alzheimer 's disease ( ad ) is a progressive neurodegenerative disease characterized by accruing cognitive and noncognitive deficits . among the latter , aberrant motor behavior with either overall slowing or hyperactivity , and depression are common symptoms [ 15 ] .   in patients with ad , presence of apathy
as indicated by decreased motor activity and decreased agitation / hyperactivity as indicated by increased motor activity is associated with faster functional and cognitive decline [ 57 ] .
levels of dopamine , noradrenaline , and serotonin are decreased in patients with ad [ 811 ] . in animal models of ad , dopamine , noradrenaline , and serotonin all
bupropion is a monoamine reuptake inhibitor selective for dopaminergic and to a lesser extent noradrenergic neurotransmission but has no effect on serotonergic neurotransmission .
bupropion improved visual memory in patients with major depressive disorder . in rodent animal models ,
bupropion significantly decreased the duration of immobility on the forced swim test   and increased locomotor activity in freely moving animals .
citalopram is a potent selective inhibitor of serotonin reuptake   and increases extracellular serotonin concentrations in the hippocampus of rats   but has no effect on the uptake of noradrenaline and dopamine .
citalopram was recently reported to improve spatial memory in rats   and to decrease immobility time in the forced swim test .
a standard paradigm for the assessment of cognition in animal research is the investigation of spatial learning in water and dry - land mazes [ 2325 ] . while early work on spatial orientation in rodents was performed in complex dry - land mazes , since the mid 1980s complex spatial tasks predominantly are assessed in water mazes .
hence , water maze learning likely not only assesses cognitive processes of spatial memory but is confounded by noncognitive components such as anxiety .
it was the goal of the present study to assess whether common substances used for treatment of depression in humans affect spatial learning in a transgenic animal model of ad .
three groups of 4.5-month - old male app23 mice ( charles river ) and one group of same aged male wild - type mice were used in this study .
three or four animals were housed in a cage and were maintained on a 12  h light / dark cycle in a temperature ( 22  2c ) and humidity ( 55  5% ) controlled room similar to previous protocols [ 23 , 27 , 28 ] .  
injection of bupropion ( 20  mg / kg body weight ) , another with citalopram ( 10  mg / kg body weight ) , respectively , starting fourteen days prior to onset of experiments .
one group of app23 mice and wild - type mice were nacl - sham treated with the same protocol . to assess spatial memory
, we used a complex maze that has been described previously   ( figure 1 ) .
starting on the date of the last treatment , animals were trained four times a day for three consecutive days and two times on the fourth day .
they had a maximum time of 300  s to find the exit , where they were rewarded with a food pellet .
different parameters , for example , duration , moving and resting time were recorded by a tracking system ( multitrack , accuscan , usa ) .
all statistical analyses were carried out using the statistics program spss ( spss 17.0 for windows , spss inc .
both wild - type and app23 animals improved their performance during repeated exposure to the dry - land maze as shown by a significant effect of trial on total time ( two - way anova ; f 
 13,154 = 6.751 , p < 0.001 ) , resting time ( two - way anova ; f 
 13,154 = 5.042 , p < 0.001 ) , and moving time ( two - way anova ; f 
 13,154 = 9.157 , p < 0.001 ) .
both groups increased their running speed over all trials ( two - way anova ; f 
 13,154 = 11.577 , p < 0.001 ) with wild - type animals more so than app23 animals ( two - way anova ; f 
 1,154 = 28.676 , p < 0.001 ) ( figure 2(a ) ) . to catch the efficacy of spatial learning ,
both wild - type and app23 animals improved their performance during repeated exposure to the dry - land maze as shown by a significant effect of trial on distance ( two - way anova ; f 
 13,154 = 4.942 , p < 0.001 ) ( figure 2(b ) ) .
path length was shorter for wild - type animals than for app23 animals ( two - way anova ; f 
 1,154 = 37,767 , p < 0.001 ) .   to assess the effect of treating app23 animals
, we performed a two - way anova with treatment groups sham treatment , bupropion treatment , and citalopram - treatment .
there was a significant effect of treatment group on total time ( f 
 2,224 = 12.794 , p < 0.001 ) with fisher lsd multiple comparison testing indicating significant differences ( table 1 , figure 3 ) .
likewise , a significant effect of treatment group was found on resting time ( f 
 2,224 = 18.103 , p < 0.001 ) with fisher lsd multiple comparison testing indicating significant differences for treatment with bupropion but not for citalopram treatment ( table 1 , figure 3 ) .
contrary , no overall effect of treatment was found on moving time ( f 
 2,224 = 2.224 , p = 0.111 ; table 1 , figure 3 ) .  
analysis of running speed featured significant treatment differences ( f 
 2,224 = 17.507 , p < 0.001 ) with fisher lsd multiple comparison testing showing that bupropion - treated animals run faster while citalopram - treated animals run with less speed than sham - treated animals ( table 2 , figure 4(a ) ) .
further there was no significant effect of treatment group on distance ( f 
 2,224 = 0.124 , p = 0.883 ) ( table 2 , figure 4(b ) ) .
maze studies are an established means to investigate spatial learning in experimental animals , both in water mazes   and dry - land mazes . compared to wild - type animals , the total , moving , and resting time to find the goal zone
were decreased in app23 transgenic animals and the running speed was increased . however , path length was also shorter in wild - type than app23 animals .
we conclude that the difference between wild - type and app23 animals reflects both , better spatial learning and higher psychomotor activity .
this is in good harmony with previous studies showing diminished learning in middle - aged app23 animals [ 29 , 30 ] .
reduced running speed in app23 is in good harmony with a previous study with reduced psychomotor activity in another transgenic mouse model of ad , the app / ps1 transgenic model .  
citalopram has been used in dosages from 0.01  mg / kg to 8  mg / kg .
the effects on spatial cognition remain ambiguous and depend on dosage , paradigm , species , and the interaction thereof . at low dosages
, citalopram did not affect spatial learning or even improved it   but had negative effects in dosages higher than 4  mg / kg in rats . at moderate dosages of about 5  mg / kg , citalopram decreased immobility time in the forced swim test . to our knowledge
, the present study is the first to address the effects of citalopram on spatial learning in a transgenic mouse model of ad . in this model ,
high dosages of citalopram did not change path length , total , moving , or resting time , while running speed was slightly decreased .
we interpret this such as to indicate that spatial learning per se is unaffected but that psychomotor activity is slightly decreased .
this is in good harmony with previous reports showing either a slight decrease of psychomotor activity on administration of comparable dosages of citalopram   or unchanged locomotor activity . at least in clinical studies ,
no benefit on cognition was found on treating ad patients with citalopram [ 35 , 36 ] . on treatment of app23 animals with bupropion ,
resting time decreased and running speed increased while length of path and moving time remained unchanged .
we interpret this finding such as to indicate that bupropion does not improve spatial learning per se but that it increases psychomotor activity .
this is in good harmony with a previous study in mice showing an increased locomotor activity in dosages from 1  mg / kg to 20  mg / kg .  
altogether , bupropion and citalopram differentially affect psychomotor activity in the app23 transgenic mouse model of ad while spatial learning per se is unaffected .
 
 background . incipient alzheimer 's disease 
 is often disguised as depressive disorder . over the course of ad , depressive symptoms are even more frequent . 
 hence , treatment with antidepressants is common in ad . 
 it was the goal of the present study to assess whether two common antidepressants with different mechanisms of action affect spatial learning in a transgenic animal model of alzheimer 's disease . 
 methods . 
 we assessed spatial memory of male wild - type and b6c3-tg(appswe , psen1de9)85dbo ( app23 ) transgenic animals in a complex dry - land maze . 
 animals were treated with citalopram ( 10  mg / kg ) and bupropion ( 20  mg / kg ) . 
 results . moving and resting time until finding the goal zone decreased in 4.5-month - old sham - treated wild - type animals and , to a lesser extent , in app23 animals . compared with sham - treated app23 animals , treatment with bupropion reduced resting time and increased speed . on treatment with citalopram , moving and resting time were unchanged but speed decreased . 
 length of the path to the goal zone did not change on either bupropion or citalopram . 
 conclusion . 
 bupropion increases psychomotor activity in app23 transgenic animals , while citalopram slightly reduces psychomotor activity . 
 spatial learning per se is unaffected by treatment with either bupropion or citalopram . 
1. Introduction
2. Methods
3. Results
4. Discussion