Evidence for a vocal signature in the rat and its reinforcing effects: a key role for the subthalamic nucleus

Although rodents have a well-structured vocal form of communication, like humans and non-human primates, there is, to date, no evidence for a vocal signature in the well-known 50- and 22-kHz ultrasonic vocalizations (USVs) emitted by rats. Here, we show that rats can recognize the identity of the USV emitter since they choose to preferentially self-administer playback of 50-kHz USVs emitted by a stranger rat over those of their cagemate. In a second experiment, we show that only stranger, but not familiar, 50-kHz USVs reduce cocaine self-administration. Finally, to study the neurobiological substrate of these processes, we have shown that subthalamic nucleus (STN)-lesioned rats did not lever press much for any USV playback, whatever their emotional valence, nor did they seem able to differentiate familiar from stranger peer. Advocating for the existence of a vocal signature in rats, these results highlight the importance of ultrasonic communication in the socio-affective influence of behaviour, such as the influence of proximal social factors on drug consumption and confirm the role of the STN on this influence.

Assessment of the Reinforcing Properties of Orally Administered MDMA ('Ecstasy') in Rats

<p>The so-called “party drug” 3,4-Methylenedioxymethamphetamine (MDMA, or ecstasy) may share many of the addictive properties common to other CNS stimulants. In humans MDMA is primarily consumed orally in one more pills per session. However, animal research has mostly focused on examining the effects of MDMA as a function of other routes of administration. Route of administration can have profound effects on the subjective and reinforcing properties of drugs of abuse. This thesis assessed the locomotor-activating and reinforcing properties of MDMA when delivered orally. MDMA-induced hyperlocomotion was used to examine magnitude of response and onset of action as a function of ip, sc and oral administration. Significant route-dependant effects were found with ip producing higher locomotor activity than sc and oral respectively. Onset of action was slower for subcutaneous administration compared with both ip and oral administration. The reinforcing properties of MDMA were examined by use of the self-administration procedure. Oral MDMA self-administration was firstly examined using simple schedules of reinforcement as a function of two different vehicle substrates, water (under water deprivation) and saccharin. Oral MDMA maintained responding and reliable dose-response curves were obtained under both water and saccharin vehicle conditions. However, both saccharin and water vehicle conditions also acted as strong reinforcers in these studies. Further studies utilising a behavioural economic approach were conducted in order to delineate the reinforcing effects of MDMA from that of its parent vehicle. In addition, demand-curve analysis using both the Linear-Elasticity model (Hursh et al., 1988, 1989) and the Exponential Model of Demand (Hursh & Silberberg, 2008) were compared in order to evaluate each model and assess the relative reinforcing efficacy of oral MDMA. Demand curves for the oral self-administration of MDMA revealed that responding for MDMA was more elastic (lower Pmax) than responding for saccharin-alone indicating that saccharin functioned as stronger reinforcer than did MDMA+saccharin. The results of these studies provide evidence for the positive-reinforcing effects of MDMA when it is delivered via the oral route of administration, however, the relative reinforcing efficacy of orally delivered MDMA appears to be low.</p>

Assessment of the Reinforcing Properties of Orally Administered MDMA ('Ecstasy') in Rats

<p>The so-called “party drug” 3,4-Methylenedioxymethamphetamine (MDMA, or ecstasy) may share many of the addictive properties common to other CNS stimulants. In humans MDMA is primarily consumed orally in one more pills per session. However, animal research has mostly focused on examining the effects of MDMA as a function of other routes of administration. Route of administration can have profound effects on the subjective and reinforcing properties of drugs of abuse. This thesis assessed the locomotor-activating and reinforcing properties of MDMA when delivered orally. MDMA-induced hyperlocomotion was used to examine magnitude of response and onset of action as a function of ip, sc and oral administration. Significant route-dependant effects were found with ip producing higher locomotor activity than sc and oral respectively. Onset of action was slower for subcutaneous administration compared with both ip and oral administration. The reinforcing properties of MDMA were examined by use of the self-administration procedure. Oral MDMA self-administration was firstly examined using simple schedules of reinforcement as a function of two different vehicle substrates, water (under water deprivation) and saccharin. Oral MDMA maintained responding and reliable dose-response curves were obtained under both water and saccharin vehicle conditions. However, both saccharin and water vehicle conditions also acted as strong reinforcers in these studies. Further studies utilising a behavioural economic approach were conducted in order to delineate the reinforcing effects of MDMA from that of its parent vehicle. In addition, demand-curve analysis using both the Linear-Elasticity model (Hursh et al., 1988, 1989) and the Exponential Model of Demand (Hursh & Silberberg, 2008) were compared in order to evaluate each model and assess the relative reinforcing efficacy of oral MDMA. Demand curves for the oral self-administration of MDMA revealed that responding for MDMA was more elastic (lower Pmax) than responding for saccharin-alone indicating that saccharin functioned as stronger reinforcer than did MDMA+saccharin. The results of these studies provide evidence for the positive-reinforcing effects of MDMA when it is delivered via the oral route of administration, however, the relative reinforcing efficacy of orally delivered MDMA appears to be low.</p>

Reinforcing Effects of Ring Plates on a Detachable Spudcan Subjected to Eccentric Load

A detachable spudcan enables the operation of a jackup barge on any seabed. A general detachable spudcan uses a pin to connect the separate footing and leg. However, this type of structure can cause excessive stress on the pin. In this study, a new type of detachable spudcan reinforced with ring plates (upper and lower) is proposed to improve the structural performance of the conventional detachable spudcan. Finite element analysis revealed that the stress concentration in the connection part was relieved by reinforcing the lower and upper rings. In particular, reinforcing both lower and upper rings resulted in superior structural performance under eccentric supported conditions than when reinforcing only the lower ring. The structural strength of the spudcan when both the upper and lower rings were reinforced was found to be 120% of the spudcan as compared to when only the lower ring was reinforced. It is thought that the safety of the connection part can be secured when designing a detachable spudcan using the reinforcement plan verified in this study.

Study on the Reinforcing Effects of the FRP-PCM Method on Tunnel Linings for Dynamic Strengthening

In recent years, fiber-reinforced plastic (FRP) has been widely used in the reinforcement of concrete structure fields due to its favorable properties such as high strength, low weight, easy handling and application, and immunity to corrosion, and the reinforcing effects with FRP grids on tunnel linings should be quantitatively evaluated when the tunnels encounter an earthquake. The aim of the present study is to estimate the reinforcing effects of fiber-reinforced plastic (FRP) grids embedded in Polymer Cement Mortar (PCM) shotcrete (FRP-PCM method) on tunnel linings under the dynamic load. A series of numerical simulations were performed to analyze the reinforcing effects of FRP-PCM method quantitatively, taking into account the impacts of tunnel construction method and cavity location. The results showed that the failure region on lining concrete is improved obviously when the type CII ground is encountered, regardless the influences of construction method and cavity location. With the increment of ground class from CII to DII, the axial stress reduction rate R σ increases from 13.18% to 48.60% for tunnels constructed by the NATM, while for those tunnels constructed by the NATM, R σ merely varies from 0.72% to 2.11%. R σ decreases from 43.35% to 34.80% when a cavity exists on the shoulder of lining, while decreasing from 14.7% to 0.12% when a cavity exists on the crown of lining concrete. All those conclusions could provide valuable guidance for the reinforcing of underground structures.

Evidence of individual differences in motives for nicotine seeking in classical nicotine self-administration and associated outcomes of varenicline administration

Background Smokers vary in their motives for tobacco seeking, suggesting that they could benefit from personalized treatments. However, these variations have received little attention in animal models for the study of tobacco dependence. In the most classically used model, ie. intravenous self-administration of nicotine in the rat, seeking behaviour is reinforced by the combination of intravenous nicotine with a discrete stimulus (eg. discrete cue light). In both human and animals, two types of psychopharmacological interactions between nicotine and environmental stimuli have been evidenced. Whether these two types of interactions contribute equally to nicotine seeking in all individuals is unknown. Methods We combined behavioural pharmacology and clustering analysis. In an outbred male rat population, we tested whether nicotine and the discrete nicotine-associated cue light contributed equally to self-administration in all individuals. Two clusters of rats were identified, in which we further studied the nature of the psychopharmacological interaction between nicotine and the cue, as well as the response to the cessation aid varenicline when nicotine was withdrawn. Results Notably, withdrawing nicotine produced drastic opposed effects on seeking behavior in the two identified clusters of rats; a 50% increase vs a 18% decrease, respectively. The first cluster of rats sought for the primary reinforcing effects of nicotine and the discrete cue light that has gained nicotine-like secondary reinforcing properties. The second cluster sought nicotine for its ability to enhance the primary reinforcing effects of the discrete cue light. Critically, the approved cessation aid Varenicline counteracted the absence of nicotine in both, but eventually decreasing seeking in the former but increasing it in the latter. Conclusions Classical rodent models for the study of the reinforcing and addictive effects of nicotine hide individual variations in the psychopharmacological motives supporting seeking behavior. These variations may be a decisive asset for improving their predictive validity in the perspective of precision medicine for smoking cessation.

Dose Related Analgesic, Motor and Reinforcing Effects of Nalbuphine in Rats

Nalbuphine, a semi-synthetic opioid drug, is a kappa (κ) agonist/ mu (μ) partial agonist. It is clinically used for moderate to severe pain. It produces the analgesic effect largely by binding to kappa opioid receptors. The present study was designed to investigate locomotor sensitization as well reinforcing effects of different doses (5, 10 and 20 mg/kg) of nalbuphine in rats. Potential analgesic and hyperalgesic effects after single and repeated administration respectively were also monitored. Reinforcing effects were monitored in a conditioned place preference (CPP) paradigm and associated changes in motor activity were monitored during a drug conditioning phase. The hot plate test was used to monitor nociceptive response. The present study showed that low (5 mg/kg) and high (20 mg/kg) doses of nalbuphine were reinforcing, while the moderate dose (10 mg/kg) had no reinforcing effect in the CPP paradigm. All doses were analgesic after the first administration and on repeated administration hyperalgesia did not develop to any dose. Analgesic effects still occurred at moderate doses of nalbuphine. Sensitization-like effects were produced following moderate and high doses of nalbuphine. These findings suggested that a moderate dose of nalbuphine did not produce reinforcing effects and hyperalgesia so this dose can be used safely for treating pain.