Neuropeptide Y signaling modulates the expression of ethanol-induced behavioral sensitization in mice.

Neuropeptide Y (NPY) and protein kinase A (PKA) have been implicated in neurobiological responses to ethanol. We have previously reported that mutant mice lacking normal production of the RIIß subunit of PKA (RIIß-/- mice) show enhanced sensitivity to the locomotor stimulant effects of ethanol and increased behavioral sensitization relative to littermate wild-type RIIß+/+ mice. We now report that RIIß-/- mice also show increased NPY immunoreactivity in the nucleus accumbens (NAc) core and the ventral striatum relative to RIIß+/+ mice. These observations suggest that elevated NPY signaling in the NAc and/or striatum may contribute to the increased sensitivity to ethanol-induced behavioral sensitization that is a characteristic of RIIß-/- mice. Consistently, NPY-/- mice failed to display ethanol-induced behavioral sensitization that was evident in littermate NPY+/+ mice. To examine more directly the role of NPY in the locomotor stimulant effects of ethanol, we infused a recombinant adeno-associated virus (rAAV) into the region of the NAc core of DBA/2J mice. The rAAV-fibronectin (FIB)-NPY(13-36) vector expresses and constitutively secretes the NPY fragment NPY(13-36) (a selective Y(2) receptor agonist) from infected cells in vivo. Mice treated with the rAAV-FIB-NPY(13-36) vector exhibited reduced expression of ethanol-induced behavioral sensitization compared with mice treated with a control vector. Taken together, the current data provide the first evidence that NPY signaling in the NAc core and the Y(2) receptor modulate ethanol-induced behavioral sensitization.

The influence of dextromethorphan on morphine analgesia in Swiss Webster mice is sex-specific.

NMDA (N-methyl-d-aspartate) antagonists are known to enhance the analgesic effects of opioids. However, virtually, all studies of this phenomenon have been done using male subjects. Here, the noncompetitive NMDA receptor antagonist dextromethorphan (DEX) was tested over a range of doses (10-200 microg intracerebroventricularly [i.c.v.]) in male and female Swiss Webster mice in combination with 5 mg/kg intraperitoneal (i.p.) morphine. Males exhibited enhanced morphine analgesia following either 100 or 200 microg DEX, but there was no evidence of DEX-mediated potentiation in females at any dose. Instead, DEX attenuated morphine analgesia in females. We also evaluated the effect of 100 microg i.c.v. DEX with different doses of morphine (1, 5 and 10 mg/kg). Again, DEX significantly enhanced morphine analgesia in male mice and attenuated it in females. Next, ovariectomized (OVX) female mice were compared to males following 5 mg/kg i.p. morphine and 100 microg i.c.v. DEX. Male and OVX females exhibited equivalent maximal levels of analgesia following administration of DEX. Morphine analgesia was not enhanced by DEX in sham-treated females and OVX mice with estradiol treatment (5 microg i.p. once daily for 7 days) also did not show DEX enhancement. These experiments demonstrate that the ability of NMDA receptor antagonists to potentiate morphine analgesia is modulated by an estrogen-sensitive mechanism and suggest that sex differences may play a critical role toward a more general understanding of the potentiation of opioid-induced analgesia through NMDA receptor antagonists.

Predictors of high ethanol consumption in RIIbeta knock-out mice: assessment of anxiety and ethanol-induced sedation.

BACKGROUND: Genetic and pharmacological evidence suggests that the cyclic adenosine monophosphate-dependent protein kinase A pathway modulates neurobiological responses to ethanol. Mutant mice lacking the RIIbeta subunit of protein kinase A (RIIbeta(-/-)) are resistant to ethanol-induced sedation and drink significantly more ethanol than littermate wild-type mice (RIIbeta(+/+)). We determined whether high ethanol intake by the RIIbeta(-/-) mice on alternate genetic backgrounds is reliably predicted by high basal levels of anxiety or resistance to the sedative effects of ethanol. METHODS: Two-bottle choice procedures and a battery of behavioral tests (elevated plus maze, open-field activity, and zero maze) were used to assess voluntary ethanol consumption and basal levels of anxiety in RIIbeta(-/-) and RIIbeta(+/+) mice on either a C57BL/6J or a 129/SvEv x C57BL/6J genetic background. Additionally, ethanol-induced sedation and blood ethanol levels were determined in RIIbeta(-/-) and RIIbeta(+/+) mice after intraperitoneal injection of ethanol (3.8 g/kg). RESULTS: RIIbeta(-/-) mice on both genetic backgrounds consumed more ethanol and had a greater preference for ethanol relative to RIIbeta(+/+) mice. However, RIIbeta(-/-) mice showed reduced basal levels of anxiety when maintained on the C57BL/6J background but showed increased anxiety when maintained on the 129/SvEv x C57BL/6J background. Consistent with prior research, RIIbeta(-/-) mice were resistant to the sedative effects of ethanol, regardless of the genetic background. Finally, RIIbeta(-/-) and RIIbeta(+/+) mice showed similar blood ethanol levels. CONCLUSIONS: These results indicate that high ethanol consumption is associated with resistance to the sedative effects of ethanol but that basal levels of anxiety, as well as ethanol metabolism, do not reliably predict high ethanol drinking by RIIbeta(-/-) mice.