RESUMEN
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RESUMEN
Pregnant Holtzman rats were exposed to a single oral dose of 0, 20, 60, or 180 ng/kg 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on the 18th day of gestation. Their adult female offspring were trained to respond on a lever for brief opportunities to run in specially designed running wheels. Once they had begun responding on a fixed-ratio 1 (FR1) schedule of reinforcement, the fixed-ratio requirement for lever pressing was increased at five-session intervals to values of FR2, FR5, FR10, FR20, and FR30. We examined vaginal cytology after each behavior session to track estrous cyclicity. Under each of the FR values, perinatal TCDD exposure produced a significant dose-related reduction in the number of earned opportunities to run, the lever response rate, and the total number of revolutions in the wheel. Estrous cyclicity was not affected. Because of the consistent dose-response relationship at all FR values, we used the behavioral data to calculate benchmark doses based on displacements from modeled zero-dose performance of 1% (ED(01)) and 10% (ED(10)), as determined by a quadratic fit to the dose-response function. The mean ED(10) benchmark dose for earned run opportunities was 10.13 ng/kg with a 95% lower bound of 5.77 ng/kg. The corresponding ED(01) was 0.98 ng/kg with a 95% lower bound of 0.83 ng/kg. The mean ED(10) for total wheel revolutions was calculated as 7.32 ng/kg with a 95% lower bound of 5.41 ng/kg. The corresponding ED(01) was 0.71 ng/kg with a 95% lower bound of 0.60. These values should be viewed from the perspective of current human body burdens, whose average value, based on TCDD toxic equivalents, has been calculated as 13 ng/kg.
Asunto(s)
Condicionamiento Operante , Contaminantes Ambientales/efectos adversos , Actividad Motora/efectos de los fármacos , Dibenzodioxinas Policloradas/efectos adversos , Administración Oral , Animales , Benchmarking , Relación Dosis-Respuesta a Droga , Contaminantes Ambientales/administración & dosificación , Estro , Femenino , Condicionamiento Físico Animal , Dibenzodioxinas Policloradas/administración & dosificación , Embarazo , Preñez , Ratas , Ratas Sprague-Dawley , Esquema de RefuerzoRESUMEN
This investigation employed a longitudinal analysis of rat operant behavior under two different schedules of reinforcement following prenatal exposure to cocaine. Offspring were derived from four maternal exposure groups: 50 mg/kg cocaine, their pair-fed controls, 25 mg/kg cocaine, and freely fed controls. Cocaine was administered via gavage from gestation day 6-20. A maternal fostering procedure was used. Pairs of male and female littermates were assigned to a 7-, 14-, or 21-month cohort and at the appropriate age were trained to respond on one lever in a two-lever operant chamber. Reinforcement was delivered with a series of random ratio (RR) schedules where the RR value was increased across sessions. After RR training, animals were examined with a delayed spatial alternation (DSA) procedure in the same chambers. Male offspring responded at higher rates than females during high-probability RR schedules, whereas advancing age was associated with lower response rates during low-probability RR schedules in both males and females. Prenatal cocaine exposure exerted only limited effects on RR responding during transition and did not affect DSA behavior. The results of this longitudinal analysis suggest that prenatal cocaine does not exert global or far-reaching learning deficits in prenatally exposed rats.
Asunto(s)
Envejecimiento/fisiología , Cocaína/toxicidad , Inhibidores de Captación de Dopamina/toxicidad , Efectos Tardíos de la Exposición Prenatal , Percepción Espacial/efectos de los fármacos , Animales , Condicionamiento Operante/efectos de los fármacos , Femenino , Masculino , Embarazo , Ratas , Ratas Long-Evans , Esquema de Refuerzo , Caracteres SexualesRESUMEN
Animal studies of the neuropathological effects of prenatal methylmercury (MeHg) seldom use regimens that represent environmental exposures. While acute administration of high doses of MeHg to developing rodents can model some of the outcomes MeHg produces in the human cerebellum, their long-term relevance to cerebellar development is unknown. The present study was undertaken to determine the effect of chronic dietary exposure to MeHg. Pregnant mice were exposed throughout gestation to 0.0 or 4.0 ppm methylmercury in their drinking water. Postpartum exposure of pups and lactating dams continued to postnatal day (PND) 30. On PND7, 14, 21, and 30, several morphometric indices of cerebellar cortex development, as well as blood and brain levels of total Hg, were measured in pairs of male and female littermates. No signs of overt toxicity were observed in the dams or offspring. Blood and brain levels of total Hg were highest in the exposed PND7 offspring and fell throughout the sampling period despite continued exposure. In a region of molecular layer in the anterodorsal lobe, MeHg exposure reduced the density of migrating cells in PND7 offspring. Molecular layer widths were reduced in PND30 offspring. In a region of the inferior lobe of PND7 offspring, MeHg exposure reduced external granular layer widths and decreased the density of migrating cells in the molecular layer. However, MeHg did not affect cerebellar cortex development in the central lobe, suggesting a regional sensitivity to chronic, low-level MeHg exposure during development.
Asunto(s)
Cerebelo/efectos de los fármacos , Lactancia , Compuestos de Metilmercurio/farmacología , Efectos Tardíos de la Exposición Prenatal , Análisis de Varianza , Animales , Mapeo Encefálico , Cerebelo/embriología , Cerebelo/crecimiento & desarrollo , Desarrollo Embrionario y Fetal/efectos de los fármacos , Femenino , Masculino , Ratones , EmbarazoRESUMEN
This investigation employed a longitudinal analysis of a complex motor skill in rats that were exposed prenatally to cocaine. Offspring were derived from four maternal treatment groups: 50 mg/kg cocaine, their pair-fed controls, 25 mg/kg cocaine, and freely fed controls. Cocaine was administered via gavage from gestation day 6-20. A maternal fostering procedure was used. Pairs of male and female littermates began training when 9, 13, or 19 months old. The behavioral procedure involved fixed-ratio (FR) lever pressing to obtain brief periods of wheel running. The oldest males from the 50 mg/kg, 25 mg/kg, and pair-fed groups performed significantly fewer wheel revolutions per opportunity than females or freely fed males. In general, animals earned fewer opportunities to run as the FR requirement was increased over sessions. However, within each age-by-gender group, subjects from the four treatment groups performed equivalent amounts of lever pressing. The specific effect on the motor aspect of the procedure may have resulted from a reduction of motor coordination, balance, or strength, or a diminished capacity of wheel running to serve as a reinforcing stimulus in a cocaine-sensitive subgroup.
Asunto(s)
Cocaína/toxicidad , Narcóticos/toxicidad , Efectos Tardíos de la Exposición Prenatal , Desempeño Psicomotor/efectos de los fármacos , Animales , Peso Corporal/efectos de los fármacos , Condicionamiento Operante/efectos de los fármacos , Dieta , Femenino , Edad Gestacional , Masculino , Actividad Motora/efectos de los fármacos , Embarazo , Ratas , Caracteres SexualesRESUMEN
Much evidence suggests that the neuropeptide cholecystokinin (CCK) functions as a neurotransmitter or neuromodulator in the central nervous system. The CCKa receptor subtype in the nucleus accumbens has been demonstrated to potentiate the behavioral and neurophysiological effects of dopamine. Since the mesolimbic dopamine system participates in the regulation of male rat sexual behavior, the present investigation was undertaken to determine if central CCK modulates this dopaminergic regulation. Electrical stimulation of the ventral tegmental area greatly enhanced several measures of appetitive and consummatory male rat sexual behavior. Administration of a CCKa receptor antagonist to the posteromedian nucleus accumbens reversed the electrically stimulated behavioral enhancement. A CCKb antagonist was without effect. In a second group of animals, administration of either a CCKa or CCKb antagonist to the anterolateral nucleus accumbens reversed the enhancement of consummatory sexual responding produced by electrical stimulation. These results agree with the growing body of evidence supporting different behavioral roles for two distinct CCK systems in the nucleus accumbens.
Asunto(s)
Conducta Animal/efectos de los fármacos , Colecistoquinina/farmacología , Copulación/efectos de los fármacos , Dopamina/metabolismo , Núcleo Accumbens/efectos de los fármacos , Animales , Relación Dosis-Respuesta a Droga , Estimulación Eléctrica , Masculino , RatasRESUMEN
The classic dopamine agonist apomorphine, microinjected into the medial preoptic area (MPOA), enhances the copulatory behavior of male rats, while pharmacological blockade of endogenous dopamine inhibits sexual behavior. We now report that MPOA injections of 10 micrograms of the selective D1 agonist dihydroxyphenyl-tetrahydrothienopyridine (THP) significantly increased the number of ejaculations, while decreasing the latency to ejaculate in a 30-min test. These effects were not observed following coadministration of the selective D1 antagonist SCH-23390 with 10 micrograms THP. This enhancement may be related to a D1-stimulated facilitation of penile erections.
Asunto(s)
Copulación/efectos de los fármacos , Dopaminérgicos/farmacología , Área Preóptica/fisiología , Receptores de Dopamina D1/efectos de los fármacos , Animales , Apomorfina/administración & dosificación , Apomorfina/farmacología , Benzazepinas/administración & dosificación , Benzazepinas/farmacología , Dopaminérgicos/administración & dosificación , Eyaculación/efectos de los fármacos , Femenino , Inyecciones , Masculino , Ovariectomía , Erección Peniana/efectos de los fármacos , Piridinas/farmacología , Ratas , Estimulación QuímicaRESUMEN
Dopamine D1 and D2 receptors may synergize with or oppose each other's effects. We suggest that stimulation of D1 and D2 receptors in the medial preoptic area (MPOA) of male rats have opposing effects on genital reflexes. In Experiment 1 a D1 agonist injected into the MPOA increased the number of ex copula erections but decreased the number of seminal emissions. In Experiment 2 a D1 antagonist had the opposite effects (decreased erections and increased seminal emissions), as had a D2 agonist previously. We also suggest that D1 and D2 mechanisms in the MPOA have different thresholds of activation. In Experiment 3 a low dose of the mixed D1/D2 agonist apomorphine increased erections and anteroflexions, an effect blocked by the D1 antagonist. In Experiments 3 and 4 a high dose of apomorphine increased seminal emissions, an effect blocked by the D2 antagonist. Thus, low levels of dopaminergic stimulation may facilitate erections and anteroflexions (controlled by the parasympathetic system and striated muscles) via D1 receptors; higher or more prolonged stimulation may shift to seminal emission (controlled by the sympathetic system) via D2 receptors. This may explain the progression from erectile to ejaculatory mechanisms during copulation.
Asunto(s)
Copulación/fisiología , Pene/fisiología , Área Preóptica/fisiología , Receptores de Dopamina D1/fisiología , Receptores de Dopamina D2/fisiología , Animales , Apomorfina/farmacología , Benzazepinas/farmacología , Copulación/efectos de los fármacos , Dopaminérgicos/farmacología , Antagonistas de los Receptores de Dopamina D2 , Eyaculación/efectos de los fármacos , Eyaculación/fisiología , Masculino , Erección Peniana/efectos de los fármacos , Erección Peniana/fisiología , Pene/efectos de los fármacos , Racloprida , Ratas , Receptores de Dopamina D1/antagonistas & inhibidores , Receptores de Dopamina D1/efectos de los fármacos , Receptores de Dopamina D2/efectos de los fármacos , Salicilamidas/farmacología , Tiofenos/farmacologíaRESUMEN
Microinjection of apomorphine into the ventral tegmental area (VTA) of male rats was previously shown to delay the onset of copulation and slow its rate, presumably by stimulating impulse-regulating autoreceptors on cell bodies of the A10 mesocorticolimbic dopamine tract. Such stimulation would be expected to slow the firing rate of these neurons and, thereby, to impair locomotion and/or motivational processes. The present experiments tested whether the delayed onset and slowed rate of copulation were related to deficits in motor performance, sexual motivation, and/or genital reflexes. In X-maze tests the speed of running to all 4 goal boxes was slowed; however, the percentage of trials on which the male chose the female's goal box was not decreased. Examination of videotaped copulation tests revealed that the male showed fewer complete copulatory behaviors (mounts, intromissions, and ejaculations), but more misdirected or incomplete copulatory attempts after apomorphine in the VTA. There were also fewer scores of active, as opposed to inactive, behaviors, and the onset and rate of copulation were slowed. The total number of female directed behaviors was not different in apomorphine tests, compared to vehicle. Finally, tests of ex copula genital reflexes revealed no significant effects of apomorphine in the VTA on erections, penile movements, or seminal emissions. These data suggest a role of the VTA in the motor aspects and/or sensorimotor integration of copulation. Sexual motivation and ex copula genital reflexes appeared to be unaffected by apomorphine in the VTA.
Asunto(s)
Apomorfina/farmacología , Copulación , Motivación , Receptores Dopaminérgicos/fisiología , Reflejo/efectos de los fármacos , Conducta Sexual Animal/efectos de los fármacos , Tegmento Mesencefálico/fisiología , Animales , Apomorfina/administración & dosificación , Relación Dosis-Respuesta a Droga , Eyaculación/efectos de los fármacos , Femenino , Masculino , Microinyecciones , Ratas , Receptores Dopaminérgicos/efectos de los fármacos , Semen/metabolismo , Tegmento Mesencefálico/efectos de los fármacosRESUMEN
The D2 dopamine receptor agonist quinelorane (LY-163502), microinjected into the paraventricular nucleus (PVN), affected genital response of restrained supine male rats in a biphasic dose-dependent fashion. A moderate dose (1 microgram) facilitated penile responses (intense erections and penile movements), and decreased the latency to the first response. A high dose of quinelorane (10 micrograms) facilitated seminal emission while inhibiting penile responses. The addition of the D1 antagonist SCH-23390 to the 1 microgram dose of quinelorane potentiated quinelorane's increase in seminal emission. We suggest that D1 receptors in the PVN may be antagonistic to D2 receptor-mediated seminal emission, and possibly also penile responses. In copulation tests 1 microgram quinelorane decreased mount latency, whereas 10 micrograms quinelorane increased mount and intromission latencies and slowed copulatory rate. Both 1 and 10 micrograms quinelorane, and also 1 and 10 micrograms of the mixed D1 and D2 agonist apomorphine, decreased the number of intromissions preceding ejaculation.
Asunto(s)
Copulación/efectos de los fármacos , Genitales Masculinos/efectos de los fármacos , Núcleo Hipotalámico Paraventricular/fisiología , Quinolinas/farmacología , Receptores Dopaminérgicos/efectos de los fármacos , Animales , Apomorfina/farmacología , Benzazepinas/farmacología , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Estradiol/farmacología , Femenino , Masculino , Microinyecciones , Ovariectomía , Erección Peniana/efectos de los fármacos , Ratas , Receptores de Dopamina D2RESUMEN
Microinjection of the dopamine antagonist cis-flupenthixol into the medial preoptic area was previously shown to impair male rat copulatory behavior. The present experiments provide further evidence of cis-flupenthixol's inhibitory effects on male sexual behavior. Following microinjections of moderate to high doses of cis-flupenthixol, males exhibited slower copulatory rates and fewer ejaculations in copula, fewer ex copula erections and penile movements, and reduced sexual motivation in an X-maze. Locomotion in the X-maze was not significantly affected. Microinjections of the inactive isomer trans-flupenthixol produced no change in any behavioral measure, indicating that cis-flupenthixol's effects were receptor mediated. We suggest that dopamine receptors in the MPOA influence copulation primarily by regulating reflexive and motivational factors, but not locomotion.
Asunto(s)
Copulación/efectos de los fármacos , Flupentixol/farmacología , Motivación , Pene/fisiología , Área Preóptica/fisiología , Conducta Sexual Animal/efectos de los fármacos , Animales , Femenino , Flupentixol/administración & dosificación , Aprendizaje , Masculino , Microinyecciones , Pene/efectos de los fármacos , Área Preóptica/efectos de los fármacos , Ratas , Valores de Referencia , Reflejo/efectos de los fármacosRESUMEN
This study investigated the effects on genital reflexes of unilateral MPOA injections of 0.1, 1, 3, and 10 micrograms of the D2 agonist quinelorane (LY-163502), and of 3 micrograms quinelorane administered together with 3 micrograms of the D1 antagonist SCH-23390. In addition, the effects of an MPOA injection of 10 micrograms apomorphine were tested. All but the lowest dose of quinelorane significantly decreased the latency to the first reflex. The 3 and 10 micrograms doses of quinelorane, and the combination of quinelorane and SCH-23390, decreased the total number of reflexes. In addition, 10 micrograms quinelorane increased the number of seminal emissions. 10 micrograms apomorphine, like 10 micrograms quinelorane, decreased the latency to the first reflex and increased the number of seminal emissions, but did not decrease the numbers of erections or penile movements. The ratio of D1/D2 activity may influence the number of erections displayed during ex copula testing.