Histone deacetylase inhibitors modulates the induction and expression of amphetamine-induced behavioral sensitization partially through an associated learning of the environment in mice

Abstract

The behavioral sensitization produced by repeated amphetamine treatment may represent the neural adaptations underlying some of the features of psychosis and addiction in humans. Chromatin modification (specifically histone hyperacetylation) was recently recognized as an important regulator of psychostimulant-induced plasticity. We have investigated the effects of treatment with the histone deacetylase (HDAC) inhibitors butyric acid (BA, 630 mg/kg, i.p.) and valproic acid (VPA, 175 mg/kg, i.p.) on the psyhcostimulant locomotor sensitization induced by amphetamine (AMPH, 2.0 mg/kg, i.p.). Neither BA nor VPA had locomotor effects alone, but both significantly potentiated the amphetamine-induced behavioral sensitization in mice. At the molecular level, VPA and amphetamine produced an increase of histone H4 acetylation in the striatum as detected by Western blot analysis, while co-treatment with VPA and AMPH produced an additive effect on histone H4 acetylation. We then administered the HDAC inhibitors after treatment with amphetamine for 8 days to establish locomotor sensitization. We found that repeated administration of VPA or BA for 6 days inhibited the expression of sensitized response following amphetamine challenge. Finally, in a context-specific model we studied the effect of HDAC inhibitors on amphetamine-induced association of the treatment environment (associative learning). We found that VPA and BA enhance the context-specificity of expression of amphetamine sensitization. Thus, HDAC inhibitors differentially modulate the induction and expression of amphetamine-induced effects. Together, these results suggest that dynamic changes in chromatin modification may be an important mechanism underlying amphetamine-induced neuronal plasticity and associative learning.

Introduction

Repeated administration of psychostimulants such as amphetamine or cocaine, induces an enhanced behavioral response to subsequent drug exposure, a phenomenon known as behavioral sensitization that can persist for months [33], [35]. Psychostimulant-induced behavioral sensitization in rodents provides a model of addictive behaviors such as those associated with craving and relapse, as well as for psychotic complications of psychostimulant abuse [18], [34], [35]. Neural sensitization itself appears to be a non-associative process, but contextual learning powerfully modulates both the induction and the expression of behavioral sensitization [35], [36]. There are two learning processes by which psychostimulant behavioral sensitization can be modified: (i) an occasion-setting mechanism [2], [37] can prevent the expression of behavioral sensitization in contexts in which the drug is not expected. (ii) Excitatory Pavlovian associations can increase drug-induced psychomotor response when animals are placed in environments where the drug is expected [2], [38], [39]. These two associative processes may combine to modulate the expression of sensitization [2], [3].

Persistent behavioral sensitization after repeated psychostimulant treatment indicates that drug-induced short- and long-term changes in gene expression may be involved [28], [29]. The transcription factors are among the relatively short-term molecular adaptations associated with the reward behavioral and psychostimulant sensitization. However, an additional mechanism such as chromatin modification involving histone acetylation is increasingly recognized as an important regulator of gene expression [17]. The acetylation state of histones is determined by the action of two families of enzymes: histone acetyltransferase (HAT), which catalyzes the transfer of an acetate group onto the histone tail, and histone deacetylase (HDAC), which catalyzes the removal of these acetates. Acetylation and deacetylation of core histone tails have been associated primarily with transcriptional activation and gene silencing, respectively [11]. Several studies suggest that dynamic histone acetylation and deacetylation processes are also active in postmitotic neurons [12], [20], [21], [27]. Recently, it has been shown that both acute and chronic cocaine administration are able to induce specific histone modification at different gene promoters in the striatum [6], [20], [22]. Furthermore, treatment with HDAC inhibitors alter locomotor and rewarding responses to cocaine [20].

We hypothesized that dynamic changes in chromatin modification (histone acetylation/deacetylation) contribute both to psychostimulant-induced molecular neuroplasticity and associative learning. The aim of our study was to evaluate the effects of HDAC inhibitors (valproic acid and butyric acid) (1) on the induction and maintenance/expression of behavioral sensitization, and (2) on associative learning of the testing environment that underlies amphetamine-induced sensitization.