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.

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.

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.

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.

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.

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.

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.

Sex differences in the behavioral response to methylphenidate in three adolescent rat strains (WKY, SHR, SD).

Methylphenidate (MPD) is the most widely used drug in the treatment of attention-deficit hyperactivity disorder (ADHD). ADHD has a high incidence in children and can persist in adolescence and adulthood. The relation between sex and the effects of acute and chronic MPD treatment was examined using adolescent male and female rats from three genetically different strains: spontaneously hyperactive rat (SHR), Wistar-Kyoto (WKY) and Sprague-Dawley (SD). Rats from each strain and sex were randomly divided into a control group that received saline injections and three MPD groups that received either 0.6 or 2.5 or 10mg/kg MPD injections. All rats received saline on experimental day 1 (ED1). On ED2 to ED7 and ED11, the rats were injected either with saline or MPD and received no treatment on ED8-ED10. The open field assay was used to assess the dose-response of acute and chronic MPD administration. Significant sex differences were found. Female SHR and SD rats were significantly more active after MPD injections than their male counterparts, while the female WKY rats were less active than the male WKY rats. Dose dependent behavioral sensitization or tolerance to MPD treatment was not observed for SHR or SD rats, but tolerance to MPD was found in WKY rats for the 10mg/kg MPD dose. The use of dose-response protocol and evaluating different locomotor indices provides the means to identify differences between the sexes and the genetic strain in adolescent rats. In addition these differences suggest that the differences to MPD treatment between the sexes are not due to the reproductive hormones.

Behavioral sensitization and cross-sensitization between methylphenidate amphetamine, and 3,4-methylenedioxymethamphetamine (MDMA) in female SD rats.

The psychostimulants amphetamine and methylphenidate (MPD/Ritalin) are the drugs most often used to treat attention deficit hyperactivity disorder (ADHD). In addition, students of all ages take these drugs to improve academic performance but also abuse them for pleasurable enhancement. In addition, other psychostimulants such as 3,4-methylenedioxymethamphetamine (MDMA/ecstasy) are used/abused for similar objectives. One of the experimental markers for the potential of a drug to produce dependence is its ability to induce behavioral sensitization and cross sensitization with other drugs of abuse. The objective of this study is to use identical experimental protocols and behavioral assays to compare in female rats the effects of amphetamine, MPD and MDMA on locomotor activity and to determine if they induce behavioral sensitization and/or cross sensitization with each other. The main findings of this study are as follows: (1) acute amphetamine, MPD and MDMA all elicited increases in locomotor activity; (2) chronic administration of an intermediate dose of amphetamine or MPD elicited behavioral sensitization; (3) chronic administration of MDMA elicited behavioral sensitization in some animals and behavioral tolerance in others; (4) cross sensitization between MPD and amphetamine was observed; and (5) MDMA did not show either cross sensitization or cross tolerance with amphetamine. In conclusion, these results suggest that MDMA acts by different mechanisms compared to MPD and amphetamine.

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.

Age and genetic strain differences in response to chronic methylphenidate administration.

Methylphenidate hydrochloride (MPD) is a psychostimulant used in the treatment of attention deficit hyperactive disorder (ADHD) in adolescents and adults alike. Adolescence involves a period of neural development that is highly susceptible to environmental and pharmacological influence. Exposure to a psychostimulant like MPD during this crucial time period may cause permanent changes in neuronal function and formation. Another factor that may influence changes in neuronal function and formation is genetic variability. It has been reported that genetic variability affects both the initial behavioral response to drugs in general and psychostimulants in particular, and subsequently whether tolerance or sensitization is induced. The objective of the present study is to investigate the dose-response effects of repeated MPD administration (0.6, 2.5, or 10.0mg/kg, i.p.) using an open field assay to investigate if there are differences between adolescent and adult Wistar-Kyoto (WKY), Spontaneously Hyperactive rat (SHR), and Sprague-Dawley (SD) rats, respectively, and if the genetic variability between the strains influences the degree of change in locomotion. The acute and chronic administration of MPD resulted in unique differences in the level of increasing intensity in locomotor activity in each rat strain, with adult rats for the most part having a more intense increase in locomotor activity when compared to their adolescent counterparts. In conclusion, significant response differences among rat strains and age to acute and chronic MPD administration were observed only following the 2.5 and 10.0mg/kg i.p. doses and not following the lower MPD dose (0.6 mg//kg i.p.). In addition the variability in activity among the rat strain and age suggests that MPD may affect the same neuronal circuit differently in each strain and age. The unique differences among the individual locomotor indices suggest also that each locomotor index is regulated by different neuronal circuits, and each affected differently by MPD.

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.

Repetitive ritalin treatment modulates the diurnal activity pattern of young SD male rats.

Attention Deficit Hyperactivity Disorder (ADHD) is a common behavioral disorder of children and is treated by psychostimulants. Psychostimulant exposure to children at the time of neuronal development can cause behavioral and physiological changes continuing during adulthood. Most of the studies on psychostimulants investigate the acute effects of the drug. The objective of this study was to investigate whether acute or chronic exposure to methylphenidate (MPD), the drug most often used to treat ADHD in children, will modulate the diurnal activity pattern of young rats. Maintaining the diurnal activity pattern is a physiological process that regulates the internal homeostasis. Dose response protocol was used to study the effect of acute and chronic MPD in four young post natal day 40 (P 40) rat groups, (each N=8), as follows: saline (control) group, and 0.6, 2.5, or 10.0 mg/kg i.p. MPD groups, respectively. The experiment was performed over 11 consecutive days of continuous locomotor activity recording using the open field assay. The data evaluation was divided into four phases as follows: acute, induction, washout and expression phases. There was a dose-dependent increase in the average locomotor activity in the first few hours post-injection. Analysis of the diurnal rhythmic pattern of locomotion in the three dose groups compared to control demonstrated that only the 10.0 mg/kg MPD elicited significant changes in diurnal pattern activity in the washout and the expression phase. In addition, this study indicated that chronic MPD treatment elicits dose dependent anticipation and/or withdrawal and behavioral sensitization.

Does repetitive Ritalin injection produce long-term effects on SD female adolescent rats?

Methylphenidate (MPD), or Ritalin, is a psychostimulant that is prescribed for an extended period of time to children and adolescents with attention deficit hyperactivity disorder. Adolescence is a time of critical brain maturation and development, and the drug exposure during this time could lead to lasting changes in the brain that endure into the adulthood. Circadian rhythms are 24 h rhythms of physiological processes that are synchronized by the master-clock, the suprachiasmatic nucleus, to keep the body stable in a changing environment. The aim of present study is to observe the effect of repeated MPD exposure on the locomotor diurnal rhythm activity patterns of female adolescent Sprague-Dawley (SD) rats using the open field assay. 31 female adolescent SD rats were divided into four groups: control, 0.6 mg/kg, 2.5 mg/kg, and 10 mg/kg MPD group. On experimental day 1, all groups were given an injection of saline. On experimental days 2-7, animals were injected once a day with either saline, 0.6 mg/kg, 2.5 mg/kg, or 10 mg/kg MPD, and experimental days 8-10 were the washout period. A re-challenge injection was given to each animal on experimental day 11 with the similar dose as the experimental days 2-7. The locomotor movements were counted by the computerized animal activity monitoring system. The data were analyzed statistically to find out whether the diurnal rhythm activity patterns were altered. The obtained data showed that repeated administrations of 2.5 mg/kg and 10 mg/kg MPD were able to change the locomotor diurnal rhythm patterns, which suggests that these MPD doses exerts long-term effects.

Dietary n-3-polyunsaturated fatty acids and energy balance in overweight or moderately obese men and women: a randomized controlled trial.

BACKGROUND: Dietary n-3-polyunsaturated fatty acids (n-3-PUFA) have been shown to reduce body weight and fat mass in rodents as well as in humans in one small short-term study. We conducted this controlled randomized dietary trial to test the hypothesis that n-3-PUFA lower body weight and fat mass by reducing appetite and ad libitum food intake and/or by increasing energy expenditure. METHODS: Twenty-six overweight or moderately obese (body mass index 28-33 kg/m²) men and women were included, and received either a diet rich in n-3-PUFA from both plant and marine sources or a control diet. Diets were administered in an isocaloric fashion for 2 weeks followed by 12 weeks of ad libitum intake. The n-3-PUFA and control diets were identical in all regards except for the fatty acid composition. All foods were provided to subjects, and leftovers were weighed back to assess actual food intake accurately for each day of the study. This design gave us 80% power to detect a difference in weight change between the n-3-PUFA and control diet groups of 2.25 kg at an α-error level of 5%. RESULTS: Both groups lost similar amounts of weight when these diets were consumed ad libitum for 12 weeks [mean (SD): -3.5 (3.7) kg in the control group vs. -2.8 (3.7) kg in the n-3-PUFA group, F(1,24) = 13.425, p = 0.001 for time effect; F(1,24) = 0.385, p = 0.541 for time x group interaction]. Consistent with this finding, we also found no differences between the n-3-PUFA and control groups with regard to appetite as measured by visual analogue scale, ad libitum food intake, resting energy expenditure as measured by indirect calorimetry, diurnal plasma leptin concentrations, or fasting ghrelin concentrations. CONCLUSION: Our results suggest that dietary n-3-PUFA do not play an important role in the regulation of food intake, energy expenditure, or body weight in humans.

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.

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.

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.

Methylphenidate (Ritalin): behavioral studies in the rat.

Attention Deficit Hyperactivity Disorder (ADHD) is a neuropsychiatric syndrome with an onset in childhood characterized by an inability to remain focused or to concentrate for prolonged periods of time. Children suffering from this disease are many times described as either inattentive or as hyperactive-impulsive depending on what form of the disease they manifest. Methylphenidate is the preferred treatment for this behavioral disorder and is used for long term disease management. Much still remains unknown concerning this stimulant and its effects on behavior and future abuse potential are pertinent questions. Since animal models are used to study the mechanism of drug action and rats are used often in drug studies, the objective of this review is to summarize the research reports that mainly have used rats as the model to investigate the action of methylphenidate. Topics discussed in this review include: (1) What effect does a single dose of methylphenidate have on locomotion activity; (2) Does repeated administration of methylphenidate result in tolerance or sensitization; and (3) Does methylphenidate have rewarding properties as measured by the self-administration and condition placed preference paradigms.