Efficacy and Pharmacokinetics Evaluation of a Single Oral Dose of Afoxolaner against Sarcoptes scabiei in the Porcine Scabies Model for Human Infestation.

Scabies is a major and potentially growing public health problem worldwide with an unmet need for acaricidal agents with greater efficacy and improved pharmacological properties for its treatment. The objective of the present study was to assess the efficacy and describe the pharmacokinetics profile of a novel acaricide, afoxolaner (AFX), in a relevant experimental porcine model. Twelve pigs were experimentally infested and either treated with 2.5 mg/kg single dose oral AFX (n = 4) or 0.2 mg/kg, two doses 8 days apart, oral ivermectin ([IVM] n = 4) or not treated for scabies (n = 4). The response to treatment was assessed by the reduction of mite counts in skin scrapings as well as clinical and pruritus scores over time. Plasma and skin pharmacokinetics profiles for both AFX and IVM were evaluated. AFX efficacy was 100% at days 8 and 14 posttreatment and remained unchanged until the study end (day 45). IVM efficacy was 86% and 97% on days 8 and 14, respectively, with a few mites recovered at the study end. Clinical and pruritus scores decreased in both treated groups and remained constant in the control group. Plasma mean residence times (MRT) were 7.1 ± 2.4 and 1.1 ± 0.2 days for AFX and IVM, respectively. Skin MRT values were 16.2 ± 16.9 and 2.7 ± 0.5 days for AFX and IVM, respectively. Overall, a single oral dose of AFX was efficacious for the treatment of scabies in experimentally infested pigs and showed remarkably long MRTs in plasma and, notably, in the skin.

The effects of energy-rich diets on discrimination reversal learning and on BDNF in the hippocampus and prefrontal cortex of the rat.

Male rats received normal chow or high-fat diets rich in dextrose (HFD) or sucrose (HFS). Half of the rats received 90-day unrestricted access to their diet prior to training, whereas the other half were food restricted throughout the study. We evaluated the effects of these dietary manipulations on discrimination and reversal performance and on post-training levels of brain-derived neurotrophic factor (BDNF) in the prefrontal cortex and the ventral and dorsal hippocampus. Neither diet nor restriction condition affected discrimination acquisition. However, prior unrestricted access to the HFD diet impaired discrimination reversal learning and reduced BDNF in the prefrontal cortex and ventral hippocampus. Also, rats given the HFD diet responded more than controls to the previously rewarded cue at the outset of discrimination reversal. The results suggest that consumption of the HFD diet may have had enduring effects on learning processes, some of which may contribute to the control of intake regulation.

Repeated quinpirole treatments produce neurochemical sensitization and associated behavioral changes in female hamsters.

RATIONALE: Repeated stimulation of dopaminergic pathways with dopamine receptor agonists can produce both neurochemical and behavioral sensitization. OBJECTIVES: The present study was designed to examine whether repeated treatment with the D2-like dopamine receptor agonist, quinpirole, would produce neurochemical sensitization of D1 dopamine receptor-mediated processes and associated behavioral changes in female hamsters in a manner analogous to that previously used to sensitize heterologous dopamine signaling pathways in derived cell lines. MATERIALS AND METHODS: Female hamsters received two injections of quinpirole (1.5 mg/kg) or saline each week for 7 weeks, during which time pouching behavior and body weight were monitored. Over the next 2 weeks, hamsters were tested for differences in prepulse inhibition of the acoustic startle response (PPI) and sexual behavior. Adenylate cyclase activation assays were then performed on dissected tissue from the nucleus accumbens and caudate-putamen. RESULTS: Repeated treatment with quinpirole increased pouching behavior and body weight and disrupted PPI. No changes in sexual activity in response to repeated quinpirole were found. Prior quinpirole treatment enhanced D1 dopamine receptor-stimulated adenylate cyclase activity in the caudate-putamen that was blocked by co-incubation with the D1 dopamine antagonist, SCH23390. CONCLUSIONS: These results show that repeated activation of D2-like receptors in vivo can produce changes in feeding behavior and sensory processing that is associated with sensitization of D1 dopamine receptor-mediated signaling in the caudate-putamen.

Sexual experience in female rodents: cellular mechanisms and functional consequences.

The neurobiology of female sexual behavior has largely focused on mechanisms of hormone action on nerve cells and how these effects translate into the display of copulatory motor patterns. Of equal importance, though less studied, are some of the consequences of engaging in sexual behavior, including the rewarding properties of sexual interactions and how sexual experience alters copulatory efficiency. This review summarizes the effects of sexual experience on reward processes and copulation in female Syrian hamsters. Neural correlates of these sexual interactions include long-term cellular changes in dopamine transmission and postsynaptic signaling pathways related to neuronal plasticity (e.g., dendritic spine formation). Taken together, these studies suggest that sexual experience enhances the reinforcing properties of sexual behavior, which has the coincident outcome of increasing copulatory efficiency in a way that can increase reproductive success.

Sexual experience alters D1 receptor-mediated cyclic AMP production in the nucleus accumbens of female Syrian hamsters.

Drugs of abuse produce long-term changes in dopamine neurotransmission and receptor-effected intracellular signaling. Similar changes in neuronal activity are mediated by motivated behaviors. To explore cellular mechanisms underlying these neuroadaptations following sexual experience, cyclic AMP accumulation following stimulation of D1 dopamine receptors, G-proteins, and adenylate cyclase was compared in the nucleus accumbens and caudate nucleus of sexually naive and experienced female hamsters following sexual behavior. Direct stimulation of adenylate cyclase with forskolin or indirectly by activation of G-proteins with Gpp(NH)p produced dose-dependent increases in the formation of cyclic AMP in the nucleus accumbens and caudate nucleus, with no effects of sexual experience on these measures. Specific D1 receptor stimulation increased Gpp(NH)p-induced adenylate cyclase activity in the nucleus accumbens and caudate nucleus of all animals. Interestingly, this stimulation was further enhanced only in membranes from the nucleus accumbens, but not from the caudate nucleus, of sexually experienced hamsters compared to the response of naive females. These results demonstrate that sexual behavior experience can sensitize mesolimbic dopamine pathways and that this sensitization occurs through an increase in D1 receptor-mediated signaling.