Prazosin differentially affects extinction of cocaine conditioned place preference on the basis of dose and initial preference

Abstract

Recent work has demonstrated that α1-adrenergic receptor blockade impairs extinction in fear conditioning paradigms in rodents. However, studies of the role of α1-adrenergic receptors in extinction using other conditioning paradigms, such as those examining the conditioned effects of drug of abuse, have provided inconsistent results. In this article, we reanalyze and extend previously-reported findings of the effect of prazosin, an α1-adrenergic receptor antagonist, on the extinction of a cocaine-induced condition place preference in rats, using a median split of performance during the initial test for preference. This new reanalysis, which includes further extinction testing, revealed a paradoxical dose effect. A single post-test administration of a lower dose of prazosin, 0.3 mg/kg IP, impaired extinction in rats that demonstrated a below-median preference during initial testing, but had no effect on extinction in rats that demonstrated an above-median preference during initial testing. In contrast, a single post-test administration of a higher dose of prazosin, 1.0 mg/kg IP, enhanced extinction in rats that demonstrated an above-median preference during initial testing, but had no effect on extinction in rats that demonstrated a below-median preference during initial testing. Consistent with other studies of fear and drug conditioning, these results suggest the involvement of the α1-adrenergic receptor in the formation of extinction memories, but also indicate a potentially important differential effect on extinction based on the dose of prazosin and the strength of the initial learning.

Evaluation of multitarget drugs on the expression of cocaine-induced locomotor sensitization in male rats: A comparative study

“…Regarding cocaine locomotor sensitization, our results show that the administration of MIR, PIN, FLX, RIS, TRZ, ZPR, OND, or PRZ in the previously described dose ranges generated a significant attenuation of cocaine locomotor sensitization. The results are consistent with previous results, which showed that, at the dose mentioned above, MIR [ 50 , 53 ], FLX [ 71 , 74 ], RIS [ 56 ], ZPR [ 75 , 76 ], OND [ 64 , 77 ], and PRZ [ [78] , [79] , [80] ] reduce hyperactivity induced by COC; decrease cocaine self-administration and attenuate the induction and expression of cocaine sensitization.…”

α1-Adrenergic Receptors in Neurotransmission, Synaptic Plasticity, and Cognition

“…α 1A -AR subtype activation stimulates GABA-mediated miniature inhibitory postsynaptic currents in the BLA ( Braga et al., 2004 ), suggesting that α 1A -ARs may regulate fear conditioning. Fear conditioning promoted the excitability of the BLA by decreasing GABAergic inhibition through α 1 -ARs ( Skelly et al., 2017 ) suggesting that blockage of α 1 -ARs may promote fear conditioned memory in the BLA ( Lazzaro et al., 2010 ; Bernardi and Lattal, 2012 ) and in the prefrontal cortex which impaired conditioned fear extinction after injection of the α 1 -AR antagonist prazosin ( Do-Monte et al., 2010 ). A subsequent study indicated that there was no effect of prazosin on the accrual of fear memory or retrieval but fear that was already established during prazosin treatment was more readily extinguished due to effects on the initial learning phase of the trauma ( Lucas et al., 2019 ).…”

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

“…The trend for decreased preference in SKF 81297-treated mice during the Post-Extinction test led us to examine whether initial preference influenced the effect of SKF 81297 on extinction (Weber et al, 2007;Bernardi and Lattal, 2012;Gruene et al, 2015). To assess high or low cocaine preference, a median preference value was calculated from all subjects (48 animals) during the Pre-Ext Test, which occurred prior to delivery of SKF 81297.…”