RESUMEN
Patients with schizophrenia exhibit deficits in motivation and affect, which suggests an impairment in the reward system. The psychotomimetic drug, phencyclidine (PCP), also induces schizophrenia-like negative symptoms, such as reduced motivation, blunted affect, and social withdrawal in both humans and animals. Previous studies have indicated that the dopaminergic neurons in the ventral tegmental area (VTA) play a pivotal role in the development of reward-associated learning and motivation. However, how PCP affects the activity of VTA neurons during performance of a reward-related task and social interaction with others in unanesthetized animals remains unclear. Here, we recorded the unit activity of VTA neurons in freely moving rats before and after systemic administration of PCP in a classical conditioning paradigm, and during social interaction with an unfamiliar partner. In the classical conditioning task, two different tones were sequentially presented, one of which accompanied electrical stimulation of the medial forebrain bundle as an unconditioned stimulus. After identifying the response properties of recorded neurons in the classical conditioning task and social interaction, animals received an intraperitoneal injection of PCP. Our study demonstrated that most VTA neurons responsive to reward-associated stimuli were also activated during social interaction. Such activation of neurons was considerably suppressed by systemic administration of PCP, thus, PCP may affect the firing activity of VTA neurons that are involved in motivation, learning, and social interaction. Disruption of the response of VTA neurons to reward stimuli and socially interactive situations may be involved in PCP-induced impairments similar to the negative symptoms of schizophrenia.
Asunto(s)
Alucinógenos/farmacología , Neuronas/efectos de los fármacos , Fenciclidina/farmacología , Recompensa , Conducta Social , Área Tegmental Ventral/citología , Potenciales de Acción/efectos de los fármacos , Potenciales de Acción/fisiología , Animales , Condicionamiento Psicológico/efectos de los fármacos , Masculino , Haz Prosencefálico Medial , Ratas , Ratas Sprague-Dawley , Tirosina 3-Monooxigenasa/metabolismo , Área Tegmental Ventral/efectos de los fármacosRESUMEN
Animals exposed to phencyclidine (PCP) during the neonatal period have fewer GABAergic interneurons in the corticolimbic area, including the hippocampus, and exhibit abnormal behaviors after attaining maturation that correspond with schizophrenic symptoms. Since a lack of inhibitory interneurons in the hippocampus has also been reported in postmortem studies of patients with schizophrenia, the deficit may induce abnormal activity of hippocampal neurons that underlies pathological states in schizophrenia. However, it remains unclear how PCP treatment during the neonatal period affects the discharge activity of hippocampal neurons in adulthood. In the current study, single unit responses of hippocampal CA3 neurons to paired auditory clicks were recorded in freely moving mice repeatedly injected with PCP or saline during the neonatal period. The recorded neurons were classified into two subpopulations, narrow-spike neurons and broad-spike neurons, based on the spike width. The spontaneous discharge rate was higher in the narrow-spike neurons than in the broad-spike neurons, indicating that the narrow-spike neurons correspond with hippocampal inhibitory neurons. The proportion of narrow-spike neurons was significantly smaller in neonatally PCP-treated mice than in saline-treated mice. The broad-spike neurons that exhibited a response magnitude to the second click as large as that to the first click (E/E-type response) showed longer response duration to the paired clicks in PCP-treated mice than in the saline-treated mice. Further, the number of neurons with E/E-type response was higher in the PCP-treated mice than in the saline-treated mice. Finally, the attenuation of an auditory-evoked potential component, N40, to the second click (sensory gating) was blunted in the PCP-treated mice when compared with that in the saline-treated mice. These results suggest that the neonatal administration of PCP induced a deficit of inhibitory interneurons and altered discharge activity of neurons in the hippocampal CA3 region to the paired clicks, thereby inducing the deficit in sensory gating.
Asunto(s)
Región CA3 Hipocampal/efectos de los fármacos , Potenciales Evocados Auditivos/efectos de los fármacos , Alucinógenos/toxicidad , Interneuronas/efectos de los fármacos , Fenciclidina/toxicidad , Estimulación Acústica , Animales , Animales Recién Nacidos , Región CA3 Hipocampal/fisiología , Electrofisiología , Potenciales Evocados Auditivos/fisiología , Interneuronas/fisiología , Masculino , Ratones , MovimientoRESUMEN
Negative symptoms of schizophrenia, such as social withdrawal and blunted affect, usually persist for a long period, making rehabilitation difficult. Many studies have demonstrated a close relationship between function of the amygdala and social behavior. Normal social behavior is disturbed in animals administered phencyclidine (PCP), which is now considered a reliable pharmacological model of schizophrenia. Recent studies have reported that disruption of social behavior in PCP-treated rats involved dysfunction of the amygdala. Disturbance of function of the amygdala has also been reported in schizophrenic patients. However, no study has yet examined the effects of PCP on the firing activity of amygdala neurons. In the present study, we recorded the unit activity of basolateral amygdala neurons while rats engaged in socially interactive behavior. After identifying the response properties of recorded neurons, we then recorded the same neurons with systemic PCP administration. Approximately half of the neurons recorded from exhibited an increase in spontaneous discharge rate during social interaction. Only a few neurons exhibited suppression of discharge rate during social interaction. Systemic administration of PCP induced long-lasting activation in half of the neurons that exhibited an increase in firing rate during social interaction. PCP activated half of basolateral amygdala neurons related to socially interactive behavior, and might in this fashion produce dysfunction of social behavior.
Asunto(s)
Potenciales de Acción/efectos de los fármacos , Amígdala del Cerebelo/citología , Alucinógenos/farmacología , Relaciones Interpersonales , Neuronas/efectos de los fármacos , Fenciclidina/farmacología , Animales , Masculino , Ratas , Ratas Sprague-Dawley , Vigilia/fisiologíaRESUMEN
Phencyclidine (PCP) is a psychotomimetic drug that elicits schizophrenia-like symptoms in healthy individuals, and animals administered PCP are now considered a reliable pharmacological model of schizophrenia. Recent studies have shown that systemically administered PCP produces long-lasting activation of medial prefrontal cortex (mPFC) neurons, and that hyperactivation of mPFC neurons plays a critically important role in the development of PCP-induced behavioral abnormalities. However, the receptors mediating this mPFC activation have not been clearly determined. Here, we examined the effects of local application of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), an AMPA/kainate glutamate receptor antagonist, scopolamine, a muscarinic acetylcholine receptor antagonist, and mecamylamine, a nicotinic acetylcholine receptor antagonist, on the increase in firing rate of mPFC neurons induced by systemic PCP in anesthetized rats. After tonic activation of mPFC neurons by PCP had been established, CNQX, scopolamine, or mecamylamine was iontophoretically applied or pressure-ejected on the recorded neuron. CNQX suppressed PCP-induced elevation of firing rate to baseline level, though scopolamine and mecamylamine each induced little change in firing rate. These findings suggest that PCP-induced activation of mPFC neurons is mediated primarily via AMPA/kainate glutamate receptors.
Asunto(s)
Ácido Glutámico/metabolismo , Neuronas/efectos de los fármacos , Fenciclidina/farmacología , Corteza Prefrontal/efectos de los fármacos , Receptores AMPA/antagonistas & inhibidores , Transmisión Sináptica/efectos de los fármacos , 6-Ciano 7-nitroquinoxalina 2,3-diona/farmacología , Potenciales de Acción/efectos de los fármacos , Potenciales de Acción/fisiología , Anestésicos/farmacología , Animales , Interacciones Farmacológicas/fisiología , Antagonistas de Aminoácidos Excitadores/farmacología , Masculino , Antagonistas Muscarínicos/farmacología , Neuronas/metabolismo , Antagonistas Nicotínicos/farmacología , Corteza Prefrontal/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores AMPA/metabolismo , Transmisión Sináptica/fisiologíaRESUMEN
To clarify some neurophysiological aspects of learning, we investigated the relationship between the course of learning and development of ERP and investigated developmental processes of ERPs. Nine male Sprague-Dawley rats were trained for a two-tone discrimination task and rat P3 and N1 component were longitudinally recorded. Both rat P3 and N1 gradually increased with learning only for target tones. An improvement in the proportion of correct responses preceded the increase in ERPs, and the increase in P3 and N1 proceeded almost simultaneously. These findings suggest that multiple kinds of information processing were acquired with learning the two-tone discrimination task. ERP development could be utilized as an index of establishment of learning.