Cortical NR2B NMDA subunit antagonism reduces inflammatory pain in male and female rats.

BACKGROUND: Studies have shown that N-methyl-D-aspartate (NMDA) receptors play a critical role in pain processing at different levels of the central nervous system. METHODS: In this study, we used adult Wistar rats to examine gender differences in the effects of NR2B NMDA antagonism at the level of the anterior cingulate cortex in phasic pain, and in the first and second phases of a formalin test. Rats underwent stereotactic surgery for cannula implantation in the anterior cingulate cortex. After recovery, paw withdrawal latency to a noxious thermal stimulus was assessed. Rats were also subjected to a formalin pain test whereby 60 µL of 5% formalin was injected into the right hind paw. RESULTS: Female and male rats that received Ro 25-6981, an NR2B antagonist, before formalin injection showed significantly reduced pain responses to the formalin test compared with saline-injected control rats (P < 0.05). No gender differences in phasic pain responses were found in rats treated with Ro 25-6981. CONCLUSION: These results suggest that cortical antagonism of the NR2B subunit reduces inflammatory pain levels in both genders of rat.

Sex-dependent effects of long-term oral methylphenidate treatment on spontaneous and learned fear behaviors.

In previous studies, chronic low-dose methylphenidate (MPH) administration during early development has been shown to increase emotional responding in adulthood. However, most studies employed male subjects, which generally show enhanced fear relative to females in laboratory tests of anxious behaviors. The present study examined the sex-dependent effects of MPH treatment on innate and learned fear behaviors. Rats were treated for 4 weeks from periadolescence through early adulthood with oral MPH. In open field testing, females showed greater levels of activity than males, and MPH (5mg/kg) decreased locomotion relative to control and 2mg/kg treatment in both sexes. In contextual fear conditioning, females exhibited less freezing than males at all retention intervals. Both sexes treated with 5mg/kg MPH showed increased fear to the shock context, although MPH treatment did not interfere with contextual discrimination in either sex. Upon reexposure to the shock context at 24h, only females treated with 5mg/kg MPH exhibited increases in freezing. MPH treatment did not disrupt extinction of contextual fear (48 h post-conditioning) in either sex. These findings illustrate subtle sex differences in the effects of prolonged MPH exposure on fear behaviors, and highlight the need to examine further the underlying mechanisms in both sexes.

Characterization of anxiety-related responses in male rats following prolonged exposure to therapeutic doses of oral methylphenidate.

Increases in the rates of attention-deficit/hyperactivity disorder (ADHD) diagnosis and the prescribed use of methylphenidate (MPH) in recent years have raised concerns over the potential effects of early MPH exposure on brain structure and function in adulthood. Animal studies have shown that long-term MPH exposure can modify anxiety-related behaviors and related neural circuitry in adulthood. The present study employed a battery of behavioral tests and repeated testing to assess the long-term effects of MPH exposure on anxious responding. Male Wistar rats beginning on post-natal day 27 were exposed to 4 or 7 weeks of twice daily MPH administration at doses of 2, 3, or 5 mg/kg. MPH was administered orally and on weekdays only in order to approximate drug treatment in clinical populations. Behavioral testing began 18 days following the last drug administration. Our results indicate that prolonged oral MPH treatment at therapeutic doses has little or no enduring effects on anxious behaviors. However, a comparison of MPH groups that received treatment for 4 or 7 weeks suggests that the two treatment periods influenced anxious behaviors in observably different manners in adulthood; namely, a more prolonged period of exposure produced less anxiety relative to the shorter period of MPH exposure as indicated by behaviors in the light-dark transition, elevated plus-maze, and fear conditioning tests. These findings were interpreted as evidence of the importance of considering length of drug exposure in pre-clinical studies aimed at investigating the effects of MPH exposure in ADHD populations.

Exposure to oral methylphenidate from adolescence through young adulthood produces transient effects on hippocampal-sensitive memory in rats.

Methylphenidate (MPH) is the most commonly prescribed medication used to treat the symptoms associated with attention-deficit hyperactivity disorder (ADHD). The increase in ADHD diagnosis and MPH use has raised concerns regarding the long-term consequences of early exposure to psychostimulants. Animals studies indicate that early developmental MPH treatment produces enduring changes in hippocampal-sensitive tasks, including novel object recognition (NOR) and long-term retention of contextual fear. We administered oral MPH to male Wistar rats at a therapeutically relevant dose (2 or 5 mg/kg) twice daily for 7 weeks beginning on post-natal day (PN) 27 through PN 71 (i.e., periadolescence through young adulthood). Behavioral tests began 18 days following the last MPH administration. MPH (5 mg/kg) produced an increase in the latency to reach criterion for sample object exploration during the first of two NOR tests, but did not produce memory deficits at either dose. MPH (5 mg/kg) enhanced freezing during the 24 h retention test, but did not affect responding at 48 h. Taken together, the results of both tasks suggest that treatment with MPH in a manner that approximates clinical exposure patterns transiently modifies hippocampal-sensitive learning in rats but does not produce cognitive impairments. We suggest that the effects of prolonged exposure to MPH treatment on cognitive processes vary as a function of the duration and pattern of drug administration, as well as task complexity, which may account for differences among studies regarding its long-term behavioral effects. Future preclinical studies examining the effects of early psychostimulant treatment should include different periods of exposure and assessment, as well as clinically relevant doses and routes of drug administration, in order to better understand the impact of pediatric medications on adult cognition.

Chronic sildenafil (Viagra) administration reduces anxiety in intact and castrated male rats.

Epidemiological research indicates that sildenafil (Viagra) abuse is associated with increased risk behaviors. The present study employs the open field, a standard animal model used in the field of anxiety research, to examine whether chronic exposure to sildenafil affects anxiety and risk-taking behaviors in gonadally intact and castrated male Wistar rats. Sildenafil (10 mg/kg) or saline were administered three times a week for three weeks. Animals were tested once a week in the open field during and after drug treatment. Sildenafil treatment increased the number of center entries and time spent in the center in intact and castrated animals during and after treatment, suggesting that repeated drug use decreases anxiety. Sildenafil also restored the deficits in exploration and locomotion produced by castration, indicating that sildenafil effects on open field behaviors are independent of endogenous androgens. We caution against generalizing from this study to human behaviors, but propose that the behavioral effects produced by a chronic high dose of sildenafil warrant further studies into its abuse potential.

Chronic sildenafil (Viagra) administration reduces anxiety in intact and castrated male rats

Estudios epidemiológicos indican que el abuso de sildenafil (Viagra) está asociado con comportamientos de riesgo. En el presente estudio utilizamos el campo abierto, un modelo animal estándar en investigaciones sobre la ansiedad, para examinar los efectos de la administración crónica de sildenafil sobre la ansiedad y comportamientos de riesgo en ratas machos Wistar intactas y castradas. Sildenafil (10 mg/kg) o suero salino fueron administrados tres veces semanalmente durante tres semanas. Se midió el comportamiento en el campo abierto una vez por semana durante y posteriormente al tratamiento. El tratamiento con sildenafil incrementó las entradas al centro del campo y el tiempo en el centro en animales intactos y castrados, lo que sugiere que la administración crónica disminuye la ansiedad. Sildenafil también restauró los déficit asociados con la castración, lo que indica que los efectos de sildenafil sobre comportamientos en el campo abierto son independientes de la presencia de andrógenos endógenos. Alertamos en contra de generalizar estos resultados a los comportamientos humanos, pero proponemos que los efectos conductuales que produce la administración crónica de una dosis alta de sildenafil justifican el estudio del potencial de abuso de esta sustancia

Epidemiological research indicates that sildenafil (Viagra) abuse is associated with increased risk behaviors. The present study employs the open field, a standard animal model used in the field of anxiety research, to examine whether chronic exposure to sildenafil affects anxiety and risk-taking behaviors in gonadally intact and castrated male Wistar rats. Sildenafil (10 mg/kg) or saline were administered three times a week for three weeks. Animals were tested once a week in the open field during and after drug treatment. Sildenafil treatment increased the number of center entries and time spent in the center in intact and castrated animals during and after treatment, suggesting that repeated drug use decreases anxiety. Sildenafil also restored the deficits in exploration and locomotion produced by castration, indicating that sildenafil effects on open field behaviors are independent of endogenous androgens. We caution against generalizing from this study to human behaviors, but propose that the behavioral effects produced by a chronic high dose of sildenafil warrant further studies into its abuse potential