Chronic oral nicotine increases brain [3H]epibatidine binding and responsiveness to antidepressant drugs, but not nicotine, in the mouse forced swim test.
BACKGROUND
Smoking rates among depressed individuals is higher than among healthy subjects, and nicotine alleviates depressive symptoms. Nicotine increases serotonergic and noradrenergic neuronal activity and facilitates serotonin and noradrenaline release. In mice, acute nicotine administration enhances the activity of antidepressants in the mouse forced swim (mFST) and tail suspension tests. Here, we investigated if this action of nicotine is also reflected in a chronic treatment regimen.


METHODS
After chronic treatment with nicotine in the drinking water, mice were challenged with nicotine, duloxetine, citalopram, and reboxetine in the mFST. Additionally, 8-OH-DPAT- and clonidine-induced hypothermia was tested in vehicle- and nicotine-pretreated mice, as a measure of 5-HT(1A) and alpha(2)-adrenoceptor function, respectively. Finally, the effects on the brain expression levels of high- and low-affinity nicotinic acetylcholine receptors (nAChRs) and the transporters for serotonin (SERT) and noradrenaline (NET) were assessed using [(3)H]epibatidine, [(3)H]alpha-bungarotoxin, [(3)H]citalopram, and [(3)H]nisoxetine binding, respectively.


RESULTS
In the mFST, nicotine-pretreated mice did not show altered response to the nicotine challenge, but increased responses to all three antidepressants tested were observed when compared to mice that had been administered drinking water without nicotine. There was no change in hypothermic responses to 8-OH-DPAT or clonidine. [(3)H]epibatidine binding was significantly increased in all brain regions investigated; whereas, [(3)H]alpha-bungarotoxin, [(3)H]citalopram, and [(3)H]nisoxetine binding were not altered, indicating that chronic oral nicotine increases the expression and/or affinity of high-affinity nAChRs, but not low-affinity nAChRs, SERT, or NET.


CONCLUSIONS
It is suggested that the increased sensitivity to antidepressants after chronic nicotine exposure involves increased high-affinity nAChR-mediated neurotransmission.
Andreasen
Jesper T
JT
Department of Affective Disorders, NeuroSearch A/S, 93 Pederstrupvej, 2750 Ballerup, Denmark. JTA@Neurosearch.dk
Nielsen
Elsebet O
EO
Redrobe
John P
JP
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D001665:Binding Sites; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000378:metabolism*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D066298:In Vitro Techniques; D051379:Mice; D008815:Mice, Inbred Strains; D009043:Motor Activity / Q000187:drug effects; D009538:Nicotine / Q000008:administration & dosage / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D009638:Norepinephrine / Q000378:metabolism; D011725:Pyridines / Q000378:metabolism*; D011869:Radioligand Assay; D011978:Receptors, Nicotinic / Q000096:biosynthesis / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D013315:Stress, Psychological / Q000378:metabolism* / Q000523:psychology
D000928:Antidepressive Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D018722:Nicotinic Agonists; D011725:Pyridines; D011978:Receptors, Nicotinic; D012701:Serotonin; D009538:Nicotine; C082748:epibatidine; D009638:Norepinephrine