Cocaine and Pavlovian fear conditioning: Dose–effect analysis

Abstract

Emerging evidence suggests that cocaine and other drugs of abuse can interfere with many aspects of cognitive functioning. The authors examined the effects of 0.1 -15 mg/kg of cocaine on Pavlovian contextual and cued fear conditioning in mice. As expected, pre-training cocaine dose-dependently produced hyperactivity and disrupted freezing. Surprisingly, when the mice were tested off-drug later, the group pre-treated with a moderate dose of cocaine (15 mg/kg) displayed significantly less contextual and cued memory, compared to saline control animals. Conversely, mice pre-treated with a very low dose of cocaine (0.1 mg/kg) showed significantly enhanced fear memory for both context and tone, compared to controls. These results were not due to cocaine's anesthetic effects, as shock reactivity was unaffected by cocaine. The data suggest that despite cocaine's reputation as a performance-enhancing and anxiogenic drug, this effect is seen only at very low doses, whereas a moderate dose disrupts hippocampus and amygdala-dependent fear conditioning. KeywordsHippocampus; Amygdala; Freezing; Memory A growing body of evidence supports the view that drugs of abuse interfere with many aspects of cognitive functioning. For example, cocaine use has been linked to deficits in such cognitive areas as attention, cognitive flexibility, and short-term and working memory [34,43]. However, these findings in humans are controversial as cocaine use is naturally confounded with many other variables [e.g. 23, 27, 31]. Some studies, in fact, provide evidence for enhancement of certain cognitive abilities in cocaine users [e.g. 27, 50]. Relatively few studies in animals have examined the effects of cocaine on learning outside of the realm of addiction (e.g. selfadministration, place preference, sensitization). Indeed, several studies have focused on the mechanisms underlying addiction, including structural plasticity [see 41 for review], but few have examined the acute, behavioral effects of cocaine in rodents on simple learning and memory paradigms. We believe that most researchers implicitly assume, as we once did, that cocaine, as a psychostimulant, would naturally enhance learning and memory. However, evidence now exists linking cocaine use with specific cognitive deficits [5,25,34,43] as well as with general problems such as unemployment [35]. Moreover, a view has emerged that addictive drugs such as cocaine may work by taking control of critical reinforcement-related learning and memory circuits in the brain [28]. If cocaine modulates such circuits, then it may 1 Address correspondence and reprint requests to: Suzanne C. Wood,

Memory and psychostimulants: modulation of Pavlovian fear conditioning by amphetamine in C57BL/6 mice

“…One difference in the results of the present study and our previous research with cocaine (Wood et al 2007) is that a range of low doses of amphetamine studied did not enhance contextual fear 24 h after training. It is unclear if the memory enhancement provided by a low dose of amphetamine is specific to cued fear, because immediate fear memory is believed to be a form of contextual fear (Fanselow 1986).…”

“…As expected, moderate doses of amphetamine administered pre-training inhibited contextual and cued fear memory, off-drug, while very low doses enhanced immediate and cued fear memory. These data are in agreement with the results of our previous work with cocaine, which induced a similar pattern of enhancements and deficits in memory (Wood et al 2007). A low dose of cocaine (0.1 mg/kg) produced an enhancement in immediate, contextual and cued fear, whereas a high dose (15 mg/kg) produced an impairment in all three measures.…”

“…A fear conditioning experiment analyzing the effects of caffeine in rats found a selective disruption of context memory (Corodimas et al 2000), suggesting hippocampal-specific deficits. However, cocaine produced enhancements (at low doses) and deficits (at high doses) that were not specific to context or tone fear memory (Wood et al 2007). …”

“…As with cocaine, several possible reasons exist as to why conditioning was inhibited (Wood et al 2007). While amphetamine does not have anesthetic properties, it could have induced a positive hedonic state in the mice.…”

“…We previously found (Wood et al 2007) that an acute dose of cocaine enhances learning on Pavlovian fear conditioning when given at a very low dose (0.1 mg/kg). Interestingly, we also found that a moderate dose of cocaine (15 mg/kg) produced a significant anterograde amnesia of fear conditioning.…”