| 1 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2008 Aug 32: 1521-6 |
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| PMID | 18565636 |
| Title | Sensitization to nicotine significantly decreases expression of GABA transporter GAT-1 in the medial prefrontal cortex. |
| Abstract | This study investigated GABA signaling following induction of behavioural sensitization to nicotine. Rats were repeatedly injected with saline, nicotine or hexamethonium for 18 days and gene expression was measured with qPCR. Nicotine upregulated GABAA alpha1 subunit expression in the nucleus accumbens (p<0.05) while no changes were observed for GABAA alpha3, alpha4 or alpha5. In the medial prefrontal cortex, no change in expression of the GABAA subunits was observed. We found that nicotine significantly decreased expression of the transporter GAT-1/SLC6A1 (p<0.05) in the medial prefrontal cortex while the expression of the GAT-3/SLC6A11 (p<0.05) transporter was increased in the nucleus accumbens. This provides the first evidence of neuroadaptive changes in the GABA system after nicotine sensitization and the first demonstration of an effect on GAT-1 or GAT-3 transporters in the addiction field. The GAT-1 findings also provide evidence for an alternative theory of why most schizophrenic individuals also use tobacco products. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 2 | Front Behav Neurosci 2010 -1 4: 32 |
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| PMID | 20589092 |
| Title | Ethanol and phencyclidine interact with respect to nucleus accumbens dopamine release: differential effects of administration order and pretreatment protocol. |
| Abstract | Executive dysfunction is a common symptom among alcohol-dependent individuals. Phencyclidine (PCP) injection induces dysfunction in the prefrontal cortex of animals but little is known about how PCP affects the response to ethanol. Using the in vivo microdialysis technique in male Wistar rats, we investigated how systemic injection of 5 mg/kg PCP would affect the dopamine release induced by local infusion of 300 mM ethanol into the nucleus accumbens. PCP given 60 min before ethanol entirely blocked ethanol-induced dopamine release. However, when ethanol was administered 60 min before PCP, both drugs induced dopamine release and PCP's effect was potentiated by ethanol (180% increase vs 150%). To test the role of prefrontal cortex dysfunction in ethanol reinforcement, animals were pretreated for 5 days with 2.58 mg/kg PCP according to previously used 'PFC hypofunction protocols'. This, however, did not change the relative response to PCP or ethanol compared to saline-treated controls. qPCR illustrated that this low PCP dose did not significantly change expression of glucose transporters Glut1 (SLC2A1) or Glut3 (SLC2A3), monocarboxylate transporter MCT2 (SLC16A7), glutamate transporters GLT-1 (SLC1A2) or GLAST (SLC1A3), the immediate early gene Arc (Arg3.1) or GABAergic neuron markers GAT-1 (SLC6A1) and parvalbumin. Therefore, we concluded that PCP at a dose of 2.58 mg/kg for 5 days did not induce hypofunction in Wistar rats. However, PCP and ethanol do have overlapping mechanisms of action and these drugs differentially affect mesolimbic dopaminergic transmission depending on the order of administration. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 3 | Eur Arch Psychiatry Clin Neurosci 2013 Jun 263: 285-97 |
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| PMID | 22968646 |
| Title | Aripiprazole differentially regulates the expression of Gad67 and ?-aminobutyric acid transporters in rat brain. |
| Abstract | The molecular etiology of schizophrenia comprises abnormal neurotransmission of the amino acid GABA (?-aminobutyric acid). Neuropathological studies convincingly revealed reduced expression of glutamic acid decarboxylase (Gad67) in GABAergic interneurons. Several antipsychotics influence the expression of GABAergic genes, but aripiprazole (APZ), a partial dopaminergic and serotonergic receptor agonist, has not been involved into these studies so far. We treated Sprague-Dawley rats for 4 weeks or 4 months with APZ suspended in drinking water and doses of 10 and 40 mg per kg body weight. Gene expression of Gad67, the vesicular GABA transporter Slc32a1 (solute carrier family, Vgat), the transmembrane transporters SLC6A1 (Gat1) and SLC6A11 (Gat3) was assessed by semiquantitative radioactive in situ hybridization. APZ treatment resulted in time- and dose-dependent effects with qualitative differences between brain regions. In the 10-mg group, SLC6A1 was strongly induced after 4 weeks in the hippocampus, amygdala, and cerebral cortex, followed by an induction of Gad67 in the same regions after 4 months, while frontocortical regions as well as basal ganglia showed dose-dependent reductions of Gad67 expression after 4 months. In several frontocortical and subcortical regions, we observed a decrease of Slc32a1 and an increase of SLC6A11 expression. In conclusion, APZ modulates gene expression of GABAergic marker genes involved into pathogenetic theories of schizophrenia. APZ only partially mirrors the effects of other antipsychotics with some important differences regarding brain regions. The findings might be explained by regulatory connections between serotonergic, GABAergic, and dopaminergic neurotransmission and should be validated in behavioral animal models of psychotic disorders. |
| SCZ Keywords | schizophrenia, schizophrenic |