Transgenic overexpression of adenosine kinase in brain leads to multiple learning impairments and altered sensitivity to psychomimetic drugs.
The neuromodulator adenosine fulfills a unique role in the brain affecting glutamatergic neurotransmission and dopaminergic signaling via activation of adenosine A1 and A2A receptors, respectively. The adenosine system is thus ideally positioned to integrate glutamatergic and dopaminergic neurotransmission, which in turn could affect behavior and cognition. In the adult brain, adenosine levels are largely regulated by its key metabolic enzyme adenosine kinase (ADK), which may assume the role of an 'upstream regulator' of these two neurotransmitter pathways. To test this hypothesis, transgenic mice with an overexpression of ADK in brain (Adk-tg), and therefore reduced brain adenosine levels, were evaluated in a panel of behavioral and psychopharmacological assays to assess possible glutamatergic and dopaminergic dysfunction. In comparison to non-transgenic control mice, Adk-tg mice are characterized by severe learning deficits in the Morris water maze task and in Pavlovian conditioning. The Adk-tg mice also exhibited reduced locomotor reaction to systemic amphetamine, whereas their reaction to the non-competitive N-methyl-d-aspartate receptor antagonist MK-801 was enhanced. Our results confirmed that ADK overexpression could lead to functional concomitant alterations in dopaminergic and glutamatergic functions, which is in keeping with the hypothesized role of ADK in the balance and integration between glutamatergic and dopaminergic neurotransmission. The present findings are of relevance to current pathophysiological hypotheses of schizophrenia and its pharmacotherapy.
Yee
Benjamin K
BK
Laboratory of Behavioral Neurobiology, Swiss Federal Institute of Technology Zurich, Schwerzenbach, Switzerland.
Singer
Philipp
P
Chen
Jiang-Fan
JF
Feldon
Joram
J
Boison
Detlev
D
D000248:Adenosine Kinase / Q000235:genetics / Q000378:metabolism*; D000661:Amphetamine / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000201:enzymology*; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D003214:Conditioning, Classical / Q000187:drug effects; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005106:Exploratory Behavior / Q000187:drug effects; D046352:Freezing Reaction, Cataleptic / Q000187:drug effects; D007859:Learning Disabilities / Q000201:enzymology* / Q000235:genetics; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008568:Memory / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D011597:Psychomotor Performance / Q000187:drug effects; D013037:Spatial Behavior / Q000187:drug effects
D000697:Central Nervous System Stimulants; D018691:Excitatory Amino Acid Antagonists; D016291:Dizocilpine Maleate; D000661:Amphetamine; D000248:Adenosine Kinase