A low-fat high-carbohydrate diet reduces plasma total adiponectin concentrations compared to a moderate-fat diet with no impact on biomarkers of systemic inflammation in a randomized controlled feeding study.

PURPOSE: We compared the effects of a eucaloric moderate-fat diet (18% protein, 36% fat, and 46% carbohydrate), a eucaloric low-fat high-carbohydrate diet (18% protein, 18% fat, and 64% carbohydrate), and a low-calorie (33% reduced) low-fat high-carbohydrate diet on biomarkers of systemic inflammation. METHODS: We randomly assigned 102 participants (age 21-76 years and BMI 19.2-35.5 kg/m(2)) to the three different diets for 6 weeks in a parallel design intervention trial. All foods were provided. Ninety-three participants completed all study procedures; 92 were included in the analyses. Endpoints included plasma C-reactive protein (CRP), interleukin-6 (IL-6), soluble tumor necrosis factor receptors I and II (sTNFRI and II), and adiponectin. RESULTS: In the unadjusted primary analyses, none of the endpoints were differentially affected by the dietary interventions despite the significantly greater reductions in body weight and fat mass in participants consuming the low-calorie low-fat diet compared to the eucaloric diets (p < 0.001). When including weight change in the model in secondary analysis, adiponectin tended to be increased with weight loss (time × weight change interaction, p = 0.051). Adjusted for weight change, adiponectin was reduced in the groups consuming the low-fat diets relative to the moderate-fat diet (p = 0.008). No effect of the intervention diets or weight loss on CRP, IL-6, or sTNFRI and II was seen in these secondary analyses. CONCLUSIONS: In relatively healthy adults, moderate weight loss had minimal effects on systemic inflammation, and raised plasma adiponectin only modestly. A lower dietary fat and higher carbohydrate content had little impact on measures of systemic inflammation, but reduced adiponectin concentrations compared to a moderate-fat diet. The latter may be of concern given the consistent and strong inverse association of plasma adiponectin with many chronic diseases.

Acute and chronic psychostimulant treatment modulates the diurnal rhythm activity pattern of WKY female adolescent rats.

The psychostimulants considered the gold standard in the treatment of attention deficit hyperactivity disorder, one of the most common childhood disorders, are also finding their way into the hands of healthy young adults as brain augmentation to improve cognitive performance. The possible long-term effects of psychostimulant exposure in adolescence are considered controversial, and thus, the objective of this study was to investigate whether the chronic exposure to the psychostimulant amphetamine affects the behavioral diurnal rhythm activity patterns of female adolescent Wistar-Kyoto (WKY) rat. The hypothesis of this study is that change in diurnal rhythm activity pattern is an indicator for the long-term effect of the treatment. Twenty-four rats were divided into two groups, control (N = 12) and experimental (N = 12), and kept in a 12:12-h light/dark cycle in an open-field cage. After 5-7 days of acclimation, 11 days of consecutive non-stop behavioral recordings began. On experimental day 1 (ED1), all groups were given an injection of saline. On ED2 to ED7, the experimental group was injected with 0.6 mg/kg amphetamine followed by 3 days of washout from ED8 to ED10, and amphetamine re-challenge on ED11 similar to ED2. The locomotor movements were counted by the computerized animal activity monitoring system, and the cosinor statistical test analysis was used to fit a 24-h curve of the control recording to the activity pattern after treatment. The horizontal activity, total distance, number of stereotypy, vertical activity, and stereotypical movements were analyzed to find out whether the diurnal rhythm activity patterns were altered. Data obtained using these locomotor indices of diurnal rhythm activity pattern suggest that amphetamine treatment significantly modulates the locomotor diurnal rhythm activity pattern of female WKY adolescent rats.

Methylphenidate cross-sensitization with amphetamine is dose dependent but not age dependent.

Psychostimulants such as methylphenidate (MPD) and amphetamine (AMP) are often prescribed to young children and adolescents to treat behavioral disorders, or used to improve their intellectual performance in our competitive society. This is concerning as the temporal effects of how MPD exposure at a young age influences the response to MPD and AMP administration later in adulthood remains unclear. The objective of this study was to test whether MPD has the characteristics of substances that elicit behavioral symptoms of dependence and whether those effects are influenced by the initial age of MPD exposure. Three control and nine experimental groups of male rats were used. They were exposed to repetitive (chronic) 0.6, 2.5, or 10.0 mg/kg MPD in adolescence only, adulthood only, or adolescence and adulthood respectively. Then all groups were subsequently re-challenged with a single AMP dose in adulthood to test whether cross-sensitization between MPD and AMP was expressed, potentially as a result of prior MPD consumption. Exposure to 2.5 mg/kg and 10.0 mg/kg MPD in adolescence and adulthood or in adulthood alone led to cross-sensitization with AMP while exposure to 0.6 mg/kg MPD in adolescence and adulthood or in adulthood alone did not lead to cross-sensitization with AMP. Thus, these results indicate that MPD cross-sensitization with AMP is dose dependent.

Protocol optimization of a targeted sequencing panel for genomic profiling of bronchoalveolar lavage fluid in lung cancer.

INTRODUCTION: We investigated a commercially available sequencing panel to study the effect of sequencing depth, variant calling strategy, and targeted sequencing region on identifying tumor-derived variants in cell-free bronchoalveolar lavage (cfBAL) DNA compared with plasma cfDNA. METHODS: Sequencing was performed at low or high coverage using two filtering algorithms to identify tumor variants on two panels targeting 77 and 197 genes respectively. RESULTS: One hundred and four sequencing files from 40 matched DNA samples of cfBAL, plasma, germline leukocytes, and archival tumor specimens in 10 patients with early-stage lung cancer were analyzed. By low-coverage sequencing, tumor-derived cfBAL variants were detected in 5/10 patients (50%) compared with 2/10 (20%) for plasma. High-coverage sequencing did not affect the number of tumor-derived variants detected in either biospecimen type. Accounting for germline mutations eliminated false-positive plasma calls regardless of coverage (0/10 patients with tumor-derived variants identified) and increased the number of cfBAL calls (5/10 patients with tumor-derived variants identified). These results were not affected by the number of targeted genes.

The effect of environment on cross-sensitization between methylphenidate and amphetamine in female rats.

Methylphenidate (MPD) and amphetamine (AMP) are both psychostimulants that are often used to treat behavioral disorders. More recently, it has also been increasingly used illicitly for recreation as well as to improve intellectual performance. Many factors such as age, gender, genetic background, and environment govern the development of behavioral sensitization to MPD and cross-sensitization with other drugs, which are experimental behavioral markers indicating potential of substance dependence and abuse. This study examines the effects of the environment and age when MPD was exposed in adulthood alone as well as in adolescence into adulthood on cross-sensitization with AMP in female SD rats by randomizing animals to either receive the drug in a home cage or a test cage during adolescence, adulthood, or both. In a 34 day experiment, 16 groups of animals starting in adolescence were treated with saline on experimental day one (ED1), followed by a 6 day (ED2-ED7) treatment with either saline, 0.6 mg/kg AMP, 0.6, 2.5, or 10.0 mg/kg MPD. Experimental groups were then subject to a 3-day washout period (ED8-ED10) and then a retreatment with the respective drug on ED11 in adolescence (P-38 to P-49). Experiments continued in the same animal groups now in adulthood (P-60) with a saline treatment (ED1), followed by the same sequence of treatments in adolescence (ED2-ED11;P-61 to P-69). A rechallenge with the same AMP or MPD dose was performed on ED11 (P-70) followed by a single exposure to 0.6 mg/kg AMP on ED12 (P-71) to assess for cross sensitization between MPD and AMP. Animals treated with MPD in both adolescence and adulthood and in the last experimental day of AMP (ED12) showed higher intensity of cross-sensitivity between MPD and AMP as compared to animals treated with MPD only in adulthood. AMP and MPD treatment in adolescence and into adulthood in the home or test cage resulted in significantly higher responses to the drug as compared to those treated only in adulthood. Overall, we conclude that environmental alteration and adolescent exposure to MPD appeared to increase the risk of cross-sensitization to AMP in female SD rats i.e, using MPD in adolescence may increase the probability of becoming dependent on drugs of abuse. This further indicates that age, sex, and environment all influence the response to MPD and AMP, and further work is needed to elucidate the risks associated with MPD and AMP use.

Repetitive methylphenidate administration modulates the diurnal behavioral activity pattern of adult female SD rats.

Diurnal rhythms influence many of the physiological processes that act to maintain homeostasis of the body in response to different environmental changes. Thus, disturbances in diurnal rhythms can lead to various physiological complications. Repeated exposure to psychostimulants may cause long-term effects by disturbing diurnal rhythms. The aim of the present study is to use the open field assay to determine whether repeated exposure to the psychostimulant methylphenidate (MPD) changes diurnal locomotor activity patterns of female adult Sprague-Dawley (SD) rats. As much as 31 female adult SD rats were divided into four groups. On experimental day (ED) 1, all groups were given an injection of saline. On ED 2-7, animals were injected once a day with either saline, or 0.6 mg/kg MPD, or 2.5 mg/kg MPD, or 10 mg/kg MPD depending on the group. On ED 8-10, no injections were given (washout period). On ED 11, animals were treated as they were on ED 2-7. Locomotor movements were recorded using a computerized animal activity monitoring system. The horizontal activity (HA), total distance traveled (TDT), and number of stereotypies (NOS) were analyzed by cosine curve statistical analysis (CCSA) test. The HA and TDT diurnal rhythm activity patterns of ED 2, 7, 8, and 11 were significantly different (p < 0.05) from the control recording of ED 1 according to the CCSA test. The observation obtained in this study suggests that repeated administration of MPD (all doses tested) is able to change diurnal locomotor patterns, which indicates that chronic MPD treatment exerts long-term effects.

Trophic factors GDNF and BDNF improve function of retinal sheet transplants.

The aim of this study was to compare glial-derived neurotrophic factor (GDNF) treatment with brain-derived neurotrophic factor (BDNF) treatment of retinal transplants on restoration of visual responses in the superior colliculus (SC) of the S334ter line 3 rat model of rapid retinal degeneration (RD). RD rats (age 4-6 weeks) received subretinal transplants of intact sheets of fetal retina expressing the marker human placental alkaline phosphatase (hPAP). Experimental groups included: (1) untreated retinal sheet transplants, (2) GDNF-treated transplants, (3) BDNF-treated transplants, (4) none surgical, age-matched RD rats, (5) sham surgery RD controls, (6) progenitor cortex transplant RD controls, and (7) normal pigmented rat controls. At 2-8 months after transplantation, multi-unit visual responses were recorded from the SC using a 40 ms full-field stimulus (-5.9 to +1 log cd/m(2)) after overnight dark-adaptation. Responses were analyzed for light thresholds, spike counts, response latencies, and location within the SC. Transplants were grouped into laminated or rosetted (more disorganized) transplants based on histological analysis. Visual stimulation of control RD rats evoked no responses. In RD rats with retinal transplants, a small area of the SC corresponding to the position of the transplant in the host retina, responded to light stimulation between -4.5 and -0.08 log cd/m(2), whereas the light threshold of normal rats was at or below -5 log cd/m(2) all over the SC. Overall, responses in the SC in rats with laminated transplants had lower response thresholds and were distributed over a wider area than rats with rosetted transplants. BDNF treatment improved responses (spike counts, light thresholds and responsive areas) of rats with laminated transplants whereas GDNF treatment improved responses from rats with both laminated and rosetted (more disorganized) transplants. In conclusion, treatment of retinal transplants with GDNF and BDNF improved the restoration of visual responses in RD rats; and GDNF appears to exert greater overall restoration than BDNF.

A2AR Antagonism with DZD2269 Augments Antitumor Efficacy of Irradiation in Murine Model.

Accumulated extracellular adenosine suppresses antitumor immunity via adenosine 2A receptor (A2AR). Blockade of A2AR with DZD2269 can inhibit phosphorylation of cAMP response element-binding protein mediated by adenosine analogue in vitro and in vivo. Irradiation can cause the release of adenosine and lead to a rapid increase in free extracellular adenosine in the tumour area. DZD2269, a novel A2AR Antagonism, induces incomplete antitumor responses in multiple syngeneic mouse tumour models. Combining DZD2269 with IR can induce a synergistic anticancer effect. IR increases the infiltration of various subtypes of T cells, including CD4+, CD8+ and Foxp3+ T cells, into the tumour area. Combining IR and DZD2269 improves the tumour immune microenvironment, leading to suppressed infiltration of regulatory T (Treg) cells and enhanced IFN-γ expression by tumour-infiltrating lymphocytes. The results support the use of A2AR antagonism with DZD2269 as a therapeutic strategy for monotherapy or combination therapy with IR.

Prolonged methylphenidate treatment alters the behavioral diurnal activity pattern of adult male Sprague-Dawley rats.

Methylphenidate (MPD) is becoming a drug of abuse among adult professionals and students, alike. Yet, few studies have investigated its long-term effects on the adult population. We hypothesized that prolonged administration of MPD leads to changes in the diurnal horizontal activity (HA) pattern, an effect persisting beyond acute drug effects. Four groups of adult male Sprague-Dawley rats (N=32) were divided into a saline/control, 0.6, 2.5, or 10.0 mg/kg MPD group. Each group was treated with saline on experimental day 1, followed by six consecutive days of designated treatment (days 2-7), then, after three consecutive days of washout (days 8-10), each group was re-challenged with its respective treatment (day 11). Activity was monitored continuously throughout the 11 experimental days. There was a dose-dependent increase in HA in the first hour post-injection. The 0.6 mg/kg MPD group exhibited changes in diurnal activity pattern only during the wash-out period. The 2.5 mg/kg MPD group exhibited the most profound changes in HA after 6 days of continuous injection, washout, and MPD re-challenge (p<0.05, p=0.001, p<0.001) respectively, and the 10.0 mg/kg MPD group exhibited changes during the washout and re-challenge periods (p<0.01, p<0.001), respectively. In conclusion, prolonged administration of MPD modulated the diurnal HA pattern in a dose-dependent manner.

Adolescent and adult male spontaneous hyperactive rats (SHR) respond differently to acute and chronic methylphenidate (Ritalin).

Eight groups of male adolescent and adult spontaneous hyperactive rats (SHR) were used in a dose response (saline, 0.6, 2.5, and 10 mg/kg) experiment of methylphenidate (MPD). Four different locomotor indices were recorded for 2 hours postinjection using a computerized monitoring system. Acutely, the 0.6 mg/kg dose of MPD did not elicit an increase in locomotor activity in either the adolescent or in the adult male SHR. The 2.5 and the 10.0 mg/kg doses increased activity in the adolescent and the adult rats. Chronically, MPD treatment when comparing adolescent and adult gave the following results: the 0.6 mg/kg dose of MPD failed to cause sensitization in the adolescent group but caused sensitization in the adult group, while the 2.5 and 10 mg/kg both caused sensitization in the adolescent and adult groups.

Does a rat's exposure to cocaine during adolescence affect its response to cocaine in adulthood?

Many contradictory responses to cocaine have been observed in adolescent rats as compared to adult rats including increased and decreased activity levels. Previous studies reported that adolescent exposure to cocaine affects adulthood response to cocaine. However, most studies compare age differences in cocaine response in separate groups of adolescents and adults. The present study assessed the acute and chronic dose effects of cocaine on the same rats during their adolescent period and again when they matured into young adults. Forty-eight female Sprague-Dawley rats were randomly divided into four treatment groups. Group 1 served as our control and received saline for 6 consecutive days, 3 days washout, and a day of rechallenge. Groups 2-4 received either 3.0, 7.5, or 15 mg/kg cocaine respectively for 6 consecutive days, 3 days washout, and a day of rechallenge. Adolescent rats did not show an acute or chronic response to 3.0 mg/kg cocaine whereas as adults they responded to the acute treatment and moreover became sensitized to this dose. The 7.5 and 15 mg/kg cocaine doses significantly increased the locomotor activity following the initial (acute) injection and therefore induced sensitization in adolescents, whereas as adults these doses elicited different responses. The same rats as adults developed tolerance to the 7.5 mg/kg cocaine and failed to respond significantly to the 15 mg/kg cocaine dose. The results of this study indicate that chronic cocaine exposure during adolescence alters the same rats' responses to cocaine during their adulthood.

Exposure to methylphenidate in adolescence and adulthood modulates cross-sensitization to amphetamine in adulthood in three genetically variant female rat strains.

Attention Deficit Hyperactivity Disorder (ADHD) is a developmental, behavioral disorder that is characterized by patterns of impulsivity and limited attention. Stimulants, such as methylphenidate (MPD) and amphetamine (Amph), are utilized as first-line agents in the treatment of ADHD. While Amph is known to elicit dependence, MPD is not. Interdependence between MPD and Amph is a growing concern. Therefore, it is important to explore this interaction in animal models to gain insight on its mechanisms. In experimental studies, drugs that elicit behavioral sensitization and cross-sensitization in animals are considered to have the potential to elicit dependence. This study evaluated whether chronic repetitive MPD exposure in adolescence and/or adulthood in various genetic strains of female rats elicits behavioral sensitization as well as cross-sensitization with Amph. We used three strains: SHR (ADHD model), WKY, and SD rats. The three rat strains were exposed to chronic MPD in their adolescence and adulthood or exposed to chronic MPD only in adulthood. When the female rats were treated with MPD only in adulthood, the SHR strain exhibited cross-sensitization to Amph but the WKY and SD strains did not. Whereas, when the female rats were pretreated with MPD in adolescence and adulthood, the SHR and WKY strains exhibited cross-sensitization response to Amph, but the SD strain did not. This study showed that the genetic strain and age of exposure to MPD plays a crucial role in cross-sensitization to Amph in female rodents. Furthermore, we showed that genetics associated with ADHD pre-dispose animals to dependence between drugs even if the exposure starts in adulthood compared to control strains that did not show dependence with adult only MPD exposures. Genetic variability, age of initial drug exposure, and sex of the subject are key variables that should be accounted in studies that explore effects of psychostimulants.

Sex differences in the intensity of cross-sensitization between methylphenidate and amphetamine in adolescent rats.

Chronic use of psychostimulants such as methylphenidate (MPD) and amphetamine (Amph) leads to abuse and dependence. Cross-sensitization occurs when exposure to a drug causes a significant intensified response to a different drug as compared to the effect of the drug in subjects with no previous exposure. Cross-sensitization is used as an experimental correlate for a drug's potential to elicit dependence. The present study uses male and female adolescent rats to examine whether cross-sensitization occurs with MPD, a drug not traditionally considered to elicit dependence, and Amph, a drug considered to elicit dependence. The results showed that there is cross-sensitization with MPD to Amph in adolescent rats and that there is a significant difference in male and female responses. Cross-sensitization between MPD and Amph was observed in a linear dose dependent manner in males and in an inverted U-shape pattern in females. Males treated with the highest dose of 10.0 mg/kg MPD and females treated with the mid-dose of 2.5 mg/kg MPD showed the most robust cross-sensitization. Overall, adolescent female rodents had a greater intensity of response to MPD, Amph, and cross-sensitization between MPD and Amph. This study shows that there are significant sex differences in psychostimulant cross-sensitization in adolescence, indicating the maturity of the gonadal system is not the predominant reason for differences between male and female responses to psychostimulant drugs.

Methylphenidate treated at the test cage--dose-dependent sensitization or tolerance depend on the behavioral assay used.

Methylphenidate is the drug most often used to treat attention deficit/hyperactivity disorder (ADHD), a common behavioral disorder of children and young adults. The objectives of this study are (1) to use two different experimental assays of measuring animal activity--the wheel-running activity and the computerized open field--to establish which is more sensitive to acute and repetitive methylphenidate (MPD) administration and (2) to determine whether repetitive MPD treatment elicits adverse effects such as tolerance and behavioral sensitization. The dose-response protocol of MPD (0.6, 2.5, and 10.0 mg/kg) administration was performed in three groups of animals, with an additional saline control group as follows: single saline injection as the control/baseline followed by 6 consecutive days of MPD injections (0.6, 2.5, or 10.0 mg/kg MPD), 3 days of washout, and a day of MPD rechallenge. In general, the two different activity assays showed similar observations for the acute effect of MPD by eliciting increases in activity in a dose-dependent manner. The groups receiving repetitive 0.6 and 2.5 mg/kg MPD tested in the open-field assay exhibited further increase in activity that can be interpreted as behavioral sensitization, whereas the groups receiving 10 mg/kg MPD exhibited a reduction in activity, suggesting that tolerance was developed to the drug. All the groups (0.6, 2.5, and 10.0 mg/kg MPD) tested following repetitive MPD in the wheel-running assay exhibited a further increase in their activity, for example, all the groups exhibited behavioral sensitization. These different observations were interpreted as potentially measuring different kinds of locomotor activity.

Chronic administration of methylphenidate produces neurophysiological and behavioral sensitization.

The electrophysiological properties of acute and chronic methylphenidate (MPD) on neurons of the prefrontal cortex (PFC) and caudate nucleus (CN) have not been studied in awake, freely behaving animals. The present study was designed to investigate the dose-response effects of MPD on sensory evoked potentials recorded from the PFC and CN in freely behaving rats previously implanted with permanent electrodes, as well as their behavioral (locomotor) activities. On experimental day 1, locomotor behavior of rats was recorded for 2 h post-saline injection, and sensory evoked field potentials were recorded before and after saline and 0.6, 2.5, and 10 mg/kg, i.p., MPD administration. Animals were injected for the next five days with daily 2.5 mg/kg MPD to elicit behavioral sensitization. Locomotor recording was resumed on experimental days 2 and 6 after the MPD maintenance dose followed by 3 days of washout. On experimental day 10, rats were connected again to the electrophysiological recording system and rechallenged with saline and the identical MPD doses as on experimental day 1. On experimental day 11, rat's locomotor recording was resumed before and after 2.5 mg/kg MPD administration. Behavioral results showed that repeated administration of MPD induced behavioral sensitization. Challenge doses (0.6, 2.5, and 10.0 mg/kg) of MPD on experimental day 1 elicited dose-response attenuation in the response amplitude of the average sensory evoked field potential components recorded from the PFC and CN. Chronic MPD administration resulted in attenuation of the PFC's baseline recorded on experimental day 10, while the same treatment did not modulate the baseline recorded from the CN. Treatment of MPD on experimental day 10 resulted in further decrease of the average sensory evoked response compared to that obtained on experimental day 1. This observation of further decrease in the electrophysiological responses after chronic administration of MPD suggests that the sensory evoked responses on experimental day 10 represent neurophysiological sensitization. Moreover, two different response patterns were obtained from PFC and CN following chronic methylphenidate administration. In PFC, the baseline and effect of methylphenidate expressed electrophysiological sensitization on experimental day 10, while recording from CN did not exhibit any electrophysiological sensitization.

Chronic methylphenidate modulates locomotor activity and sensory evoked responses in the VTA and NAc of freely behaving rats.

Repeated exposure to psychostimulants leads to behavioral sensitization. The mode of action of brain circuitry responsible for behavioral sensitization is not well understood. There is some evidence that psychostimulants, such as amphetamine and cocaine, activate the ventral tegmental area (VTA) and nucleus accumbens (NAc). However, little is known about the effect of methylphenidate (MPD) on the electrophysiological properties of VTA and NAc neurons. The study was designed to investigate the chronic effects of MPD administration on sensory evoked field potentials of VTA and NAc in freely behaving rats previously implanted with permanent electrodes. On experimental day 1, locomotor behavior was recorded for 2 h post-saline injection followed by sensory evoked field potential recordings after saline and three different escalating (0.6, 2.5, and 10.0 mg/kg) MPD doses. After completion of the last recording, the rat was returned to its home cage. To induce behavioral sensitization, animals were injected for five days with 2.5 mg/kg MPD. Following a rechallenge with saline and identical MPD doses as those given on experimental day 1, locomotor recording of the rat was also performed on experimental days 2, 6 and 11. Results showed that repeated administration of MPD increased locomotion in dose-response manner and elicited behavioral sensitization, while the amplitude of the sensory evoked field responses of the VTA and NAc exhibited dose-response attenuation on both recording days (days 1 and 10). In addition, repeated administration of MPD resulted in attenuating the baseline amplitudes of sensory input on experimental day 10, while MPD administration on experimental day 10 elicited further attenuation of the VTA and NAc sensory evoked responses. Such further attenuation can be interpreted as electrophysiological sensitization.

Dose-response characteristics of methylphenidate on locomotor behavior and on sensory evoked potentials recorded from the VTA, NAc, and PFC in freely behaving rats.

BACKGROUND: Methylphenidate (MPD) is a psychostimulant commonly prescribed for attention deficit/hyperactivity disorder. The mode of action of the brain circuitry responsible for initiating the animals' behavior in response to psychostimulants is not well understood. There is some evidence that psychostimulants activate the ventral tegmental area (VTA), nucleus accumbens (NAc), and prefrontal cortex (PFC). METHODS: The present study was designed to investigate the acute dose-response of MPD (0.6, 2.5, and 10.0 mg/kg) on locomotor behavior and sensory evoked potentials recorded from the VTA, NAc, and PFC in freely behaving rats previously implanted with permanent electrodes. For locomotor behavior, adult male Wistar-Kyoto (WKY; n = 39) rats were given saline on experimental day 1 and either saline or an acute injection of MPD (0.6, 2.5, or 10.0 mg/kg, i.p.) on experimental day 2. Locomotor activity was recorded for 2-h post injection on both days using an automated, computerized activity monitoring system. Electrophysiological recordings were also performed in the adult male WKY rats (n = 10). Five to seven days after the rats had recovered from the implantation of electrodes, each rat was placed in a sound-insulated, electrophysiological test chamber where its sensory evoked field potentials were recorded before and after saline and 0.6, 2.5, and 10.0 mg/kg MPD injection. Time interval between injections was 90 min. RESULTS: Results showed an increase in locomotion with dose-response characteristics, while a dose-response decrease in amplitude of the components of sensory evoked field responses of the VTA, NAc, and PFC neurons. For example, the P3 component of the sensory evoked field response of the VTA decreased by 19.8% +/- 7.4% from baseline after treatment of 0.6 mg/kg MPD, 37.8% +/- 5.9% after 2.5 mg/kg MPD, and 56.5% +/- 3.9% after 10 mg/kg MPD. Greater attenuation from baseline was observed in the NAc and PFC. Differences in the intensity of MPD-induced attenuation were also found among these brain areas. CONCLUSION: These results suggest that an acute treatment of MPD produces electrophysiologically detectable alterations at the neuronal level, as well as observable, behavioral responses. The present study is the first to investigate the acute dose-response effects of MPD on behavior in terms of locomotor activity and in the brain involving the sensory inputs of VTA, NAc, and PFC neurons in intact, non-anesthetized, freely behaving rats previously implanted with permanent electrodes.

Chronic exposure to MDMA (Ecstasy) elicits behavioral sensitization in rats but fails to induce cross-sensitization to other psychostimulants.

BACKGROUND: The recreational use of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) among adolescents and young adults has become increasingly prevalent in recent years. While evidence suggests that the long-term consequences of MDMA use include neurodegeneration to serotonergic and, possibly, dopaminergic pathways, little is known about susceptibility, such as behavioral sensitization, to MDMA. METHODS: The objectives of this study were to examine the dose-response characteristics of acute and chronic MDMA administration in rats and to determine whether MDMA elicits behavioral sensitization and whether it cross-sensitizes with amphetamine and methylphenidate. Adult male Sprague-Dawley rats were randomly divided into three MDMA dosage groups (2.5 mg/kg, 5.0 mg/kg, and 10.0 mg/kg) and a saline control group (N = 9/group). All three MDMA groups were treated for six consecutive days, followed by a 5-day washout, and subsequently re-challenged with their respective doses of MDMA (day 13). Rats were then given an additional 25-day washout period, and re-challenged (day 38) with similar MDMA doses as before followed by either 0.6 mg/kg amphetamine or 2.5 mg/kg methylphenidate on the next day (day 39). Open-field locomotor activity was recorded using a computerized automated activity monitoring system. RESULTS: Acute injection of 2.5 mg/kg MDMA showed no significant difference in locomotor activity from rats given saline (control group), while animals receiving acute 5.0 mg/kg or 10.0 mg/kg MDMA showed significant increases in locomotor activity. Rats treated chronically with 5.0 mg/kg and 10.0 mg/kg MDMA doses exhibited an augmented response, i.e., behavioral sensitization, on experimental day 13 in at least one locomotor index. On experimental day 38, all three MDMA groups demonstrated sensitization to MDMA in at least one locomotor index. Amphetamine and methylphenidate administration to MDMA-sensitized animals did not elicit any significant change in locomotor activity compared to control animals. CONCLUSION: MDMA sensitized to its own locomotor activating effects but did not elicit any cross-sensitization with amphetamine or methylphenidate.

Sensory-evoked potentials recordings from the ventral tegmental area, nucleus accumbens, prefrontal cortex, and caudate nucleus and locomotor activity are modulated in dose-response characteristics by methylphenidate.

Most of the studies investigating the effects of methylphenidate (MPD) are using behavioral and biochemical approaches. There are some electrophysiological studies about the effects of MPD on spontaneous electrical activity; however, there is none about the effects of MPD on sensory inputs. The objectives of the present study were to investigate the MPD dose-response characteristics on locomotor activity and sensory inputs using acoustic stimuli. Freely behaving rats previously implanted with semi-microelectrodes were used to record from four brain areas known to be sites of psychostimulant action. For locomotor behavior assessment, rats received saline on experimental day 1 and an acute administration of MPD (0.6, 2.5, or 10.0 mg/kg, i.p.) on experimental day 2. Using an automated, computerized activity-monitoring system, locomotor behavior was recorded for 2-h postinjection on both days. For the electrophysiological experiments, animals were implanted with permanent electrodes in the ventral tegmental area (VTA), nucleus accumbens (NAc), prefrontal cortex (PFC), and caudate nucleus (CN) under general anesthesia. Five to seven days after electrode implantation, they were used to study the effects of three different MPD doses on the response to sensory inputs. The lowest dose of MPD (0.6 mg/kg, i.p.) failed to alter locomotor activity, while the two higher MPD doses (2.5 and 10.0 mg/kg) elicited increase in locomotion, with the 10.0 mg/kg dose increased at least twice as much as the 2.5 mg/kg dose. However, the same three MPD doses elicited significant attenuation of sensory inputs in dose-response characteristics, i.e., as MPD dose increased, evoked sensory inputs decreased. These opposite effects (motor activation and sensory input suppression) were further discussed.

The role of age, genotype, sex, and route of acute and chronic administration of methylphenidate: a review of its locomotor effects.

Children with attention deficit hyperactivity disorder (ADHD) are treated for extended periods of time with the psychostimulant methylphenidate (MPD). The psychostimulants cocaine, amphetamine, and MPD exhibit similar structural configuration and pharmacological profile. The consequence of the long-term use of psychostimulants such as MPD as treatment for ADHD in the developing brain of children is unknown. Repeated treatment with psychostimulants has been shown to elicit adverse effects in behavior, such as dependence, paranoia, schizophrenia, and behavioral sensitization. Behavioral sensitization and cross-sensitization between two drugs are used as experimental markers to determine the potential of a drug to develop dependence/addiction. Although there are many reviews written about behavioral sensitization involving psychostimulants, scarcely any have focused specifically on MPD-elicited behavioral sensitization and cross-sensitization with other psychostimulants. Moreover, the response to MPD and the expression of ADHD vary among females and males and among different populations due to genetic variability. Since the interpretation and synthesis of the data reported are controversial, this review focuses on the adverse effects of MPD and the role of age, sex, and genetic composition on the acute and chronic effects of MPD, such as MPD-elicited behavioral sensitization and cross-sensitization with amphetamine in animal models. Animal models of drug-induced locomotor stimulation, particularly locomotor sensitization, can be used to understand the mechanisms underlying human drug-induced dependence.