Modulation of the brain aversive system by GABAergic and serotonergic mechanisms

Abstract

Experiments performed in our laboratory, using electrical stimulation combined with microinjection of drugs in the dorsal midbrain central grey (CG) of the rat, evidenced that direct stimulation of GABA receptors with locally administered gamma-aminobutyric acid (GABA) or the GABAA receptor agonists 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol, isoguvacine and muscimol raised the aversive threshold, defined as the lowest electrical current intensity inducing flight or escape behaviour when applied to the dorsal CG. The GABAB receptor agonist baclofen was ineffective. Also, enhancement of endogenous GABA action through local injection of the benzodiazepines chlordiazepoxide and midazolam or of pentobarbital resulted in anti-aversive effects. Ro 15-1788 antagonized both chlordiazepoxide and midazolam, suggesting benzodiazepine receptor mediation. In contrast to pro-GABAergic drugs, microinjection of the GABA antagonists bicuculline and picrotoxin into the CG elicited flight behaviour, like the electrical stimulation. Similar experiments with drugs influencing serotonergic neurotransmission evidenced that intra-CG microinjection of serotonin (5-HT) or of the direct 5-HT receptor agonist 5-methoxy-N,N-dimethyltryptamine increased the aversive threshold. The anti-aversive effect of 5-HT was potentiated by the selective inhibitor of 5-HT neuronal uptake, zimelidine. Also, the latter drug increased the aversive threshold when given alone. The anti-aversive effect of 5-HT was antagonized by local pretreatment with either metergoline or ketanserin, the latter being a selective blocker of 5-HT2 receptors. In contrast to the GABA antagonists mentioned above, the 5-HT receptor blockers did not evoke aversive behaviour per se. Therefore, both GABAergic and serotonergic mechanisms are likely to play an inhibitory role in the dorsal CG integrating aversive behaviour.(ABSTRACT TRUNCATED AT 250 WORDS)

Serotonergic Modulation of Prefrontal Cortex during Negative Feedback in Probabilistic Reversal Learning

“…Based on evidence for a role of 5-HT in the processing of aversive signals, as well as models of depression as an oversensitivity to negative feedback (Elliott et al, 1997;Steffens et al, 2001;Murphy et al, 2003;Graeff et al, 1986;Smith and Kennedy, 2003), we hypothesize that the increased BOLD signal in the dorsomedial PFC reflects enhanced processing of aversive signals (error feedback) leading to enhanced response conflict on both switch and nonswitch trials. Clearly, the task does not fully dissociate negative feedback, conflict and behavioral switching: negative feedback initiates conflict and subsequent reversal, and a probabilistic task places demands on inhibitory control to maintain responding after misleading feedback.…”

“…Serotonin (5-HT) has been extensively implicated in depressed mood and the processing of motivational signals (Graeff et al, 1986;Soubrie, 1986;Deakin, 1991;Wilkinson et al, 1995). Animal research has demonstrated that 5-HTenhancing drugs attenuate the aversive effects of brain stimulation (Patkina and Lapin, 1976;Graeff et al, 1986;Smith and Kennedy, 2003), and, conversely, potentiate selfstimulation in so-called 'reward' centers and enhance the motivational properties of stimuli predictive of rewards (Redgrave and Horrell, 1976;Aronson et al, 1995;SasakiAdams and Kelley, 2001;Orosco et al, 2004).…”

“…Animal research has demonstrated that 5-HTenhancing drugs attenuate the aversive effects of brain stimulation (Patkina and Lapin, 1976;Graeff et al, 1986;Smith and Kennedy, 2003), and, conversely, potentiate selfstimulation in so-called 'reward' centers and enhance the motivational properties of stimuli predictive of rewards (Redgrave and Horrell, 1976;Aronson et al, 1995;SasakiAdams and Kelley, 2001;Orosco et al, 2004). Reduced motivation (anhedonia, apathy) is a cardinal feature of depression, where neuropsychological studies have further emphasized the relevance of incentive motivation and the processing of reinforcement; depression has been associated with a 'catastrophic response to perceived failure' (Beats et al, 1996) or an oversensitivity to negative feedback (Elliott et al, 1997;Steffens et al, 2001;Murphy et al, 2003).…”

Serotonin Modulates Sensitivity to Reward and Negative Feedback in a Probabilistic Reversal Learning Task in Rats

“…Serotonin (5-hydroxytryptamine, 5-HT) has long been implicated in the pathophysiology of mood and anxiety disorders, and in the processing of affective stimuli (Deakin, 1991;Graeff et al, 1986). More specifically, central 5-HT has long been thought to have a critical role in the adaptation of the animals to aversive events (Deakin and Graeff, 1991) and, recently, to mediate a negative prediction error signal for future threat and punishment (Cools et al, 2008a;Daw et al, 2002).…”

Tryptophan Depletion Disrupts the Motivational Guidance of Goal-Directed Behavior as a Function of Trait Impulsivity

“…Serotonin (5-HT) has been extensively implicated in depressed mood and is well known to affect the motivational properties of stimuli predictive of rewards (Fletcher et al, 1999;Sasaki-Adams and Kelley, 2001;Deakin, 1983;Wilkinson et al, 1995;Graeff et al, 1986), probably through interaction with the mesolimbic dopamine (DA) system (Robbins et al, 1989;Robbins and Everitt, 2002). Treatment with selective serotonin reuptake inhibitors (SSRIs) dose dependently decreases brain self-stimulation thresholds (Harrison and Markou, 2001), while the reinforcing effects of cocaine, cocaine-associated stimuli, and other stimuli predictive of rewards are potentiated by SSRI treatment and, conversely, attenuated by central 5-HT depletion (Aronson et al, 1995;Sasaki-Adams and Kelley, 2001;Redgrave and Horrell, 1976).…”