The 5-HT6R agonist E-6837 and the antagonist SB-271046 reverse the psychotic-like behaviors induced by ketamine.

Schizophrenia is a serious mental disorder that affects 1% of the world's population. Although various therapeutic tools have been developed since the appearance of the first generation of antipsychotics, the effect of these agents does not manage to attenuate a significant part of psychotic symptoms. Ketamine is an anesthetic agent able to produce psychotic-like symptoms through the antagonism of the glutamatergic N-methyl-d-aspartic acid (NMDA) receptors (NMDARs). This drug has been widely used to study new pharmacological tools with potential antipsychotic properties. On the contrary, it is known that the 5-HT6 receptor agonist and antagonist drugs induce procognitive, anxiolytic and antidepressant effects in different preclinical models. Therefore, the aim of this study was to evaluate the behavioral actions of the 5-HT6 receptors' agonist E-6837 and the antagonist SB-271046, in ICR-CD1 mice previously treated with a subchronic ketamine scheme (10 mg/kg i.p. daily for 5 days). Results showed that repeated administration of ketamine induced recognition memory deficit, anxiogenic effects, obsessive-compulsive behaviors and stereotyped movements. The acute administration of both 5-HT6 agents reversed the memory deficit and induced a decrease in anxiety, whereas SB-271046 administration produced a decrease in climbing behavior. The injection of either of these 5-HT6 drugs had no effect in the light-dark test. Surprisingly, when these drugs were injected together with ketamine, anxiogenic actions were produced. Current findings suggest that both agonist and antagonist 5-HT6 drugs play an important role in modulating psychotic-like symptoms induced by the subchronic blockade of NMDAR.

[Efecto de la amigdalotomía e hipotalamotomía unilateral en pacientes con agresividad refractaria].

BACKGROUND: Neurosurgical treatment, although controversial, is considered a useful resource in the treatment of chronic psychiatric diseases such as refractory aggressiveness. OBJECTIVE: To evaluate the clinical results and side effects of posteromedial hypothalamotomy associated with amygdalotomy in patients with refractory aggressiveness. METHOD: A clinical trial was conducted in patients with chronic aggressiveness and refractory to pharmacological treatment. A central amygdalotomy associated with posteromedial hypothalamotomy was performed using thermo-coagulation by radiofrequency. The degree of aggressiveness was quantified by the Yudofsky's global scale of aggression. Postoperative changes in aggressive behavior continued to be evaluated every 6 months for at least 36 months. RESULTS: A statistically significant change in aggressive behavior was observed during 36 months of follow-up. The collateral effects of the association of both procedures are described, the most frequent being drowsiness and some cases of reduction in sexual behavior. CONCLUSION: Symmetric and simultaneous unilateral lesions of the central nucleus of the amygdala and the posteromedial hypothalamus contralateral to motor dominance give the same clinical effect in the reduction of the pathological aggression that the bilateral lesions.

ANTECEDENTES: El tratamiento neuroquirúrgico, aunque polémico, se considera un recurso útil en el tratamiento de enfermedades psiquiátricas crónicas como la agresividad refractaria. OBJETIVO: Evaluar los resultados clínicos y los efectos colaterales de la hipotalamotomía posteromedial (HPM) asociada a amigdalotomía en pacientes con agresividad refractaria. MÉTODO: Se realizó un ensayo clínico en pacientes con agresividad crónica y refractaria a tratamiento farmacológico. Se les realizó amigdalotomía central asociada a HPM mediante termocoagulación por radiofrecuencia. El grado de agresividad se cuantificó mediante la escala global de agresividad de Yudofsky. Los cambios postoperatorios en la conducta agresiva continuaron siendo evaluados cada 6 meses durante al menos 36 meses. RESULTADOS: Se observó un cambio estadísticamente significativo de la conducta agresiva, a lo largo de 36 meses de seguimiento. Se describen los efectos colaterales de la asociación de ambos procedimientos, siendo el de mayor frecuencia la somnolencia y algunos casos de reducción en la conducta sexual. CONCLUSIÓN: Las lesiones unilaterales simétricas y simultáneas del núcleo central de la amígdala y del hipotálamo posteromedial contralaterales a la dominancia motora dan el mismo efecto clínico en la reducción de la agresividad patológica que las lesiones bilaterales.

Effect of unilateral amygdalotomy and hypothalamotomy in patients with refractory aggressiveness.

BACKGROUND: Neurosurgical treatment, although controversial, is considered a useful resource in the treatment of chronic psychiatric diseases such as refractory aggressiveness. OBJECTIVE: To evaluate the clinical results and side effects of posteromedial hypothalamotomy associated with amygdalotomy in patients with refractory aggressiveness. METHOD: A clinical trial was conducted in patients with chronic aggressiveness and refractory to pharmacological treatment. A central amygdalotomy associated with posteromedial hypothalamotomy was performed using thermo-coagulation by radiofrequency. The degree of aggressiveness was quantified by the Yudofsky's global scale of aggression. Postoperative changes in aggressive behavior continued to be evaluated every 6 months for at least 36 months. RESULTS: A statistically significant change in aggressive behavior was observed during 36 months of follow-up. The collateral effects of the association of both procedures are described, the most frequent being drowsiness and some cases of reduction in sexual behavior. CONCLUSION: Symmetric and simultaneous unilateral lesions of the central nucleus of the amygdala and the posteromedial hypothalamus contralateral to motor dominance give the same clinical effect in the reduction of the pathological aggression that the bilateral lesions.

Proliferation and apoptosis of HeLa cells induced by in vitro stimulation with digitalis.

In the HeLa tumor cell line, we studied the characteristics of the dual effect of digitalis compounds on cell growth (proliferation and death). In addition, we explored whether both effects occur by means of the same mechanism. HeLa cell cultures were exposed to increasing concentrations (0.01 nM-10 microM) of ouabain, strophantidin, digoxin, and digoxigenin at 24-96 h intervals. Cell growth in treated cultures was compared with cell growth under nontreated conditions. Additionally, we studied changes in nuclear morphology, as well as in genomic DNA degradation, cytochrome c release, and caspase-9 and -3 presence and processing induced by toxic concentrations of digitalis. Digitalis compounds increased HeLa cell number when exposed to concentrations <10 nM during a 48 h period. Ethacrynic acid (a nonsteroid inhibitor for Na+/K+-ATPase) did not induce cell growth at these concentrations. Digitalis concentrations >10 nM induced cell death in a concentration- and exposure period-dependent fashion. Changes in nuclear morphology, DNA fragmentation, mitochondrial cytochrome c release, and proteolytic processing of caspases-9 and -3, suggest apoptotic cell death. The IC50 for the inducing effect of apoptosis by ouabain at 96 h was 18 nM and corresponds with the IC50 for the Na+/K+-ATPase inhibition in HeLa cells. In conclusion, the dual effect of digitalis compounds on HeLa cells growth is concentration and time-dependent. The apoptosis-inducing effect correlates with inhibition of Na+/K+-ATPase. Proliferation does not appear to be mediated through this pathway. The apoptosis-induction pathway is possibly cytochrome c-dependent.

Efecto de la amigdalotomía e hipotalamotomía unilateral en pacientes con agresividad refractaria / Effect of tonsillotomy and unilateral hypothalamotomy in patients with refractory aggressiveness

Resumen Antecedentes: El tratamiento neuroquirúrgico, aunque polémico, se considera un recurso útil en el tratamiento de enfermedades psiquiátricas crónicas como la agresividad refractaria. Objetivo: Evaluar los resultados clínicos y los efectos colaterales de la hipotalamotomía posteromedial (HPM) asociada a amigdalotomía en pacientes con agresividad refractaria. Método: Se realizó un ensayo clínico en pacientes con agresividad crónica y refractaria a tratamiento farmacológico. Se les realizó amigdalotomía central asociada a HPM mediante termocoagulación por radiofrecuencia. El grado de agresividad se cuantificó mediante la escala global de agresividad de Yudofsky. Los cambios postoperatorios en la conducta agresiva continuaron siendo evaluados cada 6 meses durante al menos 36 meses. Resultados: Se observó un cambio estadísticamente significativo de la conducta agresiva, a lo largo de 36 meses de seguimiento. Se describen los efectos colaterales de la asociación de ambos procedimientos, siendo el de mayor frecuencia la somnolencia y algunos casos de reducción en la conducta sexual. Conclusión: Las lesiones unilaterales simétricas y simultáneas del núcleo central de la amígdala y del hipotálamo posteromedial contralaterales a la dominancia motora dan el mismo efecto clínico en la reducción de la agresividad patológica que las lesiones bilaterales.

Abstract Background: Neurosurgical treatment, although controversial, is considered a useful resource in the treatment of chronic psychiatric diseases such as refractory aggressiveness. Objective: To evaluate the clinical results and side effects of posteromedial hypothalamotomy associated with amygdalotomy in patients with refractory aggressiveness. Method: A clinical trial was conducted in patients with chronic aggressiveness and refractory to pharmacological treatment. A central amygdalotomy associated with posteromedial hypothalamotomy was performed using thermo-coagulation by radiofrequency. The degree of aggressiveness was quantified by the Yudofsky's global scale of aggression. Postoperative changes in aggressive behavior continued to be evaluated every 6 months for at least 36 months. Results: A statistically significant change in aggressive behavior was observed during 36 months of follow-up. The collateral effects of the association of both procedures are described, the most frequent being drowsiness and some cases of reduction in sexual behavior. Conclusion: Symmetric and simultaneous unilateral lesions of the central nucleus of the amygdala and the posteromedial hypothalamus contralateral to motor dominance give the same clinical effect in the reduction of the pathological aggression that the bilateral lesions.

Relaciones entre la ansiedad y la conducta sexual en roedores / Relationships between anxiety and sexual behavior in rats

En la presente revisión se resumen las relaciones que existen entre la ansiedad y la conducta sexual desde diferentes puntos de vista: en el primero se observó el efecto que produce la ansiedad sobre la ejecución de la conducta sexual en el macho; en segundo término, se analizó el efecto que tiene la actividad sexual del macho sobre los niveles de ansiedad. Finalmente se estudió la variación en el estado de ansiedad y el posible efecto diferencial del diazepam a lo largo del ciclo estral en la rata. Las relaciones entre la ansiedad y la conducta sexual se estudiaron utilizando una aproximación farmacológica. En el análisis de la conducta sexual se registraron los parámetros convencionales establecidos. Para dererminar los niveles de ansiedad se utilizó una prueba conductual denominada "enterramiento defensivo condicionado", ya que tiene ciertas ventajas sobre otras pruebas. En este estudio se presentan evidencias que muestran que la ansiedad inducida farmacológicamente produce un efecto bifásico sobre la conducta sexual en el macho. Así, la ansiedad moderada facilita la conducta sexual, mientras que la ansiedad extrema la inhibe. Por el contrario, la administración del ansiolítico diazepam entorpece la ejecución de la cópula. Este efeto, aunque también está regulado a nivel central, no parece deberse a la actividad ansiolítica de este fármaco sino a su acción miorrelajante. Con el fin de estudiar el efecto facilitador de la ansiedad sobre la cópula, hemos propuesto una manipulación experimental denominada "intervalo forzado de intromisión" (IFI), como un modelo de ansiedad sexual. La caracterización farmacológica del IFI mostró que la facilitación de la conducta sexual debida a esta manipulación se puede bloquear en forma específica por el tratamiento con varios ansiolíticos, y se sugiere su relación con un incremento en la ansiedad. En cuanto al efecto que tiene la actividad sexual sobre los niveles de ansiedad, se observó que la eyaculación induce una dismunición en ésta, que se mantiene a lo largo de las siguientes series copulatorias. La explicación para este fenómeno de ansiolisis posteyaculatoria está sustentada en diversos estudios que muestran un incremento en el tono Gabaérfico durante el período posteyaculatorio. En vista de que varios estudios proponen la participación del receptor Gaba-benzodiacepínico en la regulación de la ansiedad, sugerimos que este sistema neurotransmisión está involucrado en el fenómeno antedicho...