Laurie Davison <ldavison at ukcc.uky.edu> wrote:
>I suppose I should clarify what I'm after. I need to know whether
>bromocriptine or other D2 agonists (or antagonists, for that matter) can
>stimulate GnRH release. I am aware that both the Ant. Pituitary and
>Median eminence lie outside the barrier, but I need to be sure that the
>agonist I use will reach the hypothalamus itself. Since dopamine does not
>cross the barrier, this is a concern.
> -Laurie Davison-
Hi Laurie!
First of all, it must be said that bromocriptine
(2-bromo-alpha-ergocryptine) is NOT just a selective and potent D2
agonist; indeed, it also is an agonist for D3 receptors and an
antagonist for D1 receptors. In this respect, its pharmacodynamics are
similar to lisuride's, which, however, also stimulates 5-HT receptors.
The other well-known ergoline, called pergolide, is a D2 and D1
agonist.
Bromocriptine DOES, indeed, cross the BBB, and this is also the case
for the other ergolines (e.g., lisuride, pergolide). As a matter of
fact, virtually all the pharmacological actions of bromocriptine
result from stimulation of dopamine receptors in the CNS,
cardiovascular system, pituitary-hypothalamic axis (PHA) and
gastrointestinal tract.
It seems that you are more interested in the endocrinological aspects
of bromocriptine, so lets talk a little more about its effects on the
PHA...
As you certainly know, bromocriptine has an antiprolactinemic effect
that is used in the treatment of prolactinomas (prolactin-producing
tumors of the pituitary) that is explained by two mechanisms: (1) a
direct and reversible inhibition of the cells of the anterior
pituitary that secrete prolactin, and (2) a dopaminergic action on the
hypothalamus, which leads to the release of a prolactin-release
inhibiting hormone - PRIH (that may in fact be dopamine), which is
carried by the hypothalamicoadenohypophyseal portal system to the
adenohypophysis, where it inhibits prolactin secretion.
Another indication for the clinical use of bromocriptine is the
treatment of intrasellar somatropinomas that do not respond to
radiation therapy and that could not beneficiate from surgical
removal. In these settings, secretion of growth hormone can be
supressed with dopaminergic agonists such as bromocriptine. This
effect is paradoxical because dopaminergic agonists cause an INCREASED
secretion of GH in normal individuals. Presumably, this reflects the
clonal expansion of cells closely related to stem cells
(somatomammotrophs) in such tumors, which apparently express the
inhibitory dopaminergic regulation of secretion that is characteristic
of lactotrophs.
Concerning the capacity to stimulate the release of GnRH, all I know
is that a potent peptide of 56 amino acid residues that is capable of
inhibiting prolactin release in vivo exists in rats; it is synthesized
along with GnRH in a single precursor molecule. The peptide has
intrinsic GnRH activity as well, and its physiological role is under
study. It may exist in the human being and function as one of the
PRIH.
Besides pergolide and lisuride (already mentioned), another drug that
acts as a dopamine agonist is quinpirole, which has great affinity for
D2 and D3 receptors. If you're looking for a selective D2 antagonist,
I suggest spiperone, (-) sulpiride, or haloperidol, though spiperone
is also a D3 and D4 antagonist (but this shouldn't matter if you're
studying only the PHA, since D3 receptors are only found in the limbic
system and D4 receptors are only found in the frontal cortex, midbrain
and amygdala).
Well. I suppose that's all! If you need any clarification, just leave
me an e-mail!
See you around, Laurie! ;-)
ooooooooooooo
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