Morphine deprivation increases self-administration of the fast- and short-acting mu-opioid receptor agonist remifentanil in the rat.

Opiate dependence and withdrawal have long been hypothesized to enhance the reinforcing effects of opiates; however, opiate agonist self-administration in these states has yet to be systematically assessed. To address this issue, the reinforcing property of the short-acting mu-opioid agonist, remifentanil, was assessed in morphine-dependent (MD), morphine-dependent and -withdrawn (MW), and nondependent, control (C) rats. Dependence was established by twice daily administration of increasing doses of morphine for 4 days (10, 20, 30, and 40 mg/kg s.c.) and then maintained with a daily injection of the large dose. Morphine deprivation-induced withdrawal (defined by weight loss and hyperalgesia) was apparent 24, but not 12, h after morphine treatment. Remifentanil self-administration (0.4, 0.8, 1.6, 3.2, or 6.4 mug/kg/infusion) was assessed over 20 successive, daily, 1-h sessions, either 12 or 24 h after the maintenance dose of morphine. Compared with the control group, the MD group demonstrated suppressed remifentanil self-administration, whereas the MW group exhibited enhanced responding for every dose of remifentanil. The increased responding observed in the MW group compared with the control and MD groups resulted in an upward shift in the remifentanil dose-response curve, an effect that was expressed only after repeated exposure to the contingency, demonstrating that morphine withdrawal ultimately enhances the reinforcing effects of remifentanil.

Behavioral sensitization to cocaine in rats: evidence for temporal differences in dopamine D3 and D2 receptor sensitivity.

RATIONALE: Cocaine-induced changes in D(2) receptors have been implicated in the expression of sensitized behavioral responses and addiction-like behaviors; however, the influence of D(3) receptors is less clear. OBJECTIVES: To characterize the effects of repeated cocaine administration on the sensitivity of rats to D(2)- and D(3)-mediated behaviors, as well as the binding properties of ventral striatal D(2)-like and D(3) receptors. METHODS: Pramipexole was used to assess the sensitivity of rats to D(3)/D(2) agonist-induced yawning, hypothermia, and locomotor activity, 24 h, 72 h, 10, 21, and 42 days after repeated cocaine or saline administration. The locomotor effects of cocaine (42 day) and the binding properties of ventral striatal D(2)-like and D(3) receptors (24 h and 42 days) were also evaluated. RESULTS: Cocaine-treated rats displayed an enhanced locomotor response to cocaine, as well as a progressive and persistent leftward/upward shift of the ascending limb (72 h-42 day) and leftward shift of the descending limb (42 days) of the pramipexole-induced yawning dose-response curve. Cocaine treatment also decreased B (max) and K (d) for D(2)-like receptors and increased D(3) receptor binding at 42 days. Cocaine treatment did not change pramipexole-induced hypothermia or locomotor activity or yawning induced by cholinergic or serotonergic agonists. CONCLUSIONS: These studies suggest that temporal differences exist in the development of cocaine-induced sensitization of D(3) and D(2) receptors, with enhancements of D(3)-mediated behavioral effects observed within 72 h and enhancements of D(2)-mediated behavioral effects apparent 42 days after cocaine. These findings highlight the need to consider changes in D(3) receptor function when thinking about the behavioral plasticity that occurs during abstinence from cocaine use.

Ciliary entry of the kinesin-2 motor KIF17 is regulated by importin-beta2 and RanGTP.

The biogenesis, maintenance and function of primary cilia are controlled through intraflagellar transport (IFT) driven by two kinesin-2 family members, the heterotrimeric KIF3A/KIF3B/KAP complex and the homodimeric KIF17 motor. How these motors and their cargoes gain access to the ciliary compartment is poorly understood. Here, we identify a ciliary localization signal (CLS) in the KIF17 tail domain that is necessary and sufficient for ciliary targeting. Similarities between the CLS and classic nuclear localization signals (NLSs) suggest that similar mechanisms regulate nuclear and ciliary import. We hypothesize that ciliary targeting of KIF17 is regulated by a ciliary-cytoplasmic gradient of the small GTPase Ran, with high levels of GTP-bound Ran (RanGTP) in the cilium. Consistent with this, cytoplasmic expression of GTP-locked Ran(G19V) disrupts the gradient and abolishes ciliary entry of KIF17. Furthermore, KIF17 interacts with the nuclear import protein importin-beta2 in a manner dependent on the CLS and inhibited by RanGTP. We propose that Ran has a global role in regulating cellular compartmentalization by controlling the shuttling of cytoplasmic proteins into nuclear and ciliary compartments.