Dopamine and extinction: A convergence of theory with fear and reward circuitry

Abstract

Research on dopamine lies at the intersection of sophisticated theoretical and neurobiological approaches to learning and memory. Dopamine has been shown to be critical for many processes that drive learning and memory, including motivation, prediction error, incentive salience, memory consolidation, and response output. Theories of dopamine’s function in these processes have, for the most part, been developed from behavioral approaches that examine learning mechanisms in reward-related tasks. A parallel and growing literature indicates that dopamine is involved in fear conditioning and extinction. These studies are consistent with long-standing ideas about appetitive-aversive interactions in learning theory and they speak to the general nature of cellular and molecular processes that underlie behavior. We review the behavioral and neurobiological literature showing a role for dopamine in fear conditioning and extinction. At a cellular level, we review dopamine signaling and receptor pharmacology, cellular and molecular events that follow dopamine receptor activation, and brain systems in which dopamine functions. At a behavioral level, we describe theories of learning and dopamine function that could describe the fundamental rules underlying how dopamine modulates different aspects of learning and memory processes.

Activation of D1/5 Dopamine Receptors: A Common Mechanism for Enhancing Extinction of Fear and Reward-Seeking Behaviors

“…There are many possibilities for this, including consolidation of the prediction error that occurred in extinction (Abraham et al, 2014), a D1-mediated prolonged window of inhibitory memory activity (Wagner, 1981), or counterconditioning of aversive fear memory by the rewarding properties of SKF81297 (Holmes and Westbrook, 2014). Our findings that SKF81297 induced a CPP when it was used as the US suggest that counterconditioning is a possibility for the enhanced fear extinction effects, and previous studies have shown that fear learning is subject to opponent interactions between appetitive and aversive processes (Nasser and McNally, 2012).…”

Effects of post-extinction l-DOPA administration on the spontaneous recovery and reinstatement of fear in a human fMRI study

“…There is increasing evidence that the long-term consolidation of extinction memories involves dopaminergic signalling (Abraham et al, 2014(Abraham et al, , 2012Haaker et al, 2013a;Holtzman-Assif et al, 2010;Mueller et al, 2010;Singewald et al, 2015). We have found in mice that systemic administration of the dopamine precursor L-DOPA immediately after extinction learning (i.e., during memory consolidation) prevents the ROF that normally occurs upon CS re-confrontation in a spatial context that is different from the extinction context (renewal), after a mere passage of time (spontaneous recovery), or after prior re-confrontation with the US (reinstatement) (Haaker et al, 2013a).…”

Facilitation of fear extinction by novelty depends on dopamine acting on D1-subtype dopamine receptors in hippocampus

“…The timehonored D1-family antagonist SCH23390 (SCH) does not discriminate between D1 and D5 receptors, and drugs acting on enzymes downstream of them have to be used to see if a given effect blocked by this drug is due to one or the other (29). It has been recently found to control the enhancing effect of novelty on spatial alimentary conditioning and its accompanying LTP, which was also attributed to a tagging-and-capture mechanism (35).D1 and D5 dopamine receptors are expressed in the CA1 region of the hippocampus and play a role in hippocampal neuroplasticity and memory, but they can have different roles in different tasks and situations (28,32,33,36). Also, both PKA and PKC participate in the modulation of hippocampal synaptic plasticity and memory consolidation (6).…”

“…Discrimination between the two types of D1-family receptors is possible by the simultaneous administration of drugs acting on PKA and PKC (29). Both D1-family receptor types are expressed in brain regions important for learning and memory, such as the hippocampus and amygdala (30, 31), and affect learning and memory (29,(32)(33)(34). The timehonored D1-family antagonist SCH23390 (SCH) does not discriminate between D1 and D5 receptors, and drugs acting on enzymes downstream of them have to be used to see if a given effect blocked by this drug is due to one or the other (29).…”

“…D1 and D5 dopamine receptors are expressed in the CA1 region of the hippocampus and play a role in hippocampal neuroplasticity and memory, but they can have different roles in different tasks and situations (28,32,33,36). Also, both PKA and PKC participate in the modulation of hippocampal synaptic plasticity and memory consolidation (6).…”