Acute effects of a glucose energy drink on behavioral control.

There has been a dramatic rise in the consumption of glucose energy drinks (e.g., Amp, Monster, and Red Bull) in the past decade, particularly among high school and college students. However, little laboratory research has examined the acute objective and subjective effects of energy drinks. The purpose of this study was to investigate the acute effects of a glucose energy drink (Red Bull) on cognitive functioning. Participants (N = 80) were randomly assigned to one of five conditions: 1.8 ml/kg energy drink, 3.6 ml/kg energy drink, 5.4 ml/kg energy drink, placebo beverage, or no drink. Participants completed a well-validated behavioral control task (the cued go/no-go task) and subjective measures of stimulation, sedation, and mental fatigue both before and 30 minutes following beverage administration. The results indicated that compared with the placebo and no drink conditions, the energy drink doses decreased reaction times on the behavioral control task, increased subjective ratings of stimulation and decreased ratings of mental fatigue. Greatest improvements in reaction times and subjective measures were observed with the lowest dose and improvements diminished as the dose increased. The findings suggest that energy drink consumption can improve cognitive performance on a behavioral control task, potentially explaining the dramatic rise in popularity of these controversial new beverages. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Does dizocilpine (MK-801) selectively block the enhanced responsiveness to repeated amphetamine administration?

In order to examine the hypothesis that N-methyl-{d}-aspartate (NMDA) receptors are selectively involved in the development of stimulant sensitization, we characterized the interaction between acute and chronic dizocilpine (MK-801)?+?amphetamine using a detailed behavioral analysis, including concurrent assessment of the locomotor and stereotypy components of the stimulant response and continuous monitoring of all the various phases of the emergent sensitization. The results showed that MK-801 (0.125 mg/kg) significantly affected the acute response to amphetamine (0.5, 1.75, 4.0 mg/kg), increasing or decreasing locomotor activity depending on dose. Repeated administration of MK-801?+?amphetamine resulted in a suppression of stereotyped behaviors and a potentiated locomotor sensitization. These findings suggest that rather than blocking the development of sensitization, MK-801 pretreatment may produce a unique behavioral augmentation that is apparent during coadministration and that persists for up to 48 hr in the response to amphetamine challenge. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Individual differences in the biphasic effects of ethanol

Ethanol exerts both stimulant-like and sedative-like subjective and behavioral effects in humans depending on the dose, the time after ingestion and, we will argue, also on the individual taking the drug. This study assessed stimulant-like and sedative-like subjective and behavioral effects of ethanol during the ascending and descending limbs of the blood alcohol curve across a range of doses in nonproblem social drinkers. Forty-nine healthy men and women, 21 to 35 years old, consumed a beverage containing placebo or ethanol (0.2, 0.4, or 0.8 g/kg) on four separate laboratory sessions, in randomized order and under double-blind conditions. Subjective and behavioral responses were assessed before and at regular intervals for 3 hr after ingestion of the beverage. The lowest dose of ethanol (0.2 g/kg) only produced negligible subjective effects compared to placebo. The moderate dose (0.4 g/kg) increased sedative-like effects 90 min after ethanol ingestion but did not increase ratings of stimulant effects at any time. The highest dose (0.8 g/kg) increased ratings of both stimulant- and sedative-like effects during the ascending limb and produced only sedative-like effects during the descending limb. Closer examination of the data revealed that individual differences in response to the highest dose of ethanol accounted for this unexpected pattern of results: about half of the subjects reported stimulant-like effects on the ascending limb and sedative-like effects on the descending limb after 0.8 g/kg ethanol, whereas the other half did not report stimulant-like effects at any time after administration of ethanol. These results challenge the simple assumption that ethanol has biphasic subjective effects across both dose and time, and extend previous findings demonstrating individual differences in response to ethanol.     

Neuroethological assessment of amphetamine-induced behavioral changes and their reversal by neuroleptics: focus on the amygdala and nucleus accumbens

1. An ethological approach was combined with intracerebral infusions of amphetamine to broaden understanding of how this drug acts on mesolimbic neuronal systems to alter behavior. 2. Rats, tested in sets of three, were allowed to interact with each other or with various novel objects in an open-field arena. Specific behavioral responses were assessed and grouped into several broad categories: motivation (movement directed toward novel objects), social (movement involving contact with other rats), and motor (movement without obvious direction toward environmental stimuli) as well as no movement (quiet rest). 3. Infusion of d-amphetamine (10 micrograms/microliter) into either the amygdala or nucleus accumbens elevated motor behavior relative to control rats in the set, but only amygdaloid infusions also increased the motivation score. Intra-amygdaloid clozapine or haloperidol blocked the increase in this score, but only clozapine also blocked the motor effects of intra-amygdaloid amphetamine. 4. Although neither neuroleptic in the accumbens blocked the amphetamine-induced increase in the motor category, both clozapine and haloperidol lowered the motivation score below the amphetamine level. 5. The results suggest a role for the amygdala in the motivational component of amphetamine-induced behavioral effects. Both neuroleptics, moreover, appear to reverse this component perhaps by acting via either amygdaloid or accumbal mechanisms. Although follow-up studies are warranted, a neuroethological approach is likely to shed new light on the neuronal systems underlying the complex behavioral changes induced by amphetamine and related stimulants.     

The effects of transnasal butorphanol on mood and psychomotor functioning in healthy volunteers

Transnasal butorphanol is effective in relieving migraine and postoperative pain. The extent to which this drug preparation impacts on cognitive and psychomotor performance, as well as mood, has not been examined. Accordingly, the cognitive and psychomotor, subjective, and physiological effects of two clinically relevant doses of transnasal butorphanol (1 and 2 mg) were compared to that of placebo, and a common analgesic drug combination given for pain relief in ambulatory settings, 600 mg of acetaminophen and 60 mg of codeine, in healthy volunteers (n = 10). The larger transnasal butorphanol dose impaired psychomotor performance for up to 2 h, and produced subjective effects for up to 3 h. The smaller dose had no psychomotor-impairing effects, but had subjective effects (including increased ratings of "sleepy"). All three active drug conditions including miosis. These laboratory results suggest that patients should use caution when using the 1-mg dose of transnasal butorphanol, and should curtail certain activities if they administer the 2-mg dose of transnasal butorphanol for analgesia.     

Repeated injection of GBR 12909, but not cocaine or WIN 35,065-2, into the ventral tegmental area induces behavioral sensitization

A role for the mesolimbic dopamine system in the development of behavioral sensitization to psychostimulants, such as cocaine and amphetamine, is well established. Previous reports have suggested that the ventral tegmental area (VTA) is involved in the initiation of, while the nucleus accumbens is in involved in the expression of behavioral sensitization. This hypothesis is supported in part, by studies which demonstrated that behavioral sensitization could be induced by repeated intra-VTA, but not intra-accumbal, administration of amphetamine. The present studies were designed to determine whether repeated intra-VTA cocaine would similarly induce behavioral sensitization. Rats receiving four daily injections of cocaine (1.5, 5 or 15 nmol/side) into the VTA did not show a sensitized behavioral response when challenged with cocaine (15 mg/kg, ip) 1 week later. In contrast to this, repeated injection of the specific dopamine reuptake inhibitor, GBR 12909 (15 nmol/side) produced behavioral sensitization to a challenge injection of cocaine. Repeated injections of the cocaine analog WIN 35,065-2 did not induce behavioral sensitization to cocaine, suggesting that the local anesthetic properties of cocaine were not responsible for the inability of intra-VTA cocaine to induce sensitization. In summary, the data suggest that sensitization to cocaine may involve mechanisms different from amphetamine.     

Relationship of blood pressure, heart rate and behavioral mood state to norepinephrine kinetics in younger and older men following caffeine ingestion

OBJECTIVE: To examine age-related differences in blood pressure, heart rate, behavioral mood state and norepinephrine kinetics after caffeine ingestion in younger and older men. DESIGN: Placebo-controlled, double-blind study. SETTING: General Clinical Research Center, University of Vermont. SUBJECTS: 10 older (O) (65-80 y) and 10 younger (Y) (19-26 y) healthy men who were moderate consumers of caffeine (Y= 126+/-30 mg/d; O = 160 44 mg/d:NS; mean +/- s.e.m.). INTERVENTION: All volunteers were characterized for fasting plasma glucose, insulin and caffeine levels, body composition, anthropometry, physical activity, and energy intake. Before and after placebo and caffeine ingestion (5 mg/kg fat-free mass) test days, the following variables were measured in all subjects: heart rate, blood pressure, mood state, and norepinephrine concentrations (NEconc), appearance (NEapp) and clearance (NEcl). MAIN OUTCOME MEASURES: Systolic and diastolic blood pressure, heart rate, mood state, and norepinephrine kinetic responses to placebo and caffeine ingestion. RESULTS: Following caffeine ingestion, plasma caffeine levels were similar in Y and O men. Systolic (SBP) and diastolic (DBP) blood pressure increased significantly (P < 0.01) from baseline by 9% (130+/-6 vs 142+/-6 mmHg) and 3% (75+/-3 vs 77+/-3 mmHg), respectively, in O men following caffeine ingestion, but remained unchanged in Y men. Self-reported feelings of tension (P < 0.05) and anger (P = 0.06) decreased in O men, while anger tended to increase in Y men (P < 0.06) following caffeine ingestion. Heart rates in both groups were unaltered following caffeine ingestion. No differences were noted at baseline between O and Y men for NEconc, NEapp and NEcl. After caffeine ingestion, NEconc were significantly greater in O than Y men, whereas NEapp and NEcl rates did not differ from baseline in either group. Blood pressure and subjective mood state effects of caffeine were not related to changes in norepinephrine kinetics. CONCLUSION: Age may play a role in augmenting blood pressure response and reducing subjective feelings of anger and tension following caffeine ingestion, suggesting that the elderly are more reactive to the pressor and less sensitive to the subjective effects of the drug. These effects do not appear to be mediated by changes in sympathetic nervous system activity.     

Effects of repeated-dose isradipine on the abuse liability of cocaine.

Despite preclinical studies suggesting that isradipine may antagonize the abuse liability of cocaine, pretreatment with sustained-release isradipine did not reduce euphoric mood in cocaine-using volunteers. This double-blind, within-subject, crossover laboratory study determined whether maximal dose-loading with isradipine could antagonize effects of cocaine in 12 cocaine-dependent research volunteers administered intravenous cocaine doses (0, 0.325, and 0.65 mg/kg) on different days after 5 days of treatment with isradipine or placebo. Isradipine dose was 30 mg sustained release nightly plus 15 mg immediate release 2 hr before cocaine infusion. Cocaine produced dose-related increases in cocaine's subjective effects and a behavioral measure of reinforcement. Isradipine enhanced, rather than antagonized, subjective effects, indicating that isradipine does not antagonize cocaine's abuse liability in dependent research volunteers. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Enhanced mood and psychomotor performance by a caffeine-containing energy capsule in fatigued individuals.

Caffeine produces mild psychostimulant effects that may be particularly evident in individuals whose mood or performance is impaired by sleep restriction or caffeine withdrawal. Caffeinated energy drinks have been shown to improve energy and cognition but expectancy effects cannot be ruled out in these studies. Very few studies have examined the effects of caffeine-containing energy capsules upon behavioral and subjective measures. This study compared the effects of a caffeine-containing (200 mg) supplement (CAF) or placebo in capsule form after prolonged wakefulness, in participants who varied in their level of habitual caffeine use. Thirty-five healthy volunteers (16 male, 19 female) participated in two experimental sessions in which they remained awake between 5 p.m. and 5 a.m. At 3:30 a.m. they consumed CAF or placebo in random order under double-blind conditions. Participants completed subjective effects questionnaires and performed computerized attention tasks before and after consuming capsules. Heart rate and blood pressure were monitored at regular intervals. Compared to measures at 5 p.m., participants reported more tiredness and mood disturbance at 3 a.m., and exhibited longer reaction times and more attentional lapses. Heavier caffeine consumers exhibited the greatest decreases in Profile of Mood States (POMS) Vigor. CAF produced stimulant-like effects and significantly improved mood and reaction times upon the tasks. These effects did not vary with level of habitual caffeine consumption. These findings indicate that consumption of a caffeine-containing food supplement improves subjective state and cognitive performance in fatigued individuals that is likely a result of its caffeine content. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Cumulative pregnancy rates and selective drop-out of patients in in-vitro fertilization treatment

Rats were given repeated infusions of i.v. amphetamine in association with placement in a novel test environment, a protocol that produces behavioral sensitization, or in the home cage, a protocol that fails to induce sensitization. In several brain areas amphetamine altered calmodulin content, but only in the group treated in a novel environment, suggesting that amphetamine-induced alterations in calmodulin may occur only when drug treatments induce behavioral sensitization.     

Avoiding labor problems during vaginal birth after cesarean delivery

Dopamine has been proposed to mediate some of the behavioral effects of caffeine. This review discusses cellular mechanisms of action that could explain the role of dopamine in the behavioral effects of caffeine and summarizes the results of behavioral studies in both animals and humans that provide evidence for a role of dopamine in these effects. Caffeine is a competitive antagonist at adenosine receptors and produces a range of central and physiological effects that are opposite those of adenosine. Recently, caffeine has been shown to enhance dopaminergic activity, presumably by competitive antagonism at adenosine receptors that are colocalized and interact functionally with dopamine receptors. Thus, caffeine, as a competitive antagonist at adenosine receptors, may produce its behavioral effects by removing the negative modulatory effects of adenosine from dopamine receptors, thus stimulating dopaminergic activity. Consistent with this interpretation, preclinical behavioral studies show that caffeine produces behavioral effects similar to classic dopaminergically mediated stimulants such as cocaine and amphetamine, including increased locomotor activity, increased turning behavior in 6-hydroxydopamine-lesioned animals, stimulant-like discriminative stimulus effects, and self-administration. Furthermore, caffeine potentiates the effects of dopamine-mediated drugs on these same behaviors, and some of caffeine's effects on these behaviors can be blocked by dopamine receptor antagonists. Although more limited in scope, human studies also show that caffeine produces subjective, discriminative stimulus and reinforcing effects that have some similarities to those produced by cocaine and amphetamine.     

Effects of testosterone on locomotor performance and growth in field-active northern fence lizards, Sceloporus undulatus hyacinthinus

BACKGROUND: Short-term exposures to increased CO2 concentrations in breathing air up to 5% are assumed to have only negligible behavioral effects. In the present study it was examined to what extent prolonged exposures to moderately elevated levels of CO2 in the ambient air affect human performance. METHOD: During two phases of 26 d of confinement in a diving chamber a group of four subjects was exposed to two different levels of CO2 (0.7% and 1.2%). Cognitive, visuo-motor, and time-sharing performance were assessed repeatedly before, during, and after the exposure by means of a task battery including grammatical reasoning, memory search, unstable tracking, and dual tasks. In addition, subjective workload and mood ratings were collected. A second group of four subjects served as a control group who performed the different tasks on the same 26-d time schedule without being exposed to confinement and elevated CO2. RESULTS: During exposure to 0.7% CO2 only tracking performance was slightly disturbed compared with baseline levels, whereas performance of the control group remained stable. The time course of this effect suggested that it was related to chamber adaptation rather than to increased levels of CO2. During exposure to 1.2% CO2, tracking performance again was significantly impaired. In contrast to the lower exposure condition, the time course of this effect appeared to be related to the CO2 load and covaried with a loss of subjective alertness. CONCLUSIONS: The study indicates that at least visuomotor performance might be affected by CO2 concentrations in the ambient atmosphere as small as 1.2% if subjects are chronically exposed to these concentrations in a confined environment. The strength of these effects, however, does not appear to be of operational relevance.     

Sensitization of amphetamine-induced stereotyped behaviors during the acute response

The quantitative and qualitative features of the behavioral response to amphetamine-like stimulants in rats can be dissociated from the dopamine response. This dissociation is particularly evident in the temporal profiles of the extracellular dopamine and stereotypy responses to higher doses of amphetamine. One possible mechanism contributing to this temporal dissociation is that during the acute response to amphetamine, dopamine receptor mechanisms are enhanced such that stereotyped behaviors can be supported by synaptic concentrations of dopamine which are not sufficient to initiate these behaviors. To further explore the dynamics of stimulant sensitivity during the acute response, we examined the behavioral and extracellular dopamine responses to a low, nonstereotypy-producing dose of amphetamine (0.5 mg/kg) at various times after an acute, priming injection of 4.0 mg/kg when stereotypies had subsided and extracellular dopamine was approaching predrug baseline levels. The low-dose challenge produced intense stereotypies although the regional dopamine responses were not significantly different from control animals. Blockade of the expression of stereotypies during the priming response by the D2 antagonist haloperidol or the D1 antagonist SCH 23390 prevented the expression of an enhanced stereotypy response to the challenge injection. Our results suggest that an exposure to amphetamine results in a rapid sensitization of the stereotypy response which does not involve changes in the extracellular dopamine response but requires activation of dopamine receptors. Such a mechanism may be significantly implicated during binge patterns of stimulant abuse and may also play a role in the sensitization associated with repeated amphetamine administration.     

Evidence for involvement of ventral tegmental area cyclic AMP systems in behavioral sensitization to psychostimulants

The present study investigated the role of ventral tegmental area (VTA) cyclic AMP (cAMP) systems in the behavioral sensitivity to psychostimulants in male Sprague-Dawley rats. Bilateral microinjections of cholera toxin (CTX) into the VTA (50-500 ng/500 nl/side) dose-dependently sensitized animals to the locomotor stimulant effects of systemic d-amphetamine, cocaine and apomorphine, but were without effects on morphine-induced locomotion 24 hr after microinjection. The CTX-induced behavioral sensitization to amphetamine was even greater 72 hr after microinjection, but was no longer present 14 days after intra-VTA CTX pretreatment. Coadministration of the cAMP-dependent protein kinase inhibitor H8 into the VTA blocked CTX-induced sensitization to amphetamine, suggesting that the sensitization is dependent on phosphorylation events in the VTA mediated by cAMP-dependent protein kinase. Pretreatment with CTX did not enhance amphetamine-induced dopamine release in the nucleus accumbens relative to saline controls 24 hr after microinjection. A single bilateral injection of d-amphetamine into the VTA (5 micrograms/side) produced a significant sensitization to systemic amphetamine challenge 72 hr later, and this effect was also blocked by coadministration of H8 into the VTA. These results extend previous studies which have established the importance of the VTA in the development of behavioral sensitization and suggest that cAMP systems may play a crucial role in this neuroadaptive process.     

Acute behavioral effects of triazolam and caffeine, alone and in combination, in humans.

The acute behavioral effects of triazolam (0, 0.375, and 0.75 mg/70 kg) and caffeine (0, 250, and 500 mg/70 kg), alone and in combination, were assessed in 9 male volunteers. Ss received all possible dose combinations according to a Latin square design. Triazolam administered alone dose dependently disrupted learning and performance on the Repeated Acquisition and Performance procedure and the Digit Symbol Substitution Test and increased S ratings of sedation. Caffeine administered alone did not significantly affect learning or performance measures, but it did dose dependently increase S ratings of drug strength. Caffeine significantly attenuated triazolam-induced decrements in learning and performance. Consistent with effects on learning and performance, caffeine offset triazolam-induced increases in S ratings of sedation. Combining caffeine and triazolam did not significantly alter increases in S ratings of drug strength observed with caffeine alone. These effects are qualitatively similar to those observed with other benzodiazepines (e.g., lorazepam) and document a high degree of consistency in the behavioral pharmacology of benzodiazepine-caffeine combinations in humans. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Clozapine and haloperidol block the induction of behavioral sensitization to amphetamine and associated genomic responses in rats

Behavioral sensitization resulting from repeated, intermittent exposure to psychostimulants such as amphetamine (Amp) is hypothesized to model pathophysiology of psychotic disorders. The present study was designed to characterize the effects of a typical and an atypical antipsychotic drug, haloperidol and clozapine, respectively, on the induction of context-independent sensitization to Amp. Peripheral Amp treatment for five days (2 mg/kg/day, s.c.) produced an augmented stimulant response to an acute Amp challenge (2 mg/kg, s.c.) given seven days after the last pretreatment injection. Interestingly, preexposure to high doses of either clozapine (20 mg/kg) or haloperidol (0.5 mg/kg) alone also led to a sensitized behavioral response to an acute Amp challenge. The cross-sensitization between Amp and high doses of the haloperidol and clozapine may have occluded any blockade of Amp behavioral sensitization by the antipsychotics. Indeed, administration of a lower dose of clozapine (4 mg/kg) or haloperidol (0.1 mg/kg) with Amp during the preexposure phase clearly blocked the induction of behavioral sensitization. In addition to the behavioral sensitization, Amp-pretreated rats showed a reduction in the ability of the acute Amp challenge to induce c-fos mRNA in the medial prefrontal cortex and neurotensin/neuromedin N (NT/N) mRNA in the nucleus accumbens-shell. At doses that blocked the initiation of behavioral sensitization to Amp, clozapine fully and haloperidol partially restored the capacity of acute Amp to induce c-fos and NT/N gene expression. These data lend support to the psychostimulant-sensitization model of psychosis and a role of dopamine D2-like receptors in the phenomenon.     

Effects of daytime naps on performance and mood in a college student population.

Studied the effects of daytime naps on performance and mood in 18 healthy male university students who habitually slept 1/2 hr-2 hrs in the afternoon. Measurements were obtained from an auditory reaction time task and a mood adjective checklist 20 min before and after a control condition and 2 EEG recorded afternoons of sleep. The experimental conditions comprised a 2-hr period of wakefulness, a 1/2hr nap from 4:35-5:05 PM and a 2-hr nap from 3:05-5:05 PM. Following each sleep treatment there were statistically significant shift, of improved reaction time performance and elevated subjective arousal, as assessed by the mood scales, when compared with the control condition. The effect of increased efficiency following sleep was approximately equivalent in extent between 2-hr and 1/2-hr naps. These findings indicate that behavioral and psychological functions are facilitated by short periods of habitual sleep in the afternoon. (49 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Regional differences in the effects of amphetamine withdrawal on dopamine dynamics in the striatum. Analysis of circadian patterns using automated on-line microdialysis

The purpose of the study is to determine the relationship between behavioral symptoms of amphetamine withdrawal and the extracellular concentration of dopamine (DA) in the dorsolateral caudate nucleus and the nucleus accumbens across the entire light-dark cycle. This was accomplished using automated on-line microdialysis sampling in behaving rats. Animals were pretreated with escalating doses of d-amphetamine (or saline) over a 6-week period and then were withdrawn from amphetamine for 3, 7, or 28 days before testing. There were regional differences in the effects of amphetamine withdrawal on the concentrations of DA and DA metabolites in dialysate. Early during withdrawal (3 and 7 days), when animals showed postamphetamine withdrawal behavioral depression (nocturnal hypoactivity), there was a significant decrease in DA and DA metabolites in the dorsolateral caudate nucleus and a disruption in the normal circadian pattern of DA activity. In contrast, there was no effect of amphetamine withdrawal on DA dynamics in the nucleus accumbens. By 28 days after the discontinuation of amphetamine pretreatment, after basal DA in the caudate returned to normal, there was a significant increase in basal DA metabolism in both the caudate and the accumbens. This increase in DA metabolism may be related to the expression of sensitization, including a hypersensitivity to an amphetamine challenge. It is concluded that the role of the dorsal striatum in psychostimulant drug withdrawal syndromes deserves further consideration.     

Behavioral sensitization to amphetamine is not accompanied by a decrease in the number of c-Fos containing cells in the striatum

The expression of c-Fos-like immunoreactivity (FLI) and chronic Fos-related antigen-like immunoreactivity (FRALI) accompanying behavioral sensitization to amphetamine was assessed in male rat striatum. Animals were treated for four days with amphetamine (A; 5 mg/kg) or vehicle (V) and challenged with A or V on the fifth day. The number of FLI-positive cells in the striatum was enhanced in V-A and A-A groups as compared to control (V-V), while the number of FRALI-positive cells in the striatum was enhanced in the A-V and A-A groups as compared to control. These results suggest that the absence of a decrease in the number of striatal FLI-positive cells accompanying chronic amphetamine treatment is not due to antibody cross-reactivity with chronic FRAs, and that behavioral sensitization to amphetamine is not accompanied by a change in the number of striatal cells expressing c-Fos.     

Differential development of autoreceptor subsensitivity and enhanced dopamine release during amphetamine sensitization

Various changes in the function of dopamine neurons have been proposed to underly the development of behavioral sensitization to the locomotor stimulant effects of d-amphetamine. The present study examined the relative importance of two such mechanisms after both short (3-4 days off) and longer (10-14 days off) withdrawals from repeated amphetamine or saline injection (1 mg/kg/day, days 1-5 and 8-12). First, single-unit recording was used to examine the sensitivity of impulse-regulating somatodendritic autoreceptors located on mesoaccumbens dopamine neurons in the rat ventral tegmental area. Second, in vivo microdialysis was used to examine the ability of amphetamine challenge to increase extracellular dopamine levels in the rat nucleus accumbens. Amphetamine-treated rats exhibited robust behavioral sensitization at both time points as compared to saline-treated rats. At 3 to 4 days off, autoreceptor subsensitivity was observed in the ventral tegmental area of amphetamine-treated rats, but there was no significant change in the ability of amphetamine to increase extracellular dopamine levels in nucleus accumbens. However, after 10 to 14 days off, autoreceptor subsensitivity was no longer observed, but amphetamine challenge resulted in a significantly greater increase in extracellular dopamine levels in amphetamine-treated as compared to saline-treated rats. These findings suggest that autoreceptor subsensitivity is a transient effect which may be related to the development of sensitization, whereas enhancement of amphetamine-stimulated dopamine release does not accompany early stages of behavioral sensitization, but may be involved in the persistence of the phenomenon after longer withdrawal periods.