A Role for Serotonin in Modulating Opposing Drive and Brake Circuits of Impulsivity.

Impulsivity generally refers to a deficit in inhibition, with a focus on understanding the neural circuits which constitute the "brake" on actions and gratification. It is likely that increased impulsivity can arise not only from reduced inhibition, but also from a heightened or exaggerated excitatory "drive." For example, an action which has more vigor, or is fueled by either increased incentive salience or a stronger action-outcome association, may be harder to inhibit. From this perspective, this review focuses on impulse control as a competition over behavioral output between an initially learned response-reward outcome association, and a subsequently acquired opposing inhibitory association. Our goal is to present a synthesis of research from humans and animal models that supports this dual-systems approach to understanding the behavioral and neural substrates that contribute to impulsivity, with a focus on the neuromodulatory role of serotonin. We review evidence for the role of serotonin signaling in mediating the balance of the "drive" and "brake" circuits. Additionally, we consider parallels of these competing instrumental systems in impulsivity within classical conditioning processes (e.g., extinction) in order to point us to potential behavioral and neural mechanisms that may modulate the competing instrumental associations. Finally, we consider how the balance of these competing associations might contribute to, or be extracted from, our experimental assessments of impulsivity. A careful understanding of the underlying behavioral and circuit level contributions to impulsivity is important for understanding the pathogenesis of increased impulsivity present in a number of psychiatric disorders. Pathological levels of impulsivity in such disorders are likely subserved by deficits in the balance of motivational and inhibitory processes.

Prelimbic prefrontal cortical encoding of reward predictive cues.

Animals appoint incentive value and learn to approach otherwise behaviorally inert stimuli if these stimuli come to predict the delivery of reward. Interestingly, this adaptive Pavlovian learning process has been implicated in behavioral control disorders, such as drug addiction. One brain region implicated in directing conditioned approach behavior is the prelimbic region of the prefrontal cortex. The present study employed in vivo electrophysiology in the prelimbic cortex to characterize the distribution of neural responses to the presence of a cue that had acquired incentive value after being associated with a primary reward. Male rats were trained in a Pavlovian autoshaping task in which a lever was presented prior to reward delivery. Following repeated pairings of lever availability and reward delivery, rats pressed the lever even though reward delivery was not contingent on any interaction with the lever. Neurons in the prelimbic cortex selectively encoded the presentation of the reward-predicting lever. Although the response was heterogeneous, most responsive neurons decreased their firing rate in response to the presence of the lever. These findings characterize the varied responses of prelimbic cortical neurons to reward cues and are consistent with evidence that the role of the prelimbic cortex in reward learning depends on the downstream target.

Chronic Stress Prevents Cortico-Accumbens Cue Encoding and Alters Conditioned Approach.

Chronic stress impairs the function of multiple brain regions and causes severe hedonic and motivational deficits. One brain region known to be susceptible to these effects is the PFC. Neurons in this region, specifically neuronal projections from the prelimbic region (PL) to the nucleus accumbens core (NAcC), have a significant role in promoting motivated approach. However, little is known about how activity in this pathway changes during associative learning to encode cues that promote approach. Less is known about how activity in this pathway may be altered by stress. In this study, an intersectional fiber photometry approach was used in male Sprague Dawley rats engaged in a Pavlovian autoshaping design to characterize the involvement of the PL-NAcC pathway in the typical acquisition of learned approach (directed at both the predictive cue and the goal), and its potential alteration by stress. Specifically, the hypothesis that neural activity in PL-NAcC would encode a Pavlovian approach cue and that prior exposure to chronic stress would disrupt both the nature of conditioned approach and the encoding of a cue that promotes approach was tested. Results of the study demonstrated that the rapid acquisition of conditioned approach was associated with cue-induced PL-NAcC activity. Prior stress both reduced cue-directed behavior and impaired the associated cortical activity. These findings demonstrate that prior stress diminishes the task-related activity of a brain pathway that regulates approach behavior. In addition, the results support the interpretation that stress disrupts reward processing by altering the incentive value of associated cues.SIGNIFICANCE STATEMENT Chronic stress causes hedonic and motivational deficits and disrupts the function of the PFC. A specific projection from the prelimbic region of the PFC to the nucleus accumbens core (PL-NAcC) promotes approach behavior and is a strong candidate for contributing to stress-induced disruptions in motivation. However, it is not known how activity in this pathway encodes cues that promote approach, and how this encoding may be altered by stress. Here we show that the rapid acquisition of conditioned approach is associated with cue-induced activity in the PL-NAcC pathway. Prior stress both reduces cue-directed behavior and impairs the associated cortical activity. These findings demonstrate that stress diminishes task-related activity in a brain pathway that regulates approach behavior.

Assessing the role of serotonergic receptors in cannabidiol's anticonvulsant efficacy.

Cannabidiol (CBD) is a phytocannabinoid that has demonstrated anticonvulsant efficacy in several animal models of seizure. The current experiment validated CBD's anticonvulsant effect using the acute pentylenetetrazol (PTZ) model. Furthermore, it tested whether CBD reduces seizure activity by interacting with either the serotonergic 5HT1A or 5HT2A receptor. 120 male adolescent Wistar-Kyoto rats were randomly assigned to 8 treatment groups in two consecutive experiments. In both experiments, subjects received either CBD (100mg/kg) or vehicle 60min prior to seizure testing. In Experiment 1, subjects received either WAY-100635 (1mg/kg), a 5HT1A antagonist, or saline vehicle injection 80min prior to seizure testing. In Experiment 2, subjects received either MDL-100907 (0.3mg/kg), a specific 5HT2A antagonist, or 40% DMSO vehicle 80min prior to seizure testing. 85mg/kg of PTZ was administered to induce seizure, and behavior was recorded for 30min. Seizure behaviors were subsequently coded using a 5-point scale of severity. Across both experiments, subjects in the vehicle control groups exhibited high levels of seizure activity and mortality. In both experiments, CBD treatment significantly attenuated seizure activity. Pre-treatment with either WAY-100635 or MDL-100907 did not block CBD's anticonvulsant effect. WAY-100635 administration, by itself, also led to a significant attenuation of seizure activity. These results do not support the hypothesis that CBD attenuates seizure activity through activation of the 5HT1A or 5HT2A receptor. While this work further confirms the anticonvulsant efficacy of CBD and supports its application in the treatment of human seizure disorders, additional research on CBD's mechanism of action must be conducted.

The effects of adolescent cannabinoid exposure on seizure susceptibility and lethality in adult male rats.

There is substantial evidence in rodent models that chronic exposure to cannabinoids during adolescence can alter the development of neurobiological systems that are implicated in regulating brain activity and seizure. The current study explored whether adolescent cannabinoid treatment affects subsequent, adult seizure susceptibility. Sixty male Wistar Kyoto rats were treated with either the synthetic cannabinoid, CP 55,940 (0.4mg/kg, one treatment per day), or vehicle between 35 and 45days old. Subjects were then allowed to mature to adulthood. At 68-69days of age, subjects were tested for seizure susceptibility using the pro-convulsant, pentylenetetrazol (PTZ). Subjects received an acute injection of either 35mg/kg or 50mg/kg PTZ immediately prior to a 30-min behavioral seizure test. PTZ doses were chosen to produce low-to-moderate levels of seizure activity in control subjects. There were no significant differences between treated and control subjects in: latency to first seizure, mean seizure severity, percentage who displayed any seizure activity, percentage who displayed clonic seizure, or percentage who displayed tonic-clonic seizure. However, CP 55,940-treated subjects had a higher mortality rate compared to controls at both PTZ doses, suggesting that adolescent cannabinoid exposure may increase the lethality of severe seizures experienced in adulthood.