Selective enhacement of mesocortical dopaminergic transmission by noradrenergic drugs: therapeutic opportunities in schizophrenia

Abstract

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.

Persistent gating deficit and increased sensitivity to NMDA receptor antagonism after puberty in a new mouse model of the human 22q11.2 microdeletion syndrome: a study in male mice

“…25 Briefly, after collection of baseline DA dialysate fractions, extracellular DA levels were measured following reverse dialysis by application of the depolarizing agent veratridine (50 mM, local 20-min pulse) and the DA/NA transporter uptake inhibitor nomifensine (50 mM, local application during 8 fractions). We subcutaneously administered PCP (2.5 + 2.5 mg/kg) systemically in the same animals the following day.…”

Noradrenaline neuron degeneration contributes to motor impairments and development of L-DOPA-induced dyskinesia in a rat model of Parkinson's disease

“…If this is the case, the L-DOPA-derived extracellular levels would be increased in the double lesioned rats, which in turn could lead to more severe dyskinesia. To investigate this possibility, we pretreated the rats with a NA transporter blocker, reboxetine at two doses, 3 and 10 mg/kg, shown to be effective in previous studies (Masana et al, 2011;Ortega et al, 2010;Sacchetti et al, 1999), and the dyskinesia induced by L-DOPA at 12 mg/kg was monitored. Contrary to the hypothesis, reboxetine did not worsen dyskinesia in the 6-OHDA rats (Fig.…”

Noradrenergic antidepressants increase cortical dopamine: Potential use in augmentation strategies

“…Microdialysis experiments were conducted as previously described (Masana et al, 2011). Briefly, concentric dialysis probes were implanted under pentobarbital anesthesia (60 mg/kg, i.p.)…”

“…Briefly, concentric dialysis probes were implanted under pentobarbital anesthesia (60 mg/kg, i.p.) at the following brain coordinates (in mm, from bregma and duramater; Paxinos and Watson, 1998) Monoamine concentrations in dialysate samples were determined by HPLC with electrochemical detection (Hewlett Packard 1049, Palo Alto, CA, USA, +0.6 or +0.7 V) as described (Bortolozzi and Artigas, 2003;Masana et al, 2011).…”

“…This strategy is based on the observation that a substantial fraction of extracellular DA in PFC derives from noradrenergic axons (Devoto and Flore, 2006;Devoto et al, 2001Devoto et al, , 2005Kawahara et al, 2001;Masana et al, 2011) being also sensitive to noradrenergic drugs (Masana et al, 2011).…”