RESUMEN
Repeated administration of the stimulant methylphenidate (MPD) produces sensitization to its own effects. Glutamate, dopamine, and GABA have been implicated in the underlying mechanism of sensitization to stimulants such as amphetamine and cocaine. We have investigated effects of the GABAergic agent sodium valproate (VAL) on the locomotor response to MPD. Activities of male Sprague-Dawley rats were continuously recorded by a computerized activity monitoring system for 15 days. We studied the dose effect of valproate 1) at 50, 100, and 200 mg/kg (i.p.) on motor activities, 2) on the acute response of motor activities to 2.5 mg/kg MPD, and 3) on behavioral sensitization to subsequent repeated injections of MPD. Valproate alone did not significantly affect motor activities. All three doses of valproate attenuated the acute locomotor effects of MPD, while only the 50 mg/kg dose blocked the development of sensitization to subsequent administration. Possible mechanisms involving substrates for the effect of GABA agonists on sensitization are discussed.
Asunto(s)
Metilfenidato/farmacología , Actividad Motora/efectos de los fármacos , Conducta Estereotipada/efectos de los fármacos , Ácido Valproico/farmacología , Animales , Estimulantes del Sistema Nervioso Central/antagonistas & inhibidores , Estimulantes del Sistema Nervioso Central/farmacología , Esquema de Medicación , GABAérgicos/farmacología , Masculino , Metilfenidato/administración & dosificación , Metilfenidato/antagonistas & inhibidores , Actividad Motora/fisiología , Ratas , Ratas Sprague-Dawley , Conducta Estereotipada/fisiología , Factores de Tiempo , Ácido Valproico/administración & dosificaciónRESUMEN
Behavioral responses to stimulants can be progressively and persistently enhanced by their repeated administration. This phenomenon, called behavioral sensitization, may underlie substance abuse, psychosis, recurrence in bipolar disorder, or other psychiatric problems. A growing body of work has implicated excitatory amino acid systems in behavioral sensitization. Most of the evidence for a role of excitatory amino acids has come from experiments demonstrating prevention of sensitization by excitatory amino acid antagonists, especially the noncompetitive NMDA receptor antagonist MK-801. Results of studies with MK-801 have varied, however, leading to conflicting interpretations of its relationship to behavioral sensitization. This paper critically discusses the design of experiments that have used MK-801, and interprets data from these experiments in terms of the two leading explanations for the role of MK-801: 1) that sensitization is an example of the family of plastic events that require excitatory amino acid transmission or 2) that interoceptive cues associated with MK-801 lead to state-dependent learning that modifies sensitization because, in essence, the animal does not recognize the stimulant as the same drug if it is given in close association with MK-801. Based on conflicting reports on effects of MK-801, we propose 1) strategies for distinguishing components of MK-801's effects on responses to stimulants, 2) a model that is a hybrid of the two interpretations of its effects on sensitization, and 3) experimental strategies for testing this model.
Asunto(s)
Encéfalo/efectos de los fármacos , Estimulantes del Sistema Nervioso Central/farmacología , Maleato de Dizocilpina/farmacología , Interacciones Farmacológicas/fisiología , Antagonistas de Aminoácidos Excitadores/farmacología , Aminoácidos Excitadores/metabolismo , Trastornos Relacionados con Anfetaminas/tratamiento farmacológico , Trastornos Relacionados con Anfetaminas/metabolismo , Trastornos Relacionados con Anfetaminas/fisiopatología , Animales , Conducta Animal/efectos de los fármacos , Conducta Animal/fisiología , Encéfalo/metabolismo , Aminoácidos Excitadores/antagonistas & inhibidores , HumanosRESUMEN
The role of MK-801's locomotor effect in blocking the development of sensitization to methylphenidate was investigated utilizing a computerized locomotor activity monitoring system. After 7 days of acclimation to a 12:12 light-dark cycle (lights on at 07:00), male Sprague-Dawley rats (n=62) were housed in test cages and motor activity was recorded continuously for 16 days. The first 2 days of recording served as a baseline for each rat, and on day 3 each rat received a saline injection. On days 4 to 9 rats were randomly divided into seven groups: Rats received either six daily s.c. injections of methylphenidate (2.5 mg/kg; Group 1), or six daily i.p. injections of 0.30 mg/kg, 0.05 mg/kg MK-801 (Groups 2 and 3, respectively); two MK-801 pre-treatment groups received a single i.p. injection of 0.05, or 0.30 mg/kg MK-801 one hour prior to 2.5 mg/kg methylphenidate (n=8 each) on day 4 followed by five daily injections of 2.5 mg/kg methylphenidate; and finally, two cotreatment groups received a challenge dose of 2.5 mg/kg methylphenidate on day 4 followed by either 0.05 or 0.30 mg/kg MK-801 i.p. one hour prior to 2.5 mg/kg methylphenidate from days 5 to 9. All groups were allowed five days of no treatment before being re-challenged on day 15 with the same treatment they received on day 4. Methylphenidate and 0.30 mg/kg MK-801 sensitized to their own locomotor effects, but 0.05 mg/kg MK-801, which had no acute motor effects, did not. The administration of MK-801 (0.30 mg/kg) prior to methylphenidate either singly on day 4, or coadministered throughout the repeated methylphenidate treatment phase, blocked the development of sensitization to methylphenidate. However, MK-801 at 0.05 mg/kg delayed the development of sensitization when co-administered on days 5 to 9, but a single injection 1 h prior to methylphenidate on day 4 did not prevent sensitization to subsequent methylphenidate administration. In conclusion, MK-801 prevents sensitization to methylphenidate; motor stimulation by MK-801 is not necessary for short-term prevention or delay of sensitization to methylphenidate but may be necessary for a persistent blockade of sensitization.
Asunto(s)
Estimulantes del Sistema Nervioso Central/farmacología , Maleato de Dizocilpina/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Metilfenidato/farmacología , Actividad Motora/efectos de los fármacos , Animales , Relación Dosis-Respuesta a Droga , Antagonismo de Drogas , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
Using a computerized monitoring system, we investigated the development of motor sensitization to methylphenidate (MPD) in the rat, and determined whether sensitization was dependent on the time of drug administration. Male Sprague-Dawley rats were housed in test cages and motor activity was recorded continuously for 16 days. The first 2 days served as baseline for each rat, and on day 3 each rat received a saline injection. The locomotor response to 0.6, 2.5, or 10 mg/kg of MPD was tested on day 4, followed by 5 days of single injections of 2.5 mg/kg MPD (days 5-9). After 5 days without injection (days 10-14) rats were re-challenged (day 15) with the same doses they received on day 4. There were three separate challenge doses and four different times of administration: 08:00, 14:00, 20:00, or 02:00 h. Horizontal activity, total distance, vertical activity, stereotypic activity, and number of stereotypic movements were recorded. Sensitization to MPD was dependent on the time of administration, the motor index studied, and the challenge dose used. It was more pronounced for forward ambulation than for rearing, with no augmented response to stereotypic effects. The expression of the sensitized response was dose-dependent and mainly observed with the 0.6 and 2.5 mg/kg challenge dose groups. The development of sensitization to MPD was also time-dependent with the most robust sensitization occurring during the light phase, while no sensitization was observed during the middle of the dark phase. In addition, repeated MPD administration caused a significant increase in the amount of nocturnal forward ambulation that persisted long after cessation of drug treatment.
Asunto(s)
Estimulantes del Sistema Nervioso Central/farmacología , Ritmo Circadiano/efectos de los fármacos , Ritmo Circadiano/fisiología , Metilfenidato/farmacología , Actividad Motora/efectos de los fármacos , Animales , Encéfalo/citología , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Masculino , Actividad Motora/fisiología , Enmascaramiento Perceptual/fisiología , Ratas , Ratas Sprague-Dawley , Trastornos Relacionados con Sustancias/etiología , Trastornos Relacionados con Sustancias/fisiopatología , Factores de TiempoRESUMEN
Male Sprague-Dawley rats were divided to three groups (each n = 8) and were housed in test cages where motor activity was recorded continuously for 16 days using a computerized motor activity monitoring system to determine whether repeated administration of MK-801 could block the development and/or the expression of sensitization to the locomotor effects of methylphenidate (MPD). One group of rats received six daily injections (days 4-9) of 0.30 mg/kg MK-801, followed by 5 days without injection (days 10-14) and re-challenged (day 15) with 0.30 mg/kg MK-801. The second group received a challenge dose of 2.5 mg/kg MPD (day 4) followed by 5 days of co-treatment with MK-801 (0.30 mg/kg) given 1 h prior to MPD (days 5-9). This group was then re-challenged with MPD (2.5 mg/kg) on day 15. The last group received six daily injections of 2.5 mg/kg MPD (days 4-9). They were then split into two subgroups of rats which received either no treatment (control) or five daily injections of 0.30 mg/kg MK-801 (days 10-14) before being re-challenged on day 15 with 2.5 mg/kg MPD. MK-801 sensitized to its own locomotor effects. MK-801 given after sensitization had developed (i.e., days 10-14) was able to mask the expression of a sensitized response on day 15, but the effect was only transient since the sensitized response was present 3 weeks later. Moreover, MK-801, when coadministered during the repeated treatment phase was able to block the development of a sensitized response, which suggest that NMDA receptors involved in the process of MPD sensitization.
Asunto(s)
Conducta Adictiva/tratamiento farmacológico , Conducta Adictiva/fisiopatología , Estimulantes del Sistema Nervioso Central/farmacología , Maleato de Dizocilpina/farmacología , Interacciones Farmacológicas/fisiología , Antagonistas de Aminoácidos Excitadores/farmacología , Metilfenidato/farmacología , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Animales , Encéfalo/efectos de los fármacos , Encéfalo/fisiopatología , Relación Dosis-Respuesta a Droga , Combinación de Medicamentos , Masculino , Ratas , Ratas Sprague-Dawley , Receptores de N-Metil-D-Aspartato/efectos de los fármacos , Receptores de N-Metil-D-Aspartato/metabolismo , Factores de TiempoRESUMEN
A computerized motor activity monitoring system was used to investigate the development and time dependence of sensitization to repeated exposure of amphetamine. Male Sprague-Dawley rats were acclimated for 7 days to light/dark cycle (0700 h:1900 h) in the testing room, and were then housed in the test cages for 16 days of continuous recording. The locomotor responses to s.c. administration of amphetamine (0.3, 0.6, or 1.2 mg/kg) were compared before and after five daily injections of 0.6 mg/kg of amphetamine. Different groups of rats were administered drug at either 0800 h, 1400 h, 2000 h, or 0200 h. The locomotor indices studied were total distance and vertical activity. Sensitization was more pronounced for total distance (i.e., forward ambulation) than for vertical activity (i.e., rearing), and its expression was dependent on the challenge dose. Sensitization was also time-dependent, with the strongest sensitized response occurring during the middle of the dark cycle (0200 h). Repeated administration of amphetamine (0.6 mg/kg) did not cause post-stimulant depression as has been seen at higher doses.
Asunto(s)
Anfetamina/farmacología , Ritmo Circadiano , Actividad Motora/efectos de los fármacos , Animales , Relación Dosis-Respuesta a Droga , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
The non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist MK-801 has been shown to modulate both the effects of stimulants, such as amphetamine and cocaine, in producing locomotion and the chronic effects of stimulants in producing sensitization. In this study, we examine the interactions between MK-801 and the stimulant methylphenidate. Three different doses of MK-801 were administered 60 min prior to methylphenidate injection (2.5 mg/kg) and the acute response to MK-801 alone and the coadministration with methylphenidate were characterized. MK-801 alone was found to produce dose-dependent locomotor activation. The 0.15 mg/kg dose of MK-801 had no effect on the response to methylphenidate, while the 0. 3 and 0.6 mg/kg doses augmented the methylphenidate response. The effect of pretreatment with MK-801 on subsequent repeated methylphenidate administration was assessed. For all three doses tested, MK-801 pretreatment blocked the progressive locomotor sensitization expected during repeated methylphenidate administration. These findings suggest that MK-801 may exert a long-lasting effect on learning and memory process that result in a blocking of the development of sensitization.
Asunto(s)
Estimulantes del Sistema Nervioso Central/farmacología , Maleato de Dizocilpina/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Metilfenidato/farmacología , Animales , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Masculino , Ratas , Ratas Sprague-Dawley , Factores de TiempoRESUMEN
The objective of this study was to characterize the lasting effects of fluoxetine on the locomotor behavior of rats using a computerized activity-monitoring system. Challenge dosages (8, 16, and 24 mg/kg i.p.) of fluoxetine 2 h into the dark phase resulted in dose-dependent suppression of locomotor activity for 4 h following injection. Escalating (10-30 mg/kg i.p.) semidaily fluoxetine administration for the next five days resulted in decreasing locomotor activity during the multiple-administration period relative to saline control. Circadian activity patterns at the conclusion of the regimen were unchanged in shape, but featured uniform decreases in locomotor activity at every hour which were more significant during the phase. Upon discontinuation, fluoxetine-treated rats showed a significant increase in activity during the first 4 h following the first "missed" dose which was not seen in subsequent washout. Ninety-six h after the final maintenance dose, the initial three dosages were readministered, and the locomotor activity suppression in response to the rechallenge dose of fluoxetine was significantly lessened compared to initial challenge. These findings suggest that tolerance and withdrawal were obtained.
Asunto(s)
Conducta Animal/efectos de los fármacos , Fluoxetina/farmacología , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Síndrome de Abstinencia a Sustancias/psicología , Animales , Relación Dosis-Respuesta a Droga , Tolerancia a Medicamentos , Fluoxetina/administración & dosificación , Fluoxetina/efectos adversos , Masculino , Actividad Motora/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Inhibidores Selectivos de la Recaptación de Serotonina/administración & dosificación , Inhibidores Selectivos de la Recaptación de Serotonina/efectos adversos , Factores de TiempoRESUMEN
The dose-response characteristics and time-course of amphetamine's effect on motor activity after a single injection given to rats at four different times of the light/dark cycle was investigated using a computerized infrared motor activity recording system. After 7 days of acclimation and 2 days of baseline activity recording, rats received a single subcutaneous injection of vehicle (saline) or 0.6, 1.25 or 10 mg/kg amphetamine at 08.00, 14.00, 20.00 or 02.00. Recording was then resumed for an additional 36 to 48 h. The locomotor indices analyzed were horizontal activity, total distance, vertical activity, stereotypic activity and number of stereotypic movements. All doses (0.6. 1.25 and 10 mg/kg) significantly elevated (P < 0.01) locomotor activity compared to baseline at all times of administration. At all injection times, the maximum increase over baseline generally occurred following the 1.25 mg/kg dose of amphetamine (P < 0.001). The effect of the lower doses (0.6 and 1.25 mg/kg) on forward locomotion remained the same throughout the light/dark cycle regardless of the large difference in baseline motor activity between the light and dark phases. However, the effects of 10 mg/kg amphetamine on general stereotypic behavior, as well as the ability to cause subsequent depression of nocturnal forward ambulation, were dependent on the time of drug administration. These results showed that the circadian rhythms of locomotor and stereotypic effects of amphetamine are different.
Asunto(s)
Anfetamina/farmacología , Ritmo Circadiano/fisiología , Actividad Motora/efectos de los fármacos , Animales , Relación Dosis-Respuesta a Droga , Masculino , Actividad Motora/fisiología , Ratas , Ratas Sprague-Dawley , Conducta Estereotipada/fisiologíaRESUMEN
The dose-related motor effects of d-amphetamine given at the beginning of the light and dark cycle of rats were investigated using a computerized activity-monitoring system that recorded five different motor behavior indices. After 7 days of acclimatization and 2 days of baseline monitoring, rats were randomized into either a no-treatment time control group (n = 12), or to receive 0 (vehicle), 0.6, 1.25, 2.5, or 10 mg/kg d-amphetamine (n = 8 each) either 1 h into the light phase (0800) or another five groups at 1 h into the dark phase (2000) of day 3. The time control group exhibited a stable baseline level of activity for the length of the experiment. All doses (0.6, 1.25, 2.5, and 10 mg/kg) significantly elevated (p < 0.01) locomotor activity compared to baseline at both times of administration, but not all motor indices followed the same pattern of response. At both injection times, the maximum increase over baseline generally occurred following the 1.25 mg/kg dose of amphetamine (p < 0.001). The duration of the drug effect also increased with each dose. The stereotypic effects produced by high doses of AMP (10 mg/kg) was different when applied at the light phase compared to the dark phase, but the amphetamine effect on locomotor behavior remained the same regardless of the difference in motor activity baseline between the activity phases.
Asunto(s)
Anfetamina/farmacología , Estimulantes del Sistema Nervioso Central/farmacología , Ritmo Circadiano/fisiología , Actividad Motora/efectos de los fármacos , Animales , Oscuridad , Relación Dosis-Respuesta a Droga , Luz , Masculino , Ratas , Ratas Sprague-Dawley , Conducta Estereotipada/efectos de los fármacos , Factores de TiempoRESUMEN
A computerized activity monitoring system was used to investigate whether repeated exposure to methylphenidate (MPD) could produce sensitization to its locomotor effects in the rat. Male Sprague-Dawley rats were housed in test cages and activity was recorded continuously for 16 days as follows: Baseline activity (Day 1-2), recording following saline injection (Day 3), MPD Challenge Doses--either 0.6, 2.5, or 10 mg/kg of MPD (Day 4); five days of a repeated dose of 2.5 mg/kg (Day 5-9), five additional recording days of no treatment (Days 10-14), and MPD Re-Challenge (Day 15). Each group was re-challenged with the same doses as on day 4. Recording was resumed for an additional post-treatment day (Day 16). All injections were at 14:00. Horizontal activity, total distance, vertical activity, stereotypic activity, and number of stereotypic movements were recorded and analyzed. An augmented response (i.e., sensitization) was observed only to the lower MPD doses of 0.6 and 2.5 mg/kg. The sensitized response was more pronounced for forward ambulation than for rearing, with a complete lack of sensitization to the stereotypic effects of MPD.
Asunto(s)
Metilfenidato/farmacología , Actividad Motora/efectos de los fármacos , Animales , Relación Dosis-Respuesta a Droga , Masculino , Metilfenidato/administración & dosificación , Ratas , Ratas Sprague-DawleyRESUMEN
The dose-response relationship and time course of effect on motor activity after a single dose of methylphenidate given at different times of the light/dark cycle was investigated using a computerized infrared activity analysis system. After 5 to 7 days of acclimation and 2 days of baseline activity recording, rats received a single subcutaneous injection of vehicle (saline) or of 0.6, 2.5, 10 or 40 mg/kg methylphenidate at 08:00, 14:00, 20:00, or 02:00. Recording was then resumed for an additional 36 to 48 hours. The locomotor indices analyzed were horizontal activity, total distance, vertical activity, stereotypic activity, and number of stereotypic movements. Saline and 0.6 mg/kg did not alter motor activity, but 2.5, 10 and 40 mg/kg significantly increased (P < 0.01) motor activity. The time to the maximum effect and the duration of effect increased with dose. Ten mg/kg had the most robust effect on locomotor activity, while the largest dose, 40 mg/kg, elicited a more focused stereotyped activity that limited the amount of forward ambulation. A single injection of methylphenidate had only transient effects. The locomotor stimulating effects of the lower doses were similar whether given during the light or dark phase, despite the large diurnal variations in baseline activity between the activity phases. The stereotypic effects of the highest dose of methylphenidate, however, varied between the light and dark phase, with a smaller stereotypic effect during the dark phase when compared to administration during the light phase.
Asunto(s)
Estimulantes del Sistema Nervioso Central/farmacología , Ritmo Circadiano/efectos de los fármacos , Locomoción/efectos de los fármacos , Metilfenidato/farmacología , Conducta Estereotipada/efectos de los fármacos , Animales , Conducta Animal/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Masculino , Actividad Motora/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Factores de TiempoRESUMEN
Using a computerized infrared activity analysis system, the dose-response relationship, timing, and duration for stimulation of motor activity after a single dose of methylphenidate was studied in Sprague-Dawley rats. After 5 days of acclimation and 2 days of monitored baseline activity, rats received a single subcutaneous injection of vehicle or of 0.6, 2.5, 10 or 40 mg/kg methylphenidate 1 h into the dark cycle. Recording was then resumed for an additional 36 h. Five locomotor indices were analyzed. Each locomotor parameter monitored different aspects of motor activity. The doses of 2.5, 10 and 40 mg/kg significantly increased (P < 0.01) locomotor activity. The time to maximal effect (20, 50, and 90 min) and duration of effect (70, 210, and 280 min) increased with dose respectively. Ten mg/kg had the maximum effect on locomotor activity, while the largest dose, 40 mg/kg, elicited a more focused stereotyped activity that limited the amount of forward ambulation. Single injections of methylphenidate did not alter motor activity the next day. Pharmacological parameters and specific locomotor parameters describing the effects of methylphenidate at the beginning of the dark cycle can later be used in chronopharmacologic studies. They will also provide the basis for investigation of adaptive mechanisms during repeated or chronic administration of methylphenidate.
Asunto(s)
Ritmo Circadiano , Metilfenidato/farmacología , Actividad Motora/efectos de los fármacos , Análisis de Varianza , Animales , Oscuridad , Relación Dosis-Respuesta a Droga , Luz , Masculino , Ratas , Ratas Sprague-Dawley , Conducta Estereotipada/efectos de los fármacos , Factores de TiempoRESUMEN
The motor effects of a single dose of d-amphetamine on internally synchronized male Sprague Dawley rats and its dose response relationship at the beginning of the light cycle was investigated using a computerized monitoring system. After 7 days of acclimatization to light/dark cycle and 2 days of baseline monitoring, rats were randomized to a no-treatment time control group (n = 12) or to receive 0 (vehicle), 0.6, 1.25, 2.5, or 10 mg/kg d-amphetamine (n = 8 each) 1 h into the light cycle of day 3, and monitored for an additional post-treatment day 4. In the time control group, there was a stable baseline level of activity for both light and dark phases. All doses (0.6, 1.25, 2.5, and 10 mg/kg) significantly elevated (P < 0.01) locomotor activity compared to baseline, but not all activity parameters (horizontal activity, total distance, vertical activity, stereotypic activity, and number of stereotypic movements) followed the same pattern of response. The maximum increase in all parameters, except vertical activity, occurred at 1.25 mg/kg (P < 0.001). The duration of drug effect increased with dose, with increased activity lasting until the fifth hour after injection of 10 mg/kg. ANOVA revealed no consistent long term effects, with all parameters returning to baseline levels on the day after treatment. The range of variables and the establishment of baseline values at the time of injection for each rat provides the potential to characterize circadian patterns of locomotor activity and chronopharmacologic effects of drugs on motor activity, including sensitization and tolerance.
Asunto(s)
Anfetamina/farmacología , Estimulantes del Sistema Nervioso Central/farmacología , Actividad Motora/efectos de los fármacos , Fotoperiodo , Animales , Ritmo Circadiano , Relación Dosis-Respuesta a Droga , Inyecciones Subcutáneas , Masculino , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley , Conducta Estereotipada/efectos de los fármacosRESUMEN
The issue of extraintestinal infection by Eimeria nieschulzi in the rat was addressed by transferring various tissues from infected to uninfected rats by mouth. All 6 rats receiving liver, spleen, or small intestine from rats killed at 3 or 8 hr postinoculation (PI), and all 5 rats receiving spleen and small intestine from rats killed 8 days PI, showed infections. Rats receiving tissues from rats killed at 8 days PI showed infections 24 hr later, indicating that fourth-generation merozoites were transferred. This is the first demonstration of an extraintestinal rodent eimerian.