Acute and repeated administration of cocaine differentially regulates expression of PSA-NCAM-positive neurons in the rat hippocampus

Abstract

Recent data indicating that addictive substances are able to alter brain plasticity and its morphology inclined us to determine whether acute and chronic cocaine administration could modify the expression of a polysialylated form of the neuronal cell adhesion molecule (PSA-NCAM) in the dentate gyrus of the rat hippocampus. Alterations in the PSA-NCAM expression are known to effect a variety of neuroanatomical rearrangements in the brain structure. Cocaine was administered acutely (15 mg/kg, i.p.) or repeatedly (15 mg/kg, i.p. once a day for five consecutive days). The number of PSA-NCAM immunopositive cells was determined at six time points after cocaine treatment: 6 h and 1, 2, 4, 6, and 10 days (both in acute and repeated treatment). It was found that a single injection of cocaine induced a time-dependent decrease in the number of PSA-NCAM cells in the dentate gyrus. The decrease was observed on day 1 after cocaine treatment and lasted for at least 6 days. In contrast, an increase in the number of PSA-NCAM-positive cells in the dentate gyrus was observed 2 and 4 days after the last dose of repeated cocaine. It is concluded that cocaine can evoke long-lasting changes in the PSA-NCAM protein expression in the dentate gyrus and that the direction of cocaine-induced PSA-NCAM changes depends on the regimen of cocaine administration. It is postulated that cocaine may have impact on hippocampal plasticity and subsequent processes that are controlled by plastic changes in the hippocampal structure.

Introduction

Drugs of abuse induce a constellation of adaptations which leads to alteration in function of motivational circuitry, resulting in compulsive behaviors focused on drug-seeking [18]. Signs of such an adaptation are observed at the molecular, cellular, neurochemical and behavioral levels [18], [28], [31]. There is also a growing body of evidence that drugs of abuse evoke plastic changes in brain cytoarchitecture (for a recent review see [32]). At the neuroanatomical level, drugs of abuse given for a long period of time induce structural changes in the dendritic branching and spine density not only in medium spiny neurons of the nucleus accumbens and in pyramidal cells of the medial prefrontal cortex [32] which are primarily involved in the reward circuitry, but also in the CA1 region of hippocampus, which has been discovered only recently [6]. The above anatomical alterations are thought to reflect changes in the pattern of synaptic connections, which alter their operation, and are believed to reflect some of the persistent behavioral sequelae associated with the repeated use of drugs of abuse [32]. Plastic changes in long-term potentiation and depression (LTP and LTD, respectively; for a recent reviews see [48]), which also require modifications of synaptic arrangements have been observed, as well [33]. Among the molecules that may operate as modulators of synaptic arrangements, participating in the remodeling of neuronal shape and generation of LTP, a polysialylated form of the neuronal cell adhesion molecule (PSA-NCAM) is one of the candidates. The neural cell adhesion molecule (NCAM) [38] belongs to the class of membrane-bound glycoproteins [35]. In functional terms, its role has been linked with cell to cell and cell to extracellular matrix adhesion [35]. NCAM is capable of binding 2,8 polysialic acid (PSA) [11]. The negatively charged long chains of PSA, attached to NCAM, confer anti-adhesive properties on the molecule [11]. A high degree of NCAM polysialylation by PSA on neuronal fragments promotes a variety of developmental events such as axonal growth and fasciculation [8], [50], cell migration [4], [29] or initiation of synaptic reorganization [41] and synaptogenesis [33]. It has also been demonstrated that alterations in PSA-NCAM expression are linked with the formation of memory traces [9] and formation of LTP [2], [23]. The expression of PSA-NCAM is particularly high in the developing brain [37] and in the brain regions of adults which undergo persistent and sustained synaptic plastic changes, such as the hypothalamo-neurohypophysial system [44], olfactory bulb [21], piriform and entorhinal cortices [37], amygdala [27] or hippocampus [26], [38], [40]. Thus, alterations in the expression of PSA-NCAM may reveal plastic changes occurring in the adult brain. The elevated expression of PSA-NCAM may reflect plastic changes while the decrease in its expression points to the stiffening of neuronal shape and arrest of dynamic changes in synaptic structure [36]. Given a potential role of plastic changes in the process of addiction [32], [48], and recent data that the hippocampus may be involved in association between contextual cues and experience of cocaine or incentive motivation [42], [43], [45], it was interesting to extend the number of drugs of abuse which are capable of altering expression of PSA-NCAM in the hippocampus. Available data indicate that nicotine and morphine altered expression of PSA-NCAM in the hippocampus [1], [17]. Given a potential role of plastic changes in the process of addiction and recent data about the role of the hippocampus in addiction, we investigated whether cocaine, a classic addictive psychostimulant, was capable of altering the expression of PSA-NCAM in the hippocampus.