Female preproenkephalin-knockout mice display altered emotional responses

The endogenous opioid system has been implicated in sexual behavior, palata ble intake, fear, and anxiety. The present study examined whether ovariecto mized female transgenic preproenkephalin-knockout (PPEKO) mice and their wi ld-type and heterozygous controls displayed alterations in fear and anxiety paradigms, sucrose intake, and lordotic behavior. To examine stability of responding, three squads of the genotypes were tested across seasons over a 20-month period. In a fear-conditioning paradigm, PPEKO mice significantly increased freezing to both fear and fear + shock stimuli relative to contr ols. In the open field, PPEKO mice spent significantly less time and traver sed significantly less distance in the center of an open field than wild-ty pe controls. Further, PPEKO mice spent significantly less time and tended t o be less active on the light side of a dark-light chamber than controls, i ndicating that deletion of the enkephalin gene resulted in exaggerated resp onses to fear or anxiety-provoking environments. These selective deficits w ere observed consistently across testing squads spanning 20 months and diff erent seasons. In contrast, PPEKO mice failed to differ from corresponding controls in sucrose, chow, or water intake across a range (0.0001-20%) of s ucrose concentrations and failed to differ in either lordotic or female app roach to male behaviors when primed with estradiol and progesterone. thereb y arguing strongly for the selectivity of a fear and anxiety deficit which was not caused by generalized and nonspecific debilitation. These transgeni c data strongly suggest that opioids, and particularly enkephalin gene prod ucts, are acting naturally to inhibit fear and anxiety.