Alpha₂‐adrenoceptor mediated co‐release of dopamine and noradrenaline from noradrenergic neurons in the cerebral cortex

Abstract

Previous results suggest that extracellular dopamine (DA) in the rat cerebral cortex originates from dopaminergic and noradrenergic terminals. To further clarify this issue, dialysate DA, dihydroxyphenylacetic acid (DOPAC) and noradrenaline (NA) were measured both in the medial prefrontal cortex (mPFC) and in the occipital cortex (OCC), with dense and scarce dopaminergic projections, respectively. Moreover, the effect of the a 2 -adrenoceptor antagonist RS 79948 and the D 2 -receptor antagonist haloperidol on extracellular DA, DO-PAC and NA was investigated. Extracellular DA and DOPAC concentrations in the OCC were 43% and 9%, respectively, those in the mPFC. Haloperidol (0.1 mg/kg i.p.) increased DA and DOPAC (by 35% and 150%, respectively) in the mPFC, but was ineffective in the OCC. In contrast, RS 79948 (1.5 mg/kg i.p.) increased NA, DA and DOPAC, both in the mPFC (by approximately 50%, 60% and 130%, respectively) and the OCC (by approximately 50%, 80% and 200%, respectively). Locally perfused, the DA transporter blocker GBR 12909 (10 lM) was ineffective in either cortex, whereas desipramine (DMI, 100 lM) markedly increased extracellular NA and DA in both cortices. The weak haloperidol effect on DA efflux was not enhanced after DA-and NA-transporter blockade, whereas after DMI, RS 79948 markedly increased extracellular NA, and especially DA and DOPAC in both cortices. The results support the hypothesis that most extracellular DA in the cortex is co-released with NA from noradrenergic terminals, such co-release being primarily controlled by a 2 -adrenoceptors.

Asenapine Increases Dopamine, Norepinephrine, and Acetylcholine Efflux in the Rat Medial Prefrontal Cortex and Hippocampus

“…Increased NE efflux, rather than, or in addition to, DA efflux, may be important for the ability of atypical antipsychotic drugs to improve cognitive function in schizophrenia (Arnsten and Li, 2005;Rossetti and Carboni, 2005). Increases in NE and DA release in the rat mPFC have been reported with 5-HT 1A -receptor agonists (Hajos-Korcsok et al, 1999;Owen and Whitton, 2003); the a 2 -adrenoceptor antagonists RS79948 (Devoto et al, 2004) and 1-(2-pyrimidinyl-piperazine) (Gobert et al, 1999); and the selective 5-HT 2C antagonist, SB242084 . As previously noted, ASE is a potent 5-HT 2C -receptor and a 2 -adrenoceptor antagonist (Schotte et al, 1996;Shahid et al, 2007).…”

“…The basis for the cognitive impairment in schizophrenia is complex; it has principally been related to diminished or dysregulated brain dopaminergic (Weinberger et al, 1988), noradrenergic (Arnsten and Li, 2005), cholinergic (Meltzer and McGurk, 1999;Bymaster et al, 2002), glutamatergic (Hirsch et al, 1997), and g-aminobutyric acid (GABA) activity (Benes and Berretta, 2000), to neuronal or neuropil loss (Selemon and GoldmanRakic, 1999), and to abnormalities in connectivity (Pantelis et al, 1997;Nakamura et al, 2005). Thus, the ability of atypical antipsychotic drugs to preferentially increase extracellular efflux of dopamine (DA), norepinephrine (NE), and acetylcholine (ACh) in the medial prefrontal cortex (mPFC) and hippocampus (HIP) has been postulated to contribute to their ability to improve cognition, in schizophrenia, and possibly negative symptoms and depression (Assie et al, 2005;Devoto et al, 2004;Ichikawa et al, 1998;Ichikawa et al, 2002a, b, c;Kuroki et al, 1999;Zhang et al, 2000). The effects of atypical antipsychotic drugs on glutamatergic transmission has also been suggested to contribute to their ability to improve cognitive impairment in schizophrenia (Konradi and Heckers, 2003;Coyle, 2006).…”

Human Methamphetamine Pharmacokinetics Simulated in the Rat: Single Daily Intravenous Administration Reveals Elements of Sensitization and Tolerance

“…The room temperature (221C) and humidity (5575%) were controlled and maintained on a reversed 12-h dark (0700 to 1900 hours) and 12-h light cycle to allow for the start of treatment during the normal active phase of the rat's awake/sleeping cycle (Devoto et al, 2004). During the dark period, all facilities were illuminated with red light to facilitate observation of the animals.…”

Catecholamine-Mediated Increases in Gain Enhance the Precision of Cortical Representations

“…Furthermore, in cortical areas, the norepinephrine transporter is responsible for the reuptake not only of norepinephrine but also of dopamine (Devoto and Flore, 2006). Thus, by blocking norepinephrine, norepinephrine transporter blockers must increase both norepinephrine and dopamine levels throughout the cortex, a prediction borne out by available data (Bymaster et al, 2002;Devoto et al, 2004). …”