High resolution micro‐SPECT scanning in rats using ¹²⁵I β‐CIT: Effects of chronic treatment with carbamazepine

Abstract

SUMMARYPurpose: Carbamazepine (CBZ) is a first-line antiepileptic agent with mood-stabilizing effects in bipolar disorder. It has been reported to influence extracellular concentrations of serotonin and dopamine, suggesting an interaction with monoamine transporters. We have investigated this effect using in vivo single photon emission computed tomography (SPECT) in rats. Methods: Adult male rats received 3 mg/kg/h CBZ via mini-osmotic pump. After 14 days continuous treatment, animals underwent two consecutive SPECT scans, using 125 I b-CIT as a radiotracer to label serotonin transporter (SERT) and dopamine transporter (DAT) sites in the brain. Pharmacologic distinction was enabled by 125 I b-CIT SPECT imaging in rats acutely exposed to the serotonin and dopamine transporter inhibitors, fluoxetine and GBR12909. The interaction between CBZ and 125 I b-CIT binding to SERT and DAT was investigated using in vitro autoradiography. Results: Carbamazepine (10 lM) did not affect binding of 125 I b-CIT to isolated rat brain slices, thereby excluding a direct effect on ligand binding to SERT and DAT. SPECT studies with fluoxetine and GBR12909 highlighted SERT binding in thalamus, hippocampus, centromedial nuclei, and occipital cortex, and DAT binding in the caudate. Prolonged treatment with CBZ failed to influence 125 I b-CIT binding to either SERT or DAT in any of the brain regions examined. Discussion: This study employed the novel technique of small animal SPECT imaging to investigate the effects of CBZ on monoamine transporters in rat brain. Following prolonged treatment, the drug was without effect on SERT or DAT availability. The mechanism by which CBZ exerts its mood stabilizing effects remains elusive.

RETRACTED: Dysregulated glutamate and dopamine transporters in postmortem frontal cortex from bipolar and schizophrenic patients

“…Further, we hypothesize that the hyperdopaminergic function in BD and SZ is due to a decreased level of the DAT, since drugs effective in treating BD and SZ have anti-dopaminergic properties (Basselin et al 2006; Basselin et al 2008; Creese et al 1976). The drugs effective in treating BD and SZ do not alter the SERT expression in rat brain and we speculate that SERT may not be changed in BD and SZ brains (Cain et al 2009; Tarazi et al 2000). To test these hypotheses, we measured protein and mRNA levels of EAAT1 to 4, of the DAT and of the SERT in postmortem frontal cortex from patients with BD and SZ, and from controls.…”

“…Our finding that frontal cortex SERT expression was unchanged in both BD and SZ is consistent with earlier reports showing no change in the density of SERT in postmortem brain from BD and SZ patients (Dean et al 1996; Dean et al 2001; Dean et al 1999). Chronic exposure to the mood stabilizer carbamazepine or to antipsychotic drugs does not change SERT levels in the rat brain (Cain et al 2009; Tarazi et al 2000). Altogether, these studies do not support a role of SERT in BD or SZ.…”

Differential drug effects on spontaneous and evoked pain behavior in a model of trigeminal neuropathic pain

“…Carbamazepine (30 mg/day), baclofen (1.06 mg/day), morphine hydrochloride (5 mg/day), and clomipramine (4.18 mg/day) were used. The drugs were dissolved in vehicle (= dimethyl sulfoxide, propylene glycol, ethyl alcohol, and acetone at a ratio of 42:42:15:1) 23 and were subcutaneously administered with one osmotic pump. The sham-operated and IoN-CCI vehicle control rats were implanted with a vehicle pump.…”

“…The doses refer to the free base and were chosen based on previous studies (efficacy and side effects) and taking into account solubility limitations. 13 , 18 , 23 – 25 …”

Assessment of [125I]WYE-230949 as a Novel Histamine H3 Receptor Radiopharmaceutical

“…SPECT scanning was performed using a MollyQ 50 microSPECT scanner (Neurophysics Corp., Shirley, MA, U.S.A.). Rats were anaesthetised for the duration of scan (2–3% isoflurane in 70/30% N 2 O/O 2 ) and physiological parameters were maintained as described previously [34] . The scanning protocol was designed to ensure that a forebrain slice encompassing structures dense in H 3 bindings sites including cortex, striatum, hippocampus and thalamus was captured; the first slice being 14.4 mm caudal to the eyes, approximately at the level of the caudate nucleus.…”