Role of matrix metalloproteinases in the acquisition and reconsolidation of cocaine-induced conditioned place preference

Abstract

Persistent drug seeking/taking behavior involves the consolidation of memory. With each drug use, the memory may be reactivated and reconsolidated to maintain the original memory. During reactivation, the memory may become labile and susceptible to disruption; thus, molecules involved in plasticity should influence acquisition and/or reconsolidation. Recently, matrix metalloproteinases (MMPs) have been shown to influence neuronal plasticity, presumably by their regulation of extracellular matrix (ECM) molecules involved in synaptic reorganization during learning. We hypothesized that inhibition of MMP activity would impair the acquisition and/or reconsolidation of cocaine-conditioned place preference (CPP) in rats. Intracerebral ventricular (i.c.v.) microinjection of a broad spectrum MMP inhibitor, FN-439, prior to cocaine training suppressed acquisition of CPP and attenuated cocaine-primed reinstatement in extinguished animals. In a separate experiment, the cocaine memory was reactivated on two consecutive days with a cocaine priming injection. On these two days, artificial cerebral spinal fluid (aCSF) or FN-439 was administered either 30 min prior to or 1 min after cocaine-primed reinstatement sessions. Infusion of FN-439 partially impaired retrieval of the cocaine-associated context when given 30 min prior to cocaine. In both groups, however, FN-439 suppressed reinstatement compared with controls on the third consecutive test for cocaine-primed reinstatement, when no FN-439 was given. Control experiments demonstrated that two injections of FN-439 + cocaine given in the home cage, or of FN-439 + saline priming injections in the CPP chambers did not disrupt subsequent cocaine-primed reinstatement. These results show for the first time that (1) MMPs play a critical role in acquisition and reconsolidation of cocaine-induced CPP, and (2) rats demonstrate apparent disruption of reconsolidation by an MMP inhibitor after extinction and while they are under the influence of cocaine during reinstatement.

Extracellular Matrix Plasticity and GABAergic Inhibition of Prefrontal Cortex Pyramidal Cells Facilitates Relapse to Heroin Seeking

“…Although inhibition of MMP activity in other brain regions other than the mPFC and NAc may have contributed to this effect as well, it suggests that downregulation of ECM proteins after cessation of heroin selfadministration renders animals more sensitive to reinstatement by heroin-conditioned cues. The present observation is in line with the finding that inhibition of MMP activity impairs reinstatement of cocaine seeking in a conditioned place preference paradigm (Brown et al, 2007). However, the decrease in heroin seeking appears to be in contrast with the rapid upregulation of Bcan in the mPFC and Tnr in the NAc that we observed following a reinstatement test.…”

“…Studies on the role of the ECM in plasticity of the visual cortex (Pizzorusso et al, 2002(Pizzorusso et al, , 2006 and hippocampal-dependent learning (Meighan et al, 2006) gave way to the intriguing prospect that the ECM contributes to various forms of persistent neuroadaptation (Wright and Harding, 2009), including those resulting from repeated drug exposure. In support of this, a study by Brown et al (2007) suggests that alteration of ECM plasticity by inhibition of matrix metalloproteinase (MMP) activity reduces the conditioned rewarding effects of cocaine in a conditioned place preference model.…”

“…Consequently, response inhibition to drug-associated cues may be impaired (Peters et al, 2008a;Van den Oever et al, 2009). Moreover, the observation that inhibition of MMP activity also impairs acquisition and reconsolidation of cocaine conditioned place preference (Brown et al, 2007), suggests that long-term adaptation of the ECM may have a more general role in the persistence of drug-seeking behavior.…”

“…In order to show a direct relationship between the downregulation of ECM proteins in the mPFC and NAc, and reinstatement of heroin seeking, we injected animals with the broad-spectrum metalloproteinase inhibitor FN-439 (Odake et al, 1994), through intracerebral ventricular (ICV) microinjection 90 min before the first reinstatement test (Brown et al, 2007). A second reinstatement test was performed 24 h later.…”

“…FN-439 (35 mg; Sigma Aldrich, Zwijndrecht, The Netherlands) was injected 90 min before the first reinstatement test (Brown et al, 2007). The microinjector (30-gauge) penetrated 3.7 mm below the dura and the compound was infused in a volume of 5 ml over 60 s. The injector was left in situ for another 120 s. For immunoblotting after reinstatement testing, rats were decapitated 3 h after the second reinstatement test and brains were rapidly frozen and stored until further use.…”