Clinician's perspectives of the relocation of a regional child and adolescent mental health service from co-located to stand alone premises.

INTRODUCTION: Australia's National Mental Health Strategy's statement of rights and responsibilities states that children and adolescents admitted to a mental health facility or community program have the right to be separated from adult patients and provided with programs suited to their developmental needs. However, in rural Australia, where a lack of healthcare services, financial constraints, greater service delivery areas and fewer mental healthcare specialists represent the norm, Child and Adolescent Mental Health Services (CAMHS) are sometimes co-located with adult mental health services. The aim of the present study was to evaluate the impact of a recent relocation of a regional CAMHS in Victoria from co-located to stand alone premises. METHOD: Six CAMHS clinicians who had experienced service delivery at a co-located setting and the current stand-alone CAMHS setting were interviewed about their perceptions of the impact of the relocation on service delivery. An exploratory interviewing methodology was utilized due to the lack of previous research in this area. Interview data were transcribed and analysed according to interpretative phenomenological analysis techniques. RESULTS: Findings indicated a perception that the relocation was positive for clients due to the family-friendly environment at the new setting and separation of CAMHS from adult psychiatric services. However, the impact of the relocation on clinicians was marked by a perceived loss of social capital from adult psychiatric service clinicians. CONCLUSION: These results provide increased understanding of the effects of service relocation and the influence of co-located versus stand-alone settings on mental health service delivery - an area where little prior research exists.

Sensitivity of synaptic GABA(A) receptors to allosteric modulators in hippocampal oriens-alveus interneurons.

GABA(A) receptors are heteropentamers that are heterogeneously distributed at different synapses in the central nervous system. Although the modulation of GABA(A) receptors received much attention in hippocampal pyramidal cells, information is scarce regarding the pharmacology of these receptors in inhibitory interneurons. We investigated the pharmacological properties of GABA(A)-mediated miniature inhibitory postsynaptic currents (mIPSCs) using whole-cell voltage clamp recordings in two morphologically identified types of hippocampal CA1 interneurons, horizontal and vertical cells of stratum oriens-alveus. The negative modulators zinc (200 microM) and furosemide (600 microM) significantly decreased the amplitude of mIPSCs. Benzodiazepine agonists also produced significant effects: 10 microM zolpidem increased the amplitude, rise time, and decay time constant (decay tau) of mIPSCs, whereas 10 microM flunitrazepam affected similarly the amplitude and decay tau, but not the rise time. The neurosteroid allopregnanolone (10 microM) prolonged the decay tau of mIPSCs. Since these modulators act on different GABA(A) receptor subunits, this pharmacological profile suggests that GABA(A) receptors at spontaneously active inhibitory synapses onto vertical and horizontal interneurons are heterogeneous and formed by co-assembly of different combinations of subunits (alpha(1-5)beta(1-3)gamma(1-3)). Furthermore, these synaptic GABA(A) receptors appear in large part pharmacologically similar to those of pyramidal cells.

Late maturation of GABA(B) synaptic transmission in area CA1 of the rat hippocampus.

Whole cell voltage clamp recordings were used to investigate the postnatal development of GABA(B) synaptic transmission in CA1 pyramidal cells of rat hippocampal slices. In the presence of antagonists of glutamate and GABA(A) ionotropic receptors, electrical stimulation evoked slow IPSCs in pyramidal cells from mature animals (35-45 days postnatal, P35-45). Brief trains of stimulation evoked slow IPSCs of greater magnitude. I-V relations of slow IPSCs were inwardly rectifying, with a mean equilibrium potential near -75 to -80 mV. Slow IPSCs were completely antagonized by the GABA(B) antagonist CGP55845A (0.5 microM). In cells from young animals (P12-14), similar stimulation evoked either no or very small slow IPSCs (mean conductance approximately 10% of adult). In cells from animals of intermediate age (P22-24), slow IPSCs were more frequent and their mean conductance was approximately 60-80% of adult values. Bath application of 20 microM baclofen evoked outward currents in cells of animals P35-45. I-V relations of baclofen currents showed inward rectification and reversed near -80 mV. Baclofen currents were absent or minimal in animals P12-14, and of intermediate magnitude in animals P22-24. These results indicate that baclofen and GABA(B) postsynaptic currents are virtually absent 2 weeks postnatally, and appear gradually until 35-45 days postnatal. Thus, GABA(B) synaptic transmission appears to mature late in area CA1 of the rat hippocampus.

Distinct GABAB actions via synaptic and extrasynaptic receptors in rat hippocampus in vitro.

Intracellular recordings were obtained from pyramidal cells to examine gamma-aminobutyric acid-B (GABAB)-mediated synaptic mechanisms in the CA1 region of rat hippocampal slices. To investigate if heterogeneous ionic mechanisms linked to GABAB receptors originate from distinct sets of inhibitory fibers, GABAB-mediated monosynaptic late inhibitory postsynaptic potentials (IPSPs) were elicited in the presence of antagonists of ionotropic glutamate and GABAA receptors and of an inhibitor of GABA uptake and were compared after direct stimulation of inhibitory fibers in three different CA1 layers: stratum oriens, radiatum, and lacunosum-moleculare. No significant differences were found in mean amplitude, rise time, or time to decay to half-amplitude of IPSPs evoked from the three layers. Mean equilibrium potential (Erev) of late IPSPs was similar for all groups and close to the equilibrium potential of K+. Bath application of the GABAB antagonist CGP55845A blocked all monosynaptic late IPSPs. During recordings with micropipettes containing guanosine-5'-O-(3-thiotriphosphate) (GTPgammaS), the mean amplitude of all GABAB IPSPs gradually was reduced. Bath application of Ba2+ completely eliminated monosynaptic late IPSPs evoked from any of the stimulation sites. Late IPSPs were blocked completely during Ba2+ applications that reduced the GABAB-mediated hyperpolarizations elicited by local application of exogenous GABA only by approximately 50%. These results indicate that heterogenous K+ conductances activated by GABAB receptors do not originate from separate sets of inhibitory fibers in these layers. To examine if synchronous release of GABA from a larger number of inhibitory fibers could activate heterogeneous GABAB mechanisms, giant GABAB IPSPs were induced by 4-aminopyridine (4-AP) in the presence of antagonists of ionotropic glutamate and GABAA receptors. The amplitude and time course 4-AP-induced late IPSPs were approximately double that of evoked monosynaptic late IPSPs, but their voltage sensitivity, Erev, and antagonism by the GABAB antagonist CGP55845A and intracellular GTPgammaS were similar. Ba2+ completely abolished 4-AP-induced late IPSPs, whereas responses elicited by exogenous GABA were only reduced by approximately 50% in the same cells. These results indicate that synchronous activation of large numbers of inhibitory fibers, as induced by 4-AP, may not activate heterogenous GABAB-mediated conductances. Similarly, Ba2+ almost completely blocked late inhibitory postsynaptic currents evoked by stimulus trains. Overall, our results show that exogenous GABA can activate heterogenous K+ conductances via GABAB receptors, but that GABA released synaptically, either by electrical stimulation or 4-AP application, can only activate K+ conductances homogeneously sensitive to Ba2+. Thus GABAB receptors located at synaptic and extrasynaptic sites on hippocampal pyramidal cells may be linked to distinct K+ conductances.

The problem of assessing effective neuroprotection in experimental cerebral ischemia.

In animal models of global and focal ischemia neuroprotection is typically determined by quantifying the degree of cell loss or reduction in infarct volume shortly after the ischemic insult. These methods are unable to reliably detect more subtle forms of neuronal death and dysfunction that arise from injury to non-homogeneous cell populations (e.g. hilar and striatal neurons), or to dendrites (e.g. loss of structural proteins or decreased synaptic transmission). It is argued that this type of covert injury contributes to a wide range of functional impairments (e.g. decreased working memory, altered field potentials, loss of forelimb dexterity) that are rarely used as outcome measures in experimental studies even though they are of paramount importance clinically. The limitations of a purely histological approach in assessing neuroprotection are clearly illustrated using examples of protective drug therapies, mild hypothermia and ischemic preconditioning. An alternative strategy that incorporates behavioural, electrophysiological and histological endpoints is put forth as a more powerful method for gauging neuroprotection. The strength of this approach will be increased if these assessments are performed on the same animals. By incorporating functional measures and longer postischemic survival into their experimental protocols, investigators will increase the validity of their models and hopefully reduce the likelihood of advancing ineffective therapies into costly clinical trials.

Hypothermic neuroprotection. A global ischemia study using 18- to 20-month-old gerbils.

BACKGROUND AND PURPOSE: Previous studies from this laboratory have shown that mild intraischemic or prolonged (i.e., 12 to 24 hours) postischemic hypothermia conveys long-lasting (1 to 6 months) protection against CA1 injury. However, these studies have used young animals (aged approximately 3 to 5 months). Stroke incidence rises sharply in late middle age at a time when changes in brain chemistry could alter the response to neuroprotective treatments. Therefore, we evaluated the efficacy of hypothermia in an older population (aged 18 to 20 months) of gerbils. METHODS: Three groups of gerbils were exposed to a 5-minute episode of global ischemia or sham occlusion. One group was cooled during ischemia (mean brain temperature of 32 degrees C). A second group was maintained at normothermia (36.4 degrees C) during occlusion and the first hour of reperfusion. Beginning 1.0 hour after occlusion, these gerbils were gradually cooled to 32 degrees C and maintained at this level before gradual rewarming to 37 degrees C at 25 hours after ischemia. The third ischemic group was kept at normothermia during surgery and the first hour of reperfusion. After surgery, all animals were tested for acute (i.e., within 30 hours of ischemia) changes in locomotor activity as well as for chronic (i.e., 5, 10, and 30 days after ischemia) habituation deficits in an open field test. RESULTS: Both intraischemic and postischemic hypothermia provided robust protection (P < .0001) of hippocampal CA1 neurons when assessed 30 days after ischemia. However, intraischemic hypothermia was more effective than postischemic hypothermia in providing behavioral protection. CONCLUSIONS: This study demonstrates that both intraischemic and prolonged postischemic hypothermia provide robust and lasting (30-day survival) histological protection against a severe ischemic insult. The extent of behavioral protection with postischemic hypothermia was less than that previously observed in younger animals. This suggests that neuroprotective treatments in young animals may lose efficacy as a result of aging.

Do GABAA and GABAB inhibitory postsynaptic responses originate from distinct interneurons in the hippocampus?

GABAergic inhibition of hippocampal pyramidal cells is mediated by two distinct subtypes of postsynaptic receptors, GABAA and GABAB. Electrical stimulation of inhibitory cells or fibres in the CA1 subfield of the hippocampus yields a biphasic inhibitory postsynaptic potential (IPSP) in pyramidal cells, consisting of an early GABAA- and a late GABAB-mediated component. CA1 interneurons are a heterogeneous population of cells, which differ on the basis of their morphology, physiological properties, target selectivity onto principal cells, and network connectivity. Inhibitory synaptic circuitry appears to be specialized, since feedback inhibition may invoke only postsynaptic GABAA receptors, whereas feedforward inhibition may invoke both postsynaptic GABAA and GABAB receptors. In this review, we examine the evidence for and against the notion that distinct interneurons may be responsible for GABAA- and GABAB-mediated inhibition. Overall, the evidence suggests that (i) certain interneurons may generate solely GABAA inhibition, but the available data do not distinguish whether other interneurons mediate (ii) solely GABAB inhibition or (iii) a combination of both GABAA and GABAB.

Neuroprotection after several days of mild, drug-induced hypothermia.

Stroke trials are initiated after demonstrated pharmacological protection in animal models. NBQX protects CA1 neurons against global ischemia; however, this glutamate antagonist induces a period of subnormal temperature (e.g., a decrease of only 1.0-1.5 degrees C) lasting several days. In this study, NBQX (3 x 30 mg/kg, i.p.) was administered starting 60 min after reperfusion, and brain temperature had declined significantly below vehicle-treated animals by 2 h after reperfusion. When the postischemic brain temperature of NBQX-treated gerbils was regulated, no neuronal protection was found. Mimicking an NBQX-induced temperature profile for 28 h postischemia yielded histological protection 4 days later comparable to that of NBQX. However, both the NBQX and temperature simulation groups showed decreased protection after 10-day survival. Our data suggest that a protracted period of subnormal temperature during postischemic period can obscure the interpretation of preclinical drug studies.

Direct measurement of brain temperature during and after intraischemic hypothermia: correlation with behavioral, physiological, and histological endpoints.

The aim of the present study was to evaluate critically the protection afforded by hypothermia against ischemic injury to the hippocampus. Hypothermic treatment was applied selectively to the brain during a 5 min carotid artery occlusion in gerbils. Following a period of recovery, two independent measures were used to assess hippocampal function: (1) an open field test of spatial memory (assessment was made during the first 10 d after ischemia) and (2) measurement of evoked potentials from area CA1 in hippocampal slices (3 weeks after the ischemic episode). The functional outcome portrayed by these tests was compared to a morphological evaluation of CA1 pyramidal cells at three rostrocaudal levels. All evaluations were carried out in the same animals. We found converging evidence that intraischemic hypothermia provides virtually complete protection against a 5 min episode of cerebral ischemia. Animals treated with hypothermia performed as well as sham-operated controls in a spatial memory task, had field potentials that were indistinguishable from normal animals and CA1 cells appeared normal when assessed histologically. In contrast, ischemia at normothermia resulted in a deficit in open field behavior (p < 0.01), diminished field potentials in stratum radiatum (p < 0.01), and near total loss of pyramidal cells in dorsal CA1 (p < 0.01). There was a remarkably high correlation between these diverse measures (r ranged from 0.7 to 0.9, p < 0.01), which provides strong support for the use of hypothermia as an effective treatment for ischemia. This study introduces a novel approach for the evaluation of putative anti-ischemic treatments: combining behavioral, electrophysiological, and histological measures.(ABSTRACT TRUNCATED AT 250 WORDS)

Pubertal development of the pouch and teats in the marsupial Macropus eugenii.

In the female tammar wallaby, Macropus eugenii, which has a highly seasonal breeding pattern, teat eversion and enlargement of the pouch occur at puberty, about 40 weeks after birth. The most obvious sign of puberty is teat eversion: 22 of 23 wild caught, and 23 of 24 captive postpubertal animals had fully everted or everting teats. Full eversion of the teats took on average two to three weeks after puberty. The pouch opening enlarged at puberty, and the rate of enlargement from 2 weeks before puberty to 2 weeks after puberty was significantly greater than the rate before puberty. In a group of pouch young ovariectomized at 5-10 weeks of age, no such changes in either teats or pouch were observed by 46 weeks of age. However, after treatment with oestradiol (0.5 microgram kg-1 body mass), four of five young showed teat eversion within 3-4 weeks. Progesterone (2 mg kg-1) had no effect on inverted teats. In these ovariectomized females oestradiol treatment caused a significant increase in the rate of growth of the pouch opening. During progesterone injections the size of the pouch remained the same. Thus, at puberty the teats and pouch of the tammar wallaby undergo rapid developmental changes and growth. Ovariectomy at an early stage of gonadal differentiation disrupts these normal changes, but treatment of these animals with physiological doses of oestradiol at the age when puberty would normally have occurred can restore teat and pouch maturation. Teat eversion and pouch enlargement can therefore be used as markers for puberty.(ABSTRACT TRUNCATED AT 250 WORDS)

Spontaneous postischemic hyperthermia is not required for severe CA1 ischemic damage in gerbils.

We have recently shown that brain temperature can drop even though rectal and skull readings are maintained near 37 degrees C during global forebrain ischemia in the gerbil. In this study gerbils were subjected to 5 min of ischemia followed by 85 min of extended halothane anesthesia, while rectal and skull temperatures were kept at normal values. This extended anesthesia procedure prevented the development of spontaneous postischemic hyperthermia. However, it occasionally produced mild brain hypothermia both during ischemia and throughout anesthesia. In addition, the degree of brain hypothermia positively correlated with CA1 preservation; with some gerbils showing complete protection. In contrast, animals with normal brain temperature displayed extensive CA1 cell loss. These data suggest that postischemic hyperthermia is not a prerequisite for extensive CA1 loss in gerbils exposed to 5 min of ischemia. Second, rectal and skull recordings are not always reliable indicators of brain temperature, especially during anesthesia.

Temperature changes associated with forebrain ischemia in the gerbil.

Changes in brain temperature during and following ischemia have not been systematically examined in the gerbil. In this study, gerbils were subjected to a 5-min bilateral carotid artery occlusion. During surgery, skull and body temperatures were maintained with a heated water blanket and a homeothermic blanket unit, respectively. Rectal, skull and brain temperatures were monitored throughout ischemia and for up to 3 h in the post-ischemic period. Intra-ischemic brain temperature fell by approximately 1.5 degrees C even though skull and rectal temperatures remained at normal values. Since brain temperature modulates the extent of ischemic injury it may not be sufficient to rely on skull and/or rectal temperature readings, especially during periods of anesthesia.

Impaired acquisition of the Morris water maze following global ischemic damage in the gerbil.

Five minutes of global ischemia in the Mongolian gerbil impaired acquisition of a Morris water maze task when testing began 72 h after surgery. In spite of extensive damage to CA1 pyramidal cells, ischemic animals eventually learned to locate a submerged platform and performed normally on a subsequent retention test. Animals that were allowed a more protracted recovery period (21 days) acquired the task as readily as control gerbils. These results suggest that undamaged structures within and external to the hippocampal formation allow spatial learning to proceed at a somewhat reduced rate.