Increases in inspired CO2 consistently altered the local concentration of the brain extracellular space marker alpha-naphthalene sulfonate (alpha-NS) as measured with ion-selective micropipettes in the rat thalamus. Stereotaxic injection of lidocaine in the region of the locus coeruleus attenuated this effect of CO2, and amitriptyline, a tricyclic anti-depressant and amine reuptake inhibitor, potentiated the effect. These results suggest that metabolic demand, as mimicked here by the addition of CO2, alters the fluid environment of the brain and central noradrenergic mechanisms may modulate this response.