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           Dr. Feifel's Animal Laboratory


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        Testing Neuropeptide Based Treatments



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.






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).






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).



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




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).



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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