RESUMEN
BACKGROUND: Metabotropic glutamate receptor 4 (mGluR4) and dopamine D2 receptors are specifically expressed within the indirect pathway neurons of the striato-pallidal-subthalamic pathway. This unique expression profile suggests that mGluR4 and D2 receptors may play a cooperative role in the regulation and inhibitory control of behaviour. We investigated this possibility by testing the effects of a functionally-characterised positive allosteric mGluR4 modulator, 4-((E)-styryl)-pyrimidin-2-ylamine (Cpd11), both alone and in combination with the D2 receptor antagonist eticlopride, on two distinct forms of impulsivity. METHODS: Rats were trained on the five-choice serial reaction time task (5-CSRTT) of sustained visual attention and segregated according to low, mid, and high levels of motor impulsivity (LI, MI and HI, respectively), with unscreened rats used as an additional control group. A separate group of rats was trained on a delay discounting task (DDT) to assess choice impulsivity. RESULTS: Systemic administration of Cpd11 dose-dependently increased motor impulsivity and impaired attentional accuracy on the 5-CSRTT in all groups tested. Eticlopride selectively attenuated the increase in impulsivity induced by Cpd11, but not the accompanying attentional impairment, at doses that had no significant effect on behavioural performance when administered alone. Cpd11 also decreased choice impulsivity on the DDT (i.e. increased preference for the large, delayed reward) and decreased locomotor activity. CONCLUSIONS: These findings demonstrate that mGluR4s, in conjunction with D2 receptors, affect motor- and choice-based measures of impulsivity, and therefore may be novel targets to modulate impulsive behaviour associated with a number of neuropsychiatric syndromes.
Asunto(s)
Antagonistas de los Receptores de Dopamina D2/farmacología , Agonistas de Aminoácidos Excitadores/farmacología , Conducta Impulsiva/efectos de los fármacos , Actividad Motora/efectos de los fármacos , Pirimidinas/farmacología , Salicilamidas/farmacología , Estirenos/farmacología , Animales , Atención/efectos de los fármacos , Atención/fisiología , AMP Cíclico/metabolismo , Descuento por Demora/efectos de los fármacos , Descuento por Demora/fisiología , Antagonistas de los Receptores de Dopamina D2/sangre , Relación Dosis-Respuesta a Droga , Agonistas de Aminoácidos Excitadores/sangre , Agonistas de Aminoácidos Excitadores/líquido cefalorraquídeo , Conducta Impulsiva/fisiología , Masculino , Actividad Motora/fisiología , Psicotrópicos/farmacología , Pirimidinas/sangre , Pirimidinas/líquido cefalorraquídeo , Ratas , Receptores de Dopamina D2/metabolismo , Receptores de Glutamato Metabotrópico/agonistas , Receptores de Glutamato Metabotrópico/metabolismo , Salicilamidas/sangre , Estirenos/sangre , Estirenos/líquido cefalorraquídeo , Percepción Visual/efectos de los fármacos , Percepción Visual/fisiologíaRESUMEN
Objective methods for critically evaluating the toxic effect of industrial solvents are highly desirable. As many of these solvents are suspected to cause vertigo, an animal experimental model was set up for studying the effects of solvents on the vestibular systems. The vestibular function was studied by registration of involuntary eye movements--nystagmus--which are elicited via central vestibulo-oculomotor connections. During exposure to styrene a so-called positional nystagmus was demonstrated that indicated vestibular disturbances. Nystagmus is normally elicited by rotatory acceleration. During exposure to styrene the direction of this rotatory nystagmus was reversed. The incidence of the positional nystagmus correlated well with the blood level of the solvent, measured by gas chromatography. Kinetic studies also demonstrated a rapid equilibration between the level of the solvent in arterial blood and cerebrospinal fluid, and therefore suggested that estimation of the arterial level reliably indicates the level in the central nervous system.