The reinforcing effects of chronic D-amphetamine and morphine are impaired in a line of memory-deficient mice overexpressing calcineurin

Abstract

It has recently emerged that there is a commonality in the molecular mechanisms underlying long-term neuronal changes in drug addiction and those mediating synaptic plasticity associated with learning and memory. In the hippocampus, the calcium-calmodulin-dependent protein phosphatase calcineurin plays a pivotal role in the molecular mechanisms that underlie learning and memory functions. Transgenic mice that express an active form of calcineurin specifically in forebrain structures have previously been shown to have a deficit in the transition from short- to long-term memory. Here, we investigated the involvement of calcineurin in the motivational effects of amphetamine and morphine using this line of transgenic mice (CN98). Our results showed that amphetamine and morphine did not induce conditioned place preference in calcineurin-mutant mice, whereas food remained an efficient reinforcer. In addition, behavioural sensitization to these two drugs, as measured by horizontal locomotion, was disturbed in the transgenic mice. In contrast, neither the horizontal locomotion in response to acute D-amphetamine or morphine nor the somatic signs of morphine withdrawal were affected in calcineurin mutant mice compared to their wild-type littermates. Our data indicate that calcineurin-mediated protein dephosphorylation in the hippocampus is involved in the long-term effects of drugs of abuse without influencing the motivational response to a natural reward or the physical component of opioid withdrawal. The present results emphasize the essential role of hippocampal-dependent learning and memory in the development of drug addiction.

Figure 1

Effects of acute d-amphetamine and morphine in CN98 WT and mutant mice. Values represent mean ± SEM (n = 8–10). *P < 0.05, **P < 0.01, ***P < 0.001, vs. saline-treated mice of the same genotype (ANOVA followed by Fisher’s test).

Figure 2

Effects of repeated administration of d-amphetamine and morphine in CN98 WT and mutant mice. Values represent mean ± SEM (n = 12–14). *P < 0.05, **P < 0.01, ***P < 0.001 vs. saline-treated mice of the same genotype at the same time point; #P < 0.05, ##P < 0.01, ###P < 0.001 vs. the first pairing day within the same treatment group; § P < 0.05, §§P < 0.01, WT vs. mutant mice at the same time point (ANOVA followed by Fisher’s test).

Figure 3

Conditioned place preference in CN98 WT and mutant mice. Scores represent the difference in seconds between the post- and pre-conditioning time spent in the drug-associated compartment. Values represent mean ± SEM (n = 12–14). *P < 0.05, **P < 0.01, ***P < 0.001 vs. saline-treated mice of the same genotype (ANOVA followed by Fisher’s test).

Figure 4

Naloxone-precipitated morphine withdrawal syndrome in CN98 WT and mutant mice. Values represent mean ± SEM (n = 6). *P < 0.05, **P < 0.01, ***P < 0.001 vs. saline-treated mice of the same genotype (ANOVA followed by Fisher’s test).