The role of neurotensin in vulnerability for self-injurious behaviour: studies in a rodent model.

Abstract

Self-injurious behaviour is a debilitating characteristic that is commonly expressed in people with autism and other neurodevelopmental disorders, but the neurobiological basis of this maladaptive behaviour is not understood. Abnormal dopaminergic and glutamatergic neurotransmission has been implicated, especially in relation to basal ganglia and mesocorticolimbic circuits. As neurotensin is an important modulator of dopamine and glutamate in these circuits, we investigated its potential role in vulnerability for self-injury, using the pemoline model in rats. Male Long-Evans rats were injected once daily with the psychostimulant pemoline or peanut oil vehicle on each of five consecutive days. Self-injury was quantified by measuring the area of injuries for each rat on each day of the experiment. Each brain was harvested on the sixth day, and the striatum and ventral tegmentum were dissected. Neurotensin-like immunoreactivity was quantified by radioimmunoassay from the dissected brain regions of some of the rats. Membrane and intracellular neurotensin receptor NTS1 were assayed from the striata of the remaining pemoline-treated or vehicle-treated rats by Western blot. In an additional experiment, male Long-Evans rats were treated with daily injections of vehicle or pemoline, and the NTS1 neurotensin receptor agonist PD149163 or the NTS1 receptor antagonist SR48692 (or respective vehicle solutions) was co-administered twice daily throughout the pemoline treatment regimen. The areas of injured tissue were measured, and the duration of self-injurious oral contact was quantified by video-recorded time samples throughout each day. Striatal neurotensin immunoreactivity was found to be significantly higher in pemoline-treated than in vehicle-treated rats. Moreover, both membrane-bound and intracellular levels of NTS1 receptor were significantly higher in the striata of pemoline-treated rats than in the striata of the vehicle-treated controls. When the NTS1 receptor agonist PD149163 was co-administered during the pemoline treatment regimen, it prolonged the daily durations of self-injurious oral contact and increased the severity of the injuries in the self-injurious rats. Conversely, co-administration of the NTS1 receptor antagonist SR48692 diminished the daily durations of self-injurious oral contact and decreased the severity of the injuries. The elevation of striatal neurotensin immunoreactivity during pemoline treatment, coupled with the effects of the NTS1 agonist and antagonist, suggests that neurotensin transmission in the striatum may be an important modulator of self-injurious behaviour in the pemoline model. Overall, the convergence of the behavioural and biochemical findings suggests that neurotensin signalling could be an important target for pharmacotherapeutic interventions for self-injurious behaviour.