Antipsychotic drug-like facilitation of latent inhibition by a brain-penetrating neurotensin-1 receptor agonist.

Latent inhibition (LI) is a measure of cognitive gating and refers to reduced conditioned learning when there is pre-exposure to the conditioned stimulus (CS) before it is paired with the unconditioned stimulus (US). Dysregulation of LI is associated with some neuropsychiatric disorders, including schizophrenia, and the ability to facilitate LI in rodents is a reasonably good predictive test for antipsychotic drugs. Converging evidence supports neurotensin-1 receptor (NTS1) agonists as novel drugs for schizophrenia. Therefore, we investigated the ability of a brain-penetrating, selective NTS1 agonist, PD149163, to facilitate LI in heterozygous Brattleboro rats, a strain that exhibits naturally low LI. Conditioned taste aversion to flavored water (FW; 0.1% saccharin) was induced by pairing it with malaise-inducing injections of lithium chloride (LiCl). Prior to LiCl-FW pairing, rats received subcutaneous injections of saline, or PD149163 (100 µg/kg or 200 µg/kg). Half the rats in each drug group had been allowed to drink FW the day before the LiCl-FW pairing (pre-exposed rats). Two days after pairing, the amount of FW each rat consumed was recorded. LI, defined as significantly greater FW drinking in the pre-exposed group compared with the non pre-exposed group, was exhibited only among rats that received 200 µg/kg of PD149163. These results further support NTS1 agonists as potentially novel drugs for the treatment of schizophrenia.

Peripherally administered oxytocin modulates latent inhibition in a manner consistent with antipsychotic drugs.

BACKGROUND: Peripherally administered oxytocin (OT) has produced antipsychotic drug (APD)-like effects in animal tests that are predictive of APD efficacy. However, these effects have mainly been demonstrated using animal models of schizophrenia-like deficits in prepulse inhibition (PPI) of the startle reflex. Another schizophrenia-relevant abnormality that is the basis of a predictive animal test for APD efficacy is deficient latent inhibition (LI). LI is the normal suppression of a classically conditioned response when the subject is pre-exposed to the conditioned stimulus (CS) before it is paired with the unconditioned stimulus (UCS). Conditioned taste aversion (CTA), the normal avoidance of ingesting a food or liquid by animals when its taste is associated with an aversive experience, was used to test whether OT facilitates LI consistent with APDs. METHODS: Brown Norway rats, known to naturally display attenuated LI, were aversively conditioned on two consecutive exposures to flavored drinking water (0.1% saccharin) by pairing it with malaise-inducing lithium chloride injections. Concurrent with conditioning, rats received subcutaneous OT (0.02, 0.1, 0.5mg/kg) or saline. Some rats were pre-exposed to the flavored water prior to its aversive conditioning (pre-exposed) while others were not (non pre-exposed). Two days after aversive conditioning the amount of flavored water consumed during a 20-min session was recorded. RESULTS: As expected, LI, defined as greater consumption by pre-exposed vs. non pre-exposed rats was only weakly exhibited in Brown Norway rats and OT enhanced LI by reducing CTA in pre-exposed rats in a dose-dependent manner, with the 0.02 mg/kg dose producing the strongest effect. CONCLUSIONS: The facilitation of LI by OT is consistent with the effects produced by APDs and provides further support for the notion that OT has therapeutic potential for schizophrenia.

Growth hormone-regulatory peptides (GHRH and somatostatin) and feeding: a model for the integration of central and peripheral function.

The present paper provides an overview of findings that implicate growth hormone-releasing hormone (GHRH) and somatostatin (SS), the two peptides that regulate growth hormone secretion, in the central regulation of feeding. Evidence is presented that GHRH and SS increase food intake, in the rat, via a common centrally mediated mechanism involving the suprachiasmatic nucleus. Food intake is increased by increasing motivation to eat as evidenced by facilitation of operant behavior. Macronutrient-choice studies indicate that GHRH (and possibly SS) selectively facilitate protein consumption. Time of day is also important, with evidence that endogenous GHRH and SS-induced feeding is most strong in the early nocturnal period. GHRH and SS, together with other nutrient-specific signals, such as neuropeptide Y, noradrenaline and galanin, may determine the circadian expression of food intake in animals. Other behavioral and physiological effects of these peptides, both central and peripheral, are reviewed in the context of a possible mechanism by which these peptides integrate diverse, but complimentary, central and peripheral functions related to nutrition, metabolism and growth.

Vasopressin-deficient rats exhibit sensorimotor gating deficits that are reversed by subchronic haloperidol.

BACKGROUND: Brattleboro (BB) rats are Long Evans rats with a single base pair genetic mutation that impairs their ability to synthesize vasopressin, a neurotransmitter and neurohormone. Brattleboro rats are known to have deficits in memory, emotional reactivity, motivation, attention, and social recognition, abnormalities associated with schizophrenia. Prepulse inhibition (PPI) of the acoustic startle reflex (ASR) is a measure of sensorimotor gating. Prepulse inhibition is deficient in unmedicated schizophrenia patients, and PPI deficits in schizophrenia may be related to the cognitive and behavioral abnormalities associated with this disorder. In this study we tested the hypothesis that BB rats exhibit PPI deficits analogous to those exhibited by schizophrenia patients. METHODS: In one experiment, BB rats homozygous (BB-Ho) or heterozygous (BB-Hz) for the mutated vasopressin gene were compared with normal Long Evans (LE) rats from the same breeder source. In separate studies, BB-Ho and LE rats were treated with acute or subchronic (22 days) injections of haloperidol. RESULTS: Both BB-Ho and BB-Hz rats had significantly higher ASR and significantly lower PPI compared with LE rats, with BB-Ho rats exhibiting the lowest PPI among all three genotypes. Furthermore, a single subcutaneous (SC) injection of haloperidol (0.5 mg/kg) did not reverse the PPI deficits in BB rats. In contrast, daily SC administration of haloperidol for 22 days reversed PPI deficits in BB rats. CONCLUSIONS: These results suggest that PPI deficient BB rats may be an important genetic model of PPI deficits, which may help elucidate genetic, pharmacologic, and pathophysiologic mechanisms underlying PPI deficits and the effects of antipsychotic drugs on PPI.

Sensorimotor gating deficits in bipolar disorder patients with acute psychotic mania.

BACKGROUND: Deficits in sensorimotor gating as assessed by prepulse inhibition (PPI) and habituation of the human startle response have been noted in schizophrenia and other patients with known dysfunction in the brain substrates that regulate PPI. During acute mania, bipolar disorder (BD) and schizophrenia patients present with symptoms that are similar. To determine if these clinical similarities extend to neurophysiologic domains, PPI and startle habituation were assessed in BD patients with acute psychotic mania and compared with a sample of acutely psychotic schizophrenia patients and a normal comparison group. METHODS: Fifteen BD patients, 16 schizophrenia patients, and 17 control subjects were assessed on PPI and startle habituation. RESULTS: The BD patients had significantly lower PPI than did the control subjects in two of the three PPI conditions (60- and 120-msec interstimulus intervals) as well as less startle habituation. The BD patients did not statistically differ from the schizophrenia patients in PPI or habituation. CONCLUSIONS: These findings of sensorimotor gating deficits among bipolar disorder patients are consistent with other findings using different measures of information processing and suggest that the neurobiological substrates underlying sensorimotor gating may be dysregulated during acute manic and psychotic states.

Attitudes toward psychiatry as a prospective career among students entering medical school.

OBJECTIVE: The number of U.S. medical graduates choosing careers in psychiatry is in decline. In order to determine whether this disinclination toward psychiatry occurs before versus during medical school, this study surveyed medical students at the start of their freshman year. METHOD: Within the first 2 weeks of medical training, 223 freshman medical students from three Southwestern medical schools were surveyed with a questionnaire designed to assess their perceptions of careers in various specialties. RESULTS: Responses suggest that new medical students most strongly value aspects of doctoring that seem to comport well with the actual practice of psychiatry: desire for interpersonal contact, helping patients, attractive lifestyle, and challenging work. However, these students begin their medical training viewing a career in psychiatry as distinctly and consistently less attractive than other specialties surveyed. More than one-quarter of the new medical students had already definitively ruled out a career in psychiatry. New medical students rated psychiatry significantly lower than each of the other specialties in regard to the degree to which it was a satisfying job, financially rewarding, enjoyable work, prestigious, helpful to patients, dealing with an interesting subject matter, intellectually challenging, drawing on all aspects of medical training, based on a reliable scientific foundation, expected to have a bright and interesting future, and a rapidly advancing field of understanding and treatment. CONCLUSIONS: Contrasting these results with previous studies suggests that an erosion has occurred over the past two decades in the attitudes that new medical students hold toward psychiatry. The authors suggest that some of the negative attitudes are based on objectifiably false beliefs that should be actively targeted for remediation within the medical school curriculum.

Antipsychotic potential of CCK-based treatments: an assessment using the prepulse inhibition model of psychosis.

Systemic injections of cholecystokinin (CCK), a "gut-brain" peptide, have been shown to modulate brain dopamine function and produce neuroleptic-like effects on such dopamine-regulated behaviors as locomotor activity. However, clinical trials of CCK agonists in schizophrenia patients showed mixed results. To re-examine the antipsychotic potential of CCK-based treatments, we examined systemic injections of CCK analogs in an animal model with strong face and construct validity for sensorimotor-gating deficits seen in schizophrenia patients and with strong predictive validity for antipsychotic drug activity. Prepulse inhibition (PPI) occurs when a weak acoustic lead stimulus ("prepulse") inhibits the startle response to a sudden loud sound ("pulse"). PPI is significantly reduced in schizophrenia patients and rats treated with dopamine agonists. Antipsychotics reverse decreased PPI in rats to a degree highly correlated with their clinical efficacy. Subcutaneous (s.c.) injections of caerulein (10 micrograms/kg) a mixed CCKA/B agonist, partially reversed amphetamine-induced reduction of PPI; whereas, s.c. haloperidol (0.5 mg/kg) totally reversed amphetamine-induced disruption of PPI. Caerulein's effect on PPI was blocked by pretreatment with a CCKA antagonist (devazepide) but not a CCKB antagonist (L-365,260). CCK-4, a preferential CCKB agonist, had no significant effect on PPI. These results suggest that caerulein produces a weak neuroleptic-like effect on PPI that is mediated by stimulation of CCKA receptors. Possible circuities in this effect are discussed. In a separate experiment, s.c. caerulein produced to a more potent neuroleptic-like profile on amphetamine-induced hyperlocomotion, suggesting that selection of preclinical paradigms may be important in evaluating the antipsychotic potential of CCK-based treatments.

Startle and sensorimotor gating in rats lacking CCK-A receptors.

Otsuka Long Evans Tokushima Fatty (OLETF) rats lack CCK-A receptors because of a genetic mutation. Previous studies have shown that CCK-A receptors seem to play a role in the regulation of prepulse inhibition (PPI) of the startle reflex, an operational measure of sensorimotor gating. This study investigated baseline and drug-disrupted PPI in OLETF rats and their non-mutant counterparts, Long Evans Tokushima Otsuka (LETO) rats. Baseline PPI did not differ significantly between the two rat genotypes but OLETF rats exhibited a higher acoustic startle response compared to LETO rats. Amphetamine (2 mg/kg), and the non-competitive NMDA antagonist, dizocilpine (0.1 mg/kg), disrupted PPI in LETO rats but not in the OLETF rats. Apomorphine (0.5 mg/kg) failed to disrupt PPI in both LETO and OLETF rats, and haloperidol (0.5 mg/kg) produced a comparable facilitation of PPI in both groups. In a separate study, OLETF rats were found to be less sensitive to the locomotor stimulating effects of amphetamine. These results suggest that CCK-A receptors play a significant role in the behavioral effects of amphetamine and dizocilpine. The PPI response of OLETF rats to amphetamine and dizocilpine is similar to normal rats pretreated with atypical antipsychotics, suggesting that CCK-A receptors may play an important role in the restoration of drug-disrupted PPI by antipsychotics.

Rationale and guidelines for the inpatient treatment of acute psychosis.

For patients hospitalized with acute episodes of psychosis, rapid stabilization of intense positive symptoms, hostility, and agitation is typically a preeminent therapeutic goal. These goals often differ from those of the nonhospitalized patient with psychosis for whom long-term treatment goals such as improvement of negative symptoms, cognitive function, compliance, and reduction in side effect burden may be paramount. Therefore, when selecting an antipsychotic treatment for hospitalized patients, efficacy against positive symptoms and hostility as well as speed of therapeutic onset should strongly be considered. At the same time, selection of antipsychotic treatment in the inpatient setting should establish a definitive treatment that will address long-term goals effectively after discharge. This article presents the rationale and practical guidelines for selection of treatment regimens for patients hospitalized due to acute psychosis.

Iron overload among a psychiatric outpatient population.

BACKGROUND: Iron overload has been suggested to be an unrecognized cause of psychiatric morbidity. This study sought to estimate the prevalence of iron overload in a large outpatient psychiatric clinic. METHOD: A retrospective review of screening blood chemistries was conducted on 661 active outpatients at a large, university outpatient psychiatric clinic to identify elevated iron status results (plasma iron, percentage of iron saturation) suggestive of iron overload. Patients with positive profiles were asked to undergo a subsequent blood chemistry to confirm positive results (plasma iron, percentage of iron saturation, plus plasma ferritin). Patients with positive repeated iron chemistry results were considered likely candidates for iron overload. RESULTS: Twenty-one patients (3.2%) were identified as meeting one of the criteria suggestive of iron overload on initial screening reports. Thirty-one percent of those who underwent subsequent, confirmatory testing (5/16) continued to meet one of the criteria. On the basis of these results, we estimated a 1% (3.2 x 0.31) prevalence rate of likely candidates for iron overload. A review of these patients' charts indicated that they carried an unexpectedly high rate of bipolar affective disorder (80%) as a diagnosis and were, without exception, atypical in that they were resistant to conventional psychiatric treatment and lacked a family history for this disorder. The prevalence of positive iron overload profiles on a routine blood chemistry was similar to the prevalence of positive thyroid abnormalities based on TSH results in this population. CONCLUSION: Blood chemistry profiles suggestive of iron overload may be associated with a small portion of treatment-resistant psychiatric patients. Routine screening for iron abnormalities, especially in treatment-resistant patients, should be considered. Further studies are required to determine the causal association, if any, between iron excess and primary psychiatric illnesses.

Safety and tolerability of a rapidly escalating dose-loading regimen for risperidone.

BACKGROUND: Risperidone is an "atypical" antipsychotic with strong binding affinity for dopamine-2 and serotonin-2 receptors. Risperidone is often used to treat hospitalized patients who have acute psychotic decompensation, and the therapeutic target dose commonly used is 2 to 6 mg/day. The most common clinical practice is to titrate the dose of risperidone to the target therapeutic dose over several days. This study investigated the safety and tolerability of a rapid oral-loading regimen for risperidone developed to achieve therapeutic doses of this antipsychotic within 24 hours. METHOD: Rapid-loaded risperidone was initiated with 1 mg. Subsequent doses were increased by 1 mg every 6 to 8 hours up to 3 mg. Dose increases were contingent on tolerance of last administered dose. RESULTS: Of a sample of 11 consecutive inpatients admitted to an acute psychiatric facility who were treated with this protocol, 7 tolerated the most rapid titration, achieving a standing dose of 3 mg b.i.d. in 16 hours. Three required a slightly slower titration and achieved this target dose in 24 hours. One patient could not tolerate the 3-mg dose but tolerated a standing regimen of 2 mg t.i.d. No patient experienced serious extrapyramidal side effects, sedation, or any other adverse event during the rapid titration, and in no case did risperidone have to be discontinued. CONCLUSION: These results suggest that aggressive dosing of risperidone is well tolerated in most psychiatric inpatients.

Individual differences in prepulse inhibition of startle as a measure of individual dopamine function.

This study investigated whether individual differences in prepulse inhibition (PPI) of the acoustic startle reflex reflect meaningful trait differences in the function of dopaminergic substrates that regulate it. Baseline PPI of individual rats showed strong test-retest reliability across 3 consecutive test days, and there was a significant negative correlation between individual baseline PPI and both disruption of PPI produced by apomorphine and facilitation of PPI by haloperidol. The test-retest reliability and the inverse association between baseline PPI and drug-induced effects were stronger with 8-10 dB prepulses compared with less intense prepulses. These results demonstrate that individual differences in baseline PPI predict individual differences in sensitivity of PPI to drugs that affect the dopamine system and that PPI produced by more intense prepulses may be more representative of these individual differences.

Feeding effects of growth hormone-releasing factor in rats are photoperiod sensitive.

By examining the influence of photoperiod, this study extended previous findings showing that centrally administered growth hormone-releasing factor (GRF) increases feeding. Rats received intracerebroventricular injections of GRF (0, 0.4, 4.0, and 40.0 pmol) during either the light or dark phase of the photocycle. GRF produced a dose-dependent increase in 90-min food intake during the light photoperiod but a dose-dependent suppression during the dark photo-period. GRF did not significantly alter 24-hr feeding or locomotor activity, and a biologically inactive analog of GRF had no effect on feeding. Possible mechanisms underlying GRF's photoperiod dependency are discussed, including a suggestion that endogenous GRF may play a role in the regulation of circadian feeding.

The effects of subchronic haloperidol on intact and dizocilpine-disrupted sensorimotor gating.

RATIONALE: Reversal of deficits in prepulse inhibition (PPI) of the startle reflex in rats is considered a preclinical screen for potential antipsychotics. Whereas acutely administered antipsychotics consistently reverse apomorphine-induced deficits in PPI, some antipsychotics, including haloperidol, are unable to reverse deficits in PPI produced by non-competitive NMDA antagonists such as phencyclidine or dizocilpine (MK-801). Acute administration of antipsychotics tends to facilitate baseline PPI. However, the effect is generally not large enough in magnitude nor reliable enough to be considered a useful preclinical screen for antipsychotic activity. OBJECTIVE: Because the clinical effects of antipsychotics typically require subchronic administration, this study tested the hypothesis that reversal of NMDA antagonist-induced deficits in PPI by antipsychotics require subchronic administration. A second aim of this study was to determine if subchronic administration of an antipsychotic produces a more potent facilitation of baseline PPI than acute administration. METHODS: Rats received a subcutaneous injection of 0, 0.025, 0.1 or 0.5 mg/kg haloperidol for 16 consecutive days. On day 16, half the rats in each haloperidol dose group received a second subcutaneous injection consisting of either dizocilpine (0.1 mg/kg) or saline. RESULTS: None of the haloperidol doses tested had a significant effect on baseline PPI. The 0.1 mg/kg dose of haloperidol diminished but did not completely reverse dizocilpine-induced disruption of PPI. The other doses had no significant effect. CONCLUSIONS: These results suggest that time course factors may partially modify the effects of haloperidol on dizocilpine-induced disruption of PPI but not its effect on baseline PPI.

Oxytocin modulates psychotomimetic-induced deficits in sensorimotor gating.

Oxytocin plays an important role in the regulation of normal cognitive functions and behaviors, which are disturbed in schizophrenia. Several studies suggest that oxytocinergic function is abnormal in schizophrenia patients. Thus, oxytocin may be involved in the pathophysiology associated with this disorder. This study investigated the regulatory effects of oxytocin on deficits in prepulse inhibition (PPI) associated with schizophrenia. Prepulse inhibition (PPI) is an operational measure of sensorimotor gating which can be measured across many species. PPI is the normal suppression of the startle reflex when the intense startling stimulus ("pulse") is immediately preceded by a weaker stimulus ("prepulse"). Subcutaneously administered oxytocin (0.04-1.0 mg/kg) dose-dependently restored PPI that had been reduced in rats by dizocilpine, a non-competitive NMDA antagonist, and by amphetamine, an indirect dopamine agonist. Oxytocin did not produce a significant effect on baseline PPI or PPI decreased by the direct dopamine agonist, apomorphine. The underlying startle response amplitude was also not significantly altered by oxytocin. These results suggest that oxytocin may play an important role in the modulation of dopaminergic and glutamatergic regulation of PPI, and that it may act as a novel endogenous antipsychotic.

SR146131, a cholecystokinin-A receptor agonist, antagonizes prepulse inhibition deficits produced by dizocilpine and DOI.

RATIONALE: Converging evidence has demonstrated that cholecystokinin (CCK) inhibits mesolimbic brain dopamine (DA) function via activation of CCK-A (CCK-1) receptors. These effects of CCK have stimulated interest in the potential use of CCK agonists as antipsychotic drugs. Most research on the antipsychotic-like drug effects of CCK has used CCK or CCK analogues that nonselectively activate both CCK-A and CCK-B (CCK-2) receptors, which may produce opposite effects. SR146131, a CCK-A selective nonpeptide agonist, has recently been developed (Sanofi-Synthelabo). OBJECTIVE: To determine whether SR146131 exhibits antipsychotic-like qualities in the prepulse inhibition (PPI) paradigm. METHODS: We performed experiments to determine whether SR146131 (vehicle, 0.01, 0.1, 1.0 mg/kg) would attenuate PPI deficits induced by amphetamine (2.0 mg/kg), an indirect dopamine agonist, and dizocilpine (0.1 mg/kg), a noncompetitive N-methyl-D-aspartate (NMDA) antagonist. Since SR146131 demonstrated significant effects on PPI disrupted by the noncompetitive NMDA antagonist, an effect associated with drugs that inhibit serotonin (5HT)2A transmission, we also tested the effects of SR146131 on PPI disruption produced by 2,5-dimethoxy-4-iodoamphetamine (DOI, 0.5 mg/kg), a direct 5HT2A agonist. RESULTS: SR146131 did not significantly affect startle magnitude, baseline PPI, or amphetamine-induced PPI deficits. However, it dose-dependently antagonized dizocilpine and DOI-induced PPI deficits. CONCLUSIONS: The lack of an effect of SR146131 on amphetamine-induced disruption of PPI suggests that a selective nonpeptide CCK-A agonist may not produce antipsychotic-like effects on dopamine transmission. However, the unexpected effects of SR146131 on dizocilpine and DOI-induced PPI deficits are consistent with the effects of drugs that inhibit transmission in the 5HT2A receptor system, including atypical antipsychotic drugs. Possible mechanisms underlying these findings are discussed.

Neurotensin agonists block the prepulse inhibition deficits produced by a 5-HT2A and an alpha1 agonist.

RATIONALE: Neurotensin (NT) agonists have been proposed as potential antipsychotics based exclusively upon their ability to inhibit dopamine-2 (D2) receptor transmission. Several other pharmacological mechanisms have been implicated in enhancing the antipsychotic profile produced by D2 inhibition alone. These include inhibition of 5-HT2A and alpha1-adrenoceptors. Recently, we reported that systemic administration of the neurotensin agonist PD149163 blocks deficits in prepulse inhibition (PPI) of the startle reflex produced by the 5-HT2A receptor agonist DOI. This suggested that NT agonists could inhibit 5-HT2A modulation of neurotransmission. OBJECTIVE: To determine if other peripherally administered NT agonists shared this effect, we examined the effects of NT69L, another NT agonist, on DOI-induced PPI deficits. In addition, to determine if NT agonists also inhibit alpha1-adrenoceptor neurotransmission, we examined the effects of PD149163 and NT69L on PPI deficits induced by the alpha1-adrenoceptor agonist, cirazoline. METHODS: In the NT69L/DOI study, rats received subcutaneous (SC) injections of NT69L (0, 0.1, 1, or 2 mg/kg) followed 30 min later by SC saline or DOI (0.5 mg/kg). In the NT agonist/cirazoline studies, animals received SC injections of either PD149163 (0, 0.01, 0.1, or 1 mg/kg) or NT69L (0, 0.01, 0.1, or 1 mg/kg) followed 30 min later by SC saline or cirazoline (0.7 mg/kg). Animals were tested in startle chambers 20 min later. RESULTS: In all three experiments the PPI disruption produced by DOI and cirazoline was blocked by the NT agonists. CONCLUSIONS: These findings provide strong evidence that NT agonists inhibit 5-HT2A and alpha1-adrenoceptor modulation of neurotransmission, pharmacological effects that, in conjunction with their known inhibition of dopamine transmission, strengthen the antipsychotic potential of NT agonists.

Blockade of endogenous GRF at dark onset selectively suppresses protein intake.

This study examined whether endogenous central GRF activity contributes to the increase in macronutrient intake shown by rats at dark onset. Animals were habituated to two diets: carbohydrate-fat and protein-fat. Antiserum raised against GRF (aGRF; 1% and 10% solutions) was microinjected into the suprachiasmatic nucleus/medial preoptic area (SCN/MPOA) at dark onset, and macronutrient intake was determined at 1, 2, and 4 h postinjection. aGRF blocked the increase in protein intake normally seen at dark onset, but had no effect on carbohydrate intake. These findings suggest that endogenous GRF activity in the SCN/MPOA region of the brain contributes to the circadian and nutritional organization of food intake.

Pro-dopamine effects of neurotensin on sensorimotor gating deficits.

Neurotensin is a neuropeptide which coexists with mesolimbic dopamine and has exhibited neuroleptic-like activity in the nucleus accumbens. This study examined the effects of neurotensin infused into the nucleus accumbens on prepulse inhibition (PPI) of the rat's acoustic startle reflex, a measure which is relevant to the sensorimotor gating deficits seen in schizophrenia. Neurotensin (5 micrograms) had no effect on the amplitude of the acoustic startle reflex nor on baseline PPI, but it potentiated the disruption of PPI produced by amphetamine and apomorphine. This is the first report of a pro-dopamine action for intra-accumbens neurotensin, and suggests that a complex behavioral pharmacology is associated with this neuropeptide.

Centrally administered hypothalamic growth hormone-releasing factor stimulates food intake in free-feeding rats.

Intracerebroventricular injections of rat hypothalamic growth hormone-releasing factor (rhGRF) were examined for effects on food intake in free-feeding rats. It was found that, in picomole doses, rhGRF had a stimulatory effect on food intake. Examination of higher doses of rhGRF revealed a decrease in the facilitatory effects and an inhibitory trend at the highest dose (4 nanomoles). The present results are consistent with previous results from our laboratory showing that central injections of rhGRF stimulate food intake in food-deprived rats.