Epinephrine administration at birth prevents long-term changes in dopaminergic parameters caused by Cesarean section birth in the rat

Rationale  Obstetric complications involving birth hypoxia are implicated in the etiology of disorders with dopaminergic dysfunction, such as schizophrenia. Cesarean section (C-section) birth in both humans and rats is associated with increased mild respiratory distress and with reduced levels of circulating catecholamines at birth, which normally serve to prime the lungs and activate other processes promoting extrauterine adaptation. Using a rat model, it has been found that C-section birth can produce long-term changes in central nervous system (CNS) dopamine function, compared to vaginal birth. Objective  The present experiments tested if administering exogenous epinephrine at birth could reverse long-term changes in dopaminergic parameters in C-sectioned rats. Results  In the absence of stress at adulthood, no differences were observed between C-sectioned and vaginally born rats in levels of in vivo tyrosine hydroxylase (TH) activity and dopamine transporter (DAT) binding. However, after repeated mild stress at adulthood, C-sectioned rats showed increased TH activity in nucleus accumbens and increased DAT in dorsal striatum and accumbens, compared to vaginally born controls. A single injection of epinephrine to C-sectioned rats just after birth prevented the increased TH activity and DAT binding seen in C-sectioned rats after repeated mild stress at adulthood. There was also a trend for epinephrine at birth to partially reverse an increase in amphetamine-induced locomotion seen in C-sectioned rats at adulthood. Conclusions  These results suggest that variations in levels of circulating catecholamines in the neonate at the time of birth could contribute to subtle long-term changes in CNS function.     

Caesarean section birth produces long term changes in dopamine D1 receptors and in stress-induced regulation of D3 and D4 receptors in the rat brain.

Schizophrenia is associated with increased birth complications and altered mesocorticolimbic dopaminergic (DA) transmission, whereas stress also influences psychotic symptoms. Given this, the present study tested effects of two birth complications, Caesarean section (C-section) birth with or without acute global anoxia, on brain DA receptors in rats at adulthood. Effects of repeated stress at adulthood were also tested. Before stress, C-sectioned rats showed increased D1-like receptor binding in limbic areas, compared to vaginally born controls. There were no differences between birth groups in D2-like, D3, or D4-like receptor binding before stress. After stress, C-sectioned animals showed decreased D3 receptors in accumbens and increased D4-like receptors in dorsal striatum, accumbens, and olfactory tubercles, compared to vaginal birth. This occurred because stress upregulated D3 receptors only with vaginal birth and upregulated D4-like receptors only with C-section. Animals born by C-section + anoxia showed no change in DA receptors relative to vaginal birth, before or after stress. It is concluded that interactions between an individual's experience of stress at adulthood, together with other environmental events in their history, such as birth complications, can be important determinants of brain DA receptor levels.     

Functional behavioral homology between rat 5-HT1B and guinea pig 5-HT1D receptors in the modulation of prepulse inhibition of startle

The serotonin (5-HT) 1B receptor in rats and mice appears to be homologous to the 5-HT_1D receptor found in other mammals, such as guinea pigs and humans. The present series of experiments explored the functional similarity between the rat 5-HT_1B receptor and the guinea pig 5-HT_1D receptor on two behavioral measures known to be influenced by 5-HT_1B receptor manipulations in rats: prepulse inhibition of the startle response (PPI) and locomotor activity. Because the 5-HT_1B agonist RU 24969 disrupts PPI and stimulates locomotor behavior in rats, it was predicted that the 5-HT_1D agonist, SDZ 219–964, would demonstrate a similar behavioral profile in guinea pigs. In support of this hypothesis, SDZ 219–964 was found to disrupt PPI dose-dependently (1.0 and 2.0 mg/kg) without significantly affecting startle amplitude and to increase locomotor activity (0.5–2.0 mg/kg) in guinea pigs. In guinea pigs, RU 24969 failed to affect PPI, although it did increase locomotor activity, indicating that RU 24969 may have activity at the 5-HT_1D receptor. As expected, RU 24969 in rats disrupted PPI (2.5 and 5.0 mg/kg) and significantly increased locomotor activity (1.25–5.0 mg/kg). In rats, however, SDZ 219–964 had generalized, stimulatory effects on startle reactivity, without independent effects on PPI or locomotor activity. The spatial patterns of locomotion exhibited by guinea pigs treated with SDZ 219–964 versus those of rats treated with RU 24969 demonstrate important qualitative differences in structure, indicating that the neural substrates subserving these effects may be different. It is concluded that a functional similarity exists between 5-HT_1D and 5-HT_1B receptors with regard to the modulation of sensorimotor inhibition and, to a lesser extent, locomotor activity.     

A comparison of the effects of amphetamine, strychnine and caffeine on prepulse inhibition and latent inhibition

Sensorimotor gating deficits characterize several neuropsychiatric disorders, including schizophrenia. Prepulse inhibition (PPI) and latent inhibition (LI) are measures that are used to assess sensorimotor gating and have been found to be reduced in schizophrenia patients. In PPI, a weak stimulus presented immediately prior to a startling stimulus attenuates the startle response. In LI, pre-exposure to a stimulus retards the subsequent association of that stimulus with a consequence (e.g. footshock). In rats, indirect dopamine (DA) agonists such as amphetamine disrupt both PPI and LI. Amphetamine has also been reported to increase exploratory locomotion at doses that decrease PPI and LI. Such behavioral activation might complicate the interpretation of amphetamine-induced changes in measures of sensorimotor gating. The present study was conducted in order to compare the effects of three behaviorally activating drugs on PPI, LI and locomotor activity. Separate groups of rats were treated with either vehicle, the DA releaser amphetamine (1.5mg/kg), the glycine antagonist strychnine (0.75mg/kg), or the adenosine receptor antagonist caffeine (10mg/kg) and then tested in either startle chambers (for PPI) or an active avoidance chamber (for LI). Locomotion was measured by inter-trial crossing in the avoidance chamber. Amphetamine stimulated locomotion and disrupted both PPI and LI, but did not elevate startle amplitude. In contrast, caffeine increased locomotion, but had no effect on PPI or LI. Strychnine did not increase locomotion significantly, but did increase startle amplitude and disrupt PPI and LI. Hence, neither increased startle amplitude nor locomotor activation are necessary or sufficient conditions for disruption of sensorimotor gating as measured by PPI and LI.     

Neural monoaminergic mediation of the effect of St. John's wort extract on prepulse inhibition of the acoustic startle response in rats

Prepulse inhibition (PPI) of startle response is a valuable paradigm for sensorimotor gating processes by which an organism filters sensory information. Disruption of PPI is evident in schizophrenia and Huntington's disease among other neuropsychiatric disorders characterized by sensorimotor gating deficit. In such disorders, increased brain monoamines' transmission was suggested to underlie PPI disruption. The effect of St. John's wort extract on PPI of startle response is yet to be investigated despite research findings indicating augmented levels of brain monoaminergic function after acute administration of the extract. In this study, the effect of acute oral administration of St. John's wort extract (62.5, 125, 250 and 500 mg/kg) was tested on PPI of an acoustic startle response in rats. A disruption of PPI resulted after the administration of the highest dose of the extract and therefore its effect on dopaminergic, serotonergic and noradrenergic neurotransmission was investigated in a number of rat brain areas involved in mediation of PPI response. Results demonstrated that 500 mg/kg of the extract augmented dopaminergic transmission in the thalamus together with elevating noradrenergic transmission in both brainstem and hippocampus. In addition, increased serotonin levels in brainstem, thalamus, cortex and hippocampus were evident after administration of the same dose of the extract. It was therefore concluded that St. John's wort extract (500 mg/kg) reduced PPI response possibly through enhancing monoaminergic transmission in brainstem, thalamus, cortex and/or hippocampus. Clinical investigations are therefore needed to determine whether St. John's wort extract may affect sensorimotor gating in both schizophrenia and Huntington's disease.     

Long-term effects of fluoxetine or vehicle administration during pregnancy on behavioral outcomes in guinea pig offspring

Rationale Assessment of the benefits versus risks associated with antidepressant use during pregnancy must include an analysis of possible drug effects on fetal development. Human studies indicate that prenatal fluoxetine exposure is associated with adverse neonatal outcomes. Animal modeling may provide useful information concerning possible long-term effects of prenatal fluoxetine exposure. Limitations in previous such studies using rat models may be overcome using a guinea pig model in which fluoxetine is delivered by osmotic pump throughout pregnancy.Methods Initial experiments measured the half-life of fluoxetine and dosing required to achieve human therapeutic blood levels in the guinea pig. In subsequent experiments, guinea pigs received fluoxetine or vehicle via osmotic pump or no treatment throughout pregnancy. Outcome measures included: pregnancy characteristics, weight gain, and, in offspring as adults, pain threshold, acoustic startle responses and prepulse inhibition.Results There was no effect of treatment group on gestation length, number of live-births or still-births, maternal or offspring weight gain, and acoustic startle responses. In adult offspring, pain threshold was decreased by vehicle treatment during gestation. Prenatal fluoxetine increased pain threshold, relative to vehicle controls. Prepulse inhibition of startle was increased in adult offspring treated prenatally with either vehicle or fluoxetine compared to no treatment.Conclusions The guinea pig provides a practicable and clinically relevant model of prenatal fluoxetine exposure. Adult guinea pigs exposed to fluoxetine prenatally showed increased thermal pain thresholds but no change in prepulse inhibition, indicating selective long-term effects of prenatal fluoxetine on serotonin-modulated behaviors. Further studies on long-term effects of prenatal fluoxetine on nociception are warranted.     

Effects of corticotropin-releasing factor on prepulse inhibition of the acoustic startle response in two rat strains

RATIONALE: Prepulse inhibition (PPI) of the acoustic startle response is altered by manipulations that affect brain monoamine neurotransmission. Corticotropin-releasing factor (CRF), a neurotransmitter that is released during stress, and CRF receptors are expressed in areas of the brain which contribute to PPI, and central administration of CRF changes extracellular concentrations of the monoamines. Therefore, CRF is in a position to alter PPI, either by causing the release of other neurotransmitters, or by direct effects at CRF receptors. OBJECTIVES: The present experiments were conducted to test the hypothesis that intracerebroventricular (ICV) administration of CRF would decrease PPI in rats. Additionally, these experiments were used to examine whether CRF results in differential changes in PPI in rat strains that show high and low basal PPI, and whether CRF-induced grooming behavior and increased startle amplitude are also strain-dependent. METHODS: Male Wistar-Kyoto (WKY) rats inbred in our colony in La Jolla, WKY rats obtained from Charles River, and Brown Norway (BN) rats from Harlan, Sprague-Dawley were tested for grooming behavior, PPI and startle amplitude following ICV infusion of either CRF (1.0-3.0 microg) or saline. RESULTS: CRF significantly decreased PPI in both BN rats, which show relatively little PPI in the basal condition and, in WKY rats. The amplitude of the acoustic startle response was increased in WKY rats only and, only by the 3.0 microg dose of CRF. CRF increased grooming behavior in the La Jolla colony WKY and BN rats. However, within the time frame during which the rats were being observed, CRF failed to significantly increase grooming in Charles River WKY rats. CONCLUSIONS: CRF diminished PPI of the acoustic startle response in rats that show high (WKY) and low (BN) basal PPI. This effect does not appear to be dependant on CRF-induced changes in startle amplitude. The results suggest the possibility that stress-induced exacerbation of symptoms in schizophrenia, which is characterized by deficient PPI, may be CRF-dependent.     

Lamotrigine prevents ketamine but not amphetamine-induced deficits in prepulse inhibition in mice

Rationale Lamotrigine, a broad-spectrum anticonvulsant known to block brain sodium channels, is effective in the treatment of persons with bipolar disorder, perhaps by virtue of its ability to reduce glutamate release. Furthermore, lamotrigine decreases the perceptual abnormalities produced by the N-methyl-d-aspartate (NMDA) antagonist ketamine in humans, similar to the effects of the atypical antipsychotic clozapine. Acutely manic bipolar patients, like persons with schizophrenia, Tourette's, and obsessive compulsive disorder, exhibit decreases in sensorimotor gating, as measured by prepulse inhibition of the startle response (PPI). Objective We assessed the ability of lamotrigine to reduce the PPI–disruptive effects of ketamine and the dopaminergic agent amphetamine in two inbred mouse strains, C57BL/6J and 129SvPasIco. Methods Mice were tested in a standard PPI paradigm after administration of lamotrigine (0, 6.7, 13, or 27 mg/kg) or a combination of lamotrigine (27 mg/kg) and either d-amphetamine (10 mg/kg) or ketamine (100 mg/kg). Results In the 129SvPasIco mice, lamotrigine reversed the ketamine-induced PPI deficit, without altering PPI in control mice. In C57BL/6J mice, however, 27 mg/kg lamotrigine generally increased PPI in both control and ketamine-treated mice. Lamotrigine did not ameliorate the amphetamine-induced PPI deficit in either strain. Conclusions In conclusion, lamotrigine can increase PPI on its own and prevent ketamine-induced, but not amphetamine-induced, disruptions of PPI. These results suggest that lamotrigine may exert its effects on PPI through the glutamatergic system.     

The adenosine A2A agonist CGS 21680 reverses the reduction in prepulse inhibition of the acoustic startle response induced by phencyclidine, but not by apomorphine and amphetamine

Systemic administration of the selective adenosine A2A agonist CGS 21680, at the highest dose tested (0.5 mg/kg), selectively reversed the reduction in prepulse inhibition (PPI) of the acoustic startle response induced by the NMDA antagonist phencyclidine (PCP), but not by the dopaminergic agonists apomorphine and amphetamine. CGS 21680 by itself was without effect on PPI, but did reduce the amplitude of the startle response. PCP also reduced startle amplitude, but there was no additive or synergistic effect between PCP and CGS 21680 on the startle response. CGS 21680 (0.5 mg/kg) blocked the locomotor activating effect of amphetamine, but this may have been secondary to a reduction in spontaneous locomotion induced by this compound. Taken together, these results indicate that stimulation of adenosine A2A receptors produce no consequence on dopamine agonist-induced disruption in PPI, but regulate the inhibitory effect of NMDA receptor blockade on PPI. This finding raises the possibility that adenosine A2A agonists possess antipsychotic-like properties.     

Interconversions of haloperidol and reduced haloperidol in guinea pig and rat liver microsomes

An alcohol metabolite of haloperidol, reduced haloperidol, is present in the tissues of haloperidol-treated patients. We have studied whether rat and guinea pig liver microsomes have the capability to reduce haloperidol and thus serve as models for human haloperidol metabolism. Interestingly, the rat microsomes did not reduce haloperidol, but possessed an NADPH-dependent, carbon monoxide-inhibited mechanism to oxidize the reduced haloperidol back to haloperidol. Guinea pig microsomes efficiently reduced haloperidol molecules in a fashion not dependent on nicotinamide cofactors and not inhibited by carbon monoxide. Both of these activities were confined to the microsomal fraction. In guinea pigs, reduction of haloperidol was observed also in kidney slices, whereas brain slices proved inactive. Reduced haloperidol was also oxidized to haloperidol to a small extent in guinea pig microsomes. These in vitro experiments confirm our findings in vivo, which showed that in rats haloperidol is not reduced, while guinea pigs have a very active mechanism for reducing haloperidol. Thus, guinea pigs constitute a model for human haloperidol metabolism, and they should be used for further characterization of the reductive drug-metabolizing system.     

Behavioural changes after different stress paradigms: prepulse inhibition increased after physical, but not emotional stress.

Physical (PS) and emotional (ES) stress have opposite long-term effects on open field behaviour, i.e., response to novelty. PS induced a long-term reduction in locomotor activity, while ES increased it. Additionally, sensitivity to rewarding stimuli was differentially affected by PS and ES. Whether the stress effects were specific for locomotor activity and reward or if these two stress treatments also have differential effects on other behaviours and brain functions is not known. In the present study, temperature regulation, sensory gating, learning capacity, locomotor activity and coping style were examined. PS consisted of a repeated mild foot shock treatment, which the ES animals witnessed. The tests pose additional challenges, to which all groups can respond differently depending on their previous experience. All tests were performed several days after the last stress treatment. Stress effects were specifically observed on locomotor activity, startle response and prepulse inhibition (PPI). The PS animals showed a potentiated inhibition of the startle when a prepulse (PPI) was used, although the initial startle response was already significantly lower than that of controls. ES animals did not differ from controls on PPI and startle. Additionally PS animals showed an initial decrease in activity, which turned into an increase when the tests continued. ES showed a constant increase in activity compared to controls. Stress effects on the tests for other brain processes and behaviour were not found. In addition, PS animals appeared to be less sensitive to the dopamine agonist apomorphine than control animal. In summary, physical and emotional stress induce differential changes on locomotor activity, startle response and PPI. Underlying mechanisms explaining the differences in stress effects are discussed, i.e., the role of the mesolimbic dopamine system and opioid systems.     

血管紧张素Ⅱ对缺氧自发性高血压大鼠和豚鼠主动脉血管收缩力的影响

观察血管紧张素Ⅱ（ＡｎｇⅡ）对缺氧及不缺氧自发性高血压大鼠（ＳＨＲ）和豚鼠主动脉的影响。发现缺氧后ＡｎｇⅡ明显加强豚鼠血管的收缩力，而ＡｎｇⅡ对ＳＨＲ血管收缩力影响不大，缺氧后ＡｎｇⅡ并没有加强其对ＳＨＲ血管的收缩作用。另外，用放免测定法测得缺氧后ＳＨＲ主动脉ＡｎｇⅡ含量显著减少，但豚鼠主动脉缺氧前后ＡｎｇⅡ含量却无明显变化，说明缺氧后ＳＨＲ血管对ＡｎｇⅡ的反应性与正常血管的不同。     

Relationship between gnawing compulsion and central dopaminergic mechanism in guinea pigs (author's transl)

It has been reported that an increased in dopaminergic activity in the striatum can induce gnawing compulsion, a stereotyped behavior. Apomorphine, amphetamine and L-DOPA also produce such effects, particularly in the rat. However, it has been reported that the gnawing compulsion in the guinea pig cannot be induced with L-DOPA and is not related to the levels of catecholamine in the brain. It is of essential importance in this kind of research to clarify whether or not a dopaminergic mechanism is equally involved in gnawing compulsion of the rodent in general. The present study dealt with the mechanism of gnawing compulsion with L-DOPA administration to guinea pigs. Gnawing compulsion was amplified by crystal pick-up and amplifiers and was continuously recorded by an inkwriting-oscilloscope. The recorded data were scored for quantitative and objective analysis. Certainly, L-DOPA alone did not induce continuous gnawing, but the gnawing was obviously induced by pretreatment with benserazide, a peripheral decarboxylase inhibitor. The induced gnawing complusion was inhibited by pimozide and haloperidol which are both dopamine receptor blockers. When catecholamine synthesis was inhibited pretreatment with alpha-methyl-p-tyrosine, the amphetamine induced gnawing compulsion alone was markedly inhibited, but the apomorphine or L-DOPA induced gnawing compulsion following the pretreatment with benserazide was not inhibited. Therefore, it was deduced that gnawing compulsion was induced with amphetamine directly by dopamine release, with apomorphine by its direct stimulation of the dopamine receptor, and with L-DOPA by its action on the dopamine receptor, after having been converted to dopamine. Based on these results, it was concluded that the dopaminergic mechanism is closely involved in gnawing compulsion seen in the guinea pig as well as in the rat.     

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 (SC) injections of caerulein (10 μg/kg) a mixed CCK_A/B agonist, partially reversed amphetamine-induced reduction of PPI; whereas, SC haloperidol (0.5 mg/kg) totally reversed amphetamine-induced disruption of PPI. Caerulein’s effect on PPI was blocked by pretreatment with a CCK_A antagonist (devazepide) but not a CCK_B antagonist (L-365,260). CCK-4, a preferential CCK_B 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 CCK_A receptors. Possible circuities in this effect are discussed. In a separate experiment, SC 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.     

Effects of ovariectomy and estradiol on acoustic startle responses in rats

Long-term (3 months) ovariectomized (OVX) rats were used to model hormone withdrawal as occurring in menopause. We previously reported alterations in brain dopamine (DA), GABA and serotonin receptors following ovariectomy in this model. To assess the functional effect of these biochemical changes, we compared rats that were intact, OVX and OVX-treated with 17beta-estradiol (E(2); OVX+E(2)) for 2 weeks on measures of their acoustic startle responses (ASR) and prepulse inhibition (PPI) of acoustic startle. The effects of a mixed D(1)/D(2) dopaminergic agonist, apomorphine (APO; 0.25, 0.5 and 0.75 mg/kg sc) were tested on ASR and PPI of acoustic startle. Without APO, all groups of rats showed no difference in baseline ASR or PPI of acoustic startle. Following administration of APO (0.25, 0.5 and 0.75 mg/kg), ASR was significantly increased in OVX rats compared to intact rats and this was corrected with E(2) treatment. In all groups of animals, APO decreased PPI of acoustic startle. APO disrupted PPI to a lesser extent in OVX animals with or without E(2) treatment compared to intact rats. However, when group differences in APO-induced ASR were statistically controlled for, there were no longer any differences in APO disruption of PPI among the three treatment groups. These results indicate that long-term ovariectomy has persistent effects on the modulation of ASR, and these effects can be at least partly corrected with E(2) replacement therapy.     

Prenatal immune challenge disrupts sensorimotor gating in adult rats. Implications for the etiopathogenesis of schizophrenia.

Increasing evidence associates schizophrenia with prenatal exposure to infection. Impaired ability to "gate out" sensory and cognitive information is considered to be a central feature of schizophrenia and is manifested, among others, in disrupted prepulse inhibition (PPI) of the acoustic startle reflex. We analyzed the effect of a prenatal immune challenge- peripheral administration of bacterial endotoxin lipopolysaccharide (LPS) to pregnant female rats-upon PPI and immune function in adult offspring. Prenatal LPS treatment disrupted PPI which was reversed by antipsychotics. Serum levels of interleukin-2 and interleukin-6 were increased. In addition, histopathological features in brain areas related with PPI circuitry were observed. These results illustrate the critical influence of prenatal immune events upon adult CNS functioning in association with the putative role of the immune system in the etiopathogenesis of schizophrenia.     

Significant differences in the disposition of cyclic prodrugs of opioid peptides in rats and guinea pigs following IV administration

The stabilities of DADLE ([D-Ala2,D-Leu5]-Enk, H-Tyr-D-Ala-Gly-Phe-D-Leu-OH), the capped derivative Ac-DADLE-NH2, and the oxymethyl-coumarinic acid (OMCA)-based cyclic prodrug of DADLE and [D-Ala2,Leu5]-Enk (H-Tyr-D-Ala-Gly-Phe-Leu-OH) were determined at 37 degrees C in rat and guinea pig liver microsomes in the presence and absence of paraoxon, an esterase B inhibitor, and ketoconazole, a CYP3A4 inhibitor. These studies showed that the order of stability in microsomes was: DADLE > Ac-DADLE-NH2 > OMCA-DADLE = OMCA-[D-Ala2,Leu5]-Enk. While paraoxon produced no significant effect on the stability of the studied compounds in liver microsomes, ketoconazole inhibited the metabolism, suggesting that the capped peptide and the cyclic prodrugs are substrates for cytochrome P450 enzymes. For pharmacokinetic studies, the cyclic prodrugs of DADLE and [D-Ala2,Leu5]-Enk were administered i.v. to rats and guinea pigs. Various biological fluids and tissue (brain, bile, and blood) were collected and analyzed for the free peptide and the prodrugs by high performance liquid chromatography with tandem mass spectrometric detection (LC-MS-MS). These studies showed that the conversion of the cyclic prodrugs to the respective linear peptides (i.e., DADLE and [D-Ala2,Leu5]-Enk) was rapid in rat and guinea pig. In terms of drug elimination, only trace amounts of OMCA-DADLE and OMCA-[D-Ala2,Leu5]-Enk were recovered in guinea pig bile (3.3% and 0.82%, respectively), while significant amounts were recovered in rat bile (38.1% and 51.7%, respectively). Brain uptake of the cyclic prodrugs in guinea pigs compared to previously determined brain uptake of OMCA-DADLE in rats was also significantly different. For OMCA-DADLE, the brain levels of the cyclic prodrug and DADLE in guinea pigs were approximately 80 and 8.5 times greater, respectively, than the levels observed in rat brain. The brain-to-plasma prodrug concentration ratios in guinea pigs (>or= 0.6) were significantly higher than the ratio observed in rats (0.01). These species differences are most likely due to the different substrate specificities of the efflux transporters that facilitate liver clearance of these prodrugs and limit their permeation into the brain.     

Dopamine D1 rather than D2 receptor agonists disrupt prepulse inhibition of startle in mice.

Although substantial literature describes the modulation of prepulse inhibition (PPI) by dopamine (DA) in rats, few reports address the effects of dopaminergic manipulations on PPI in mice. We characterized the effects of subtype-specific DA agonists in the PPI paradigm to further delineate the specific influences of each DA receptor subtype on sensorimotor gating in mice. The mixed D1/D2 agonist apomorphine and the preferential D1-family agonists SKF82958 and dihydrexidine significantly disrupted PPI, with differing or no effects on startle. In contrast to findings in rats, the D2/D3 agonist quinpirole reduced startle but had no effect on PPI. Pergolide, which has affinity for D2/D3 and D1-like receptors, reduced both startle and PPI, but only at the higher, nonspecific doses. In addition, the D1-family receptor antagonist SCH23390 blocked the PPI-disruptive effects of apomorphine on PPI, but the D2-family receptor antagonist raclopride failed to alter the disruptive effect of apomorphine. These studies reveal potential species differences in the DA receptor modulation of PPI between rats and mice, where D1-family receptors may play a more prominent and independent role in the modulation of PPI in mice than in rats. Nevertheless, due to the limited selectivity of DA receptor agonists, further studies using specific receptor knockout mice are warranted to clarify the respective roles of specific DA receptor subtypes in modulating PPI in mice.     

The effects of smoking high nicotine cigarettes on prepulse inhibition, startle latency, and subjective responses

RATIONALE: Several previous investigations with animals and humans have suggested that nicotine enhances prepulse inhibition of the startle reflex (PPI). However, the administration of nicotine activates mesolimbic dopamine, and activation of mesolimbic dopamine is known to attenuate prepulse inhibition of the startle reflex (PPI), which might suggest that nicotine would decrease PPI. OBJECTIVE: The primary aim of this study was to test rigorously the effects of smoking high nicotine cigarettes on PPI and other measures (e.g., heart rate, craving, and mood) when the concentration of nicotine peaks in the brain (i.e., immediately after smoking). METHODS: Thirty smokers participated in two experimental sessions 1 week apart. Two high nicotine cigarettes were smoked in one session, and two control cigarettes were smoked in the other session after overnight deprivation. RESULTS: The results indicated that smoking the high nicotine cigarettes decreased PPI and that PPI increased across trials in both conditions. The interaction between nicotine dose and trial was not significant, although it appeared that high nicotine may have reversed an increase in PPI across trials in the control condition. High nicotine cigarettes also significantly increased heart rate, decreased the latency to peak startle response on control trials, but did not alter the magnitude of the startle response. DISCUSSION: The findings suggest that either high nicotine cigarettes reduced PPI, or possibly, that high nicotine cigarettes may have reversed an increase in PPI across trials as evident in the control condition.     

Disruption of the prepulse inhibition of the startle reflex in vasopressin V1b receptor knockout mice: reversal by antipsychotic drugs.

In the present study, we investigated whether mice lacking the arginine vasopressin (AVP) V1b receptor (V1bR) exhibit deficits of prepulse inhibition (PPI) of the startle reflex, reminiscent of the sensorimotor gating deficits observed in a large majority of schizophrenic patients. V1bR knockout (KO) mice displayed significantly reduced levels of PPI of the startle reflex. In addition to PPI deficits, V1bR KO mice showed increased acoustic startle response. However, acoustic startle response was not significantly correlated to the PPI of the startle reflex in V1bR KO mice. V1bR KO mice also showed a decrease in basal levels of extracellular dopamine (DA) in the medial prefrontal cortex, which is thought to be an important brain region for PPI. Moreover, PPI deficits observed in the V1bR KO mice are significantly reversed by atypical antipsychotics such as risperidone and clozapine but not by a typical neuroleptic haloperidol, like in schizophrenic patients. By contrast, we did not observe any significant differences between V1bR KO mice and wild-type mice in the open-field, light/dark, elevated plus maze, and forced swimming tests. The results of the present study indicate that V1bR may be involved in the regulation of PPI of the startle reflex. The V1bR has been considered an important molecular target for the development of antipsychotic drugs.