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Current
Antipsychotics
The core mechanism underlying all established antipsychotics in current
use is the binding and blockade of dopamine to one type of dopamine
receptor (D2).
First generation antipsychotics such as haloperidol work by binding and
blocking D2 receptors exclusively. Second generation or
“atypical” antipsychotics work by binding D2 as well as serotonin-2
receptors.
There is a great need to find antipsychotics that work through novel
mechanisms compared to current antipsychotics. Antipsychotics
that work by novel mechanisms may produce greater overall efficacy,
greater speed of onset, and improved safety and tolerability.
What
is Neurotensin?
Neurotensin is a neuropeptide that exists in the periphery and in the
central nervous system. It is composed of 13 amino acids.
Interest in neurotensin as a possible antipsychotic arose in the 1980s
when it was found that neurotensin is produced and released from the
same brain cells that contain dopamine, a neurotransmitter strongly
implicating in the symptoms of psychosis. The prospect that drugs
that target the neurotensin system could be developed as
antipsychotics was enhanced when it was discovered that neurotensin
administered directly into the brain of animals opposed the effects of
dopamine. The mechanism proposed for this was an
interaction between activated neurotensin receptors and D2 receptors
resulting in a decrease in the affinity of dopamine for the D2
receptor. In essence, like established antipsychotics,
neurotensin was decreasing dopamine transmission in the brain but
instead of directly blocking D2 receptors it appeared to have this
effect via an indirect mechanism.
The
Neurotensin Agonists Display Antipsychotic-Like Effects
The Feifel laboratory was the first laboratory to test the
antipsychotic potential of
neurotensin by measuring its effects on schizophrenia-like deficits in
prepulse inhibition (PPI). Click
here to learn more about PPI.
Initially, to test its antipsychotic effects, we administered
neurotensin directly into the brains of rats (Feifel et al., 1999). Recently,
neurotensin agonists that cross the blood brain barrier and activate
neurotensin receptors in the brain have been developed. Our
laboratory has been intensively studying the effects of these
neurotensin agonists in animal models of deficient PPI and other
relevant animal models. These
studies have produced very interesting and unexpected results that have
implications for the development of neurotensin agonists as novel
antipsychotics.
In one study we found that the neurotensin agonist PD149163 (PD), given
by subcutaneous injection, reversed amphetamine’s disrupting effect on
PPI (Feifel et al., 1999).
This is an expected effect given the evidence that neurotensin opposes
the action of the D2 receptor; however, other studies from our
laboratory suggested that the effect of PD and other neurotensin
agonists given subcutaneously produce effects that were
antipsychotic-like in nature but not attributable simply to the
inhibition of D2 receptors. For example, PD and similar
neurotensin agonists reversed the PPI disrupting effects of serotonin 2
and alpha adrenergic 1 agonists as well as glutamate (NMDA)
receptor antagonists (Feifel
et al., 2003; Shilling et al., 2004). None of these effects are
produced by antipsychotics that only inhibit D2 receptors.
However, they are associated with antipsychotics and other drugs that
can inhibit other receptor systems. Evidence from our laboratory that
peripherally administered neurotensin agonists inhibit the disruption
produced by the serotonin-2A agonist, DOI (Feifel et al., 2003) indicates that these drugs
inhibit activation of the serotonin-2A receptor. This is an important
finding since inhibition of this receptor is thought to be responsible
for the superior clinical efficacy of the new generation “atypical”
antipsychotics. Inhibition of the serotonin-2A receptor is also now
implicated as a potential mechanism, either alone or in combination
with other pharmacological mechanisms (i.e., D2 receptor blockade) for
improving symptoms of bipolar disorder, depression, anxiety, obsessive
compulsive disorder, agitation and other neuropsychiatric conditions (Boyer and Blumhardt, 1992;
Toren et al., 1998; Schatzberg and DeBattista, 1999; Ramasubbu et al.,
2000). Thus, based upon our finding that neurotensin agonists
inhibit serotonin-2A function, its likely that these drugs may have
a much broader range of therapeutic benefits than previously recognized
when
it was thought that their only therapeutically relevant effect was
inhibition of D2 receptors.
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Subcutaneous
PD, a neurotensin agonist that enters the brain blocks the PPI
disrupting effect of DOI, as serotonin-2A receptor agonist. This result
indicates that neurotensin agonists can inhibit activation of
serotonin-2A receptors, a pharmacological effect that is believed to
improve symptoms of many neuropsychiatric disorders. Significantly
lower than vehicle represented by * (p<0.05). Significantly greater
than no active PD dose represented by + (p<0.05).
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Subcutaneous
PD, a neurotensin agonist that enters the brain antagonizes the PPI
disrupting effect of MK-801, an antagonist of NMDA receptors. This
result indicates that neurotensin agonists can stimulate NMDA receptor
function, a pharmacological effect that is believed to be beneficial
for many neuropsychiatric disorders. Significantly lower than vehicle
represented by * (p<0.05) and ** (p<0.01). Significantly greater
than no active PD dose represented by + (p<0.05).
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Another
line of evidence supporting neurotensin agonists as
important antipsychotic drugs comes from animal
models of psychosis developed in the Feifel laboratory. For example,
subcutaneously administered neurotensin agonists reversed the natural
PPI deficits in the Brattleboro rat a genetic model that has been
developed by our laboratory (Feifel
et al., 2004) that
exhibits strong
validity for features of schizophrenia and for predicting
antipsychotic efficacy.
This is very interesting since haloperidol, the
prototypical first generation ("typical") antipsychotic are not able to
produce this
effect, and clozapine, the prototypical second generation ("atypical")
antipsychotic are not able to match the robust effects of the
neurotensin agonist. See
graphs on haloperidol and clozapine
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Acute
subcutaneous administration PD, a neurotensin agonist that enters the
brain, strongly increased PPI in Brattleboro rats and reversed the
schizophrenia-like natural deficit in PPI that they have. In contrast,
acute haloperidol did not produce this effect (although chronic
haloperidol did) and clozapine, considered the most efficacious
antipsychotic, produced a less robust effect on Brattleboro PPI.
Significantly lower than Long Evans rats represented by ** (p<0.01).
Significantly greater than no active PD dose
represented by + (p<0.05) and ++ (p<0.01).
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Taken together, these studies from
our
laboratory indicate:
1. Neurotensin agonists administered systemically have a very
auspicious preclinical profile suggestive of an antipsychotic drug.
This profile is more similar to the newer
generation (“atypical’) antipsychotics than first generation
(“typical”) antipsychotics.
2. The antipsychotic-like mechanisms associated with neurotensin
agonists are not all accountable simply by inhibition of the function
of D2 receptors as had previously been thought.
3. Neurotensin agonists seem to be able to inhibit activity
of the serotonin-2A receptor (even though they do not bind this
receptor), which is known to be an important pharmacological effect
with therapeutic benefits in psychosis and many other neuropsychiatric
conditions including mood disorders.
4. Neurotensin agonists seem also to be able to inhibit
glutamate (NMDA) and D2 receptors in the brain which are
important pharmacological effects for antipsychotic efficacy.
These findings are exciting and suggest that drugs that target
neurotensin receptors in the brain may represent a novel class of
antipsychotics, the first type that do not exhibit binding affinity for
dopamine or serotonin receptors.
Our laboratory is actively pursuing further studies with neurotensin
agonists and investigating the extent of the antipsychotic-like
potential of treatments that target neurotensin receptors using a
number of different tools including neurotensin receptor knockout
mice.
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