An examination of synaptic proteins following chronic haloperidol in a rat model of tardive dyskinesia.

Abstract

Tardive dyskinesia (TD) is a late-onset side effect mainly affecting the orofacial region of patients treated chronically with classic antipsychotic drugs such as haloperidol (HAL). The causes of TD remain unknown. We hypothesized that faulty synaptic re-organization might be related to TD-like syndromes and used the vacuous chewing movements (VCM) model in rats to investigate the expression of four synaptic proteins, synaptophysin, syntaxin, spinophilin and PSD-95, in brains of HAL-treated rats. Male Sprague-Dawley rats were treated for 14 weeks with either haloperidol decanoate (21 mg/kg once every 3 weeks, I.M) or vehicle and VCMs were monitored on a weekly basis. As expected, VCMs developed reliably and were consistently more pronounced in some rats than in others. Using immunohistochemistry in anatomically preserved brain sections as well as Western Blot analyses of whole cells or synaptosomal fractions in striatal tissue, we found no significant effect of chronic HAL on levels of these proteins. Neither did we find significant differences in the levels of the four synaptic markers when comparing rats showing High vs. Low levels of VCMs. These results suggest that structural synaptic alterations (e.g. involving increased number of synapses) may not be the underlying mechanism of oral dyskinesias induced by chronic antipsychotic drug treatment. The possibility that functional neuroplastic changes occur remains to be investigated.

Synaptic density marker SV2A is reduced in schizophrenia patients and unaffected by antipsychotics in rats

“…The discrepancies between our findings and the post-mortem findings in these regions may reflect the fact we measured SV2A binding whilst the post-mortem studies measured other synaptic proteins, or could reflect the fact that our sample was younger and had a shorter illness duration than most of the patients in the postmortem analyses, and/or the influence of post-mortem interval on synaptic protein levels 8 . Our null findings in our preclinical study are in agreement with, and extend, previous preclinical findings in which chronic HAL exposure had no statistically significant effect on synaptophysin protein levels in the rat or nonhuman primate cortex 34,35,43 , by showing HAL did not alter the levels or specific binding of another presynaptic protein, SV2A.…”

“…Most of the volunteers with schizophrenia in our study had taken antipsychotic drugs longer than this. Whilst the null results in our preclinical study are consistent with those of others examining the effect of HAL on presynaptic protein levels using a similar duration of exposure 34,35,43 , our study was not powered to detect small effects so we cannot exclude the possibility that there is a small effect and/or that a longer duration of antipsychotic drug exposure may affect SV2A protein levels or specific binding. Notwithstanding this, our findings from our clinical and preclinical studies suggest that antipsychotic medication exposure is unlikely to account for the lower [ 11 C]UCB-J binding in schizophrenia patients.…”

“…Furthermore, we performed an exploratory analysis to test whether effects are generalised to other brain regions (occipital, parietal and temporal lobes, dorsolateral prefrontal cortex, thalamus and amygdala) where structural and/or functional alterations have been identified in schizophrenia using in vivo neuroimaging 28,32,33 , and we calculated distribution volume ratio (DVR) in each region of interest (ROI), using the centrum semiovale as a pseudoreference region for estimates of nondisplaceable binding of [ 11 C]UCB-J 31 . In our preclinical study, we used a well-validated rat model of clinically comparable antipsychotic drug exposure to investigate whether chronic antipsychotic drug exposure at clinically relevant doses alters SV2A protein levels and/or specific binding in drug-naïve rats, predicting there would be no effect given the evidence that chronic haloperidol (HAL) exposure does not impact on synaptophysin levels in the rat FC 34,35 . We report here the first direct in vivo evidence for synaptic dysfunction in schizophrenia together with results from preclinical experiments suggesting that this dysfunction is not explained by antipsychotic drug exposure at clinically relevant doses.…”

Neurobiological Basis of Dyskinetic Effects Induced by Antipsychotics: the Contribution of Animal Models

“…Examinations of synaptic proteins have reported either no change [34], decreases [35] [36] [37] or increases [38][39] [40] [41] in pre-or post-synaptic proteins in the striatum. Examinations of synaptic proteins have reported either no change [34], decreases [35] [36] [37] or increases [38][39] [40] [41] in pre-or post-synaptic proteins in the striatum.…”

“…Examinations of synaptic proteins have reported either no change [34], decreases [35] [36] [37] or increases [38][39] [40] [41] in pre-or post-synaptic proteins in the striatum. Studies that use chronic intramuscular HAL depot have generally reported no change in multiple pre-and post-synaptic proteins at the tissue, cellular or synaptosomal levels [34], whereas increases have been reported in studies using daily sub-chronic HAL treatment [45] [40]. Studies that use chronic intramuscular HAL depot have generally reported no change in multiple pre-and post-synaptic proteins at the tissue, cellular or synaptosomal levels [34], whereas increases have been reported in studies using daily sub-chronic HAL treatment [45] [40].…”