ABSTRACT
Motor activity induced in the Circling Training test (CT) during a postnatal (PN) critical period of plasticity (PN30-37) produces a long-lasting decrease in the number of binding sites and mRNA expression levels of the dopamine D2 receptor (D2R) in rat striatum. Prenatal exposure to the antipsychotic haloperidol also decreases postnatal levels of the striatal D2R in the offspring. We examined whether such fetal exposure to haloperidol could affect the activity-dependent reduction of the D2R system during the critical period. Half of the male offspring exposed to either haloperidol (2.5 mg/kg/day), i.p.) or saline during gestational days 5-18 were subjected to the CT during the critical period, while the remaining represented CT control animals. The adult number of binding sites and mRNA expression levels of the striatal D2R at PN90 were not changed by prenatal haloperidol treatment alone. On the other hand, only pups subjected to the CT during the critical period showed decreases in both studied parameters, regardless the prenatal treatment. These findings indicated that the postnatal reduction of the striatal D2R binding induced prenatally by haloperidol does not affect long-lasting activity-dependent plastic changes on the same receptor system elicited by motor activity in an ontogenetic critical period of plasticity in rat striatum.
Subject(s)
Corpus Striatum , Dopamine Antagonists/pharmacology , Fetus , Haloperidol/pharmacology , Neuronal Plasticity , Receptors, Dopamine D2/metabolism , Animals , Behavior, Animal/drug effects , Binding Sites , Corpus Striatum/drug effects , Corpus Striatum/physiology , Dopamine/metabolism , Female , Fetus/drug effects , Fetus/physiology , Gestational Age , Humans , Male , Motor Activity/drug effects , Motor Activity/physiology , Neuronal Plasticity/drug effects , Neuronal Plasticity/physiology , Pregnancy , Prenatal Exposure Delayed Effects , RNA, Messenger/metabolism , Random Allocation , Rats , Rats, Sprague-Dawley , Receptors, Dopamine D2/geneticsABSTRACT
Experience-dependent plasticity during critical periods of postnatal (PN) development shapes the adult brain anatomy and function. In rat motor system, there is a critical period of activity-dependent plasticity in the striatum (PN30-37). In this period, motor activity of running in a circular path induced in the Circling Training test (CT), elicits several plasticity changes on striatal synapses. It has been recently proposed that developmental critical periods might represent a unique pharmacological window of vulnerability to induce life-lasting behavioral modifications. In this paper we tested the hypothesis of existence of a pharmacological susceptibility to induce adult alterations on motor behavior during the striatal critical period. Due to its main action on the striatum and developmental motor behavioral effects, we applied the prototypical antipsychotic haloperidol to male rats (i.p. 0.7 or 2.5 mg/kg/day) before, during or after the period of plasticity (PN20-27, PN30-37 or PN40-47 respectively). Then, in the adulthood (PN80), we evaluated induced motor activity in the CT. The results showed that only rats exposed to the D2R blocker during the period PN30-37 increased the CT activity in comparison to control rats. Moreover, only these animals also showed an increase in the spontaneous locomotor activity at the open field test. These behavioral alterations were not accompanied by permanent striatal changes either on the number of D2R binding sites or on its mRNA expression levels. In conclusion, we have shown a pharmacological susceptibility of inducing adult motor behavior alterations by haloperidol during a natural critical period of activity-dependent plasticity (PN30-37) in rat striatum development. These results also emphasize the importance of behavioral screening for pharmacological agents to be used in developmental stages of maturation.
Subject(s)
Corpus Striatum/drug effects , Corpus Striatum/physiopathology , Dopamine Antagonists/adverse effects , Dyskinesia, Drug-Induced/physiopathology , Haloperidol/adverse effects , Neuronal Plasticity/drug effects , Age Factors , Animals , Antipsychotic Agents/adverse effects , Binding Sites/drug effects , Binding Sites/genetics , Brain Chemistry/drug effects , Brain Chemistry/genetics , Corpus Striatum/growth & development , Dopamine/metabolism , Male , Motor Activity/drug effects , Motor Activity/physiology , Neuronal Plasticity/physiology , RNA, Messenger/metabolism , Rats , Rats, Sprague-Dawley , Receptors, Dopamine D2/drug effects , Receptors, Dopamine D2/genetics , Receptors, Dopamine D2/metabolism , TimeABSTRACT
Experimental models and clinical data indicate that the incidence of motor and learning disorders may be increased in children of epileptic mothers taking phenytoin (PHT) during pregnancy. There is little data on the vulnerability of infants to PHT-induced long-term behavioral toxicity after gestational or early life exposure (i.e., infantile convulsion therapy). We examined the persistence of alterations in circling behavior induced by exposure to PHT during gestation, infancy, or both. Pregnant Sprague-Dawley rats were injected i.p. with saline (SAL) or PHT (30 mg/kg/day) during gestational days (GD) 10-18. The offspring were then administered (i.p.) SAL or PHT (60 mg/kg/day) during postnatal days (PD) 13-23. Afterward, Circling Training tests were performed at three time points. At PD40 and PD80, the clockwise direction of circling was reinforced. At PD150, counterclockwise circling was rewarded instead. At PD40, all PHT-treated groups demonstrated increased circling velocities compared to saline-treated controls. Higher spatial error rates for direction of circling were also observed in gestation-only and infancy-only exposures. At PD80, groups exposed during gestation had higher circling velocities than control or infancy-only exposed groups. At PD150, increases in circling velocity were apparent for the reverse learning task in groups exposed during gestation. These results indicate that early postnatal exposure to PHT may exacerbate the known long-term behavioral effects of gestational exposure.
Subject(s)
Anticonvulsants/toxicity , Learning Disabilities/chemically induced , Motor Activity/drug effects , Phenytoin/toxicity , Prenatal Exposure Delayed Effects , Age Factors , Animals , Animals, Newborn , Behavior, Animal/drug effects , Birth Weight/drug effects , Female , Litter Size/drug effects , Maternal Behavior/drug effects , Pregnancy , Rats , Rats, Sprague-Dawley , Reversal Learning/drug effects , Spatial Behavior/drug effects , Stereotyped Behavior/drug effects , Survival AnalysisABSTRACT
Up to 35% of pregnant women take psychotropic drugs at least once during gestation [Austin and Mitchell, 1998]. From concurrent animal and human evidence, it has been proposed that exposure to several psychoactive medications in utero or during lactation increases the risk for permanent brain disorders. Present preventive or therapy practices applied on humans for this type of long-lasting behavioral alterations are mainly based on empirical results. Here, we test an experimental approach designed to counteract a circling performance deficit that appears in Sprague-Dawley rats at puberty on exposure to the dopaminergic blocker haloperidol (HAL) during gestation [J.L. Brusés, J.M. Azcurra, The circling training: A behavioral paradigm for functional teratology testing, in: P.M. Conn (Ed.), Paradigms for the study of behavior, Acad. Press, New York, 1993, pp. 166-179. Method Neurosci. 14]. Gestational exposure to HAL (GD 5-18, 2.5 mg/kg/day ip) induced the expected circling activity decrease in the offspring at the fifth week of life. When prenatal exposure to HAL was continued through lactation (PD5-21, 1.5 mg/kg/day ip), rats otherwise showed a control-like circling performance. No difference was yet found between lactation-only, HAL-exposed pups and saline (SAL)-treated controls (n=8 each group). We further performed saturating (3H)-spiroperidol (SPI) binding assays on striatal P2 membrane fractions 2 months later. The dopamine-type D2-specific binding results suggested that above circling behavior findings could be partially explained by enduring HAL-induced neurochemical changes. The role of critical periods of sensitivity as transient windows for opportunistic therapies for behavioral teratology is discussed.
Subject(s)
Haloperidol , Prenatal Exposure Delayed Effects , Stereotyped Behavior/drug effects , Stereotypic Movement Disorder/drug therapy , Analysis of Variance , Animals , Animals, Newborn , Behavior, Animal/drug effects , Brain/drug effects , Dopamine Antagonists/pharmacokinetics , Dopamine Antagonists/therapeutic use , Dopamine Antagonists/toxicity , Female , Haloperidol/therapeutic use , Haloperidol/toxicity , Male , Pregnancy , Radioligand Assay/methods , Random Allocation , Rats , Rats, Sprague-Dawley , Spiperone/pharmacokinetics , Stereotypic Movement Disorder/chemically induced , Tritium/pharmacokineticsABSTRACT
Circling training during rat striatum postnatal critical period (PN30 to 37 days) induces a life-lasting co-reduction of muscarinic acetylcholine receptors (mAChR) and dopamine D2 receptors (D2R) binding. Here, we evaluated the expression of D1R and D2R under similar experimental conditions. Trained rats showed a decrease of 40% in D2R binding sites (p<0.01) and of 45% in the D2R mRNA expression which involve short (p<0.05) and long (p<0.01) isoforms. In contrast, D1R binding sites nor its mRNA expression levels were affected by training, indicating a differential synaptic refinement during this ontogenetically fixed period.
Subject(s)
Corpus Striatum/metabolism , Critical Period, Psychological , Motor Activity/physiology , Receptors, Dopamine D1/biosynthesis , Receptors, Dopamine D2/biosynthesis , Animals , Corpus Striatum/growth & development , Gene Expression Regulation/physiology , Male , Rats , Rats, Sprague-Dawley , Receptors, Dopamine D1/genetics , Receptors, Dopamine D2/geneticsABSTRACT
During the critical period of activity-dependent plasticity in rat striatum (30-37 days after birth) physiological circling behavior induces delayed modifications in GAP-43/B-50 phosphorylation by PKC. Postexercise, ipsi- and contralateral striatum to the circling direction show a similar temporal pattern of GAP-43/B-50 phosphorylation, with an initial decrease followed by a subsequent increase. However, there is a lag between initiation of the phosphorylation response in this asymmetrical task which does not occur when animals are subjected to exercise under conditions of symmetrical motor activity.
Subject(s)
GAP-43 Protein/metabolism , Motor Activity/physiology , Neostriatum/growth & development , Neostriatum/metabolism , Neuronal Plasticity/physiology , Physical Conditioning, Animal/physiology , Animals , Functional Laterality/physiology , Learning/physiology , Male , Neostriatum/cytology , Neurons/metabolism , Phosphorylation , Rats , Rats, Sprague-Dawley , Reaction Time/physiologyABSTRACT
In central nervous system, acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) hydrolyse acetylcholine. Diminished cholinesterase activity is known to alter several mental and psychomotor functions. The symptoms of cholinergic crisis and those observed during acute attacks of acute intermittent porphyria are very similar. The aim of this study was to investigate if there could be a link between the action of some porphyrinogenic drugs on brain and the alteration of the cholinergic system. To this end, AChE and BuChE activities were assayed in whole and different brain areas. Muscarinic acetylcholine receptor (mAChR) levels were also measured. Results obtained indicate that the porphyrinogenic drugs tested affect central cholinergic transmission. Quantification of mAChR gave quite different levels depending on the xenobiotic. Veronal administration inhibited 50% BuChE activity in whole brain, cortex and hippocampus; concomitantly cortex mAChR was 30% reduced. Acute and chronic isoflurane anaesthesia diminished BuChE activity by 70-90% in whole brain instead cerebellum and hippocampus mAChR levels were only altered by chronic enflurane anaesthesia. Differential inhibition of cholinesterases in the brain regions and their consequent effects may be of importance to the knowledge of the mechanisms of neurotoxicity of porphyrinogenic drugs.
Subject(s)
Brain/metabolism , Cholinesterases/drug effects , Porphyrias/complications , 5-Aminolevulinate Synthetase/drug effects , Acetylcholinesterase/analysis , Acetylcholinesterase/drug effects , Animals , Barbital/administration & dosage , Barbital/pharmacology , Brain/anatomy & histology , Butyrylcholinesterase/analysis , Butyrylcholinesterase/drug effects , Cholinesterases/analysis , Enflurane/administration & dosage , Enflurane/pharmacology , Ethanol/administration & dosage , Ethanol/pharmacology , Griseofulvin/administration & dosage , Griseofulvin/pharmacology , Male , Mice , Nervous System Diseases/etiology , Porphyrias/chemically induced , Receptors, Muscarinic/analysis , Receptors, Muscarinic/drug effects , Starvation/metabolismABSTRACT
No hay duda que el rendimiento cognitivo de un individuo en edad escolar depende tanto de factores biológicos como no biológicos. La evaluación confiable y precoz de dichos factores para la instrumentación de acciones preventivas eficaces, constituye un objetivo que contempla necesidades de orden clínico, educacional y social. Esto requiere la implementación de técnicas de diagnóstico neuropsicológico en infantes, así como la evaluación de todos los factores determinantes de riesgo cognitivo en los mismos. Aquí presentamos una sistematización de la información relevante de los factores que participan en el desarrollo cognitivo. Esto permitirá establecer criterios de riesgo en estudios poblacionales y complementar el cuadro de riesgo de casos clínicos específicos
Subject(s)
Humans , Child, Preschool , Child , Child Development , Cognition Disorders , Learning Disabilities , Risk FactorsABSTRACT
Las escalas y tests infantiles en uso no permiten evaluar funciones cognitivas en niños menores de 3 años. Los modelos de procesamiento de información intentan medir aspectos intrínsecos de funciones cerebrales o el tiempo de dichos procesos. Su instrumentación como test psicométrico permitiría resolver problemas de diagnóstico en la clínica y aplicar nuevas estrategias terapéuticas. Además posibilitarían acciones preventivas precoces de la neuroteratología conductal. Hemos seleccionado el PPMC, en su forma tactil-visual, utilizando la preferencia para la novedad, como punto final de medición. Se diseñaron y sistematizaron una serie de objetos y se establecieron las condiciones operativas de la toma de la prueba. Esta se aplicó en una población infantil de 1 y 2 años (+ 2 semanas) respectivamente, cuyos sujetos encajan en el patrón de criterios de normalidad clínica estándares. Los resultados muestran que los valores promedio de fijación diferencial al objeto nuevo expresados en porcentajes para los grupos estudiados fueron 59,7 porciento DS 6,5 (n=54) y 58,73 por ciento DS 9,6 (n=35) para un tiempo de familiarización de 10". Se demuestra que el paradigma seleccionado es independiente de las condiciones operacionales de medición no esenciales, está desprovisto de interferencias de factores culturales y por lo tanto mide aspectos intrínsecos de procesos cerebrales
