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

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Subthalamic nucleus pathology contributes to repetitive behavior expression and is reversed by environmental enrichment.

Repetitive motor behaviors are common in neurodevelopmental, psychiatric and neurological disorders. Despite their prevalence in certain clinical populations, our understanding of the neurobiological cause of repetitive behavior is lacking. Likewise, not knowing the pathophysiology has precluded efforts to find effective drug treatments. Our comparisons between mouse strains that differ in their expression of repetitive behavior showed an important role of the subthalamic nucleus (STN). In mice with high rates of repetitive behavior, we found significant differences in dendritic spine density, gene expression and neuronal activation in the STN. Taken together, these data show a hypoglutamatergic state. Furthermore, by using environmental enrichment to reduce repetitive behavior, we found evidence of increased glutamatergic tone in the STN with our measures of spine density and gene expression. These results suggest the STN is a major contributor to repetitive behavior expression and highlight the potential of drugs that increase STN function to reduce repetitive behavior in clinical populations.

Further characterization of repetitive behavior in C58 mice: developmental trajectory and effects of environmental enrichment.

Aberrant repetitive behaviors are commonly observed in a variety of neurodevelopmental, neurological, and neuropsychiatric disorders. Little is known about the specific neurobiological mechanisms that underlie such behaviors, however, and effective treatments are lacking. Valid animal models can aid substantially in identifying pathophysiological factors mediating aberrant repetitive behavior and aid in treatment development. The C58 inbred mouse strain is a particularly promising model, and we have further characterized its repetitive behavior phenotype. Compared to C57BL/6 mice, C58 mice exhibit high rates of spontaneous hindlimb jumping and backward somersaulting reaching adult frequencies by 5 weeks post-weaning and adult temporal organization by 2 weeks post-weaning. The development of repetitive behavior in C58 mice was markedly attenuated by rearing these mice in larger, more complex environments. In addition to characterizing repetitive motor behavior, we also assessed related forms of inflexible behavior that reflect restricted and perseverative responding. Contrary to our hypothesis, C58 mice did not exhibit increased marble burying nor did they display reduced exploratory behavior in the holeboard task. The C58 strain appears to be a very useful model for the repetitive motor behavior characteristic of a number of clinical disorders. As an inbred mouse strain, studies using the C58 model can take full advantage of the tool kit of modern genetics and molecular neuroscience. This technical advantage makes the model a compelling choice for use in studies designed to elucidate the etiology and pathophysiology of aberrant repetitive behavior. Such findings should, in turn, translate into effective new treatments.

Abnormal repetitive behaviours: shared phenomenology and pathophysiology.

BACKGROUND: Self-injurious behaviour (SIB) is a devastating problem observed in individuals with various neurodevelopmental disorders, including specific genetic syndromes as well as idiopathic intellectual and developmental disability. Although an increased prevalence of SIB has been documented in specific genetic mutations, little is known about the neurobiological basis of SIB. This makes vulnerability assessment and pharmacological treatment incredibly challenging. METHOD: Here we review evidence that SIB and other repetitive, invariant behaviours, such as stereotypy, compulsions and tics, share many phenotypic similarities, are often co-morbidly expressed and have common inducing conditions. This argues for shared or overlapping pathophysiology. As much more is known about the neurobiology of these related disorders, this should make the neurobiology of SIB a more tractable problem. RESULTS: Stereotypy, compulsions and tics are diagnostic for disorders that have received focused neurobiological investigation (autism, obsessive compulsive disorder, Tourette syndrome, respectively). In addition, animal models of these repetitive behaviours have been well characterised. Collectively, these studies have found that cortical basal ganglia circuitry dysfunction mediates repetitive behaviour. Moreover, these studies provide more detailed information and potentially testable hypotheses about specific aspects of the circuitry that may be operative in SIB. CONCLUSIONS: We can use available information from clinical and animal models to make more precise hypotheses regarding the particular pathophysiology driving SIB. The results of testing such hypotheses should generate pharmacological strategies that may prove efficacious in reducing SIB.

Self-injurious behaviour: limbic dysregulation and stress effects in an animal model.

BACKGROUND: Self-injurious behaviour (SIB) is prevalent in neurodevelopmental disorders, but its expression is highly variable within, and between diagnostic categories. This raises questions about the factors that contribute to aetiology and expression of SIB. Expression of SIB is generally described in relation to social reinforcement. However, variables that predispose vulnerability have not been as clearly characterised. This study reports the aetiology and expression of self-injury in an animal model of pemoline-induced SIB. It describes changes in gross neuronal activity in selected brain regions after chronic treatment with pemoline, and it describes the impact that a history of social defeat stress has on the subsequent expression of SIB during pemoline treatment. METHODS: Experiment 1--Male Long-Evans rats were injected on each of five consecutive days with pemoline or vehicle, and the expression of SIB was evaluated using a rating scale. The brains were harvested on the morning of the sixth day, and were assayed for expression of cytochrome oxidase, an index of sustained neuronal metabolic activity. Experiment 2--Male Long-Evans rats were exposed to a regimen of 12 daily sessions of social defeat stress or 12 daily sessions of handling (i.e. controls). Starting on the day after completion of the social defeat or handling regimen, each rat was given five daily injections of pemoline. The durations of self-injurious oral contact and other stereotyped behaviours were monitored, and the areas of tissue injury were quantified. RESULTS: Experiment 1--Neuronal metabolic activity was significantly lower in a variety of limbic and limbic-associated brain structures in the pemoline-treated rats, when compared with activity in the same regions of vehicle-treated controls. In addition, neuronal activity was low in the caudate-putamen, and in subfields of the hypothalamus, but did not differ between groups for a variety of other brain regions, including nucleus accumbens, substantia nigra, ventral tegmentum, thalamus, amygdala, and cortical regions. Experiment 2--All the pemoline-treated rats exhibited SIB, and whereas the social defeat regimen did not alter the total amount of self-injurious oral contact or other stereotyped behaviours, it significantly increased the severity of tissue injury. CONCLUSIONS: A broad sampling of regional metabolic activity indicates that the pemoline regimen produces enduring changes that are localised to specific limbic, hypothalamic and striatal structures. The potential role of limbic function in aetiology of SIB is further supported by the finding that pemoline-induced self-injury is exacerbated by prior exposure to social defeat stress. Overall, the results suggest brain targets that should be investigated further, and increase our understanding of the putative role that stress plays in the pathophysiology of SIB.