding, using a DRL 30 sec schedule of food reinforcement (only lever presses more than 30 sec apart were reinforced). All rats then went 12 days without behavioral testing. During this period half the rats received daily intragastric doses of delta-9-tetrahydrocannabinol (THC) and the rest equal volumes of the THC vehicle. On day 13, some rats received THC 3 hr before behavioral testing while others received only vehicle. The former showed a sharp increase in lever press rate over baseline levels, but the vehicle control rats were unaffected. The rats with 12 prior THC doses were no less affected than those with no previous drug history. Continued testing resulted in recovery of baseline performance within 5 sessions, again with no effect of previous drug history. Similar results were obtained with doses of 4 mg/kg and 16 mg/kg, though the drug's effects were more pronounced at the higher dose. These results demonstrate that performance in the drug state can be a far more important determinant of tolerance than mere exposure to THC. Drug administration was then suspended for 1 week. Rats that had become tolerant to 4 mg/kg THC were then redivided into 3 new groups. One group received daily doses of vehicle and DRL sessions, a second received DRL sessions without vehicle, and 1 group received neither vehicle nor DRL sessions for this week. Subsequent DRL testing after THC administration showed that only the groups receiving DRL sessions in the intervening week lost their previously acquired tolerance. Experience thus appears to play an important role in loss of tolerance to THC as well as in acquisition of tolerance.     

The cytoskeleton of the vertebrate smooth muscle cell

Four experiments were conducted to determine the effects of dopamine (DA) antagonists and DA depletions on progressive-ratio responding for food reinforcement. On this schedule, ratio requirement increased by one response after each reinforcer was obtained, and rats were tested in 30-min sessions. Response rates and highest ratio completed were reduced in a dose-related manner by systemic injections of the D1 antagonist SCH 23390, and also by the D2 antagonists haloperidol and raclopride. Drug-treated rats also showed reductions in time to complete the last ratio, demonstrating that they had stopped responding before the end of the session. DA depletions produced by injections of 6-OHDA directly into the nucleus accumbens substantially decreased both the number of responses and the highest ratio completed. The deficits in response number and highest ratio completed induced by DA depletions persisted through the first 3 weeks of postsurgical testing, with some recovery by the fourth week. However, the deficits resulting from dopamine depletions were largely a manifestation of a decrease in response rate; although time to complete the last ratio was significantly reduced by dopamine depletions in the first few days of testing, rats recovered on this measure by the fifth day after surgery. Although previous work has shown that performance on several schedules (e.g., continuous, low value ratios, variable interval) is relatively unaffected by accumbens DA depletions, the present data demonstrate that such depletions do produce a substantial and persistent impairment of progressive ratio response output. Rats with accumbens DA depletions appear to have deficits in maintaining the high work output necessary for responding at large ratio values. The relative sparing of responding on some simple schedules, together with the present progressive ratio results, suggest that rats with accumbens DA depletions remain directed toward the acquisition and consumption of food, but they show deficits in work output for food.     

Drug-induced reinstatement to heroin and cocaine seeking: A rodent model of relapse in polydrug use.

The authors investigated several features of polydrug use in rats. Heroin and cocaine were self-administered following responses on different levers, with only 1 drug and 1 lever available on alternate days of training. Four doses of each drug (heroin: 25, 50, 100, and 200 μg/kg/infusion; cocaine: 0.25, 0.5, 1, and 2 mg/kg/infusion) were tested, and each rat was exposed to a single dose combination. Rats readily developed drug-specific and dose-related responding. During extinction, rats displayed a significant bias for responding on the cocaine-associated lever. Priming injections of either cocaine (20 mg/kg) or heroin (0.25 mg/kg) reinstated responding that was selective for the lever previously associated with each drug These results suggest that in this type of polydrug use, drugs have the capacity to activate drug-seeking behavior selectively oriented toward stimuli previously associated with their administration. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Assay of bropirimine in rat plasma by means of robotic solid-phase extraction and high-performance liquid chromatography

Vacuous jaw movements induced by the muscarinic agonist pilocarpine and striatal dopamine depletions were examined using a slow motion videotape system. With this procedure, rats were videotaped in a Plexiglas tube so that the profile of the head region could be seen. Vacuous jaw movements were analyzed by examining the tape at 1/6 normal speed. An observer recorded each jaw movement using a computer, and the computer program re-calculated the temporal characteristics of jaw movement responses back to normal speed. The interresponse time was recorded for each jaw movement, and each jaw movement interresponse time was assigned to a 50 ms wide time bin. Thus, the distribution of interresponse times could be used to analyze the temporal characteristics of jaw movement responses. In the first experiment, rats were administered saline vehicle, 1.0 mg/kg and 2.0 mg/kg pilocarpine. The rats were videotaped 10-15 min after injection, and the data were analyzed as described above. Pilocarpine induced very high levels of vacuous jaw movements, and the vast majority of all movements occurred in "bursts" with interresponse times of 1.0 s or less. Analysis of the interresponse time distributions showed that most of the jaw movements were within the 150-350 ms range. The modal jaw movement interresponse time was in the 150-200 ms range, which corresponds to a local frequency of 5-6.66 Hz. In the second experiment, the neurotoxic agent 6-hydroxydopamine was injected directly into the ventrolateral striatum in order to produce a local dopamine depletion. The dopamine-depleted rats were observed for jaw movements 7 days after surgery. The overall level of jaw movement activity resulting from dopamine-depletion was much lower than that produced by pilocarpine. There was a significant inverse correlation between ventrolateral striatal dopamine levels and total number of vacuous jaw movements. Videotape analysis indicated that the temporal characteristics of jaw movements induced by dopamine depletions were similar to those shown with pilocarpine. These experiments indicate that vacuous jaw movements induced by pilocarpine and striatal dopamine depletion occur in a frequency range similar to that shown in parkinsonian tremor.     

Effectiveness of slow release L-DOPA/benserazide in treatment of end-of-dose akinesia in Parkinson disease

In an open label study 63 patients with idiopathic Parkinson's disease suffering from end-of-dose akinesia were switched from a treatment with a L-DOPA standard formulation to a combined therapy of L-DOPA standard in the morning and L-DOPA slow release (levodopa, benserazide, Madopar Depot) at the remaining single doses. Substitution of L-DOPA standard by L-DOPA slow release took on average 2-4 weeks. Patients were subsequently treated for 6 months. Due to a lower bioavailability of the slow release formulation--the latter is based on the "hydrodynamically balanced system" (HBS)--, the patients remained initially on their time schedule of drug intake but received a higher dose of L-DOPA slow release compared to the preceding L-DOPA standard therapy. In 20 centers 37 men and 26 women were included into the study. 27 males and 20 females completed the 6 month treatment period. Before switching, the patients received 438 +/- 213 mg a day L-DOPA standard, after conversion, the average dose was 617 +/- 323 mg L-DOPA slow release and 107 +/- 95 mg L-DOPA standard a day. Fluctuations during the day and at night which were rated according to a newly developed clinical 5-point rating scale were significantly improved by the treatment regimen from 2.8 +/- 0.9 to 1.4 +/- 1.2. Additionally, parkinsonian symptoms were significantly reduced during the ON-phase as there was a significant decrease of the Webster rating score from 12.0 +/- 4.6 to 7.1 +/- 4.0. Quality of life as measured by subjective ratings of the patients improved. The tolerability of the new formulation of L-DOPA was rated to be good in 51.1% and very good in 48.9%. The results of this open label study suggest that the combination of L-DOPA standard in the morning and L-DOPA slow release formulation at the following time points can be an efficient therapy in parkinsonian patients who suffer form L-DOPA related end-of-dose motor akinesia.     

Effects of unilateral striatal dopamine depletion on tongue force and rhythm during licking in rats.

To quantitatively assess the orolingual dysfunctions produced by unilateral striatal dopamine depletions, rats first received 6-hydroxydopamine injections into the nigrostriatal bundle and were then trained to lap water from a force-sensing disk in 2-min sessions. Compared with controls and rats with moderate (75%) dopamine depletions showed decreases in number of licks, lick rhythm, and lick peak force. Rats with substantial lesions were also impaired in making initial, within-session adjustments in lick peak force but not in lick rhythm. The results confirm the presence of Parkinson-like deficits in tongue dynamics during consummatory licking behavior in rats. The methods used here should prove useful in providing quantitative measures of the efficacy of experimental therapies in this rodent model of Parkinson's disease. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of ventral striatal 6-OHDA lesions or amphetamine sensitization on ethanol consumption in the rat

Female rats with continuous access to water and 6% ethanol were given bilateral ventral striatal 6-OHDA infusions, which induced pronounced striatal depletions of dopamine. The postoperative ethanol consumption of these rats was not significantly affected in comparison to vehicle-infused controls. In a second experiment, female rats received escalating doses of d-amphetamine over a 5-week period (from 1 to 9 mg/kg/injection). Control females were given saline injections. Following a 3-month drug-free interval, the females were given access to ethanol, the concentration of which was gradually increased from 2% to 12% with weekly intervals. Amphetamine-sensitized rats consumed significantly more alcohol than the saline-treated controls. Taken together, these results suggest that striatal dopaminergic mechanisms, while not necessary for basal ethanol drinking, can facilitate alcohol drinking.     

Modulatory effects of L-DOPA on D2 dopamine receptors in rat striatum, measured using in vivo microdialysis and PET

Putative modulatory effects of L-3,4-dihydroxyphenylalanine (L-DOPA) on D2 dopamine receptor function in the striatum of anaesthetised rats were investigated using both in vivo microdialysis and positron emission tomography (PET) with carbon-11 labelled raclopride as a selective D2 receptor ligand. A single dose of L-DOPA (20 or 100mg/kg i.p.) resulted in an increase in [11C]raclopride binding potential which was also observed in the presence of the central aromatic decarboxylase inhibitor NSD 1015, confirming that the effect was independent of dopamine. This L-DOPA evoked D2 receptor sensitisation was abolished by a prior, long-term administration of L-DOPA in drinking water (5 weeks, 170mg/kg/day). In the course of acute L-DOPA treatment (20mg/kg), extracellular GABA levels were reduced by approximately 20% in the globus pallidus. It is likely that L-DOPA sensitising effect on striatal D2 receptors, as confirmed by PET, may implicate striato-pallidal neurones, hence a reduced GABA-ergic output in the projection area. Since the L-DOPA evoked striatal D2 receptor supersensitivity habituates during long-term treatment, the effects reported here may contribute to the fluctuations observed during chronic L-DOPA therapy in Parkinson's disease.     

Effects of FK506 on experimental membranous glomerulonephritis induced by cationized bovine serum albumin in rats

BACKGROUND: There have been no reports on the effect of FK5 06, a new immunosuppressive agent, on experimental membranous glomerulonephritis (MN) induced by an exogenous antigen. Therefore we investigated the effects of FK506 on MN induced by cationized bovine serum albumin (C-BSA) in rats. METHODS: Two weeks after the rats were immunized with 1 mg of C-BSA and Freund's complete adjuvant, they received intravenous injections of 3 mg/kg of C-BSA 3 times weekly for 4 weeks. Rats were divided into four groups: group A (n = 5) received intramuscular injections of 3 mg/kg of FK506 daily for 5 days beginning 2 days before the first immunization; group B (n =4) received 1 mg/kg of FK506 daily for 2 weeks beginning 2 weeks after the first immunization; and group C (n =4) received 1 mg/kg of FK506 daily for 2 weeks beginning 4 weeks after the first immunization. Group D (n = 5) received no FK506 and served as the control group. Rats were sacrificed 8 weeks after the first immunization. RESULTS: Administration of FK506 in the preimmunization stage almost completely suppressed the development of MN in group A. Histological findings in groups B and C were similar to those in group D, the control group. However, urinary protein excretion was significantly lower in group B (24+/-46 mg/day) and C (220+/-44 mg/day) than in group D (330+/-61 mg/day). Expression of intracellular adhesion molecule-1 in glomeruli and the number of leukocyte functioning-associated molecules-1 were significantly decreased in groups A, B, and C compared with the control group. Administration of FK506 was not associated with any significant side-effects or histological abnormalities. The whole-blood trough levels of FK506 in groups B and C were 9.1 ng/ml and 9.2 ng/ml respectively. CONCLUSIONS: The efficacy of FK506 was significantly increased when the drug was administered in the early phase of immunization in this model. The present study suggests that FK506 may be useful in patients with intractable nephrotic syndrome such as MN.     

Interactions between D1 and muscarinic receptors in the induction of striatal c-fos in rats depleted of dopamine as neonates

The contributions of striatal D1 receptors to the expression of sensorimotor behavior are qualitatively different in rats depleted of dopamine (DA) as neonates vs. as adults. In an effort to reveal neuronal mechanisms underlying these behavioral difference we determined the effects of the partial D1 agonist SKF 38393, the muscarinic antagonist scopolamine, and the combination of the two drugs on the induction of c-fos in the striatum and its projection sites, the globus pallidus and substantia nigra. Adult rats, given intracerebroventricular injections of 6-hydroxydopamine (6-OHDA, 50 micrograms/5 microliters/hemisphere) or its vehicle on postnatal day 3, were treated with SKF 38393 (1.5 mg/kg, i.p.), scopolamine (5.0 mg/kg, i.p.) or the combination of the two drugs. There was no significant induction of c-fos in vehicle-treated controls, regardless of drug administration. In DA-depleted rats, scopolamine also did not induce c-fos whereas SKF 38393 produced a significant increases in the number of FOS-positive cells in the dorsal, but not ventral, striatum. The combined administration of scopolamine and SKF 38393 resulted in a potent synergism in the number of FOS-positive cells in DA-depleted rats. These interactions between lesion condition and drugs on c-fos induction were not secondary to differences in drug-induced behavioral activity. Activity levels were no different in vehicle vs. DA-depleted rats following the combined administration of scopolamine + SKF 38393, yet the two groups of rats exhibited marked differences in the density of FOS-positive striatal neurons. The effects of scopolamine and SKF 38393 on c-fos induction in striatum are qualitatively similar to those reported in rats DA-depleted as adults and suggest that, at this single-label level of analysis, the ability of D1 and muscarinic receptors to influence striatal activity does not contribute to the marked age-related differences in the behavioral effects of DA depletions.     

Altered L-DOPA systems for blood pressure regulation in the lower brainstem of spontaneously hypertensive rats

Recent findings have enhanced our understanding of the roles played by the L-DOPA system in the baroreceptor reflex and in blood pressure regulation in the lower brainstem. L-DOPA is probably a neurotransmitter of primary baroreceptor afferents terminating in depressor sites of the nucleus tractus solitarii (NTS). It also seems to be a neurotransmitter in depressor sites of the caudal ventrolateral medulla (CVLM) and in pressor sites of the rostral ventrolateral medulla (RVLM) of normotensive Wistar rats. We have explored whether or not presynaptic and postsynaptic functions of the L-DOPA system in these areas are altered to maintain hypertension in adult spontaneously hypertensive rats, as compared with age-matched Wistar Kyoto rats. In this review article, we survey the roles of the L-DOPA system in the baroreceptor reflex and in blood pressure regulation in the rat lower brainstem.     

Therapeutic effects of HS-3, HS-6, benactyzine, and atropine in soman poisoning of dogs

Rats with intracranial self-stimulation (ICSS) electrodes in the locus coeruleus and adjacent pontine tegmental structures received stereotaxically placed bilateral injections of 6-hydroxydopamine (4 mug/2 mul) into the mesencephalic trajectory of the dorsal tegmental noradrenergic bundle. The consequent depletions of norepinephrine in the cerebral cortices and hippocampi (96.7%) did not result in significant changes in ICSS. Thus, diencephalic and telencephalic noradrenergic projections of the locus coeruleus do not appear to be critical for the occurrence of ICSS from that nucleus or its surrounding region. Nor do these projections appear to be crucially involved in the enhancement of this ICSS by D-amphetamine. Rats in this study showed two-fold increases in responding following injections of D-amphetamine sulfate (0.5 mg/kg) both before and after the lesions of the dorsal tegmental bundle. These results suggest that the ascending projections of the locus coeruleus are not critically involved in ICSS of the dorsal pontine tegmentum.     

The effects of deprenyl on methamphetamine-induced dopamine depletions

The effects of deprenyl on methamphetamine-induced dopamine depletions were studied in mice. Four SC injections of 12.5 mg/kg of methamphetamine at two-hour intervals caused substantial (72-82%) and long-lasting depletions of striatal dopamine. Pretreatment with either 25 or 40 mg/kg of deprenyl did not significantly alter the magnitude of this depletion. These results indicate that, unlike what is observed following MPTP, there is no protection afforded dopaminergic cells by deprenyl pretreatment in the methamphetamine model of parkinsonism.     

L-dopa-induced air-stepping in preweanling rats. I. Effects of dose and age

The effects of several doses of L-DOPA (25, 50, 75 and 100 mg/kg) on air-stepping were studied in rats on the day of birth and on 5, 10, 15 and 20 days of age. Occurrence of air-stepping increased and latency to air-stepping generally decreased with dose except at 10 days of age; duration of air-stepping increased with increasing dose of L-DOPA at every age. The occurrence of a variety of air-stepping gaits was age-dependent. On the day of birth, air-stepping consisted primarily of episodes of forelimb alternation; on days 5-20, diagonal progression was the predominant gait, but beginning at day 10, episodes of air-swimming, air-galloping and other locomotor patterns were interspersed. Not only could the durations of most of these gaits be increased with increasing dose of L-DOPA, but at some ages, increasing the dose of L-DOPA led to gait changes.     

Changes of behavior and monoamine metabolites in the rat brain after repeated methamphetamine administration: effects of duration of repeated administration

1. The authors studied the mechanism of the reverse-tolerance phenomenon caused by long-term administration of central stimulant drugs. Methamphetamine(MAP) was chronically administered to rats, and the reverse-tolerance phenomenon was studied in terms of behavioral changes and changes in monoamine metabolites, the latter being examined by in vivo microdialysis of the extracellular compartment of the corpus-striatum. The authors also studied [3H]SCH23390 and [3H]spiperone binding to striatal membranes after chronic MAP administration. 2. MAP(4 mg/kg) or saline was administered intraperitoneally once daily to male rats. In Groups 1 and 2, 10 and 30 injections of MAP were given, respectively. In Groups 3 and 4, animals received 10 and 30 injections of saline as controls. One week after the final injection, all rats were challenged with 4 mg/kg MAP. 3. Groups 1 and 2 displayed more intense stereotypy than Groups 3 and 4, indicating that behavioral sensitization had been achieved in the former. Dopamine(DA) levels increased rapidly in response to MAP challenge in all groups, with the increases in Groups 1 and 2 being more marked than that in Groups 3 and 4. Group 1 showed greater persistence and a higher rate of DA increase than Group 2. 4. The number of D1 and D2 dopamine receptors did not change after the repeated MAP administration. 5. The rate of increase in DA release induced by MAP was dependent on the duration of repeated administration, and there was no correlation between the intensity of stereotypy and the rate of increase in DA release induced by MAP. These findings suggest that enhancement in DA release is unlikely to be the sole cause of behavioral sensitization.