Selective alpha7 nicotinic receptor activation by AZD0328 enhances cortical dopamine release and improves learning and attentional processes.
AZD0328, a novel spirofuropyridine neuronal nicotinic receptor partial agonist, was used to investigate the role of alpha7 neuronal nicotinic receptor (NNR) activation in the modulation of midbrain dopamine neuron function, cortical dopamine release and on two behavioral tasks known to be dependent on optimal levels of cortical dopamine. In vivo recordings from area 10 (ventral tegmental area) in rat brain showed an increased firing of putative dopamine neurons in response to low (0.00138 mg/kg) doses of AZD0328. Bursting patterns of dopamine neuron activity remained largely unchanged by application of AZD0328. In vivo microdialysis in awake rats showed an increase in extracellular prefrontal cortical dopamine in response to low doses of AZD0328. Compound-stimulated dopamine release showed an inverted dose effect relation that was maximal at the lowest dose tested (0.00178 mg/kg). Peak extracellular dopamine levels were reached 2h after dosing with AZD0328. Acquisition of operant responding with delayed reinforcement in rats was dose dependently enhanced by AZD0328 with a plateau effect measured at 0.003 mg/kg. This effect was blocked by pre-treatment of animals with the selective alpha7 antagonist methyllycaconitine. AZD0328 improved novel object recognition in mice over a broad range of doses (0.00178-1.78 mg/kg) and the compound effect was found to be absent in homozygous alpha7 KO animals. Together, these data indicate that selective interaction with alpha7 NNRs by AZD0328 selectively enhances midbrain dopaminergic neuronal activity causing an enhancement of cortical dopamine levels; these neurochemical changes likely, underlie the positive behavioral responses observed in two different animal models. Our results suggest selective alpha7 NNR agonists may have significant therapeutic utility in neurologic and psychiatric indications where cognitive deficits and dopamine neuron dysfunction co-exist.
Sydserff
Simon
S
Neuroscience Department, AstraZeneca Pharmaceuticals LP, FRC B1129B, Wilmington, DE 19850, USA.
Sutton
E J
EJ
Song
Dekun
D
Quirk
Michael C
MC
Maciag
Carla
C
Li
Chaoying
C
Jonak
Gerald
G
Gurley
David
D
Gordon
John C
JC
Christian
Edward P
EP
Doherty
James J
JJ
Hudzik
Tom
T
Johnson
Edwin
E
Mrzljak
Ladislav
L
Piser
Tim
T
Smagin
Gennady N
GN
Wang
Yi
Y
Widzowski
Dan
D
Smith
Jeffrey S
JS
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001288:Attention / Q000187:drug effects*; D002460:Cell Line; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D003216:Conditioning, Operant / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism*; D005260:Female; D005663:Furans / Q000494:pharmacology*; D006801:Humans; D007858:Learning / Q000187:drug effects*; D008297:Male; D009474:Neurons / Q000502:physiology; D018722:Nicotinic Agonists / Q000494:pharmacology*; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D011812:Quinuclidines / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000502:physiology*; D021641:Recognition, Psychology / Q000187:drug effects; D012054:Reinforcement, Psychology; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000502:physiology; D014982:Xenopus laevis; D064569:alpha7 Nicotinic Acetylcholine Receptor
C579167:Chrna7 protein, human; C579166:Chrna7 protein, mouse; C579165:Chrna7 protein, rat; D005663:Furans; D018722:Nicotinic Agonists; D011812:Quinuclidines; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; C543642:spiro(1-azabicyclo(2.2.2)octane-3,2'(3H)-furo(2,3-b)pyridine); D004298:Dopamine