Procholinergic and memory enhancing properties of the selective norepinephrine uptake inhibitor atomoxetine

Abstract

Atomoxetine has been approved by the FDA as the first new drug in 30 years for the treatment of attention deficit/hyperactivity disorder (ADHD). As a selective norepinephrine uptake inhibitor and a nonstimulant, atomoxetine has a different mechanism of action from the stimulant drugs used up to now for the treatment of ADHD. Since brain acetylcholine (ACh) has been associated with memory, attention and motivation, processes dysregulated in ADHD, we investigated the effects of atomoxetine on cholinergic neurotransmission. We showed here that, in rats, atomoxetine (0.3-3 mg/kg, i.p.), -increases in vivo extracellular levels of ACh in cortical but not subcortical brain regions. The marked increase of cortical ACh induced by atomoxetine was dependent upon norepinephrine a-1 and/or dopamine D1 receptor activation. We observed similar increases in cortical and hippocampal ACh release with methylphenidate (1 and 3 mg/kg, i.p.) -currently the most commonly prescribed medication for the treatment of ADHD -and with the norepinephrine uptake inhibitor reboxetine (3-30 mg/kg, i.p.). Since drugs that increase cholinergic neurotransmission are used in the treatment of cognitive dysfunction and dementias, we also investigated the effects of atomoxetine on memory tasks. We showed that, consistent with its cortical procholinergic and catecholamine-enhancing profile, atomoxetine (1-3 mg/kg, p.o.) significantly ameliorated performance in the object recognition test and the radial arm-maze test.

Methylphenidate Enhances the Abuse-Related Behavioral Effects of Nicotine in Rats: Intravenous Self-Administration, Drug Discrimination, and Locomotor Cross-Sensitization

“…However, evidence of a primary role for dopamine in mediating the nicotine cue is lacking, as selective dopamine antagonists generally fail to alter nicotine discrimination or attenuate nicotine discrimination only at doses that suppress response rates (Brioni et al, 1994;Corrigall and Coen, 1994;Le Foll et al, 2005). Since methylphenidate also elevates extracellular levels of acetylcholine in addition to dopamine (Tzavara et al, 2006), it may be that methylphenidate enhances nicotine's discriminative stimulus effects via a primarily nondopaminergic mechanism.…”

Nicotine as a conditioned stimulus: Impact of attention-deficit/hyperactivity disorder medications.

“…The exact mechanisms by which atomoxetine antagonized these nicotine-related behaviors will require further investigation. However, research suggests a possible role of cortical norepinephrine, dopamine, and/or acetylcholine efflux (Tzavara et al, 2006). One suggestion for the procholinergic property is that converging dopamine and norepinephrine neurons modulate cortical acetylcholine release at the nucleus basalis (Tzavara et al, 2006).…”

Oral administration of the antiobesity drugs, sibutramine and rimonabant, increases acetylcholine efflux selectively in the medial prefrontal cortex of the rat

“…1,2 Forebrain cholinergic systems are essential for cognitive processes, such as learning, memory and attention, 3 and procholinergic drugs are procognitive in the clinic. 3,4 Importantly, obesity appears to be comorbid with disease states characterized by cognitive impairment, for example, attentiondeficit hyperactivity disorder (ADHD). 5 It is hypothesized that an integral prefrontal cortical function, especially in the right hemisphere, might be critical for appetite and eating control, as well as for better long-term adherence to therapeutic interventions.…”

“…2,6 We have recently shown that clinically established ADHD drugs increase acetylcholine (ACh) efflux preferentially in the medial PFC of rats, a neurochemical effect that may be related to their therapeutic action. 4 We sought to investigate the effects of the efficacious antiobesity drugs, 7 sibutramine (a monoamine reuptake inhibitor) and rimonabant (a cannabinoid CB 1 receptor antagonist), on ACh efflux in the PFC and in a subcortical brain region implicated in food reward/reinforcement processes, the nucleus accumbens (NAC), of freely moving rats by in vivo microdialysis.…”

“…4,8 Surgical procedures, microdialysis experiments and determination of ACh were detailed before. 4,8,9 The perfusion solution contained neostigmine (0.1 mM) that may have impacted the observed effects on ACh efflux in a quantitative, but not qualitative, manner. 8 Animals received the compounds (synthesized at Lilly Research Laboratories) or their respective solubilizing vehicle via oral gavage.…”