Strategic and self-regulated instruction in synthesis tasks in the university context.

Introduction: The aim of the study was to improve student skills in writing good-quality synthesis texts through a strategic, self-regulated instruction program aimed at ensuring that students properly activated reading and writing strategies required by the synthesis task. Methods: The sample consisted of 84 university students who were randomly assigned to experimental or control conditions. The experimental group received an instructional program based on the development and self-regulated implementation of reading and writing strategies for producing synthesis texts. The control group received a program involving metacognitive knowledge of various academic text types. Both programs involved eight 60-min sessions, taught by teachers in a compulsory degree subject. For the evaluations, students produced synthesis texts from different source texts. The syntheses were graded considering text product measures: information selection, idea connection, text organization, and holistic quality; and measures of reading (underlining and note-taking) and writing (planning and review) strategies. Results: The results show that the experimental group exhibited greater improvements in synthesis quality and greater improvements in activation of information organization processes, note-taking while reading, and text planning. Discussion: In conclusion, university students can, following implementation of a strategic instructional procedure in the context of a study plan, adapt and re-work their own reading and writing strategies and apply them in a self-regulated manner to synthesis tasks, improving text quality and some of the cognitive processes involved.

Rituximab intralesional en linfoma de anejos oculares / Intralesional rituximab in ocular adnexal lymphoma

No disponible

Platelet SERT as a peripheral biomarker of serotonergic neurotransmission in the central nervous system.

Alterations in serotonergic activity have been observed in many pathological conditions, including neuro psychiatric diseases, irritable bowel syndrome, and hypertension. The serotonin (5-hydroxytryptamine; 5-HT) transporter(SERT) in the brain clears 5-HT from extracellular spaces, modulating the strength and duration of serotonergic signaling.Outside the central nervous system, it is also present in platelets, where it takes up 5-HT from plasma, keeping levels very low (i.e., ~1 nM). Importantly, it is generally accepted that SERT protein expressed in platelets is identical to the one found in neurons, displaying similar structural and functional properties in both tissues. At the present time, it is technically difficult to measure SERT binding and function in vivo since imaging methods are limited by a number of factors,especially the cost and the selectivity of the available radioligands. One of the most frequently used molecular imaging techniques to study SERT is positron emission tomography (PET). Although an impressive number of PET radio ligands have been synthesized and validated, there is still a lack of suitable ligands for a large part of the 5-HT system. Interest in determining both the molecular characteristics and the regulation of SERT has been enormous over the last decade, but the difficulty in obtaining human tissues and the ethical limitations in human experiments have turned researchers to look for alternative models. This review summarizes recent clinical and preclinical data relevant to the use of blood platelets asa peripheral marker for the central 5-HT system, and outlines future directions in this field.

Active and passive MDMA ('ecstasy') intake induces differential transcriptional changes in the mouse brain.

3,4-Methylenedioxymethamphetamine (MDMA, 'ecstasy') is a recreational drug widely used by adolescents and young adults. Although its rewarding effects are well established, there is controversy on its addictive potential. We aimed to compare the consequences of active and passive MDMA administration on gene expression in the mouse brain since all previous studies were based on passive MDMA administration. We used a yoked-control operant intravenous self-administration paradigm combined with microarray technology. Transcriptomic profiles of ventral striatum, frontal cortex, dorsal raphe nucleus and hippocampus were analysed in mice divided in contingent MDMA, yoked MDMA and yoked saline groups, and several changes were validated by quantitative reverse transcription polymerase chain reaction (qRT-PCR). The comparison of contingent MDMA and yoked MDMA vs. yoked saline mice allowed the identification of differential expression in several genes, most of them with immunological and inflammatory functions, but others being involved in neuroadaptation. In the comparison of contingent MDMA vs. yoked MDMA administration, hippocampus and the dorsal raphe nucleus showed statistically significant changes. The altered expression of several genes involved in neuroadaptative changes and synapse function, which may be related to learning self-administration behaviour, could be validated in these two brain structures. In conclusion, our study shows a strong effect of MDMA administration on the expression of immunological and inflammatory genes in all the four brain regions studied. In addition, experiments on MDMA self-administration suggest that the dorsal raphe nucleus and hippocampus may be involved in active MDMA-seeking behaviour, and show specific alterations on gene expression that support the addictive potential of this drug.

Neurochemical basis of cannabis addiction.

Cannabis derivatives have become the most widely used illicit substances in developed countries, and constitute a major health concern. The psychoactive compounds contained in cannabis induce their pharmacological effects by the activation of at least two different receptors, CB1 and CB2 cannabinoid receptors. Multiple studies have demonstrated the specific involvement of CB1 cannabinoid receptors in the addictive properties of cannabinoids. Several neurotransmitter systems involved in the addictive effects of other prototypical drugs of abuse, such as the dopaminergic and the opioid system are also involved in cannabis addiction. The participation of other neurochemical systems in behavioural responses of cannabinoids related to their addictive effects has also been reported. This review describes the experimental methods now available to study the pharmacological responses of cannabinoids related to their addictive effects and how these methods have contributed to advance the knowledge of the specific contribution of different neurochemical systems in cannabis addiction.

[Reading comprehension of students with attention deficit hyperactivity disorder: what is the role of executive functions?]. / Comprensión de textos de estudiantes con trastorno por déficit de atencion/hiperactividad: qué papel desempeñan las funciones ejecutivas?

INTRODUCTION: Deficits in reading comprehension of children with attention deficit hyperactivity disorder (ADHD) have received scarce attention. However, to establish the underlying cognitive processes of ADHD and deficits in reading comprehension association could be essential for deeply understanding neurobiological bases of reading comprehension. AIM: To examine the contribution of verbal fluency, reading fluency, and executive functions (working memory, attention and suppression mechanism) in predicting mental processes of texts comprehension. PATIENTS AND METHODS: The participants in the study were 42 students, 12 to 16 year old, with a clinical diagnosis of ADHD. A battery of tests was administered to measure cognitive processes and reading processes. RESULTS AND CONCLUSIONS: Stepwise regression analysis carried out showed that the score in verbal fluency was the best single predictor of reading comprehension. Furthermore executive functions, but not reading fluency, made a significant contribution to reading comprehension. These findings underline the need for consideration of the role of executive functions in assessment and treatment of reading comprehension deficits of students with ADHD.

Oleoylethanolamide exerts partial and dose-dependent neuroprotection of substantia nigra dopamine neurons.

Oleoylethanolamide (OEA), agonist of nuclear PPAR-alpha receptors and antagonist of vanilloid TRPV1 receptors, has been reported to show cytoprotective properties. In this study, OEA-induced neuroprotection has been tested in vitro and in vivo models of 6-OHDA-induced degeneration of substantia nigra dopamine neurons. First, PPAR-alpha receptors were confirmed to be located in the nigrostriatal circuit, these receptors being expressed by dopamine neurons of the substantia nigra, and intrinsic neurons and fibers bundles of the dorsal striatum. In the substantia nigra, their location was confined to the ventral tier. The in vitro study showed that 1 microM OEA exerted a significantly neuroprotective effect on cultured nigral dopamine neurons, effects following U-shaped dose-response curves. Regarding the in vivo study, rats were locally injected with OEA into the right striatum and vehicle into the left striatum 30 min before 6-OHDA-induced striatal lesion. In the short term, signals of heme oxygenase-1 (oxidation marker, 24 and 48 h post-lesion) and OX6 (reactive microglia marker, 96 h post-lesion) were found to be significantly less intense in the striatum pretreated with 5 microM OEA. In the long term (1 month), reduction in striatal TH and synaptophysin was less intense whether the right striatum was pretreated with 5 microM OEA, and nigral TH+ neuron death was significantly reduced after pretreatment with 1 and 5 microM OEA. In vivo effects also followed U-shaped dose-response curves. In conclusion, OEA shows U-shaped partial and dose-dependent neuroprotective properties both in vitro and in vivo models of substantia nigra dopamine neuron degeneration. The occurrence of U-shaped dose-response relationships normally suggests toxicity due to high drug concentration or that opposing intracellular pathways are activated by different OEA doses.

Las anfetaminas / Amphetamines

Objetivo. Las anfetaminas son aminas simpatomiméticas de fórmula química estructural semejante a la adrenalina. Las más utilizadas, de donde derivan las más modernas drogas de este grupo, son el sulfato de d-anfetamina (dexedrina) y el sulfato de anfetamina racémica (benzedrina). Material y métodos. Se revisa la neurobiología, acciones farmacológicas, toxicidad e indicaciones de la anfetaminas. Resultados. Producen estimulación del sistema nervioso simpático con incremento del diámetro pupilar (midriasis), sequedad de boca, sudoración, temblor, tensión mandibular (trismo), movimientos masticatorios o rechinar de dientes (bruxismo) y un ligero incremento de la temperatura corporal. Aumentan la presión arterial y la frecuencia cardíaca (palpitaciones o taquicardia). Son sustancias liposolubles que pasan bien las membranas celulares y atraviesan la barrera hematoencefálica y la placenta. A nivel del sistema nervioso central producen sensación de alerta, estimulación, mejoría del rendimiento intelectual y de la ejecución de tareas manuales, sensación de energía, disminución del cansancio, del sueño y del hambre. Tienen un gran potencial de abuso y pueden causar dependencia. La acción de las anfetaminas involucra a varios neurotransmisores como son la dopamina, la serotonina, la adrenalina y la noradrenalina. Su acción consiste principalmente en aumentar los niveles sinápticos de monoaminas por varios mecanismos, incluyendo el intercambio por difusión a través de los transportadores de membrana, la perturbación del transportador vesicular de monoaminas, inhibición de la monoamino oxidasa (MAO) y promoción de la síntesis de neurotransmisor. El consumo repetido de anfetaminas se asocia a la aparición de fenómenos de tolerancia, sensibilización y dependencia. En seres humanos, la administración repetida de anfetaminas puede producir perturbaciones persistentes a nivel cognitivo y emocional y pueden aparecer cuadros psicóticos aun después de la retirada de la droga. El uso repetido de metanfetamina puede producir neurotoxicidad evidenciada por alteraciones persistentes a nivel neuroquímico y neuronal incluyendo lesiones en los axones y terminaciones que contienen monoaminas. Conclusiones. Las indicaciones terapéuticas actuales de las anfetaminas son muy reducidas. No se recomiendan para reducir el hambre en el tratamiento de la obesidad. Las dos únicas indicaciones para su uso son el tratamiento de la narcolepsia y del déficit de atención infantil. En estos niños la sustancia más utilizada es el metilfenidato

Objective. The amphetamines are sympathomimeticamines with similar chemical formulato adrenaline. The most commonly used, fromwhere most of the newer drugs derive are d-amphetamine(Dexedrine) and d-l amphetamine (Benzedrine).They produce stimulation of the sympatheticnervous system with increment of the pupildiameter, dryness of mouth, sweating, trembling,jaw tension, chewing movements, and a light increasein temperature. Material and methods. The neurobiology, pharmacological and toxicological actions, as well as theclinical use of amphetamines is reviewed.Results. They increase arterial blood pressureand heart frequency (tachycardia). Because theyare very lipophilic substances, they are readily absorbedwhen taken orally, they cross cell membranes,the blood-brain barrier and the placenta. Atthe level of the central nervous system, they produceeuphoria, stimulation and increase the sensationof energy, improve intellectual performance andexecution of manual tasks, and decrease sleep andappetite. They have great abuse potential and cancause dependence. The actions of amphetamines involvevarious neurotransmitter systems includingdopamine, serotonin, adrenaline and noradrenaline.Their action consists mainly in augmenting thesynaptic levels of monoamines by various mechanismsincluding, exchange by diffusion through theplasmalemmal transporters, disruption of the vesicularmonoamine transporters, inhibition of monoamineoxidase (MAO) and promotion of monoaminesynthesis. The repeated use of amphetamines hasbeen associated to the development of tolerance,sensitization and dependence. In humans, repeateduse of amphetamines can produce persistent cognitiveand emotional deficits, and can induce episodesof acute psychosis long after use has been discontinued.The repeated administration of methamphetaminecan produce neurotoxicity evidenced by persistentneurochemical and neuronal alterationsincluding axonal damage. Conclusions. Currently, they have few therapeutic indications. They are not recommended for appetite reduction in the treatment of obesity. The two only indications are in the management of narcolepsy and in children to treat attention deficit and hyperactivity disorder (ADHD), where the mostcommon substance used is methylfenidate

In vivo co-ordinated interactions between inhibitory systems to control glutamate-mediated hippocampal excitability.

We present an overview of the long-term adaptation of hippocampal neurotransmission to cholinergic and GABAergic deafferentation caused by excitotoxic lesion of the medial septum. Two months after septal microinjection of 2.7 nmol alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA), a 220% increase of GABA(A) receptor labelling in the hippocampal CA3 and the hilus was shown, and also changes in hippocampal neurotransmission characterised by in vivo microdialysis and HPLC. Basal amino acid and purine extracellular levels were studied in control and lesioned rats. In vivo effects of 100 mm KCl perfusion and adenosine A(1) receptor blockade with 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) on their release were also investigated. In lesioned animals GABA, glutamate and glutamine basal levels were decreased and taurine, adenosine and uric acid levels increased. A similar response to KCl infusion occurred in both groups except for GABA and glutamate, which release decreased in lesioned rats. Only in lesioned rats, DPCPX increased GABA basal level and KCl-induced glutamate release, and decreased glutamate turnover. Our results evidence that an excitotoxic septal lesion leads to increased hippocampal GABA(A) receptors and decreased glutamate neurotransmission. In this situation, a co-ordinated response of hippocampal retaliatory systems takes place to control neuron excitability.

Absence of delta -9-tetrahydrocannabinol dysphoric effects in dynorphin-deficient mice.

The involvement of dynorphin on Delta-9-tetrahydrocannabinol (THC) and morphine responses has been investigated by using mice with a targeted inactivation of the prodynorphin (Pdyn) gene. Dynorphin-deficient mice show specific changes in the behavioral effects of THC, including a reduction of spinal THC analgesia and the absence of THC-induced conditioned place aversion. In contrast, acute and chronic opioid effects were normal. The lack of negative motivational effects of THC in the absence of dynorphin demonstrates that this endogenous opioid peptide mediates the dysphoric effects of marijuana.

[Viability of colonoscopy without analgesia and conscious sedation]. / Viabilidad de la colonoscopia sin analgesia y sedación consciente.

AIM: To study the need for analgesia and sedation before colonoscopy. PATIENTS AND STUDY DESIGN: Fifty consecutive outpatients were randomly assigned to receive meperidine (0.7 mg/kg) or midazolam (0-035 mg/kg) intravenously (n = 25) or to receive no medication (n = 25) before colonoscopy. Oxygen saturation (SaO2) and heart rate were monitored. Mean blood pressure (MBP) was recorded before and after endoscopy. Patients in the group receiving no medication who experienced marked abdominal pain received sedation and analgesia similar to the premedicated group. Twenty-four hours after the procedure, the patients evaluated the degree of abdominal pain experienced during colonoscopy on a scale from 0 to 9. RESULTS: Complete colonoscopy was performed in 92% of the patients. No significant changes in heart rate were registered in either group. However, in the premedicated group mean blood pressure fell significantly (97.6 +/- 2.6 vs. 89.5 +/- 2.7 mmHg) before and after colonoscopy, respectively (p < 0.05). Nine patients experienced clinically relevant oxygen desaturation (SaO2 > 90%). Of these, five were from the premedicated group and four were from the group receiving no medication. In two patients, both from the premedicated group, the decrease in SaO2 was severe (SaO2 < 85%). The degree of abdominal pain was similar in both groups: 3.64_0.47 (premedicated) vs. 3.92 +/- 0.5 (non-medicated). In the non-medicated group, two patients required analgesia and sedation to complete the colonoscopy and 20 (80%) preferred not to receive sedation in future colonoscopies. CONCLUSIONS: Colonoscopy may be well tolerated without systematic administration of sedation and analgesia, which could be administered selectively.

Methylxanthines reverse the adipsic and aphagic syndrome induced by bilateral 6-hydroxydopamine lesions of the nigrostriatal pathway in rats.

This study investigated whether methylxanthines (caffeine and theophylline) would restore food and water intake in rats made aphagic and adipsic by bilateral 6-hydroxydopamine lesions of the nigrostriatal bundle, and these results were compared with the effects of d-amphetamine, the dopamine D(1) agonist SKF 38393, and the D(2/3) agonist quinpirole. In a separate experiment, we investigated whether the selective D(1) antagonist, SCH 23390, or the selective D(2) antagonist, sulpiride, would prevent the caffeine-induced restoration of food and water intake in bilaterally 6-hydroxydopamine denervated rats. The results showed that caffeine, theophylline, and quinpirole significantly reversed the aphagia and adipsia observed in lesioned animals. SKF 38393 had no significant effects on water intake, while it significantly restored food intake at the highest dose used. In contrast, d-amphetamine had no significant effects on food or water intake. Results from the second experiment showed that sulpiride attenuated the caffeine-induced restoration of food and water intake in lesioned rats to a greater extent than did SCH 23390. These data suggest that methylxanthines may mediate their effects on food and water intake in bilateral 6-hydroxydopamine-lesioned rats through an action at the dopaminergic system.

Effects of sub-chronic combined treatment with pergolide and caffeine on contralateral rotational behavior in unilateral 6-hydroxydopamine-denervated rats.

We studied the synergistic effects of pergolide and bromocriptine with caffeine on turning behavior in 6-OHDA denervated rats. Both pergolide and bromocriptine were synergistic with caffeine, and prevented tolerance to caffeine-induced turning. When caffeine was removed, tolerance to bromocriptine effects was observed for 1 day only, while no tolerance was observed to pergolide. These results suggest that caffeine could be useful in the treatment of Parkinson's disease, preferentially as an adjuvant of mixed dopaminergic agonists like pergolide.

Effects of adenosine and gamma-aminobutyric acid A receptor antagonists on N-methyl-D-aspartate induced neurotoxicity in the rat hippocampus.

This study investigated the modulatory actions of adenosine and gamma-aminobutyric acid (GABA) on several aspects of N-methyl-D-aspartate (NMDA)-induced neurotoxicity, including neuronal loss, atrophy, necrosis, and calcium accumulation in the hippocampus. For this purpose, we combined unilateral intrahippocampal injections of NMDA (24 nmoles) with acute injections of the selective A1 adenosine receptor antagonist DPCPX (0.03 pmoles), the selective adenosine A2a receptor antagonist CSC (1.5 pmoles), a combination of these two antagonists, and injections of the selective GABA A receptor antagonist bicuculline (60 pmoles). Fifteen days after NMDA injection, neuronal loss with preservation of architecture was observed in stratum oriens, pyramidale, radiatum, lacunosum-moleculare, and stratum moleculare of Ammon's horn, and in radial and granular layers of the dentate gyrus. NMDA plus vehicle also produced a small degree of brain tissue necrosis (holes in the structure) in four of five brains. Acute injections of CSC, but not DPCPX or bicuculline, significantly increased the extent of neuronal loss produced by NMDA plus vehicle. CSC in combination with NMDA induced significantly more necrosis than NMDA plus vehicle. A significant degree of atrophy was observed in the hippocampus after treatment with NMDA plus vehicle, and bicuculline significantly increased the magnitude of this atrophy. NMDA-induced calcium deposits were detected within the radiatum and lacunosum-moleculare layers of the hippocampus and in the hilus of the dentate, but not in the stratum oriens, stratum pyramidale, or in the granular layer of the dentate gyrus. However, treatment with the different antagonists did not significantly modify the magnitude of the NMDA-induced calcium deposits. These results reveal a selective vulnerability of certain areas of the hippocampus to the accumulation of calcium deposits, and a selective interaction between adenosine receptors and NMDA-induced neurotoxicity in the hippocampus.

Associative processes in addiction and reward. The role of amygdala-ventral striatal subsystems.

Only recently have the functional implications of the organization of the ventral striatum, amygdala, and related limbic-cortical structures, and their neuroanatomical interactions begun to be clarified. Processes of activation and reward have long been associated with the NAcc and its dopamine innervation, but the precise relationships between these constructs have remained elusive. We have sought to enrich our understanding of the special role of the ventral striatum in coordinating the contribution of different functional subsystems to confer flexibility, as well as coherence and vigor, to goal-directed behavior, through different forms of associative learning. Such appetitive behavior comprises many subcomponents, some of which we have isolated in these experiments to reveal that, not surprisingly, the mechanisms by which an animal sequences responding to reach a goal are complex. The data reveal how the different components, pavlovian approach (or sign-tracking), conditioned reinforcement (whereby pavlovian stimuli control goal-directed action), and also more general response-invigorating processes (often called "activation," "stress," or "drive") may be integrated within the ventral striatum through convergent interactions of the amygdala, other limbic cortical structures, and the mesolimbic dopamine system to produce coherent behavior. The position is probably not far different when considering aversively motivated behavior. Although it may be necessary to employ simplified, even abstract, paradigms for isolating these mechanisms, their concerted action can readily be appreciated in an adaptive, functional setting, such as the responding by rats for intravenous cocaine under a second-order schedule of reinforcement. Here, the interactions of primary reinforcement, psychomotor activation, pavlovian conditioning, and the control that drug cues exert over the integrated drug-seeking response can be seen to operate both serially and concurrently. The power of our analytic techniques for understanding complex motivated behavior has been evident for some time. However, the crucial point is that we are now able to map these components with increasing certainty onto discrete amygdaloid, and other limbic cortical-ventral striatal subsystems. The neural dissection of these mechanisms also serves an important theoretical purpose in helping to validate the various hypothetical constructs and further developing theory. Major challenges remain, not the least of which is an understanding of the operation of the ventral striatum together with its dopaminergic innervation and its interactions with the basolateral amygdala, hippocampal formation, and prefrontal cortex at a more mechanistic, neuronal level.

Scopolamine prevents tolerance to the effects of caffeine on rotational behavior in 6-hydroxydopamine-denervated rats.

Continuous administration of caffeine has been shown to induce tolerance to its psychostimulant effects. In this study, using unilateral 6-hydroxydopamine nigrostriatal denervated rats, we tested the hypothesis that the muscarinic receptor antagonist, scopolamine, would prevent the tolerance to caffeine-induced contralateral rotational behavior. For that purpose we administered either caffeine (40 mg/kg) plus saline or scopolamine (5, 10 and 20 mg/kg) plus saline, as well as caffeine in combination with the various doses of scopolamine for 7 consecutive days, and measured ipsilateral and contralateral rotational behavior. The results showed that acute injections of scopolamine plus saline produced similar levels of both ipsilateral and contralateral turning, while caffeine produced more contralateral than ipsilateral turning. Tolerance to caffeine-induced contralateral turning was observed as of the second administration, while scopolamine plus saline injections did not produce significant changes in rotational behavior with repeated treatment. Scopolamine co-administered with caffeine significantly attenuated the increased contralateral turning produced by acute injections of caffeine plus saline, but significantly prevented the tolerance effects with repeated administration. These findings strongly suggest that muscarinic cholinergic processes may be involved in tolerance to caffeine-induced contralateral turning. The results are interpreted in terms of the possible interactions between dopamine, adenosine and acetylcholine neurotransmitter systems within the basal ganglia circuitry involved in motor behavior.

Rotational behavior in dopamine nigrostriatal denervated rats: effects of a wide range of time intervals between apomorphine administrations.

Previous studies using the turning behavior animal model have shown both increases and decreases in rotational behavior following successive administrations of dopamine agonists. To clarify the results obtained with this model, we studied the variability of rotational behavior after repeated challenges with low doses of apomorphine (0.05 mg/kg) at different time intervals ranging between 2 h and 14 days. Results show a decrease in the total number of turns with time intervals of 2, 6, and 12 h between administrations, and an increase in the total number of turns when apomorphine was administered once every 24 h. In contrast, when animals were tested at 7- and 14-day intervals, a stable number of turns in successive challenges was obtained. These results suggest that when successive injections of dopamine agonists are administered at sufficiently long intervals of time, the neuroadaptations that take place due to repeated drug exposure may not be apparent. These findings are relevant for the design of future experiments using this model.

Repeated co-administration of caffeine and bromocriptine prevents tolerance to the effects of caffeine in the turning behavior animal model.

The present study examined the effects of repeated co-administrations of caffeine and bromocriptine for 9 consecutive days on contralateral turning in unilateral nigrostriatal 6-hydroxydopamine denervated rats. In agreement with previous data, our results showed that on the first administration, both caffeine and bromocriptine injected plus saline produced a significant increase in contralateral rotational behavior as compared to saline-saline injections. However, with repeated administrations, tolerance was observed to caffeine, but not to bromocriptine. The combination of different doses of bromocriptine (0.1, 0.2, 0.4 and 0.8 mg/kg) with caffeine (40 mg/kg) significantly enhanced the effects of either drug injected with saline on rotational behavior, and no tolerance was observed with repeated treatment. The continuous co-administration of both substances was necessary to maintain elevated levels of rotational behavior, since withdrawing one or the other drug led to decreased contralateral turning. These results demonstrate that when caffeine is administered repeatedly in combination with bromocriptine, tolerance to its psychostimulant effects is not observed, suggesting that caffeine could be used as an adjunctive therapeutic agent with dopamine agonists for the treatment of Parkinson's disease.