Neuropharmacological Mechanisms of Enhancement of Memory Consolidation by Nicotine, Cocaine, Heroin, and their Conditioned Stimuli

Wolter, Michael
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University of Guelph

There is recent evidence that cocaine, nicotine, and their conditioned stimuli have the ability to enhance memory consolidation tested in object recognition. The present study compared the effects of post-training heroin and of a heroin contextual conditioned stimulus (CS+) on object recognition memory and investigated the roles of opioid and beta-adrenergic receptors in heroin/CS+ memory modulation by co-administering the respective antagonists, naltrexone (NTX) and propranolol (PRO). Three experiments were performed in male Sprague-Dawley rats demonstrating that immediate, but not delayed, post-sample exposure to heroin (0.3, 1 mg/kg), or exposure (30 min) to a contextual CS+ paired with 1 mg/kg heroin (5 pairings, each 120 min), equally enhanced object memory. Importantly, while the memory enhancing effects of 1 mg/kg heroin and of the contextual CS+ were not altered by post-training co-administration of 3 mg/kg naltrexone, they were blocked by post-training co-administration of 10 mg/kg propranolol. Taken together, these data suggest that a context paired with heroin shares the memory enhancing effect of heroin itself and that these unconditioned and conditioned drug stimuli may modulate memory through the activation of beta-noradrenergic receptors. To test the hypothesis that drugs of abuse and their conditioned stimuli (CSs) enhance memory consolidation, the effects of post-training exposure to cocaine and nicotine were compared to the effects of post-training exposure to contextual stimuli that were paired with the effects of these drugs. Using the object recognition (OR) task, it was first demonstrated that both 10 and 20 mg/kg cocaine, and 0.2 and 0.4 mg/kg nicotine, enhanced recognition memory when administered immediately after, but not 6 h after the sample phase. To establish the drug CSs, rats were confined for 2 h in a chamber (the CS+) after injections of 20 mg/kg cocaine, or 0.4 mg/kg nicotine, and in another chamber (the CS−) after injections of vehicle. This was repeated over 10 d (5 drug/CS+ and 5 vehicle/CS− pairings in total). At the end of this conditioning period, when tested in a drug-free state, rats displayed conditioned hyperactivity in the CS+ relative to the CS−. More important, immediate, but not delayed, post-sample exposure to the cocaine CS+, or nicotine CS+, enhanced OR memory. Therefore, this study reports for the first time that contextual stimuli paired with cocaine and nicotine, like the drugs themselves, have the ability to enhance memory consolidation. Background: There is evidence that post-training exposure to nicotine, cocaine, and their conditioned stimuli (CS), enhance memory consolidation in rats. The present study assessed the effects of blocking noradrenergic and dopaminergic receptors on nicotine and cocaine unconditioned and conditioned memory modulation. Methods: Male Sprague-Dawley rats tested on the spontaneous object recognition task received post-sample exposure to 0.4 mg/kg nicotine, 20 mg/kg cocaine, or their CSs, in combination with 5 -10 mg/kg propranolol (PRO; beta-adrenergic antagonist), or 0.2 - 0.6 mg/kg pimozide (PIM; dopamine D2 receptor antagonist). The CSs were established by confining rats in a chamber (the CS+) after injections of 0.4 mg/kg nicotine, or 20 mg/kg cocaine, for 2 hr and in another chamber (the CS-) after injections of vehicle, repeated over 10 days (5 drug/CS+ and 5 vehicle/CS- pairings in total). Object memory was tested 72h post sample in drug-free animals. Results: Co-administration of PRO or PIM blocked the memory enhancing effects of post-training injections of nicotine, cocaine and, importantly, exposure to their CSs. Conclusions: These data suggest that nicotine, cocaine as well as their conditioned stimuli share actions on overlapping noradrenergic and dopaminergic systems to modulate memory consolidation.

Cocaine, Nicotine, Memory consolidation, Object recognition, Conditioned stimuli
Wolter M, Huff AE, Baidoo N, Jardine KH, Pulles Z, Winters BD, Leri F (2020) Modulation of object memory consolidation by heroin and heroin-conditioned stimuli: Role of opioid and noradrenergic systems. Eur Neuropsychopharmacol 33:146�??157.
Wolter M, Huff E, Speigel T, Winters BD, Leri F (2019) Cocaine, nicotine, and their conditioned contexts enhance consolidation of object memory in rats. Learn Mem 26:46�??55 DOI: 10.1101/lm.048579.118
Wolter M, Lapointe T, Melanson B, Baidoo N, Francis T, Winters BD, Leri F (2021) Memory enhancing effects of nicotine, cocaine, and their conditioned stimuli
effects of beta-adrenergic and dopamine D2 receptor antagonists. Psychopharmacology (Berl) 238:2617-2628.