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Friday, May 8, 2009
Northwest Hall (Chicago Hilton)
11:00 AM
Background: The most debilitating of all the maladaptive behaviors in autism is self-injurious behavior (SIB). SIB consists of stereotyped behaviors that can produce physical injury (e.g. head-banging, face-punching, self-biting). Pemoline, an indirect monoamine agonist, produces stereotyped self-biting in rats and is used as an animal model of human SIB. Neurotensin is a neuropeptide that interacts with dopamine and glutamate, two neurotransmitter systems that we and others have identified as being important mediators of SIB.
Objectives: We are investigating the role of neurotensin in the expression of SIB and evaluating the efficacy of a neurotensin agonist (PD149163) to reduce SIB, using the pemoline model in rats.
Methods: In experiment 1, male Long Evans rats were administered either pemoline (150 mg/kg) or peanut oil vehicle each day for five days (10 rats per group). On the sixth day the rats were killed, their brains removed, and the striatum and ventral tegmentum were rapidly dissected. A neurotensin RIA (Phoenix Pharmaceuticals) was used to measure neurotensin content within these structures. In experiment 2, rats received daily injections of pemoline (150 mg/kg/day; s.c.) and either 0, 0.01, 0.1, 1.0 mg/kg of the neurotensin 1 receptor agonist, PD149163 (s.c.), twice daily for five days. SIB was measured by quantifying the duration of self-injurious oral contact with the skin and by measuring the size of injured tissue.
Results: In experiment 1 we found that neuronal content of neurotensin in the striatum was higher in pemoline-treated rats (i.e. the self-injurers) than in vehicle controls. Although not directly evaluated in this study, previous studies have shown that similar increases in neurotensin content after administration of other psychostimulants is due to decreased release of neurotensin. No differences in ventral tegmental neurotensin content were found between pemoline- and vehicle-treated rats. Experiment 2 (studying the effects of the neurotensin 1 receptor agonist on pemoline-induced SIB) is in progress and results will be reported at the conference.
Conclusions: Although our investigations into the role of neurotensin in pemoline-induced SIB are still on-going, we suggest that targeting neurotensin neurotransmission may be a clinically relevant pharmacotherapeutic tool to reduce human SIB. Furthermore, neurotensin has been described as an endogenous antipsychotic and neurotensin agonists have recently received attention for their pro-cognitive and anxiolytic effects, which further highlight the potential of neurotensinergic drugs to improve the core symptoms of autism.
Objectives: We are investigating the role of neurotensin in the expression of SIB and evaluating the efficacy of a neurotensin agonist (PD149163) to reduce SIB, using the pemoline model in rats.
Methods: In experiment 1, male Long Evans rats were administered either pemoline (150 mg/kg) or peanut oil vehicle each day for five days (10 rats per group). On the sixth day the rats were killed, their brains removed, and the striatum and ventral tegmentum were rapidly dissected. A neurotensin RIA (Phoenix Pharmaceuticals) was used to measure neurotensin content within these structures. In experiment 2, rats received daily injections of pemoline (150 mg/kg/day; s.c.) and either 0, 0.01, 0.1, 1.0 mg/kg of the neurotensin 1 receptor agonist, PD149163 (s.c.), twice daily for five days. SIB was measured by quantifying the duration of self-injurious oral contact with the skin and by measuring the size of injured tissue.
Results: In experiment 1 we found that neuronal content of neurotensin in the striatum was higher in pemoline-treated rats (i.e. the self-injurers) than in vehicle controls. Although not directly evaluated in this study, previous studies have shown that similar increases in neurotensin content after administration of other psychostimulants is due to decreased release of neurotensin. No differences in ventral tegmental neurotensin content were found between pemoline- and vehicle-treated rats. Experiment 2 (studying the effects of the neurotensin 1 receptor agonist on pemoline-induced SIB) is in progress and results will be reported at the conference.
Conclusions: Although our investigations into the role of neurotensin in pemoline-induced SIB are still on-going, we suggest that targeting neurotensin neurotransmission may be a clinically relevant pharmacotherapeutic tool to reduce human SIB. Furthermore, neurotensin has been described as an endogenous antipsychotic and neurotensin agonists have recently received attention for their pro-cognitive and anxiolytic effects, which further highlight the potential of neurotensinergic drugs to improve the core symptoms of autism.