Individual differences in social play behaviour predict alcohol intake and control over alcohol seeking in rats

Rationale Social play behaviour is a rewarding social activity displayed by young mammals, thought to be important for the development of brain and behaviour. Indeed, disruptions of social play behaviour in rodents have been associated with cognitive deficits and augmented sensitivity to self-administration of substances of abuse, including alcohol, later in life. However, the relation between social development and loss of control over substance use, a key characteristic of substance use disorders including alcohol use disorder (AUD), has not been investigated. Moreover, it remains unknown how inherent differences in playfulness relate to differences in the sensitivity to substance use and AUD. Objective The objective of this study is to determine how individual differences in juvenile social play behaviour predict alcohol intake and loss of control over alcohol seeking. Methods Juvenile male Lister hooded rats were characterized for their tendency to engage in social play behaviour. Subsequently, alcohol consumption and conditioned suppression of alcohol seeking were assessed in the tertiles of rats that showed the most and least social play. Results The rats that engaged most in social play behaviour consumed more alcohol than their less playful counterparts. However, whereas the most playful rats showed intact conditioned suppression of alcohol seeking, the least playful rats showed no such suppression. Conclusion Individual levels of playfulness predict the sensitivity to alcohol-directed behaviour. Highly playful rats are more prone to alcohol intake, yet show greater control over alcohol seeking. These findings increase our understanding of the relationship between social development and vulnerability to AUD.

Elevated fear responses to threatening cues in rats with early life stress is associated with greater excitability and loss of gamma oscillations in ventral-medial prefrontal cortex

Stress experienced early in development can have profound influences on developmental trajectories and ultimately behaviors in adulthood. Potent stressors during brain maturation can profoundly disrupt prefrontal cortical areas in particular, which can set the stage for prefrontal-dependent alterations in fear regulation and risk of drug abuse in adulthood. Despite these observations, few studies have investigated in vivo signaling in prefrontal signals in animals with a history of early life stress (ELS). Here, rats with ELS experience on PND3-5 were then tested on a conditioned suppression paradigm during adulthood. During conditioned suppression, electrophysiological recordings were made in the ventral medial prefrontal cortex (vmPFC) during presentations of a fear-associated cues that resolved both single-unit activity and local field potentials (LFPs). Relative to unstressed controls, ELS-experienced rats showed greater fear-related suppression of lever pressing. During presentations of the fear-associated cue (CS+), neurons in the vmPFC of ELS animals showed a significant increase in the probability of excitatory encoding relative to controls, and excitatory phasic responses in the ELS animals were reliably of higher magnitude than Controls. In contrast, vmPFC neurons in ELS subjects better discriminated between the shock-associated CS+ and the neutral ("safe") CS- cue than Controls. LFPs recorded in the same locations revealed that high gamma band (65-95 Hz) oscillations were strongly potentiated in Controls during presentation of the fear-associated CS+ cue, but this potentiation was abolished in ELS subjects. Notably, no other LFP spectra differed between ELS and Controls for either the CS+ or CS-. Collectively, these data suggest that ELS experience alters the neurobehavioral functions of PFC in adulthood that are critical for processing fear regulation. As such, these alterations may also provide insight into to increased susceptibility to other PFC-dependent processes such as risk-based choice, motivation, and regulation of drug use and relapse in ELS populations.

In search of the behavioural effects of fear: a paradigm to assess conditioned suppression in humans

Conditioned fear can substantially reduce the likelihood that an individual will engage in reward- related behaviour - a phenomenon coined conditioned suppression. Despite the unmistakable relevance of conditioned suppression for excessive fears and their adverse consequences, the phenomenon has primarily been observed in animal models and is not yet well understood. Here, we aimed to develop a conditioned suppression paradigm that enables a robust quantification of the effect of Pavlovian aversive stimuli on subsequent reward-related behaviour in humans and assess its potential relation to physiological measures of fear. In phase 1, an instrumental response was incentivized with monetary rewards. In phase 2, one of two conditioned stimuli (CS+) was reinforced with an aversive unconditioned stimulus (US, i.e., electric stimulus). During aversive Pavlovian learning we assessed differential skin conductance (SCR) and fear potentiated startle responses (FPS). Lastly, we tested the effect of the aversively conditioned CS+ on the response rate of the instrumental response in a transfer phase. Despite strong aversive Pavlovian conditioning, as indicated by large effect sizes in differential SCR and FPS, we did not find any evidence for conditioned suppression: i.e., there was no significant reduction of instrumental responding in the presence of the CS+ compared to a new control stimulus. This lack of conditioned suppression is in line with previous studies that reported difficulties inducing conditioned suppression and points towards a general challenge in investigating conditioned suppression in humans. Implications and directions for future research on the highly relevant behavioural effects of fear and anxiety are discussed.

EMD386088 (5 mg/kg) has no effect on latent inhibition shown to both light and noise stimuli

Activation of 5-hydroxytyptamine6 (5-HT6) receptors stimulates attentional switching and 5-HT6 receptor antagonists are putative drugs for psychosis. Latent inhibition (LI) provides a pre-clinical model of attentional switching and ‘antipsychotic-like’ action and is known to be modulated by 5-hydroxytyptamine. In the present study, LI was shown in a fear conditioning procedure that measured suppression of drinking after conditioning with footshock. In two experiments (each n = 48) it was shown that pre-exposure to both light- and noise-conditioned stimuli reduced conditioned suppression relative to the corresponding non-pre-exposed control. However, counter to prediction, LI was intact after treatment with the 5-HT6 agonist EMD386088 (5 mg/kg).