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Neuropsychopharmacology (2004) 29, 731–738& 2004 Nature Publishing Group Reversal of Sensorimotor Gating Deficits in Brattleboro Ratsby Acute Administration of Clozapine and a NeurotensinAgonist, but not Haloperidol: a Potential Predictive Model forNovel Antipsychotic Effects David Feifel*,1, Gilia Melendez1 and Paul D Shilling1 Department of Psychiatry, University of California, San Diego, San Diego, CA, USA Prepulse inhibition (PPI) of acoustic startle is decreased in unmedicated schizophrenia patients and similar deficits can be induced in rats through pharmacological, environmental, or neuroanatomical manipulations. Recently, we reported that Brattleboro (BB) rats, a Long Evans (LE) strain with a single gene mutation, have inherent deficits in PPI homologous to those observed in schizophrenia patients. We also reported that PPI deficits in BB rats could be reversed by chronic but not acute administration of 0.5 mg/kg haloperidol. No other dose or drug was tested in that experiment. In this study, we tested the effects of acute subcutaneous administration of several doses of haloperidol as well as the second-generation antipsychotic, clozapine, and the putative novel antipsychotic, PD149163, a neurotensin mimetic that crosses the blood–brain barrier. Consistent with our previous report, BB rats exhibited PPI deficits compared to LE rats and none of the doses of haloperidol produced a significant effect on this PPI deficit. In contrast, 10 and 15 mg/kg of clozapine and all the doses of PD149163 tested reversed the PPI deficits in BB rats. In addition, haloperidol, but not clozapine or PD149163 produced significant catalepsy in BB rats, supporting the notion that PD149163 has a profile consistent with atypical antipsychotics and providing support for the predictive validity of the PPI results. These results further strengthen the notion that the BB rat is a useful predictive model of antipsychotic efficacy and suggest that this model may differentiate between antipsychotics belonging to different therapeutic categories, for example, first- and second-generation agents.
Neuropsychopharmacology (2004) 29, 731–738, advance online publication, 4 February 2004; doi:10.1038/sj.npp.1300378 Keywords: antipsychotics; Brattleboro rats; prepulse inhibition; clozapine; neurotensin; schizophrenia families including dopamine agonists such as amphetamineand apomorphine (Mansbach et al, 1988), serotonin Prepulse inhibition (PPI) of the acoustic startle reflex is the agonists such as DOI (Sipes and Geyer, 1994), and reduction in the startle response when the startle-eliciting noncompetitive NMDA antagonists such as phencyclidine stimulus is immediately preceded by a weak stimulus (PCP) and dizocilpine (MK801) (Mansbach and Geyer, (Swerdlow and Geyer, 1998). PPI, an operational measure of 1989). Antipsychotics can reverse this disruption, making sensorimotor gating, is deficient in schizophrenia patients, PPI the basis of a predictive model for antipsychotic drugs a phenomenon thought to reflect a disruption in cortico- (Geyer et al, 2001). PPI deficits produced by dopamine striatal-pallidal-pontine circuits involved in preconscious agonists can be reversed by first-generation or ‘typical’ as processing of environmental stimuli (Geyer et al, 2001). PPI well as second-generation or ‘atypical’ antipsychotics; deficits analogous to those seen in schizophrenia (Braff and therefore, this paradigm is not useful in distinguishing Geyer, 1990) can be induced in rats by administering between these two categories of antipsychotics. In contrast, psychomimetic drugs of several different pharmacological PPI deficits produced by serotonin agonists and NMDAantagonists tend to be preferentially reversed by atypical *Correspondence: Dr D Feifel, Department of Psychiatry, University of antipsychotics (Geyer et al, 2001). Therefore, the reversal of California, San Diego, 200 West Arbor Drive, San Diego, CA 92103- serotonin agonist and NMDA antagonist-induced PPI 8218, USA, Tel: þ 1 619 543 2485; Fax: þ 1 619 543 3738, disruption may be predictive of atypical antipsychotic drug Received 08 July 2003; revised 30 October 2003; accepted 04December 2003 Paradigms requiring drugs to induce PPI deficits have Online publication: 16 December 2003 at http://www.acnp.org/ certain inherent limitations as models of sensorimotor gating deficits in humans and predictive models of Reversal of sensorimotor gating deficits in BB rats antipsychotic potential. Therefore, there is significant effects on PPI are stable across the circadian cycle (Weiss interest in development of nonpharmacological paradigms et al, 1999). The rats were tested in startle chambers to of PPI deficits. Two of the most studied examples of characterize their baseline PPI and startle. Animals nonpharmacological paradigms of PPI deficits are social were assigned, based on their baseline PPI, to one of four isolation-rearing (Geyer et al, 1993) and neonatal hippo- groups matched so as to achieve comparable average PPI campal lesions (Lipska et al, 1995). PPI deficits produced by across groups. Drug treatment began 3 days after baseline social isolation rearing are reversed by both typical and atypical antipsychotics (Cilia et al, 2001; Le Pen and In one experiment 50 LE rats and 50 BB rats were Moreau, 2002). Preliminary findings suggest that PPI administered subcutaneous (s.c.) injections of either 0 deficits produced by neonatal hippocampal lesions may be (vehicle), 0.1, 0.5, or 1 mg/kg of haloperidol (UCSD Medical reversed by atypical but not typical antipsychotics (Le Pen Center, San Diego, CA). In another experiment 51 LE and 49 BB rats were administered s.c. injection of either 0 (vehicle), Brattleboro (BB) rats are Long Evans (LE) rats with a 5, 10, or 15 mg/kg clozapine (Sigma Chemicals, St Louis, single base pair mutation that results in the inability to MO). In a third study, 43 LE rats and 33 BB rats were properly synthesize the neurotransmitter and neurohor- administered s.c. injection of either 0 (vehicle), 0.5, 1, or mone vasopressin. BB rats have many behavioral and 2 mg/kg PD149163 (LYS(CH2NH)LYS-PRO-TRP-tLE-LEU- cognitive abnormalities, including deficits in memory OEt) (SRI International, NIMH chemical synthesis pro- (Laycock et al, 1983), emotion (Williams et al, 1985), social gram). Doses were selected based on their demonstrated recognition (Engelmann and Landgraf, 1994), motivation, ability to reverse PPI deficits in other reports (Feifel et al, and attention (Williams et al, 1983). They have abnormal- 1999; Geyer et al, 2001). Vehicle for haloperidol was distilled ities in brain systems including dopamine and serotonin, water and the volume injected was 1 ml/kg. Vehicle for neurotransmitters implicated in schizophrenia (Feenstra clozapine and PD149163 was 0.1 N HCl and half volume et al, 1990). BB rats also have deficits in PPI compared with 0.9% saline brought to pH 5–6 with a few drops of 1 N their wild-type, LE counterparts. We previously showed that NaOH. The volume injected for clozapine was 1.5 ml/kg and acute treatment with a single dose (0.5 mg/kg) of haloper- for PD149163 was 1 ml/kg. Each treatment group had a idol did not reverse the PPI deficits in BB rats. In contrast, chronic treatment with that dose of haloperidol reverses the Animals were tested in startle chambers (San Diego deficits, suggesting that the BB rat may be a very useful Instruments, San Diego, CA) 20 min after drug administra- genetic model of sensorimotor gating deficits associated tion. Once placed in startle chambers, each rat had a 5-min with schizophrenia that models the therapeutic time course acclimation period. A 65-dB background noise was of antipsychotic drugs (Feifel and Priebe, 2001). Since only continuously present throughout the session. The acclima- one dose of haloperidol was used in that study, it is possible tion was followed by a 15 min PPI test session during which that acute administration of higher or lower doses of rats were presented with 40 ms 120 dB startle pulses without haloperidol may reverse the PPI deficits observed in BB rats.
a prepulse, or pulses preceded 100 ms by a prepulse of Furthermore, it is not known whether haloperidol’s inability either 4, 8, or 12 dB above background. These four types of to reverse PPI deficits in BB rats after acute administration active stimuli were presented in addition to a neutral (no extends to other established or putative antipsychotic drugs.
sound) stimuli condition in pseudorandom order with an Therefore, we performed dose response experiments to average of 15 s between stimuli types.
determine if haloperidol, and the atypical antipsychotic, A startle response was recorded for all stimuli presenta- clozapine and the putative antipsychotic, PD149163, a tions. PPI for each animal was calculated as a percentage of neurotensin mimetic that has been shown in previous the pulse-alone startle magnitude using the following studies to display antipsychotic-like properties (Feifel et al, formula: (1À(startle magnitude after prepulse-pulse pair/ 1999), would attenuate BB PPI deficits. Furthermore, we startle magnitude after pulse only) Â 100). Exploratory tested the catalepsy effects of all three drugs in order to analysis of the data was conducted and indicated that PPI determine whether PD149163 resembles clozapine or deficits in BB rats were consistently more robust in the first haloperidol in this respect, and thus to facilitate interpreta- half of the startle sessions. Therefore, PPI data from this tion of the predictive validity of the PPI results.
first block of stimuli were subjected to the further statisticalanalysis. To compare treatments groups, PPI data wassubjected to a three-way ANOVA in which prepulse intensity was a within-subject factor and strain andtreatment (ie drug dose) were between-subject factors. As All experimental procedures were conducted in accordance expected, percent PPI was inversely related to prepulse with the University of California, San Diego guidelines for intensity in all three experiments (main effect of prepulse animal care and experimentation. In total, 132 male BB rats intensity) and this is a well-established relationship.
and 144 LE rats (170–350 g at testing, Harlan Laboratories, However, there was no significant two- or three- way San Diego) were housed in groups of two or three in clear interaction of prepulse intensity with any of the drugs plastic chambers in a climate controlled room under a 12/ tested. Therefore, this term was dropped from the 12 h light/dark schedule (lights on/off – 0700/1900). They model and the analysis reported is based upon a reduced were allowed free access to food and water for the extent of model examining averaged PPI from all prepulse inten- the study. Behavioral testing was performed 7 days after arrival, during the light phase of the rats’ circadian Dunnett’s one-tailed test to test the following specific illumination schedule as startle magnitude, PPI, and drug Reversal of sensorimotor gating deficits in BB ratsD Feifel et al 1. PPI in untreated BB rats is significantly lower than in 2. Treatment with the test drugs facilitates PPI in BB rats 3. Treatment of BB rats with the test drugs restores their Data of the acoustic startle response (ASR) to the startle stimuli not preceded by any prepulse were subjected to analysis using a similar two factor ANOVA.
In a separate study to compare the catalepsy effects of each drug, 48 drug-naı¨ve BB rats were given one of the following SC treatments: saline, 1 mg/kg haloperidol, 10 mg/kg clozapine, 15 mg/kg clozapine, 1 mg/kg PD149163 or 2 mg/kg PD149163 (n ¼ 8 for all groups). Doses selectedwere those that produced the greatest effect in the PPI studies. At 30 minutes after s.c. injections, animals weretested using a method described by several other authors(Stanley and Glick, 1976; Costall et al, 1978; Wadenberg, 1996). This method involved placing the forepaws of each rat in an extended position over a pencil that was suspended horizontally 9 cm above the lab bench. The time spent inthis position before the animal moved or corrected itselfwas considered a measure of catalepsy.
Figure 1 (top) illustrates PPI results in the haloperidol (F(1,92) ¼ 23.3, Po0.001) with LE rats exhibiting higher PPI than BB rats. There was no significant main effect ofhaloperidol nor was there a significant haloperidol  strain PPI (top) and ASR (bottom) 7SEM in rats treated with haloperidol. Significantly different from vehicle-treated LE rats represented interaction. PPI exhibited by vehicle-treated LE rats was by *(Po0.05) and **(Po0.01). Significantly different from vehicle-treated significantly higher (Po0.05) than BB rats for all doses of haloperidol. None of the doses of haloperidol significantlyincreased PPI in either LE or BB rats.
Figure 1 (bottom) illustrates the ASR results in the between BB and LE rats. Clozapine appeared to reduce ASR haloperidol experiment. Analysis of the ASR data indicates in both rat strains in a dose-dependent fashion, but this that BB rats had significantly higher ASR (F(1,92) ¼ 31.6, effect was slightly above the statistical cutoff for significance Po0.001), and that haloperidol significantly decreased the (P ¼ 0.051). There was no significant clozapine  strain ASR in both strains of rats (F(3,92) ¼ 13.6, Po0.001). There was no significant strain  haloperidol interaction.
Figure 3 (top) illustrates the PPI results in the PD149163 Figure 2 (top) illustrates the PPI results in the clozapine experiment. There was a significant effect of strain experiment. There was a significant main effect of strain ((F(1,68) ¼ 6.28, Po0.05), a significant main effect of (F(1,92) ¼ 14.7, Po0.001) and a strain  clozapine interac- PD149163 (F(3,68) ¼ 4.75, Po0.01), and a significant tion (F(3,92) ¼ 3.4, Po0.05), but not a main clozapine strain  PD149163 interaction (F(3,68) ¼ 4.221, Po0.01).
effect. LE rats treated with vehicle exhibited PPI that was PPI in vehicle-treated LE rats was significantly higher than significantly higher than BB rats treated with vehicle in vehicle-treated BB rats (Po0.01), but not significantly (Po0.01), but not significantly different than BB rats different from BB rats treated with any of the doses of treated with any of the doses of clozapine tested.
PD149163. BB rats treated with 1 and 3 mg/kg PD149163 Furthermore, PPI in BB rats treated with vehicle was had significantly higher PPI (Po0.01 and Po0.05, respec- significantly lower than PPI in BB rats treated with 10 mg/kg tively) than PPI exhibited by vehicle-treated BB rats. In (Po0.01) and 15 mg/kg dose (Po0.05) of clozapine. In contrast, no dose of PD149163 had a significant effect on contrast, no dose of clozapine increased PPI in LE rats.
PPI in LE rats, although there appeared to be a tendency for Figure 2 (bottom) illustrates the ASR results in the PD149163 to dose-dependently increase PPI in LE rats.
clozapine experiment. Analysis of the ASR data indicates Figure 3 (bottom) illustrates the ASR data for the that there was no significant difference in startle magnitude PD149163 experiment. There was not a significant differ- Reversal of sensorimotor gating deficits in BB rats PPI (top) and ASR (bottom) 7SEM in rats treated with clozapine. Significantly different from vehicle-treated LE rats represented by**(Po0.01). Significantly different from vehicle-treated BB rats representedby # (Po0.05).
PPI (top) and ASR (bottom) 7SEM in rats treated with PD149169. Significantly different from vehicle-treated LE rats representedby **(Po0.01). Significantly different from vehicle-treated BB rats ence in the ASR between BB and LE rats, but PD149163 represented by # (Po0.05) and ## (Po0.01).
significantly decreased the ASR in both strains of rat asevidenced by a main effect of PD149163 (F(3,68) ¼ 5.3,Po0.01). There was no significant strain  PD149163 ASR in BB rats and this effect was also reported by another interaction effect. Each dose of PD149163 significantly group (Warren and Gash, 1983). The current data are only reduced (Po0.05) the ASR in BB rats compared to vehicle, partially consistent with those reports since we observed a whereas the highest dose (3 mg/kg) reduced the ASR in LE significantly higher startle response in BB rats in the haloperidol experiment but not in the clozapine orPD149163 experiment. The reason for this variability inthe ASR strain differences is not clear; however, it indicates that there is a disassociation between the ASR straindifferences and the PPI strain differences, an observation we Figure 4 illustrates the catalepsy findings. There was a main also made in our original report. This is also supported by effect of drug treatment (F(5,42) ¼ 13.6, Po0.001). Post hoc the fact that all three drugs tended to decrease ASR in LE comparisons indicated that haloperidol (Po0.001) but no and BB rats with efficacy that did not correspond to their dose of clozapine or PD149163 significantly increased the Acute administration of haloperidol did not affect PPI in either LE or BB rats, which is also consistent with ourprevious report. Control (vehicle-treated) rats in the haloperidol group exhibited PPI that was higher (approxi- Consistent with our previous report (Feifel and Priebe, mately 40%) than the control groups in the clozapine and 2001), untreated (vehicle) BB rats exhibited reduced PPI PD149163 experiments (approximately 30%). However, it is compared to untreated LE rats in each of the three unlikely that this difference contributed to the negative drug experiments. In our previous study, we reported higher effects in the haloperidol experiment since an analysis of Reversal of sensorimotor gating deficits in BB ratsD Feifel et al phrenia (ie hallucinations, delusions), but they are lessefficacious against ‘negative’ symptoms (ie paucity ofthought, decreased emotional expression, decreased voli- tion behavior) or the cognitive deficits known to be associated with the disease (Meltzer, 2002). More recently,a second generation of antipsychotics has been developed.
These ‘atypical’ antipsychotics, of which clozapine is the prototype, appears to be more efficacious, particularly in ameliorating negative symptoms and cognitive deficitsassociated with schizophrenia (Kinon and Lieberman, 1996). Preclinical paradigms that can differentiate atypical from typical clinical profiles are needed since advances in the therapeutic field make it no longer desirable to develop compounds with first generation clinical profiles. Since it is established that atypical antipsychotics can produce desir-able clinical effects not associated with typical antipsycho- tics, it is reasonable to assume that there exist preclinical paradigms that model this atypical antipsychotic clinicaladvantage. Thus, whereas sensitivity to haloperidol wasonce considered the ‘litmus test’ for validating preclinicalmodels of antipsychotic potential, it is now desirable todevelop preclinical models that are preferentially sensitiveto atypical antipsychotics over typical antipsychotics suchas haloperidol. Indeed, several preclinical paradigms have Catalepsy scored as the time paws of rats remained on the bar been proposed to be useful for identifying putative in seconds (7SEM). Significantly different from saline group represented by antipsychotics of atypical category. Typically in these paradigms, second-generation antipsychotics have a spec-trum of effects that is distinct or broader than typical PPI produced by the weakest prepulse tested (4 dB), which antipsychotics. Examples of these effects include antagon- produced a mean PPI of 26% in the control group, was not ism of PPI disruption produced by NMDA antagonists increased by any of the haloperidol doses (PPI of 25%, 28%, (Geyer et al, 2001) and induction of a distinct regional and 28% for low, mid and high dose haloperidol, pattern of immediate early gene expression (Deutch and Duman, 1996). In this respect, it is significant that clozapine In our earlier study, we tested only a single dose of was able to reverse PPI deficits in BB rats. This reversal was haloperidol (0.5 mg/kg) and therefore we could not rule out dose dependent with the 10 and 15 mg/kg dose exhibiting the possibility that higher or lower doses would be more the greatest efficacy. It is not likely that clozapine’s ability to effective. In this experiment, higher and lower doses in acutely reverse PPI deficits in BB rats is due to a non- addition to the 0.5 mg/kg dose were tested. Since none of the specific pharmacological effect not associated with its doses of haloperidol had a significant effect, we can therapeutic mechanism, sedation for example. Whereas reasonably conclude that the PPI deficit in BB rats is not nonspecific effects such as sedation typically reduce normal affected by acute administration of haloperidol. However, it behavior, for example, locomotor activity, and can thus is known from our previous study that chronic haloperidol appear similar to the specific pharmacological effects of reverses PPI deficits in BB rats (Feifel and Priebe, 2001). The antipsychotics, restoration of deficient process, particularly lack of an effect after acute administration of any dose of an information processing deficit such as PPI, is unlikely to haloperidol in this study confirms that differences in be produced by a nonspecific effect. Consistent with this efficacy between chronic and acute haloperidol treatment notion, Depoortere et al (1997) concluded that clozapine’s are due to the temporal aspects of the two treatments, rather enhancement of PPI was not likely due to its sedating properties since sedating psychotropic drugs that do not Haloperidol is a prototype of the first generation, or have antipsychotic properties, for example, diazepam, ‘typical’ family of antipsychotic drugs. These antipsychotics decrease rather than facilitate PPI (Depoortere et al, 1997).
produce their therapeutic effects via a single pharmac- The fact that clozapine but not haloperidol reversed PPI ological mechanism, antagonism of D2 receptors (Feldman deficits in BB rats suggests that acute reversal of PPI deficits and Quenzer, 1997). Haloperidol’s lack of efficacy also in BB rats may also have utility as a predictive model for indicates that excessive dopamine transmission is not likely atypical antipsychotic-like properties among putative anti- to fully account for the PPI deficits seen in BB rats. Typical psychotics. While there is some debate as to what antipsychotics have notable limitations with respect to pharmacological properties underlie the clinical advantages clinical efficacy. For example, a significant proportion of associated with atypical antipsychotics, there is general schizophrenia patients fail to respond adequately to agreement that combination of antagonism at both the haloperidol and other antipsychotics from the typical family 5HT2A and D2 receptors is vital (Meltzer, 2002). The (Stern et al, 1994). Furthermore, experience with haloper- pattern of PPI effects observed with haloperidol and idol and other typical antipsychotics indicates that they clozapine in this and other studies may be understood if have good efficacy against ‘positive’ symptoms of schizo- inhibition of dopamine-2 transmission is sufficient to Reversal of sensorimotor gating deficits in BB rats reverse BB deficits chronically, and that other pharmaco- effects of the NMDA antagonist, MK801 (Feifel et al, 1999), logical mechanisms, for example, 5HT2 antagonism, po- and DOI, a 5HT2A agonist (Feifel et al, 2003). These results tentiate the D2 inhibition to produce a stronger, and thus suggested that PD149163 produces antipsychotic-like pre- more rapid reversal of PPI deficits. In this way, inhibition of clinical effects by mechanisms other than inhibition of D2 transmission may be necessary and sufficient for chronic reversal of PPI deficits in BB rats and necessary In the current study, PD149163 produced a very distinct but not sufficient for acute reversal.
reversal of PPI deficits in BB rats. In fact, after treatment However, other explanations are possible. For example, in with the lowest dose, PPI in BB rats was higher than LE rats, addition to sharing clinical properties with all other atypical although the difference did not reach statistical significance.
antipsychotics, clozapine is also considered by many The current results also provide further evidence that clinicians and investigators to be singular among anti- indirect inhibition of dopamine transmission cannot psychotics in regards to efficacy (Taylor and Duncan- account, by itself, for the antipsychotic-like effects of McConnell, 2000; Chakos et al, 2001; Conley and Kelly, PD149163, since PD149163 was effective in reversing BB 2001). This is particularly evident in the high success rates rat PPI deficits, whereas haloperidol, a potent D2 antago- with clozapine among treatment-resistant patients with nist, was not. In this study, PD149163’s effect on BB PPI was schizophrenia (Kane et al, 1988; Chakos et al, 2001; Kane more consistent with clozapine, than with haloperidol.
et al, 2001). Thus, rather than due to mechanisms shared by While this finding does not by itself suggest that PD149163 all atypical antipsychotics (eg D2 and 5HT2 antagonism), has potential as an antipsychotic, the current finding is clozapine’s ability to abolish PPI deficits in BB rats may be consistent with previous evidence suggesting that PD149163 due to a putative mechanism which distinguishes clozapine has a preclinical profile consistent with atypical anti- from all other currently available antipsychotics, and which psychotic drugs (Feifel et al, 2003). In this respect, is responsible for its unique efficacy profile. If this is the PD149163’s effects on PPI in BB rats supports the notion case, acute reversal of PPI deficits in BB rats may be a model that the BB rat is a predictive model for antipsychotics with for drugs with novel properties that, like clozapine, are atypical or novel mechanisms. The fact that PD149163, like associated with a superior level of efficacy to current typical clozapine, did not produce significant catalepsy, whereas and atypical antipsychotics. Studies with other typical and haloperidol did, supports the contention that PD149163 has atypical antipsychotic drugs will be important in order to a profile more similar to atypical than typical antipsychotics determine whether PPI deficits in the BB rats is a predictive and strengthens the evidence that acute PPI reversal in BB model of the clinical effects associated with atypical rats has predictive validity for drugs with atypical antipsychotics or of novel drugs useful in treatment In terms of establishing the validity of the BB model as PD149163 appeared to produce the most robust effects on predictive screen for atypical antipsychotic drugs, these PPI reversing PPI strain differences at all doses tested even findings should be considered preliminary. Additional though it appeared to produce a nonsignificant tendency to studies with other antipsychotics in the BB model will be increase PPI in LE rats. PD149163’s ability to reverse the PPI needed to address the issue of whether PD149163’s effects deficits in BB rats is consistent with the notion that the BB are shared by other atypical antipsychotics and are thus rat is a useful predictive model of antipsychotic efficacy.
suggestive of ‘atypical’ clinical features or whether Significant evidence exists that neurotensin, a neuropeptide, PD149163’s effects are shared only by clozapine and are may act as an endogenous antipsychotic and that it may, in thus suggestive of a uniquely superior efficacy similar to fact, mediate some of the clinical effects of antipsychotic clozapine. It is noteworthy that PD149163 produced the drugs (Kinkead and Nemeroff, 2002). There is also a large most robust reversal of PPI deficits in BB rats of the three body of evidence that neurotensin and neurotensin agonists compounds tested, a finding that is auspicious for the produce antipsychotic-like effects in preclinical studies.
therapeutic potential of drugs that target neurotensin This has led many investigators to propose that neurotensin agonists may have clinical potential as antipsychotic drugs In summary, the BB rat offers a model of sensorimotor (for a review, see Caceda et al, 2003). We have previously gating deficits and a predictive model of antipsychotic shown that administration of neurotensin produces anti- potential with many novel and useful features. First, this psychotic-like effects on PPI (Feifel et al, 1997). The model does not require pharmacological, environmental, or mechanism implicated in the antipsychotic-like effects neuroanotomical manipulations to produce PPI deficits.
produced by neurotensin has been inhibition of dopamine Rather, PPI deficits homologous to those seen in schizo- transmission in the mesolimbic pathway, although neuro- phrenia and other neuropsychiatric disorders are exhibited tensin does not have significant affinity for dopamine spontaneously and presumably due to the single gene receptors (Adachi et al, 1990; Nouel et al, 1992). The 8–13 abnormality associated with these rats. As a genetic model amino-acid fragment of neurotensin is the smallest of PPI deficits, the BB rat exhibits greater construct validity fragment that retains full biological activity of the parent for the neuropsychiatric disorders associated with PPI tridecapeptide (Kanba et al, 1988). PD149163 was developed deficits compared to models requiring pharmacological, by modifying neurotensin (8–13) to make it more stable to environmental, or neuroanotomical manipulations to pro- endopeptidase degradation and has been shown to cross the duce PPI deficits. This improved construct validity affords blood–brain barrier after parenteral administration (Wus- the possibility of using the BB rats to explore the trow et al, 1995). We have previously shown that PD149163 neurobiological and genetic substrates underlying sensori- antagonizes amphetamine-induced disruption of PPI (Feifel motor gating abnormalities that may also underlie the et al, 1999). PD149163 also antagonized the PPI disrupting neuropsychiatric conditions associated with such deficits.
Reversal of sensorimotor gating deficits in BB ratsD Feifel et al As in the context of acute administration, the BB rat model Feifel D, Minor KL, Dulawa S, Swerdlow NR (1997). The effects of appears to differentiate typical from nontypical antipsycho- intra-accumbens neurotensin on sensorimotor gating. Brain Res tics and/or drugs with clozapine-like efficacy from drugs with more conventional efficacy, it may also be a useful Feifel D, Priebe K (2001). Vasopressin-deficient rats exhibit predictive screen for novel antipsychotic drugs. Haloper- sensorimotor gating deficits that are reversed by subchronic idol’s effect on BB PPI is greater after chronic administra- haloperidol. Biol Psychiatry 50: 425–433.
Feifel D, Reza TL, Wustrow DJ, Davis MD (1999). Novel tion than after acute administration (Feifel and Priebe, antipsychotic-like effects on prepulse inhibition of startle 2001). Therefore, the BB rat model may also be useful for produced by a neurotensin agonist. J Pharmacol Exp Therapeut elucidating the mechanisms underlying the therapeutic time course, which is typically associated with antipsychotic Feldman RS MJ, Quenzer LF (1997). Principles of Neuropsycho- treatment in schizophrenia patients. In this regard, it will be pharmacology. Sinauer Associates, Inc.: Sunderland, MA.
important to examine how the effects of chronic adminis- Geyer MA, Krebs-Thomson K, Braff DL, Swerdlow NR (2001).
tration of clozapine and PD149163 compare to the effect of Pharmacological studies of prepulse inhibition models of acute administration of these drugs on BB PPI deficits.
sensorimotor gating deficits in schizophrenia: a decade inreview. Psychopharmacology (Berl) 156: 117–154.
Geyer MA, Wilkinson LS, Humby T, Robbins TW (1993). Isolation rearing of rats produces a deficit in prepulse inhibition ofacoustic startle similar to that in schizophrenia. Biologic DF is supported by a NIMH grant (MH62451). We are grateful for the NIMH Chemical Synthesis Program Kanba KS, Kanba S, Nelson A, Okazaki H, Richelson E (1988).
and SRI international for providing PD149163. We thank [3H]neurotensin(8–13) binds in human brain to the same sites as Dr. Neal Swerdlow for assistance with the catalepsy does [3H]neurotensin but with higher affinity. J Neurochem 50:131–137.
Kane JM, Honigfeld G, Singer J, Meltzer H (1988). Clozapine in treatment-resistant schizophrenics. Psychopharmacol Bull 24: Kane JM, Marder SR, Schooler NR, Wirshing WC, Umbricht D, Adachi DK, Kalivas PW, Schenk JO (1990). Neurotensin binding to Baker RW et al (2001). Clozapine and haloperidol in moderately dopamine. J Neurochem 54: 1321–1328.
refractory schizophrenia: a 6-month randomized and double- Braff DL, Geyer MA (1990). Sensorimotor gating and schizo- blind comparison. Arch Gen Psychiatry 58: 965–972.
phrenia. Human and animal model studies. Arch Gen Psychiatry Kinkead B, Nemeroff CB (2002). Neurotensin: an endogenous antipsychotic? Curr Opin Pharmacol 2: 99–103.
Caceda R, Kinkead B, Nemeroff CB (2003). Do neurotensin Kinon BJ, Lieberman JA (1996). Mechanisms of action of atypical receptor agonists represent a novel class of antipsychotic drugs? antipsychotic drugs: a critical analysis. Psychopharmacology Semin Clin Neuropsychiatry 8: 94–108.
Chakos M, Lieberman J, Hoffman E, Bradford D, Sheitman B Laycock JF, Gartside IB, Chapman JT (1983). A comparison of the (2001). Effectiveness of second-generation antipsychotics in learning abilities of Brattleboro rats with hereditary diabetes patients with treatment-resistant schizophrenia: a review and insipidus and Long-Evans rats using positively reinforced meta-analysis of randomized trials. Am J Psychiatry 158: operant conditioning. Prog Brain Res 60: 183–187.
Le Pen G, Moreau JL (2002). Disruption of prepulse inhibition of Cilia J, Reavill C, Hagan JJ, Jones DN (2001). Long-term evaluation startle reflex in a neurodevelopmental model of schizophrenia: of isolation-rearing induced prepulse inhibition deficits in rats.
reversal by clozapine, olanzapine and risperidone but not by Psychopharmacology (Berl) 156: 327–337.
haloperidol. Neuropsychopharmacology 27: 1–11.
Conley RR, Kelly DL (2001). Management of treatment resistance Lipska BK, Swerdlow NR, Geyer MA, Jaskiw GE, Braff DL, in schizophrenia. Biol Psychiatry 50: 898–911.
Weinberger DR (1995). Neonatal excitotoxic hippocampal Costall B, Hui SC, Naylor RJ (1978). Correlation between multitest damage in rats causes post-pubertal changes in prepulse and single test catalepsy assessment. Neuropharmacology 17: inhibition of startle and its disruption by apomorphine.
Depoortere R, Perrault G, Sanger DJ (1997). Potentiation of Mansbach RS, Geyer MA (1989). Effects of phencyclidine and prepulse inhibition of the startle reflex in rats: pharmacological phencyclidine biologs on sensorimotor gating in the rat.
evaluation of the procedure as a model for detecting anti- Neuropsychopharmacology 2: 299–308.
psychotic activity. Psychopharmacology 132: 366–374.
Mansbach RS, Geyer MA, Braff DL (1988). Dopaminergic Deutch AY, Duman RS (1996). The effects of antipsychotic drugs stimulation disrupts sensorimotor gating in the rat. Psychophar- on Fos protein expression in the prefrontal cortex: cellular localization and pharmacological characterization. Neuroscience Meltzer HY (2002). Mechanism of action of atypical antipsychotic drugs. In: Davis KLC, Joseph Coyle D, Nemeroff C (eds).
Engelmann M, Landgraf R (1994). Microdialysis administration of Neuropsychopharmacology: The Fifth Generation of Progress.
vasopressin into the septum improves social recognition in American College of Neuropsychopharmacology, Lippincot, Brattleboro rats. Physiol Behav 55: 145–149.
Feenstra MG, Snijdewint FG, Van Galen H, Boer GJ (1990).
Nouel D, Costentin J, Lugrin D, Kitabgi P, Ple N, Davoust D (1992).
Widespread alterations in central noradrenaline, dopamine, and Investigations about a direct neurotensin-dopamine interaction serotonin systems in the Brattleboro rat not related to the local by nuclear magnetic resonance study, synaptosomal uptake of absence of vasopressin. Neurochem Res 15: 283–288.
dopamine, and binding of neurotensin to its receptors.
Feifel D, Melendez G, Shilling PD (2003). A systemically administered neurotensin agonist blocks disruption of prepulse Sipes TA, Geyer MA (1994). Multiple serotonin receptor subtypes inhibition produced by a serotonin-2A agonist. Neuropsycho- modulate prepulse inhibition of the startle response in rats.
Reversal of sensorimotor gating deficits in BB rats Stanley ME, Glick SD (1976). Interaction of drug effects with Warren PH, Gash DM (1983). Hyperreflexive behavior in testing procedures in the measurement of catalepsy. Neurophar- Brattleboro rats. Peptides 4: 421–424.
Weiss IC, Feldon J, Domeney AM (1999). Circadian time does not Stern RG, Kahn RS, Davidson M, Nora RM, Davis KL (1994). Early modify the prepulse inhibition response or its attenuation by response to clozapine in schizophrenia. Am J Psychiatry 151: apomorphine. Pharmacol, Biochem Behav 64: 501–505.
Williams AR, Carey RJ, Miller M (1983). Behavioral differences Swerdlow NR, Geyer MA (1998). Using an animal model of between vasopressin-deficient (Brattleboro) and normal Long- deficient sensorimotor gating to study the pathophysiology and new treatments of schizophrenia. Schizophrenia Bulletin 24: Williams AR, Carey RJ, Miller M (1985). Altered emotionality of the vasopressin-deficient Brattleboro rat. Peptides 6(Suppl 1): Taylor DM, Duncan-McConnell D (2000). Refractory schizo- phrenia and atypical antipsychotics. J Psychopharmacol 14: Wustrow DJ DM, Akunne HC, Corbin AE, Wiley JN, Wise LD, Heffner TG (1995). Reduced amide bond neurotensin 8-13 Wadenberg ML (1996). Serotonergic mechanisms in neuroleptic- mimetics with potent in vivo activity. Bioorgan Medicin Chem induced catalepsy in the rat. Neurosci Biobehav Rev 20: 325–339.

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