Selective enhancement of mesocortical dopaminergic transmission by noradrenergic drugs: therapeutic opportunities in schizophrenia.
The superior efficacy of atypical vs. classical antipsychotic drugs to treat negative symptoms and cognitive deficits in schizophrenia appears related to their ability to enhance mesocortical dopamine (DA) function. Given that noradrenergic (NE) transmission contributes to cortical DA output, we assessed the ability of NE-targeting drugs to modulate DA release in medial prefrontal cortex (mPFC) and nucleus accumbens (NAc), with the aim of selectively increasing mesocortical DA. Extracellular DA was measured using brain microdialysis in rat mPFC and NAc after local/systemic drug administration, electrical stimulation and selective brain lesions. Local GBR12909 [a selective DA transporter (DAT) inhibitor] administration increased DA output more in NAc than in mPFC whereas reboxetine [a selective NE transporter (NET) inhibitor] had an opposite regional profile. DA levels increased comparably in both regions of control rats after local nomifensine (DAT+NET inhibitor) infusion, but this effect was much lower in PFC of NE-lesioned rats (DSP-4) and in NAc of 6-OHDA-lesioned rats. Electrical stimulation of the locus coeruleus preferentially enhanced DA output in mPFC. Consistently, the administration of reboxetine+RX821002 (an α2-adrenoceptor antagonist) dramatically enhanced DA output in mPFC (but not NAc). This effect also occurred when reboxetine+RX821002 were co-administered with haloperidol or clozapine. The preferential contribution of the NE system to PFC DA allows selective enhancement of DA transmission by simultaneously blocking NET and α2-adrenoceptors, thus preventing the autoreceptor-mediated negative feedback on NE activity. Our results highlight the importance of NET and α2-adrenoceptors as targets for treating negative/cognitive symptoms in schizophrenia and related psychiatric disorders.
Masana
Mercè
M
Department of Neurochemistry and Neuropharmacology, IIBB - CSIC (IDIBAPS), Spain.
Bortolozzi
Analía
A
Artigas
Francesc
F
D018663:Adrenergic Agents / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D003071:Cognition / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism*; D015259:Dopamine Agents / Q000494:pharmacology; D050483:Dopamine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D004558:Electric Stimulation; D006220:Haloperidol / Q000494:pharmacology; D019329:Idazoxan / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D017551:Microdialysis; D058990:Molecular Targeted Therapy; D009025:Morpholines / Q000494:pharmacology; D009638:Norepinephrine / Q000378:metabolism; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000503:physiopathology; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000503:physiopathology; D051381:Rats; D017208:Rats, Wistar; D000077593:Reboxetine; D012559:Schizophrenia / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D009435:Synaptic Transmission / Q000187:drug effects*; D017557:Ventral Tegmental Area / Q000187:drug effects
D018663:Adrenergic Agents; D014150:Antipsychotic Agents; D015259:Dopamine Agents; D050483:Dopamine Plasma Membrane Transport Proteins; D009025:Morpholines; D050484:Norepinephrine Plasma Membrane Transport Proteins; D000077593:Reboxetine; C058525:2-methoxyidazoxan; D006220:Haloperidol; D004298:Dopamine; D009638:Norepinephrine; D019329:Idazoxan