Chronic haloperidol treatment differentially affects the expression of synaptic and neuronal plasticity-associated genes

Abstract

Synaptophysin is a protein used as a marker of presynaptic terminals. We previously showed that, in dorsolateral striatum of the rat, 2 weeks' haloperidol treatment up-regulated synaptophysin mRNA. We have now investigated the effects of 16 weeks' treatment with haloperidol on synaptophysin expression in dorsolateral striatum, frontoparietal cortex and hippocampus, in order to see if the implied haloperidol-induced synaptic plasticity persists. For comparison, in both the 2-and 16-week treatment groups we determined the mRNA abundance of the neuronal plasticity-associated gene GAP-43, and the housekeeping gene cyclophilin. Sixteen weeks' haloperidol administration increased synaptophysin mRNA in striatum and frontoparietal cortex but not in hippocampus. The increase was demonstrable both regionally and per neuron. A similar trend was seen for synaptophysin protein using immunoautoradiography. GAP-43 mRNA was elevated in frontoparietal cortex by 2 weeks' haloperidol but was not significantly changed in any area in the 16-week treatment group. Cyclophilin mRNA, a marker of overall gene expression, was unaffected by haloperidol. The persistent increase in synaptophysin expression supports the evidence that chronic antipsychotic drug treatment induces synaptic reorganisation in some striatal and cortical neuron populations, whereas the GAP-43 mRNA data suggest that haloperidol does not produce a sustained alteration of neuronal plasticity. Further study of plasticity-associated gene expression may be valuable in clarifying the long-term neuronal and synaptic changes produced by antipsychotics, and how these are related to the neurochemical effects of the drugs.

Chronic Haloperidol Promotes Corticostriatal Long-Term Potentiation by Targeting Dopamine D2L Receptors

“…Based on this observation, it has recently been proposed that the promotion of plastic, slowly developing rearrangements of neuronal connectivity is essential for the mode of action of antipsychotics (Konradi and Heckers, 2001). In line with this idea, chronic but not acute haloperidol treatment causes complex ultrastructural changes of glutamatergic synapses in the striatum (Meshul and Casey, 1989;Uranova et al, 1991;Kerns et al, 1992;See et al, 1992), indicative of its ability to promote long-lasting potentiation of excitatory transmission (Eastwood et al, 1997;Toni et al, 1999;Konradi and Heckers, 2001;Steward and Worley, 2002). Such an effect might play a crucial role in the therapeutic effects of this drug because a reduced glutamate-mediated transmission has been recognized to mediate, at least in part, the symptoms of schizophrenia (Carlsson et al, 2001;Goff and Coyle, 2001), and the striatum serves not only motor, but also critical, cognitive and motivational functions altered in schizophrenia.…”

“…All these morphological changes indicate hyperactivity of glutamatergic transmission and represent structural correlates of LTP (Eastwood et al, 1997;Toni et al, 1999;Konradi and Heckers, 2001;Steward and Worley, 2002). In this context, particularly interesting is the evidence that haloperidol treatment also alters postsynaptic density (Uranova et al, 1991), an electron dense area that contains NMDA glutamate receptors and scaffolding proteins that anchor receptors to the membrane and facilitate the receptor and postreceptor events required for LTP induction (Elgersma et al, 2002).…”

Proteomic analysis of membrane microdomain-associated proteins in the dorsolateral prefrontal cortex in schizophrenia and bipolar disorder reveals alterations in LAMP, STXBP1 and BASP1 protein expression

“…Haloperidol treatment has also been shown to upregulate synaptophysin mRNA in the striatum and frontoparietal cortex. 85 There is no animal literature assessing the influence of psychotropic medications on the expression of LAMP, STXBP1 or BASP1 specifically within the mammalian brain. Future studies should aim to clarify in detail the influence of psychotropic agents, particularly mood stabilizers, on synaptic-and neuritic-associated proteins that are also involved in neuronal plasticity.…”

RNA editing of the 5-HT2C receptor is reduced in schizophrenia

“…27,28 Two micrograms of RNA were pre-treated at 37°C for 30 min with 1 unit of RQ-1 RNase-free RNase (Promega, Southampton, UK) and 10 units of RNasin RNase inhibitor (Promega) to remove residual genomic DNA, followed by 6 min at 70°C to inactivate the DNase enzyme. Reverse transcription was carried out using 200 units Moloney murine leukaemia virus reverse transcriptase (MMLV) with 10 units of RNase inhibitor (Promega), 30 ng poly dT oligonucleotides (Oswel, Southampton, UK), buffer (50 mM Tris-HCl pH 8.3, 75 mM KCl, 3 mM MgCl 2 , 10 mM DTT) and 0.5 mM of each dNTP (ABgene, Epsom, UK) for each 2 g of RNA isolated.…”