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Similarly, DOI decreased neurite density in organotypic embryonicmouse dor-
sal raphe nuclei slice cultures in the hippocampal coculture model discussed ear-
lier, after 7DIV (
Dudok et al., 2009
). However, DOI enhanced primary neurite
length and branching in cultured embryonic (E15.5) mouse thalamic neurons
(
Persico et al., 2006
). In cultured rat cortical embryonic (E14-E18) gluta-
matergic neurons, an Htr2A agonist (
a
-methyl-5-HT, 25
m
M) promoted sur-
vival but had no effect on neurite growth. Although
a
-methyl-5-HT can also
activate Htr2C, this receptor subtype is lacking in cortex during embryonic de-
velopment (
Dooley et al., 1997
). No overt morphological abnormalities or phe-
notypic differences were detected inCNS patterning of Htr2A (
Weisstaub et al.,
2006
)andHtr2C(
Heisler, Chu, & Tecott, 1998; Tecott, Logue, Wehner, &
Kauer, 1998; Tecott et al., 1995
) knockout mice. Thus,
in vitro
Htr2A/C
may have different effects on neurite growth, and the evidence is only
pharmacological. Thus, as above, Htr2A/C needs to be investigated using
genetic manipulation, and future studies should include other neuronal types,
ages, and axon regeneration models.
3.4. Htr3
Htr3 is the only ionotropic receptor subtype amongst the 5-HT receptors
(
Tierney, 2001
). Both Htr3A and Htr3B are expressed in PC12 cells (
Hanna,
Davies, Hales, & Kirkness, 2000
) and Htr3 activation leads to an increase in
intracellular Ca
2
þ
concentration (
Stewart, Davies, Kirkness, Safa, & Hales,
2003
). Elevation of intracellular Ca
2
þ
concentration by KCl has been shown
to increase neurite outgrowth in PC12 cells (
Solem, McMahon, & Messing,
1995
). 5-HT also increased neurite outgrowth in PC12 cells, presumably
through Htr3, as application of Htr3 antagonist MDL72222 or Ca
2
þ
channel
blocker nifedipine abolished both 5-HT-induced increase inCa
2
þ
and increase
in neurite outgrowth in these cells (
Homma et al., 2006; Severin&Kondratyev,
1988
). However, a 5-HT-induced increase in growth of already differentiated
PC12 cell neurites was not reported (
Homma et al., 2006; Severin &
Kondratyev, 1988
). Furthermore, Htr3 agonist 1-phenylbiguanide failed to
significantly increase neurite length of cultured E15 mouse thalamic neurons
(
Lotto et al., 1999
).
In primary neurons, the Htr3 selective agonist m-CPBG increased pri-
mary neurites' length while decreasing the number of branches in cultured
rat cortical embryonic (E16) GABAergic neurons, whereas Htr3 antagonist
Y-25130 decreased neurite growth of primary neurites and branches
(
Vitalis & Parnavelas, 2003
). In primary embryonic (E15.5) mouse thalamic
