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Abstract
Endocannabinoids, which activate cannabinoid CB1 receptors, modulate neurotransmission. The current studies used the olfactory bulbectomy rodent model, which induces neurobiological changes in the brain and behaviors that are indicative of dopaminergic dysfunction, to test the hypothesis that this behavioral and neurochemical syndrome is attributable to endocannabinoid signaling dysregulation. Locomotor responsivity to a novel open field and repeated administration of amphetamine (1 mg/kg i.p.) was investigated in olfactory bulbectomized and sham-operated rats. CB1 receptor antagonists/inverse agonists rimonabant or AM251 were administered at 1 mg/kg (i.p.) prior to exposure to a novel open field. To investigate whether enhanced cannabinoid signaling would decrease development of sensitization to amphetamine in a CB1-dependent manner, the fatty acid amide hydrolase inhibitor URB597 (0.3 mg/kg i.p.) was administered to olfactory bulbectomized and sham-operated rats alone or coadministered with rimonabant (1 mg/kg i.p.) prior to amphetamine administration. Cannabinoid receptor density 3and endocannabinoid content were measured using radioligand binding with [H]-CP55,940 and receptor autoradiography and high performance liquid chromatography mass spectrometry, respectively. Olfactory bulbectomy increased locomotor activity upon exposure to novelty and amphetamine administration relative to sham surgery. Olfactory bulbectomized rats exhibited increased locomotor responsivity to amphetamine on the first day of administration but did not develop the typical sensitization pattern that was observed in sham-operated animals. URB597 attenuated the development of locomotor sensitization to amphetamine in sham-operated animals but not in olfactory-bulbectomized rats. Rimonabant (1 mg/kg) prevented full habituation to a novel open field in olfactory bulbectomized but not sham-operated rats. AM251 (1 mg/kg) also tended to prevent full habituation in olfactory bulbectomized rats. Olfactory bulbectomy decreased endocannabinoid levels in the ventral striatum relative to sham surgery. By contrast, endocannabinoid content in the pirifirom cortex, hippocampus, and cerebellum was not altered by olfactory bulbectomy. Cannabinoid receptor levels in several brain regions and endocannabinoid content in the ventral striatum were differentially correlated with distance traveled at behaviorally relevant time points in olfactory bulbectomized and sham-operated rats. Our data provides evidence that olfactory bulbectomy induces dysregulation of the endocannabinoid signaling system which affects locomotor responses to a novel open field and amphetamine.