Generalization of fear in post-traumatic stress disorder.

Overgeneralization (i.e., the transfer of fear to stimuli not related to an aversive event) is part of alterations in associative fear learning in mental disorders. In the present experimental study, we investigated whether this holds true for post-traumatic stress disorder (PTSD) related to childhood abuse. We expected that fear generalization under experimental conditions reflects generalization of aversive stimuli to different social domains in real life. Sixty-four women with PTSD after childhood abuse and 30 healthy participants (HC) underwent a differential fear conditioning and generalization paradigm. Online risk ratings, reaction time, and fear-potentiated startle served as dependent variables. Based on the subjectively assessed generalization of triggered intrusions across different domains of life, PTSD participants were split into two groups reporting low (low-GEN) and high (high-GEN) generalization. PTSD patients reported a higher expectation of an aversive event. During fear conditioning, they assessed the risk of danger related to a safety cue slower and showed a blunted fear-potentiated startle toward the danger cue. During generalization testing, reaction time increased in the high-GEN patients and decreased in the HC group with increasing similarity of a stimulus with the conditioned safety cue. Alterations of fear learning in PTSD suggest impaired defensive responses in case of a high threat probability. Moreover, our findings bridge the gap between the generalization of aversive cues during everyday life and laboratory-based experimental parameters: impairments in the processing of cues signaling safety generalize particularly in those patients who report a spreading of PTSD symptoms across different domains of everyday life.

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.

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.

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.

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.

[Detection of antibodies against the larva of Anisakis simplex in the pollock Pollachius virens using ELISA]. / Nachweis von Antikörpern gegen Larven von Anisakis simplex beim Seelachs Pollachius virens mittels ELISA.

From the fact that older saithes (more than 5 years old) are showing significantly lower prevalence of attack by Anisakis larvae in lateral muscle than younger saithes (3-4 years old), the question arises if this phenomenon is based on a specific immune response. Therefore we have investigated serum samples from saithes of different ages by using an indirect ELISA to estimate the antibody-titer against excretory-secretory Anisakis antigen. Results showing a moderate correlation (r = 0.66) between the height of titer and the age of underfeeding saithes (post spawning) and a close correlation (r = 0.93) of saithes in an optimal condition (pre spawning). It may be concluded that the migration-distance and the lifetime of Anisakis larvae in lateral-muscle is influenced by a specific immune response which increases with the age of the saithes.

[Hypoglycemia caused by insulinoma in diabetes mellitus]. / Hypoglykämie durch Insulinom bei Diabetes mellitus.

An hyperglycaemic metabolic state disappeared and spontaneous hypoglycaemia occurred in a 58-year-old woman with non-insulin-dependent obese type II diabetes. Abnormal absence of the hunger response with provoked hypoglycaemia, increased serum insulin concentrations and reduced blood glucose/insulin ratio led to the diagnosis of pathological hyperinsulinism, which was found to be due to an insulinoma of the tail of the pancreas. After its excision the patient's carbohydrate metabolism returned to a mild type II diabetic state and there were no further hypoglycaemic attacks.