Alterations in morphine-induced reward, locomotor activity, and thermoregulation in CREB-deficient mice.

Previous studies in our lab have shown a robust decrease in the rewarding properties of morphine in CREB(alphaDelta) mutant mice. To determine whether the genetic effects of the global CREB(alphaDelta) mutation are specific to reward or generalizable, we examined a variety of morphine-induced behaviors regulated by different neural circuitry. At low doses of morphine (5 and 10 mg/kg), CREB(alphaDelta) mutant mice show a reduction in reward yet similar locomotor activity in response to morphine compared to wild type littermates. However, at a high dose (20 mg/kg), CREB(alphaDelta) mutant mice show an increase in reward and locomotor activity. Morphine-induced thermoregulation is attenuated in CREB(alphaDelta) mutant mice at high doses of morphine compared to wild type animals. The behavioral differences in response to morphine seen in CREB(alphaDelta) mutant mice are not due to changes in mu opioid receptor (MOR) mRNA expression, as the CREB deletion has no effect on baseline MOR mRNA in three of the brain regions involved in mediating these behaviors: the ventral tegmental area (VTA), nucleus accumbens (NAc), and hypothalamus. These data demonstrate that at low doses, deficits in morphine-induced changes in CREB deficient mice are limited to reward and thermoregulation. However, at higher doses, CREB mutant mice actually find morphine more rewarding and exhibit increased locomotor activity compared to their wild type littermates. Together, these results indicate that the role of CREB in dose-dependent changes in behaviors induced by morphine is different depending on the brain regions involved in mediating the behavior.