Effects of D1 receptor knockout on fear and reward learning

Abstract

Dopamine signaling is involved in a variety of neurobiological processes that contribute to learning and memory. D1-like dopamine receptors (including D1 and D5 receptors) are thought to be involved in memory and reward processes, but pharmacological approaches have been limited in their ability to distinguish between D1 and D5 receptors. Here, we examine the effects of a specific knockout of D1 receptors in associative learning tasks involving aversive (shock) or appetitive (cocaine) unconditioned stimuli. We find that D1 knockout mice show similar levels of cued and contextual fear conditioning to WT controls following conditioning protocols involving one, two, or four shocks. D1 knockout mice show increased generalization of fear conditioning and extinction across contexts, revealed as increased freezing to a novel context following conditioning and decreased freezing to an extinguished cue during a contextual renewal test. Further, D1 knockout mice show mild enhancements in extinction following an injection of SKF81297, a D1/D5 receptor agonist, suggesting a role for D5 receptors in extinction enhancements induced by nonspecific pharmacological agonists. Finally, although D1 knockout mice show decreased locomotion induced by cocaine, they are able to form a cocaine-induced conditioned place preference. We discuss these findings in terms of the role of dopamine D1 receptors in general learning and memory processes.

The Neurobiology of Fear Generalization

“…For example, mice lacking the dopamine D1 receptor (D1R) in granule cells of the dentate gyrus and the striatum exhibit poor retention of contextual fear (Ikegami et al, 2014; Sarinana et al, 2014). However, studies examining the impact of global D1R deletion on contextual fear memory have yielded mixed results (Ortiz et al, 2010; Abraham et al, 2016), which may be explained by methodological differences as well as the possibility of recruitment of compensatory pathways. Importantly, with respect to generalization, mice lacking D1R in the dentate gyrus are unable to discriminate between the training context and a novel context after exposure to contextual fear conditioning (Sarinana et al, 2014), while a modest increase in contextual fear generalization is observed when D1R is globally deleted (Abraham et al, 2016).…”

“…However, studies examining the impact of global D1R deletion on contextual fear memory have yielded mixed results (Ortiz et al, 2010; Abraham et al, 2016), which may be explained by methodological differences as well as the possibility of recruitment of compensatory pathways. Importantly, with respect to generalization, mice lacking D1R in the dentate gyrus are unable to discriminate between the training context and a novel context after exposure to contextual fear conditioning (Sarinana et al, 2014), while a modest increase in contextual fear generalization is observed when D1R is globally deleted (Abraham et al, 2016). Finally, cued fear memory may or may not be affected by D1R deletion (Ortiz et al, 2010; Sarinana et al, 2014; Abraham et al, 2016), which may be attributed to methodological differences in the studies.…”

Developmental regulation of fear memories by an obesogenic high-saturated fat/high-sugar diet

“…Several lines of evidence show that dopamine D1 receptors expressed in the NAc, the PFC, hippocampus and the amygdala play a critical role in fear learning and fear extinction (Abraham et al, 2016a;2016b;Borowski and Kokkinidis, 1998;Fadok et al, 2009;Hikind and Maroun, 2008;J. J. Li et al, 2018;Ng et al, 2018).…”

Balance of Go1α and Go2α expression regulates motor function via the striatal dopaminergic system

“…However, CPP is also decreased in animals lacking D1R (Abraham et al . ). Results obtained with constitutive Go1+2α‐/‐ mice suggest that CPP requires Go1α to develop, probably using either D1R or D2R.…”

“…In this line, CPP is nearly abolished in D2R knock out animals (Welter et al 2007). However, CPP is also decreased in animals lacking D1R (Abraham et al 2016). Results obtained with constitutive Go1+2a-/-mice suggest that CPP requires Go1a to develop, probably using either D1R or D2R.…”