The biochemical and behavioral effects of a nonpeptidic, selective, and brain-penetrant agonist at the ORL1 receptor are reported herein. This low molecular weight compound {(1S,3aS)-8-(2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one} has high affinity for recombinant human ORL1 receptors and has 100-fold selectivity for ORL1 over other members of the opioid receptor family. It is a full agonist at these receptors and elicits dose-dependent anxiolytic-like effects in a set of validated models of distinct types of anxiety states in the rat (i.e., elevated plus-maze, fear-potentiated startle, and operant conflict). When given systemically, the compound has an efficacy and potency comparable to those of a benzodiazepine anxiolytic such as alprazolam or diazepam. However, this compound is differentiated from a classical benzodiazepine anxiolytic by a lack of efficient anti-panic-like activity, absence of anticonvulsant properties, and lack of effects on motor performance and cognitive function at anxiolytic doses (0.3 to 3 mg͞kg i.p.). No significant change in intracranial self-stimulation performance and pain reactivity was observed in this dose range. Higher doses of this compound (>10 mg͞kg) induced disruption in rat behavior. These data confirm the notable anxiolytic-like effects observed at low doses with the orphanin FQ͞nociceptin neuropeptide given locally into the brain and support a role for orphanin FQ͞nociceptin in adaptive behavioral fear responses to stress.T he ORL1 orphan receptor was identified from a human cDNA library on the basis of close homology (Ϸ65% in the transmembrane domains) with the -, ␦-, and -opioid receptors (1, 2). Classical opioid ligands do not bind to ORL1, but orphanin FQ͞nociceptin (OFQ͞N), a 17-amino acid neuropeptide purified from brain extracts, was found to be the natural ligand of the G protein-coupled receptor ORL1 (3, 4). OFQ͞N, its precursor peptide, and its receptor ORL1 are located in corticolimbic regions involved in the integration of the emotional components of fear and stress as well as in the spinal cord, with a pattern distinct from that of opioid peptides and receptors in rodents (5-9). The expression of OFQ͞N or its receptor in the amygdaloid complex, septohippocampal region, periaqueductal gray matter, locus coeruleus, and dorsal raphe nucleus suggests that major brain neuronal systems may be sensitive to the action of OFQ͞N. Such sensitivity has widespread implications for many aspects of behavior including arousal, attention, neuroendocrine control, fear, and anxiety (10). In brain slices, OFQ͞N has potent inhibitory actions on neurons in the dorsal raphe nucleus, the locus coeruleus, the periaqueductal gray matter, and the amygdala (11)(12)(13)(14). In general, OFQ͞N plays an inhibitory role on synaptic transmission in the central nervous system and thereby may contribute to a reduction in responsiveness to stress. When given intracerebroventricularly to rodents, OFQ͞N reduces elementary stress-induced physiological respon...
The 16p11.2 600 kb BP4-BP5 deletion and duplication syndromes have been associated with developmental delay; autism spectrum disorders; and reciprocal effects on the body mass index, head circumference and brain volumes. Here, we explored these relationships using novel engineered mouse models carrying a deletion (Del/+) or a duplication (Dup/+) of the Sult1a1-Spn region homologous to the human 16p11.2 BP4-BP5 locus. On a C57BL/6N inbred genetic background, Del/+ mice exhibited reduced weight and impaired adipogenesis, hyperactivity, repetitive behaviors, and recognition memory deficits. In contrast, Dup/+ mice showed largely opposite phenotypes. On a F1 C57BL/6N × C3B hybrid genetic background, we also observed alterations in social interaction in the Del/+ and the Dup/+ animals, with other robust phenotypes affecting recognition memory and weight. To explore the dosage effect of the 16p11.2 genes on metabolism, Del/+ and Dup/+ models were challenged with high fat and high sugar diet, which revealed opposite energy imbalance. Transcriptomic analysis revealed that the majority of the genes located in the Sult1a1-Spn region were sensitive to dosage with a major effect on several pathways associated with neurocognitive and metabolic phenotypes. Whereas the behavioral consequence of the 16p11 region genetic dosage was similar in mice and humans with activity and memory alterations, the metabolic defects were opposite: adult Del/+ mice are lean in comparison to the human obese phenotype and the Dup/+ mice are overweight in comparison to the human underweight phenotype. Together, these data indicate that the dosage imbalance at the 16p11.2 locus perturbs the expression of modifiers outside the CNV that can modulate the penetrance, expressivity and direction of effects in both humans and mice.
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