RESUMEN
RATIONALE: Serotonin (5-HT) plays a key role in the pathophysiology of psychotic disorders, presumably through a modulation of dopamine (DA) transmission. Reduction of 5-HT signaling has been suggested to enhance dopaminergic responses in animal models of psychosis. An intriguing naturalistic strategy to reduce 5-HT brain content is afforded by the dietary restriction to its precursor, l-tryptophan (TRP). OBJECTIVE: We investigated the impact of a TRP-deficient diet in rats on the prepulse inhibition of the startle (PPI), a measure of sensorimotor gating which is typically impaired by psychotomimetic substances. MATERIALS AND METHODS: After either short-term (6 h) or long-term (14 days) TRP deprivation, rats were tested for startle reflex and PPI. Moreover, we assessed the impact of both TRP deprivation regimens on PPI reduction induced by the psychotomimetic substance d-amphetamine (AMPH). RESULTS: Both TRP-deficient regimens failed to significantly affect PPI responses. However, chronic, but not short-term, TRP-deficient diet induced a significant sensitization to the effects of AMPH (1.25-2.5 mg/kg, subcutaneous). The enhanced predisposition to PPI disruption elicited by prolonged TRP deprivation was completely reversed 24 h after reinstatement of TRP in the diet, as well as pretreatment with antipsychotic drugs haloperidol (0.1 mg/kg, intraperitoneal) and clozapine (5 mg/kg, intraperitoneal), which exert their therapeutic action mostly through blockade of DA D(2) receptors. CONCLUSIONS: The present results confirm and extend previous findings on the impact of serotonergic signaling in the modulation of DA transmission in schizophrenia and point to chronic TRP deprivation as a potential model of environmental manipulation that may produce a sensitization to psychotic-like symptoms induced by dopaminergic activation.
Asunto(s)
Reflejo de Sobresalto/fisiología , Triptófano/deficiencia , Estimulación Acústica , Aminoácidos/análisis , Aminoácidos/farmacología , Anfetamina/farmacología , Animales , Antipsicóticos/farmacología , Estimulantes del Sistema Nervioso Central/farmacología , Clozapina/farmacología , Interpretación Estadística de Datos , Dieta , Antagonistas de Dopamina/farmacología , Antagonistas de los Receptores de Dopamina D2 , Ingestión de Alimentos , Harina/análisis , Haloperidol/farmacología , Masculino , Ratas , Ratas Sprague-Dawley , Reflejo de Sobresalto/efectos de los fármacos , Zea mays/químicaRESUMEN
The anticonvulsant topiramate (TPM) has been recently proposed as a novel adjuvant therapy for bipolar disorder and schizophrenia, yet its efficacy remains controversial. As both disorders are characterized by gating deficits, we tested the effects of TPM on the behavioral paradigm of prepulse inhibition (PPI) of the acoustic startle response, a validated animal model of sensorimotor gating. TPM (10, 18, 32, 58, 100 mg/kg, intraperitoneal, i.p.) enhanced PPI in rats in a dose-dependent fashion, prevented the PPI reduction mediated by the dopaminergic agonist apomorphine (0.25 mg/kg, subcutaneous, s.c.) and potentiated the effects of the antipsychotic drugs haloperidol (0.05, 0.1 mg/kg, i.p.) and clozapine (2.5, 5 mg/kg, i.p.). Conversely, TPM elicited no significant effect on the PPI disruption mediated by the NMDA receptor antagonist dizocilpine (0.05, 0.1 mg/kg, s.c.) and surprisingly antagonized the attenuation of dizocilpine-induced PPI disruption mediated by clozapine (5 mg/kg, i.p.). Our results suggest that TPM may exert diverse actions on the neural substrates of sensorimotor gating. While the pharmacological mechanisms of such effects are still elusive, our findings might contribute to shed light on some controversies on the therapeutic action of TPM, and point to this drug as a putative novel adjuvant therapy for some clusters of gating disturbances.
Asunto(s)
Encéfalo/efectos de los fármacos , Fructosa/análogos & derivados , Inhibición Neural/efectos de los fármacos , Reflejo de Sobresalto/efectos de los fármacos , Animales , Anticonvulsivantes/farmacología , Antipsicóticos/agonistas , Trastorno Bipolar/tratamiento farmacológico , Trastorno Bipolar/metabolismo , Trastorno Bipolar/fisiopatología , Encéfalo/metabolismo , Dopamina/metabolismo , Agonistas de Dopamina/farmacología , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Antagonistas de Aminoácidos Excitadores/farmacología , Fructosa/farmacología , Ácido Glutámico/metabolismo , Masculino , Inhibición Neural/fisiología , Ratas , Ratas Sprague-Dawley , Reflejo de Sobresalto/fisiología , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/metabolismo , Esquizofrenia/fisiopatología , Transmisión Sináptica/efectos de los fármacos , Transmisión Sináptica/fisiología , TopiramatoRESUMEN
RATIONALE: Gamma-amino-butyric acid (GABA)(B) receptors play a key role in the pathophysiology of psychotic disorders. We previously reported that baclofen, the prototypical GABA(B) agonist, elicits antipsychotic-like effects in the rat paradigm of prepulse inhibition (PPI) of the startle, a highly validated animal model of schizophrenia. OBJECTIVES: We studied the role of GABA(B) receptors in the spontaneous PPI deficits displayed by DBA/2J mice. MATERIALS AND METHODS: We tested the effects of baclofen (1.25-5 mg/kg, intraperitoneal [i.p.]) in DBA/2J and C57BL/6J mice, in comparison to the antipsychotic drugs haloperidol (1 mg/kg, i.p.) and clozapine (5 mg/kg, i.p.). Furthermore, we investigated the expression of GABA(B) receptors in the brain of DBA/2J and C57BL/6J mice by quantitative autoradiography. RESULTS: Baclofen dose-dependently restored PPI deficit in DBA/2J mice, in a fashion similar to the antipsychotic clozapine (5 mg/kg, i.p.). This effect was reversed by pretreatment with the GABA(B) antagonist SCH50211 (50 mg/kg, i.p.). In contrast, baclofen did not affect PPI in C57BL/6J mice. Finally, quantitative autoradiographic analyses assessed a lower GABA(B) receptor expression in DBA/2J mice in comparison to C57BL/6J controls in the prefrontal cortex and hippocampus but not in other brain regions. CONCLUSIONS: Our data highlight GABA(B) receptors as an important substrate for sensorimotor gating control in DBA/2J mice and encourage further investigations on the role of GABA(B) receptors in sensorimotor gating, as well as in the pathophysiology of psychotic disturbances.
Asunto(s)
Encéfalo/fisiopatología , Receptores de GABA-B/metabolismo , Reflejo de Sobresalto/fisiología , Esquizofrenia/fisiopatología , Animales , Antipsicóticos/farmacología , Autorradiografía , Baclofeno/administración & dosificación , Baclofeno/farmacología , Encéfalo/metabolismo , Clozapina/farmacología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Agonistas del GABA/administración & dosificación , Agonistas del GABA/farmacología , Haloperidol/farmacología , Inyecciones Intraperitoneales , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Inhibición Neural/efectos de los fármacos , Inhibición Neural/fisiología , Receptores de GABA-B/efectos de los fármacos , Reflejo de Sobresalto/efectos de los fármacos , Esquizofrenia/tratamiento farmacológicoRESUMEN
Recent evidence highlights levetiracetam (LEV) as an advantageous treatment of absence epilepsy (AE). Thus, we investigated the effects of this drug in DBA/2J mice, a murine model of AE. Similarly to ethosuximide (200 mg/kg, intraperitoneal, i.p.) and sodium valproate (250 mg/kg, i.p.), two classic antiabsence agents, LEV (50-200 mg/kg, i.p.) reduced the occurrence of spike-and-wave discharges, AE's typical electroencephalographic patterns. Our results confirm LEV's efficacy in AE treatment.
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Anticonvulsivantes/farmacología , Electroencefalografía/efectos de los fármacos , Epilepsia Tipo Ausencia/tratamiento farmacológico , Piracetam/análogos & derivados , Animales , Anticonvulsivantes/administración & dosificación , Epilepsia Tipo Ausencia/genética , Epilepsia Tipo Ausencia/fisiopatología , Etosuximida/administración & dosificación , Etosuximida/uso terapéutico , Inyecciones Intraperitoneales , Levetiracetam , Masculino , Ratones , Ratones Endogámicos DBA , Piracetam/administración & dosificación , Piracetam/farmacología , Ácido Valproico/administración & dosificación , Ácido Valproico/uso terapéuticoRESUMEN
Clinical evidence suggests that prenatal exposure to cannabis may be conducive to long-term neurobehavioral impairments in executive and attentional domains. Such sensorimotor alterations might be related to disorders in gating functions. Hence, the present study was undertaken to assess the effects of long-term prenatal exposure to WIN 55,212-2, a potent cannabinoid receptor agonist, on prepulse inhibition of the acoustic startle reflex, a well-validated paradigm to test sensorimotor gating. In utero exposure to WIN 55,212-2 (0.5, 1 mg/kg, from day 5 to 20 of gestation) failed to alter startle magnitude in rats in comparison with controls. Similarly, prepulse inhibition of the startle was not significantly affected by such treatment, regardless of the age when behavioral testing was carried out (40, 60 or 80 days). Interestingly, prenatal treatment with WIN 55,212-2 (0.5 mg/kg, from day 5 to 20 of gestation) induced no differences in the prepulse inhibition-disrupting effects of apomorphine (0.125, 0.25 mg/kg, s.c.) and dizocilpine (0.05, 0.1 mg/kg, s.c.), suggesting that a prenatal exposure to a cannabinoid receptor agonist is likely unable to affect sensitivity of sensorimotor gating substrates to dopaminergic agonists and NMDA receptor antagonists. Our results show that prenatal exposure to cannabis does not affect reflex reactivity to environmental stimuli, ruling out that the observed impairments in executive functions are to refer to sensorimotor gating alterations.
Asunto(s)
Agonistas de Receptores de Cannabinoides , Morfolinas/farmacología , Naftalenos/farmacología , Reflejo de Sobresalto/efectos de los fármacos , Estimulación Acústica , Analgésicos/administración & dosificación , Analgésicos/farmacología , Animales , Animales Recién Nacidos , Benzoxazinas , Femenino , Masculino , Morfolinas/administración & dosificación , Naftalenos/administración & dosificación , Embarazo , Efectos Tardíos de la Exposición Prenatal , Ratas , Ratas Sprague-Dawley , Factores de TiempoRESUMEN
BACKGROUND: Compelling evidence indicates that kappa opioid receptor (KOR) agonists produce perceptual distortions in animals and humans, yet the mechanism of action and clinical relevance of such effects remain unclear. Since abnormalities in preattentional functions and informational processing are hypothesized to underlie psychotic disorders, the present study has been designed to assess the role of KOR on sensorimotor gating. METHODS: The effects of the selective KOR agonist U50488 were evaluated on the behavioral paradigm of prepulse inhibition (PPI) of the acoustic startle reflex (ASR). RESULTS: U50488 (1.25, 2.5, and 5 mg/kg, subcutaneous [SC]) induced a dose-dependent reduction of PPI, which was efficiently prevented by the selective KOR antagonist norbinaltorphimine (nor-BNI, 10 mg/kg, SC), as well as by the atypical antipsychotic clozapine (5, 8 mg/kg, intraperitoneal [IP]) but not by the typical antipsychotic haloperidol (.1, .5 mg/kg, IP). Conversely, nor-BNI (10 mg/kg, SC) failed to reverse the PPI disruption mediated by both apomorphine (.25 mg/kg, SC) and dizocilpine (.1 mg/kg, SC). CONCLUSIONS: Our results support a pivotal role of KOR in the regulation of preattentional functions and sensorimotor gating, pointing to these receptors as a possible neurobiological substrate especially relevant to the clusters of psychosis unresponsive to typical antipsychotics.
Asunto(s)
Estimulación Acústica/métodos , Inhibición Psicológica , Naltrexona/análogos & derivados , Receptores Opioides kappa/fisiología , Reflejo de Sobresalto/fisiología , 3,4-Dicloro-N-metil-N-(2-(1-pirrolidinil)-ciclohexil)-bencenacetamida, (trans)-Isómero/farmacología , Analgésicos no Narcóticos/farmacología , Análisis de Varianza , Animales , Antipsicóticos/farmacología , Apomorfina/farmacología , Clozapina/farmacología , Maleato de Dizocilpina/farmacología , Agonistas de Dopamina/farmacología , Relación Dosis-Respuesta a Droga , Relación Dosis-Respuesta en la Radiación , Interacciones Farmacológicas , Antagonistas de Aminoácidos Excitadores/farmacología , Haloperidol/farmacología , Masculino , Naltrexona/farmacología , Antagonistas de Narcóticos/farmacología , Ratas , Reflejo de Sobresalto/efectos de los fármacosRESUMEN
Although substantial evidence has shown interactions between glutamatergic and dopaminergic systems play a cardinal role in the regulation of attentional processes, their involvement in informational filtering has been poorly investigated. Chiefly, little research has focused on functional correlations between the dopaminergic system and the mechanism of action of N-methyl-D-aspartate (NMDA) receptor antagonists on sensorimotor gating. The present study was targeted at evaluating whether the activation of D1 and D2 receptors is able to interact with the disruption of prepulse inhibition (PPI) of startle mediated by dizocilpine, a selective, noncompetitive NMDA receptor antagonist. We tested the effects of SKF 38393 ((+/-)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol) (10 mg/kg, s.c.), a selective D1 agonist, and quinpirole (0.3, 0.6 mg/kg, s.c.), a D2 agonist, in rats, per se and in cotreatment with different doses of dizocilpine, ranging from 0.0015 to 0.15 mg/kg (s.c.). Subsequently, the effect of the D1 antagonist SCH 23390 ((R)-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine) (0.05, 0.1 mg/kg, s.c.) on PPI disruptions mediated by dizocilpine and by combination of dizocilpine and SKF 38393 was tested. Two further experiments were performed to verify whether the synergic effect of the D1 agonist with dizocilpine was counteracted by effective doses of haloperidol (0.1, 0.5 mg/kg, i.p.) and clozapine (5, 10 mg/kg, i.p.). All experiments were carried out using standard procedures for the assessment of PPI of the acoustic startle reflex. SKF 38393, while unable to impair sensorimotor gating alone, induced PPI disruption in cotreatment with 0.05 and 0.15 mg/kg of dizocilpine, both ineffective per se. Furthermore, this effect was reversed by SCH 23390, but not by haloperidol or clozapine. Conversely, no synergistic effect was exhibited between quinpirole and dizocilpine, at any given dose. These findings suggest that D1, but not D2 receptors, enhance the disruptive effect of dizocilpine on PPI.
Asunto(s)
Maleato de Dizocilpina/farmacología , Receptores de Dopamina D1/fisiología , Receptores de Dopamina D2/fisiología , Reflejo de Sobresalto/fisiología , 2,3,4,5-Tetrahidro-7,8-dihidroxi-1-fenil-1H-3-benzazepina/farmacología , Animales , Benzazepinas/farmacología , Agonistas de Dopamina/farmacología , Antagonistas de Dopamina/farmacología , Haloperidol/farmacología , Masculino , Ratas , Ratas Sprague-Dawley , Receptores de Dopamina D1/efectos de los fármacos , Receptores de Dopamina D2/efectos de los fármacos , Reflejo de Sobresalto/efectos de los fármacosRESUMEN
Rich evidence has highlighted that stimulation of gamma-amino-butyric acid (GABA)(B) receptors increases the occurrence of spike-and-wave discharges (SWDs), the electroencephalographic (EEG) landmark of absence epilepsy (AE). Recent findings suggest that the outcomes of GABA(B) activation in vivo are contingent on the chemical characteristics of the agonist. In particular, the endogenous ligand gamma-hydroxybutyrate (GHB) and its precursor gamma-butyro-lactone (GBL) have been shown to elicit different effects than the prototypical GABA(B) agonist baclofen. In view of these premises, the present study was aimed at the characterization of the effects of baclofen (0.5-10 mg/kg, i.p.) and GBL (5-100 mg/kg, i.p.) on the spontaneous SWDs and locomotor activity of DBA/2J mice. While both baclofen and GBL dose-dependently increased SWDs episodes, high doses of the latter (100 mg/kg, i.p.) reduced the occurrence of these phenomena and increased the number of isolated spikes. Interestingly, both compounds elicited a dose-dependent reduction of locomotor activity, in comparison with their vehicle-treated controls. The GABA(B) selective antagonist, SCH50911 (50 mg/kg, i.p.), reversed the changes in SWD occurrence and locomotion induced by baclofen and GBL, but failed to elicit intrinsic effects on either paradigm. These results indicate that GABA(B) receptor signaling might exert differential effects on SWDs in DBA/2J mice.
Asunto(s)
Epilepsia Tipo Ausencia/metabolismo , Receptores de GABA-B/metabolismo , Animales , Baclofeno/farmacología , Electroencefalografía , Epilepsia Tipo Ausencia/fisiopatología , Agonistas del GABA/farmacología , Masculino , Ratones , Ratones Endogámicos DBA , Actividad Motora/efectos de los fármacosRESUMEN
Recent evidence indicates that neuroactive steroids may participate in the pathogenesis of schizophrenia spectrum disorders, yet the mechanisms of this involvement are elusive. As 5-alpha-reductase (5AR) is the rate-limiting enzyme of one of the two major metabolic pathways in brain steroidogenesis, we investigated the effects of its blockade in several rat models of psychotic-like behavior. The 5AR inhibitor finasteride (FIN, 60 or 100 mg/kg, intraperitoneal, i.p.) dose- and time-dependently antagonized prepulse inhibition (PPI) deficits induced by apomorphine (APO, 0.25 mg/kg, subcutaneous, s.c.) and d-amphetamine (AMPH, 5 mg/kg, s.c.), in a manner analogous to haloperidol (HAL, 0.1 mg/kg, i.p.) and clozapine (CLO, 5 mg/kg, i.p.). Similar results were observed with the other 5AR inhibitors dutasteride (DUT, 40 or 80 mg/kg, i.p.) and SKF 105111 (30 mg/kg, i.p.). FIN (60 or 100 mg/kg, i.p.) also reduced hyperlocomotion induced by AMPH (1 or 3 mg/kg, s.c.) and attenuated stereotyped behaviors induced by APO (0.25 mg/kg, s.c.). Nevertheless, FIN (100 mg/kg, i.p.) did not reverse the PPI disruption induced by the N-methyl-d-aspartate receptor antagonist dizocilpine (0.1 mg/kg, s.c.). FIN (60-300 mg/kg, i.p.) induced no catalepsy in either the bar test or the paw test. Our results suggest that 5AR inhibitors elicit antipsychotic-like effects in animals and may be proposed as a putative novel target in the management of psychotic disorders.
Asunto(s)
Inhibidores de 5-alfa-Reductasa , Encéfalo/efectos de los fármacos , Encéfalo/enzimología , Finasterida/farmacología , Trastornos Psicóticos/tratamiento farmacológico , Trastornos Psicóticos/enzimología , 3-Oxo-5-alfa-Esteroide 4-Deshidrogenasa/metabolismo , Androstanos/farmacología , Androstanos/uso terapéutico , Animales , Antipsicóticos/farmacología , Antipsicóticos/uso terapéutico , Azaesteroides/farmacología , Azaesteroides/uso terapéutico , Modelos Animales de Enfermedad , Agonistas de Dopamina/farmacología , Dutasterida , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Antagonistas de Aminoácidos Excitadores/farmacología , Finasterida/uso terapéutico , Hormonas Esteroides Gonadales/metabolismo , Hipercinesia/inducido químicamente , Hipercinesia/enzimología , Hipercinesia/fisiopatología , Masculino , Trastornos Psicóticos/fisiopatología , Ratas , Ratas Sprague-Dawley , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Receptores de N-Metil-D-Aspartato/metabolismo , Filtrado Sensorial/efectos de los fármacos , Filtrado Sensorial/fisiología , Conducta Estereotipada/efectos de los fármacos , Conducta Estereotipada/fisiología , Testosterona/biosíntesis , Resultado del TratamientoRESUMEN
Sleep deprivation (SD) is known to induce perceptual impairments, ranging from perceptual distortion to hallucinatory states. Although this phenomenon has been extensively described in the literature, its neurobiological underpinnings remain elusive. In rodents, SD induces a series of behavioural patterns that might be reflective of psychosis and mania, such as hyperlocomotion and sensitization to psychotogenic drugs. Notably, such changes are accompanied by transitory alterations of dopaminergic signalling. Based on the hypothesis that both psychotic and manic disorders reflect gating impairments, the present study was aimed at the assessment of the impact of SD on the behavioural model of prepulse inhibition (PPI) of the startle reflex, a reliable paradigm for the study of informational filtering. Rats subjected to SD (24 h, 48 h, 72 h) exhibited a time-dependent increase in startle reflex and a dramatic deficit in PPI. Both alterations were reversed 24 h after termination of the SD period. Interestingly, PPI disruption was efficiently prevented by haloperidol (0.1 mg/kg i.p.) clozapine (5 mg/kg i.p.) and risperidone (1 mg/kg i.p.). Conversely, neither the anxiolytic diazepam (5 mg/kg i.p.) nor the antidepressant citalopram (5 mg/kg i.p) affected the PPI disruption mediated by SD, although diazepam reversed the enhancement in startle reflex magnitude induced by this manipulation. Our data suggest that SD induces gating deficits that might be relevant to the hallucinatory phenomena observed in humans, and provide a novel reliable animal model where such relationship can be studied.
Asunto(s)
Antipsicóticos/farmacología , Reflejo de Sobresalto/efectos de los fármacos , Reflejo de Sobresalto/fisiología , Privación de Sueño/psicología , Estimulación Acústica , Animales , Citalopram/farmacología , Interpretación Estadística de Datos , Diazepam/farmacología , Hipnóticos y Sedantes/farmacología , Masculino , Músculo Esquelético/fisiología , Ratas , Ratas Sprague-Dawley , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Sueño REM/efectos de los fármacosRESUMEN
PURPOSE: To describe the correlations between spiking pattern and EEG power spectrum frequency in DBA/2J mice, a model for murine absence seizures, after gamma-aminobutyric acid (GABA)(B) modulation. METHODS: The animals were first tested with the GABA(B) agonist l-baclofen followed by the GABA(B) antagonist SCH 50911. Moreover, digital EEGs recorded under experimental conditions were processed at baseline and 10 and 20 min after l-baclofen injection. This procedure was followed by injection of the GABA(B) antagonist SCH50911 and by an additional EEG evaluation at 10 and 20 min from drug administration. The power spectra analysis of signals was obtained for delta (0.5-3 Hz), theta (3.5-7.5 Hz), alpha (8-12 Hz), beta (13-20 Hz), and gamma (21-50 Hz) frequencies. RESULTS: The spiking pattern and power spectrum of beta activity was increased by
Asunto(s)
Corteza Cerebral/fisiopatología , Modelos Animales de Enfermedad , Electroencefalografía/estadística & datos numéricos , Epilepsia Tipo Ausencia/fisiopatología , Antagonistas del GABA/farmacología , Receptores de GABA-B/fisiología , Ritmo alfa/efectos de los fármacos , Animales , Baclofeno/farmacología , Ritmo beta/efectos de los fármacos , Cognición/efectos de los fármacos , Cognición/fisiología , Sincronización Cortical/efectos de los fármacos , Ritmo Delta/efectos de los fármacos , Ritmo Delta/estadística & datos numéricos , Electroencefalografía/efectos de los fármacos , Epilepsia Tipo Ausencia/tratamiento farmacológico , Agonistas del GABA/farmacología , Antagonistas del GABA/uso terapéutico , Humanos , Ratones , Ratones Endogámicos DBA , Morfolinas/farmacología , Receptores de GABA-B/efectos de los fármacos , Ritmo Teta/efectos de los fármacos , Ácido gamma-Aminobutírico/efectos de los fármacos , Ácido gamma-Aminobutírico/fisiologíaRESUMEN
Extracellular single-unit recordings of nigral dopamine (DA) neurons were obtained from conscious rats habituated to having their body suspended in a cloth jacket and their head immobilized in the stereotaxic frame by means of a "restraining platform" permanently fixed to the skull. The electrophysiological characteristics of DA neurons from head-restrained rats and their responses to apomorphine and haloperidol were compared with single-unit recordings obtained from rats lightly and deeply anesthetized with chloral hydrate and from mesencephalic slices. Head-restrained rats showed a higher number of spontaneously active DA neurons and a higher percentage of bursting neurons than lightly and deeply anesthetized rats. Indeed, bursting activity was rare in deeply anesthetized rats and was totally absent in slices. Haloperidol was more potent and effective in stimulating the firing rate and bursting activity in head-restrained than in lightly anesthetized rats, while it was virtually ineffective in deeply anesthetized rats and totally ineffective in slices. On the other hand, DA neurons in head-restrained rats showed the same average firing rate as DA neurons in lightly and deeply anesthetized rats and in slices. The potency of apomorphine in inhibiting the firing rate, and that of haloperidol in reversing apomorphine effect, did not vary among the different in vivo preparations. The results suggest that chloral hydrate anesthesia blunts or suppresses not only the excitatory inputs which normally sustain the number of spontaneously active DA neurons and their bursting activity, but also the feedback excitation of DA neurons following haloperidol-induced D(2) receptor blockade. On the other hand, chloral hydrate anesthesia modifies neither D(2) autoreceptor sensitivity to apomorphine and haloperidol nor the automatic genesis of action potentials. The head-restrained rat appears to be an important model for studies into the pharmacology and physiology of DA neurons.
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Potenciales de Acción/fisiología , Neuronas/efectos de los fármacos , Neuronas/fisiología , Sustancia Negra/efectos de los fármacos , Sustancia Negra/fisiología , Potenciales de Acción/efectos de los fármacos , Anestesia , Anestésicos Intravenosos , Animales , Apomorfina/farmacología , Hidrato de Cloral/farmacología , Estado de Conciencia/fisiología , Dopamina/metabolismo , Agonistas de Dopamina/farmacología , Antagonistas de Dopamina/farmacología , Electrofisiología , Haloperidol/farmacología , Inmovilización , Masculino , Técnicas de Cultivo de Órganos , Ratas , Ratas Sprague-DawleyRESUMEN
To investigate the possible long-term consequences of gestational exposure to cannabinoids on cognitive functions, pregnant rats were administered with the CB1 receptor agonist WIN 55,212-2 (WIN), at a dose (0.5 mgkg) that causes neither malformations nor overt signs of toxicity. Prenatal WIN exposure induced a disruption of memory retention in 40- and 80-day-old offspring subjected to a passive avoidance task. A hyperactive behavior at the ages of 12 and 40 days was also found. The memory impairment caused by the gestational exposure to WIN was correlated with alterations of hippocampal long-term potentiation (LTP) and glutamate release. LTP induced in CA3-CA1 synapses decayed faster in brain slices of rats born from WIN-treated dams, whereas posttetanic and short-term potentiation were similar to the control group. In line with LTP shortening, in vivo microdialysis showed a significant decrease in basal and K(+)-evoked extracellular glutamate levels in the hippocampus of juvenile and adult rats born from WIN-treated dams. A similar reduction in glutamate outflow was also observed in primary cell cultures of hippocampus obtained from pups born from mothers exposed to WIN. The decrease in hippocampal glutamate outflow appears to be the cause of LTP disruption, which in turn might underlie, at least in part, the long-lasting impairment of cognitive functions caused by the gestational exposure to this cannabinoid agonist. These findings could provide an explanation of cognitive alterations observed in children born from women who use marijuana during pregnancy.