Initial characterization of behavior and ketamine response in a mouse knockout of the post-synaptic effector gene Anks1b.

The human ANKS1B gene encodes an activity-dependent effector of post-synaptic signaling. It was recently associated with neuropsychiatric phenotypes in genome-wide studies. While the biological function of ANKS1B has been partly elucidated, its role in behavior is poorly understood. Here, we breed and characterize a full knockout (KO) for murine Anks1b. We found that the homozygous KO genotype was partially lethal, showing significant deviation from expected segregation ratios at weaning. Behaviorally, KOs exhibited no difference in baseline acoustic startle response, but showed deficits in prepulse inhibition (PPI). KOs also exhibited locomotor hyperactivity and increased stereotypy at baseline. Administration of ketamine, a non-competitive NMDA-receptor antagonist, greatly exacerbated locomotor activity in the KOs at lower doses, but genotype groups were almost indistinguishable as dose increased. Stereotypy showed a complex response to ketamine in the KOs, with elevated stereotypy at lower doses and markedly less at high doses, compared to wild type. Our study is the first to probe the behavioral phenotypes associated with ablation of Anks1b. Deficits in PPI, locomotor hyperactivity, elevated stereotypy and altered response to NMDA receptor antagonism are murine behavioral outcomes with translational relevance for psychiatric disorders. These findings are also consistent with the role of Anks1b as an effector of glutamatergic signaling. As an intermediary between post-synaptic receptor stimulation and long-term changes to neuronal protein expression, further investigation of Anks1b is warranted.

Oxycodone physical dependence and its oral self-administration in C57BL/6J mice.

Abuse of prescription opioids, such as oxycodone, has markedly increased in recent decades. While oxycodone's antinociceptive effects have been detailed in several preclinical reports, surprisingly few preclinical reports have elaborated its abuse-related effects. This is particularly surprising given that oxycodone has been in clinical use since 1917. In a novel oral operant self-administration procedure, C57BL/6J mice were trained to self-administer water before introducing increasing concentrations of oxycodone (0.056-1.0mg/ml) under post-prandial conditions during daily, 3-h test sessions. As the concentration of oxycodone increased, the numbers of deliveries first increased, then decreased in an inverted U-shape fashion characteristic of the patterns of other drugs self-administered during limited access conditions. After post-prandial conditions were removed, self-administration at the highest concentration was maintained suggesting oral oxycodone served as a positive reinforcer. In other mice, using a novel regimen of physical dependence, mice were administered increasing doses of oxycodone (9.0-33.0mg/kg, s.c.) over 9 days, challenged with naloxone (0.1-10.0mg/kg, s.c.), and then observed for 30min. Naloxone dose-dependently increased the observed number of somatic signs of withdrawal, suggesting physical dependence of oxycodone was induced under this regimen. This is the first report demonstrating induction of oral operant self-administration of oxycodone and dose-dependent precipitations of oxycodone withdrawal in C57BL/6J mice. The use of oral operant self-administration as well as the novel physical dependence regimen provides useful approaches to further examine the abuse- and dependence-related effects of this highly abused prescription opioid.

Morphine Tolerance and Physical Dependence Are Altered in Conditional HIV-1 Tat Transgenic Mice.

Despite considerable evidence that chronic opiate use selectively affects the pathophysiologic consequences of human immunodeficiency virus type 1 (HIV-1) infection in the nervous system, few studies have examined whether neuro-acquired immune deficiency syndrome (neuroAIDS) might intrinsically alter the pharmacologic responses to chronic opiate exposure. This is an important matter because HIV-1 and opiate abuse are interrelated epidemics, and HIV-1 patients are often prescribed opiates as a treatment of HIV-1-related neuropathic pain. Tolerance and physical dependence are inevitable consequences of frequent and repeated administration of morphine. In the present study, mice expressing HIV-1 Tat in a doxycycline (DOX)-inducible manner [Tat(+)], their Tat(-) controls, and control C57BL/6 mice were chronically exposed to placebo or 75-mg morphine pellets to explore the effects of Tat induction on morphine tolerance and dependence. Antinociceptive tolerance and locomotor activity tolerance were assessed using tail-flick and locomotor activity assays, respectively, and physical dependence was measured with the platform-jumping assay and recording of other withdrawal signs. We found that Tat(+) mice treated with DOX [Tat(+)/DOX] developed an increased tolerance in the tail-flick assay compared with control Tat(-)/DOX and/or C57/DOX mice. Equivalent tolerance was developed in all mice when assessed by locomotor activity. Further, Tat(+)/DOX mice expressed reduced levels of physical dependence to chronic morphine exposure after a 1-mg/kg naloxone challenge compared with control Tat(-)/DOX and/or C57/DOX mice. Assuming the results seen in Tat transgenic mice can be generalized to neuroAIDS, our findings suggest that HIV-1-infected individuals may display heightened analgesic tolerance to similar doses of opiates compared with uninfected individuals and show fewer symptoms of physical dependence.