Maternal immune activation and repeated maternal separation alter offspring conditioned avoidance response learning and antipsychotic response in male rats.

Previous work shows that repeated administration of several commonly used antipsychotic drugs, such as olanzapine (OLZ) over several days, induces an enhanced disruption of conditioned avoidance response (CAR) (termed antipsychotic sensitization) in normal adolescent and adult rats. However, it is unclear whether the same phenomenon can also be demonstrated in rat models of schizophrenia. The present study investigated OLZ sensitization in a combined maternal immune activation (MIA) and repeated maternal separation (RMS) model of schizophrenia. Sprague-Dawley male rats were first subjected to an early prenatal exposure to polyinosinic:polycytidylic acid (PolyI:C) on gestation days 13 (4 mg/kg, iv) and 15 (6 mg/kg, iv). They were then repeatedly separated from their mothers for 3 h daily during the first two weeks of postpartum. After they became adolescent (on postnatal day, PND 43), acute and OLZ sensitization effects in the CAR model was assessed. Adolescent MIA rats showed an impaired acquisition of conditioned avoidance response, but displayed a normal acute OLZ-induced avoidance suppression and OLZ sensitization effect. In adulthood (PND 81), MIA rats again showed an impairment in the acquisition of CAR. However, they showed a reduced response to OLZ (1.0 mg/kg; sc) treatment during the repeated drug test days, indicating a disruption of the induction of OLZ sensitization. In the OLZ sensitization challenge test, both MIA and control rats exhibited a robust and similar sensitization effect. In both adolescence and adulthood, RMS alone had no effect on any of the behavioral outcomes, and combined MIA-RMS even abolished the MIA alone-induced disruption of avoidance acquisition and the induction of OLZ sensitization. These results indicate that MIA disrupts associative learning and may reduce antipsychotic efficacy in the early stage of OLZ treatment. RMS does not appear to affect associative learning and behavioral responses to OLZ, and may possibly attenuate MIA-induced deficits. Our findings demonstrate that OLZ sensitization is a robust phenomenon but its magnitude can be altered by early MIA.

Critical Care Transport Time Differences Between Ground, Helicopter VFR, and Helicopter IFR Transports.

BACKGROUND: In helicopter critical care and emergency medical services (HEMS) transportation, organizations aim for efficiency of the dispatch process. Most HEMS organizations do not provide transport under instrument flight rules (IFR), due to equipment and training cost. Boston MedFlight (BMF) provides IFR HEMS transport. We set out to determine if response time of IFR transport was superior to ground transport.METHODS: A retrospective analysis of quality improvement data was performed. Data was collected by two observers sitting in the BMF control room in varying shifts. A process map of the dispatch process, from the dispatch call to the vehicle en route was developed. Critical points in the dispatch process were determined and a variety of time differences to determine the length of processes in the dispatch calculated. We compared median time differences between visual flight rules (VFR) flight and IFR flight, between IFR flight and ground transport, and between VFR and Ground for these points using a Mann-Whitney U-test.RESULTS: During the study collection period, 443 transports occurred, of which 109 transports happened while the observers were present: 37 ground, 57 VFR, and 15 IFR. Due to weather, six IFR transports were declined. The overall time from dispatch call to vehicle en route was significantly increased for IFR flights [median: 30 min:8 s (interquartile range 19:06-49:04)] over both VFR flights [11:36 (9:24-17:06); P vs. IFR: 0.001] and ground transports [9:39 (6:59-14.51); P vs. IFR: 0.001]. Most of this increase was accounted for by increases in the time from dispatch to crew acceptance, and from rotor start to vehicle en route.DISCUSSION: IFR conditions resulted in significantly increased dispatch times over both VFR flight and ground transport. The increase is likely a result of weather check, filing an IFR flight plan, and IFR release. Dispatch algorithms should be adjusted for this time delay of IFR transports.Kamine TH, Thomas L, Davis C, Cohen J. Critical care transport time differences between ground, helicopter VFR, and helicopter IFR transports. Aerosp Med Hum Perform. 2020; 91(2):98-101.

Behavioral mechanisms underlying the maternal disruptive effect of serotonin 5-HT2A receptor activation in Sprague-Dawley rats.

Recent evidence indicates that acute activation of 5-HT2A receptors causes a disruption of maternal behavior in rats. However, the behavioral mechanisms underlying such a disruption are not known. We addressed this issue using two behavioral approaches targeting the maternal motivational and emotional processing systems. First, we used the pup-separation technique to increase maternal motivation to see whether pup separation is capable of reducing the maternal disruptive effect of TCB-2 (a high-affinity 5-HT2A agonist) treatment. On postpartum days 4 and 6, different groups of Sprague-Dawley dams were treated with the TCB-2 (5.0 mg/kg, sc) or vehicle and their maternal behaviors were tested after either a 4-h pup-separation or no-pup-separation condition. Although acute TCB-2 injection disrupted maternal behavior, this disruption was not attenuated by pup separation, even after we optimized the timing of separation to maximize its increase on maternal motivation. Acute TCB-2 also impaired the retrieval of food pellets, suggesting a general effect on motivated behaviors. Next, we used a pup preference test and found that dams treated with TCB-2 exhibited an even stronger preference to pups over a male conspecific than vehicle-treated dams, indicating an enhanced motivational and emotional processing of the rewarding property of pups. These findings suggest that TCB-2 has a disruptive effect on rat maternal behavior, and this disruption is not likely due to the drug's effect on mothers' motivational and emotional processing of the incentive salience of pups, although this motivational suppression account cannot be completely ruled out. Future work could explore other possible behavioral mechanisms, such as the drug's effect on executive function.

Activation of 5-HT2A receptor disrupts rat maternal behavior.

Serotonin 5-HT2A receptor is widely distributed in the central nervous system and plays an important role in sensorimotor function, emotion regulation, motivation, executive control, learning and memory. We investigated its role in rat maternal behavior, a naturalistic behavior encompassing many psychological functions that the 5-HT2A receptor is involved in. We first showed that activation of 5-HT2A receptor by TCB-2 (a highly selective 5-HT2A agonist, 1, 2.5 or 5.0 mg/kg) disrupted maternal behavior dose-dependently, and this effect was reduced by pretreatment with a 5-HT2A receptor antagonist MDL 100907, but exacerbated by pretreatment with a 5-HT2C receptor antagonist SB242084 and a 5-HT2C receptor agonist MK212, indicating that the maternal disruptive effect of 5-HT2A activation is receptor-specific and can be modulated by 5-HT2C receptor bidirectionally. We then microinjected TCB-2 into two brain regions important for the normal expression of maternal behavior: the medial prefrontal cortex (mPFC) and the medial preoptic area (mPOA) and found that only acute intra-mPFC infusion of TCB-2 suppressed pup retrieval, whereas intra-mPOA had no effect. Finally, using c-Fos immunohistochemistry, we identified that the ventral bed nucleus of stria terminalis (vBNST), the central amygdala (CeA), and the dorsal raphe (DR) were additionally involved in the maternal-disruptive effect of TCB-2. These findings suggest that the 5-HT2A receptor in the mPFC and other maternally related regions is required for the normal expression of maternal behavior through its intrinsic action or interactions with other receptors (e.g. 5-HT2C). Functional disruption of this neuroreceptor system might contribute to postpartum mental disorders (e.g. depression and psychosis) that impair the quality of maternal care.

Sex differences in aripiprazole sensitization from adolescence to adulthood.

The present study investigated the potential sex differences in repeated aripiprazole (ARI) treatment-induced behavioral sensitization from adolescence to adulthood, and to determine whether ARI sensitization can be transferred to olanzapine (OLZ) and/or clozapine (CLZ) using the conditioned avoidance response (CAR) and phencyclidine-induced (PCP) hyperlocomotion tests of antipsychotic activity. Male and female Sprague-Dawley adolescence rats (P46) were first treated with ARI (10mg/kg) for 5 consecutive days (P46-50) and tested for avoidance response and ARI-induced inhibition of PCP-induced hyperlocomotion. After they became adults (>P68), rats were challenged with ARI (1.5mg/kg, sc) (P70), OLZ (0.5mg/kg, sc; P73), CLZ (5mg/kg, sc; P76) and again with ARI (1.5mg/kg, sc; P84) and tested for avoidance response and ARI-induced inhibition of PCP-induced hyperlocomotion again. During the drug treatment period in adolescence, repeated ARI treatment suppressed avoidance response, inhibited the PCP-induced hyperlocomotion, and these effects were progressively increased across the 5-day period in both males and females, confirming the induction of ARI sensitization. On the challenge days, rats previously treated with ARI in adolescence also had significantly lower avoidance and lower PCP-induced hyperlocomotion than the previous vehicle rats, confirming the expression of ARI sensitization and its persistence into adulthood. More importantly, female rats made significantly more avoidances than males in both ARI and vehicle groups, indicating higher sensitivity to the acute and long-term effects of ARI. Further, on the OLZ and CLZ challenge days, prior ARI treatment seemed to increase sensitivity to OLZ exposure, however, this increase was not significant. Similarly, rats also showed an ARI sensitization to OLZ and CLZ on challenge days. Collectively, results from this experiment demonstrated a sex difference in response to ARI and enhanced inhibition of PCP-induced hyperlocomotion in animals that were pretreated with ARI as compared to controls.

Behavioral, pharmacological and neuroanatomical analysis of serotonin 2C receptor agonism on maternal behavior in rats.

As a highly motivated social behavior, maternal behavior in rats has been routinely used to study psychoactive drugs for clinical, neuroscience and pharmacological purposes. Recent evidence indicates that acute activation of serotonin 2C (5-HT2C) receptors causes a disruption of rat maternal behavior. The present study was designed to elucidate the behavioral, pharmacological mechanisms and neuroanatomical basis of this 5-HT2C effect. First, we replicated the finding that acute MK212 injection (2.0mg/kg, a highly selective 5-HT2C agonist) disrupts maternal behavior, especially on pup retrieval. Interestingly, this disruption was significantly attenuated by 4-h pup separation (a procedure putatively increased maternal motivation). MK212 also suppressed food retrieval, indicating that it has a general effect on motivated behaviors. Second, we showed that MK212 disrupts maternal behavior by specifically activating 5-HT2C receptor, as pretreatment with a 5-HT2C receptor antagonist SB242084 (0.6 and 1.0mg/kg) alleviated MK212-induced disruption on pup retrieval. Third, we microinjected MK212 into various brain regions implicated in the regulation of maternal behavior: nucleus accumbens shell (25, 75, 250ng/0.5µl/side), medial prefrontal cortex (25 and 250ng, 1, 2 and 5µg/0.5µl/side), and medial preoptic area (MPOA, 75ng, 1 and 5µg/0.5µl/side). Pup retrieval and other maternal responses were not affected by any of these manipulations. Finally, we used c-Fos immunohistochemistry to identify the central mechanisms of the acute and repeated MK212 effects on maternal behavior. Acute MK212 (2.0mg/kg) disrupted pup retrieval and concurrently decreased c-Fos expression in the ventral part of lateral septal nucleus (LSv), MPOA, dentate gyrus (DG) and dorsal raphe (DR), but increased it in the central amygdala (CeA). Five days of repeated MK212 (2.0mg/kg) treatment produced a persistent disruption of pup retrieval and only decreased c-Fos expression in the DR. These findings not only confirm a role of 5-HT2C receptor in rat maternal behavior, but also suggest that the coordinated 5-HT2C activity in various limbic (e.g., LSv, DG, CeA), hypothalamic regions (e.g., MPOA) and brainstem areas (e.g. DR), is likely involved in the mediation of important psychological processes (e.g. motor function, motivation) necessary for the normal expression of maternal behavior.

Effects of repeated quetiapine treatment on conditioned avoidance responding in rats.

The present study characterized the behavioral mechanisms of avoidance-disruptive effect of quetiapine in the conditioned avoidance response test under two behavioral testing (2 warning signals vs. 1 warning signal) and two drug administration conditions (subcutaneous vs. intravenous). In Experiments 1 and 2, well-trained adult male Sprague-Dawley rats were tested under the subcutaneous (s.c.) quetiapine treatment (5.0, 15.0, 25.0, 50.0mg/kg) for 7 days in a novel procedure consisting of two conditioned stimuli (CS) (white noise serving as CS1 and pure tone as CS2). Only the highest dose (50.0mg/kg) produced a persistent suppression of the avoidance response without impairing the escape response. The magnitude of suppression of the CS1 avoidance was similar to that of CS2 avoidance. No significant group difference was found in the quetiapine (15.0mg/kg, s.c.) challenge test, indicating a lack of a long-term quetiapine effect. In Experiment 3, well-trained rats were tested under the intravenous (i.v.) quetiapine treatment (3.0, 9.0, 15.0mg/kg) for 5 days and challenged with quetiapine (6.0mg/kg, i.v. followed by 9.0mg/kg, s.c.). Only the white noise was used as the CS. Similar to what was being observed in Experiments 1 and 2, intravenously administered quetiapine dose-dependently suppressed avoidance responding during the drug test days, but did not alter drug sensitivity in the challenge days. Thus, quetiapine does not appear to show a preferential inhibition of the avoidance response to a less salient stimulus; and prior quetiapine treatment (s.c. and i.v.) does not cause a sensitization or tolerance to quetiapine.

Repeated effects of the neurotensin receptor agonist PD149163 in three animal tests of antipsychotic activity: assessing for tolerance and cross-tolerance to clozapine.

Neurotensin is an endogenous neuropeptide closely associated with the mesolimbic dopaminergic system and shown to possess antipsychotic-like effects. In particular, acute neurotensin receptor activation can inhibit conditioned avoidance response (CAR), attenuate phencyclidine (PCP)-induced prepulse inhibition (PPI) disruptions, and reverse PCP-induced hyperlocomotion. However, few studies have examined the long term effects of repeated neurotensin receptor activation and results are inconsistent. Since clinical administration of antipsychotic therapy often requires a prolonged treatment schedule, here we assessed the effects of repeated activation of neurotensin receptors using an NTS1 receptor selective agonist, PD149163, in 3 behavioral tests of antipsychotic activity. We also investigated whether reactivity to the atypical antipsychotic clozapine was altered following prior PD149163 treatment. Using both normal and prenatally immune activated rats generated through maternal immune activation with polyinosinic:polycytidylic acid, we tested PD149163 in CAR, PCP (1.5mg/kg)-induced PPI disruption, and PCP (3.2mg/kg)-induced hyperlocomotion. For each paradigm, rats were first repeatedly tested with vehicle or PD149163 (1.0, 4.0, 8.0mg/kg, sc) along with vehicle or PCP for PPI and hyperlocomotion tests, then challenged with PD149163 after 2 drug-free days. All rats were then challenged with clozapine (5.0mg/kg, sc). During the repeated test period, PD149163 exhibited antipsychotic-like effects in all three models. On the PD149163 challenge day, prior drug treatment only caused a tolerance effect in CAR. This tolerance in CAR was transferrable to clozapine, as it enhanced clozapine tolerance in the same group of animals. Although no tolerance effect was seen in the PD149163 challenge for the PCP-induced hyperlocomotion test, the clozapine challenge showed increased sensitivity in groups previously exposed to repeated PD149163 treatment. Our findings suggest that repeated exposure to NTS1 receptor agonists can induce a dose-dependent tolerance and cross-tolerance to clozapine to some of its behavioral effects but not others.