Osteocalcin and its forms respond similarly to exercise in males and females.

INTRODUCTION: Acute exercise increases osteocalcin (OC), a marker of bone turnover, and in particular the undercarboxylated form (ucOC). Males and females differ in baseline levels of total OC and it is thought the hormonal milieu may be driving these differences. Males and females adapt differently to the same exercise intervention, however it is unclear whether the exercise effects on OC are also sex-specific. We tested whether the responses of OC and its forms to acute High Intensity Interval Exercise (HIIE) and High Intensity Interval Training (HIIT) differed between males and females. Secondly, we examined whether sex hormones vary with OC forms within sexes to understand if these are driving factor in any potential sex differences. METHODS: Total OC (tOC), undercarboxylated OC (ucOC), and carboxylated OC (cOC) were measured in serum of 96 healthy participants from the Gene SMART cohort (74 males and 22 females) at rest, immediately after, and 3 h after a single bout of HIIE, and at rest, 48 h after completing a four week HIIT intervention. Baseline testosterone and estradiol were also measured for a subset of the cohort (Males = 38, Females = 20). Linear mixed models were used to a) uncover the sex-specific effects of acute exercise and short-term training on OC forms and b) to examine whether the sex hormones were associated with OC levels. RESULTS: At baseline, males had higher levels of tOC, cOC, and ucOC than females (q < 0.01). In both sexes tOC, and ucOC increased to the same extent after acute HIIE. At baseline, in males only, higher testosterone was associated with higher ucOC (ß = 3.37; q < 0.046). Finally, tOC and ucOC did not change following 4 weeks of HIIT. CONCLUSION/DISCUSSION: While there were no long-term changes in OC and its forms. tOC and ucOC were transiently enhanced after a bout of HIIE similarly in both sexes. This may be important in metabolic signalling in skeletal muscle and bone suggesting that regular exercise is needed to maintain these benefits. Overall, these data suggest that the sex differences in exercise adaptations do not extend to the bone turnover marker, OC.

Effects of calcium supplementation on circulating osteocalcin and glycated haemoglobin in older women.

One year of calcium supplementation in older women led to modest reductions in total osteocalcin and undercarboxylated osteocalcin (ucOC), with no changes in muscle or fat mass, or glycated haemoglobin. Future studies should explore whether treatments with more profound effects of suppressing ucOC may lead to impaired glycaemic control. INTRODUCTION: Total osteocalcin (TOC) is a marker of bone turnover, while its undercarboxylated form has beneficial effects on glucose metabolism in mice. This post hoc analysis of a randomised double-blind, placebo-controlled trial examined whether 1 year of calcium supplementation affected circulating TOC, undercarboxylated osteocalcin (ucOC) or glycated haemoglobin (HbA1c) in 1368 older community-dwelling women (mean age 75.2 ± 2.7 years). METHODS: Women enrolled in the Calcium Intake Fracture Outcome Study trial (1998-2003) were supplemented with 1.2 g/d of elemental calcium (in the form of calcium carbonate) or placebo. Circulating TOC, ucOC and HbA1c was measured at 1 year (1999). RESULTS: After 1 year of calcium supplementation, TOC and ucOC levels were 17% and 22% lower compared with placebo (mean 22.7 ± 9.1 vs. 27.3 ± 10.9 µg/L and 11.1 ± 4.9 vs. 13.0 ± 5.7 µg/L, both P < 0.001). Carboxylated osteocalcin/ucOC was 6% lower after calcium supplementation (P < 0.05). Despite this, no differences in HbA1c were observed (calcium, 5.2 ± 0.6 vs. placebo, 5.3 ± 0.8%; P = 0.08). Calcium supplementation did not affect BMI, whole body lean or fat mass. In exploratory analyses, total calcium (dietary and supplemental) was inversely related to TOC and ucOC, indicating calcium intake is an important dietary determinant of osteocalcin levels. CONCLUSION: One year of calcium supplementation in older women led to modest reductions in TOC and ucOC, with no changes in muscle or fat mass, or HbA1c. Future studies should explore whether treatments with more profound effects of suppressing ucOC may lead to impaired glycaemic control.

Acute continuous moderate-intensity exercise, but not low-volume high-intensity interval exercise, attenuates postprandial suppression of circulating osteocalcin in young overweight and obese adults.

Bone remodeling markers (BRMs) are suppressed following the consumption of a meal. Our findings indicate that a single session of continuous moderate-intensity exercise, but not low-volume high-intensity interval exercise, performed 1 h after a meal attenuates the postprandial suppression of BRMs. INTRODUCTION: Acute exercise transiently increases BRMs including osteocalcin (tOC) and the undercarboxylated form of osteocalcin (ucOC), a hormone that is implicated in glucose regulation. The effects of acute exercise and exercise-intensity on postprandial levels of tOC and ucOC are unknown. METHODS: Twenty-seven adults that were overweight or obese (age 30 ± 1 years; BMI 30 ± 1 kg∙m-2; mean ± SEM) were randomly allocated to perform a single session of low-volume high-intensity interval exercise (LV-HIIE; nine females, five males) or continuous moderate-intensity exercise (CMIE; eightfemales, five males) 1 h after consumption of a standard breakfast. Serum tOC, ucOC, and ucOC/tOC were measured at baseline, 1 h, and 3 h after breakfast consumption on a rest day (no exercise) and the exercise day (exercise 1 h after breakfast). RESULTS: Compared to baseline, serum tOC and ucOC were suppressed 3 h after breakfast on the rest day (- 10 ± 1% and - 6 ± 2%, respectively; p < 0.05), whereas ucOC/tOC was elevated (2.5 ± 1%; p = 0.08). Compared to the rest day, CMIE attenuated the postprandial-induced suppression of tOC (rest day - 10 ± 2% versus CMIE - 5 ± 2%, p < 0.05) and ucOC (rest day - 6 ± 4% versus CMIE 11 ± 2%, p < 0.05), and increased postprandial ucOC/tOC (rest day 3 ± 2% versus CMIE 15 ± 1%, p < 0.05). In contrast, LV-HIIE did not alter postprandial tOC, ucOC, or ucOC/tOC (all p > 0.1). CONCLUSIONS: Acute CMIE, but not LV-HIIE, attenuates the postprandial-induced suppression of tOC and ucOC. CMIE may be an effective tool to control the circulating levels of BRMs following meal consumption in overweight/obese adults.

Individual personality differences in Port Jackson sharks Heterodontus portusjacksoni.

This study examined interindividual personality differences between Port Jackson sharks Heterodontus portusjacksoni utilizing a standard boldness assay. Additionally, the correlation between differences in individual boldness and stress reactivity was examined, exploring indications of individual coping styles. Heterodontus portusjacksoni demonstrated highly repeatable individual differences in boldness and stress reactivity. Individual boldness scores were highly repeatable across four trials such that individuals that were the fastest to emerge in the first trial were also the fastest to emerge in subsequent trials. Additionally, individuals that were the most reactive to a handling stressor in the first trial were also the most reactive in a second trial. The strong link between boldness and stress response commonly found in teleosts was also evident in this study, providing evidence of proactive-reactive coping styles in H. portusjacksoni. These results demonstrate the presence of individual personality differences in sharks for the first time. Understanding how personality influences variation in elasmobranch behaviour such as prey choice, habitat use and activity levels is critical to better managing these top predators which play important ecological roles in marine ecosystems.

Sex- and age-specific differences in relaxin family peptide receptor expression within the hippocampus and amygdala in rats.

Relaxin is an essential pregnancy-related hormone with broad peripheral effects mediated by activation of relaxin-like family peptide 1 receptors (RXFP1). More recent studies suggest an additional role for relaxin as a neuropeptide, with RXFP1 receptors expressed in numerous brain regions. Neurons in an area of the brainstem known as the nucleus incertus (NI) produce relaxin 3 (RLN3), the most recently identified neuropeptide in the relaxin family. RLN3 has been shown to activate both RXFP1 and relaxin-like family peptide receptor 3 (RXFP3) receptor subtypes. Studies suggest wide-ranging neuromodulatory effects of both RXFP1 and RXFP3 activation, although to date the majority of studies have been conducted in young males. In the current study, we examined potential sex- and age-related changes in RLN3 gene expression in the NI as well as RXFP1 and RXFP3 gene expression in the dorsal hippocampus (HI), ventral hippocampus (vHI) and amygdala (AMYG) using young adult (9-12weeks) and middle-aged (9-12months) male and female rats. In addition, regional changes in RXFP1 and RXFP3 protein expression were examined in the CA1, CA2/CA3 and dentate gyrus (DG) as well as within basolateral (BLA), central (CeA), and medial (MeA) amygdaloid nuclei. In the NI, RLN3 showed an age-related decrease in males. In the HI, only the RXFP3 receptor showed an age-related change in gene expression, however, both receptor subtypes showed age-related changes in protein expression that were region specific. Additionally, while gene and protein expression of both receptors increased with age in AMYG, these effects were both region- and sex-specific. Finally, overall males displayed a greater number of cells that express the RXFP3 protein in all of the amygdaloid nuclei examined. Cognitive and emotional processes regulated by activity within the HI and AMYG are modulated by both sex and age. The vast majority of studies exploring the influence of sex on age-related changes in the HI and AMYG have focused on sex hormones, with few studies examining the role of neuropeptides. The current findings suggest that changes in relaxin family peptides may contribute to the significant sex differences observed in these brain regions as a function of aging.

Housing environment modulates physiological and behavioral responses to anxiogenic stimuli in trait anxiety male rats.

Environmental enrichment can modulate mild and chronic stress, responses to anxiogenic stimuli as well as drug vulnerability in a number of animal models. The current study was designed to examine the impact of postnatal environmental enrichment on selectively bred 4th generation high- (HAn) and low-anxiety (LAn) male rats. After weaning, animals were placed in isolated (IE), social (SE) and enriched environments (EE) (e.g., toys, wheels, ropes, changed weekly). We measured anxiety-like behavior (ALB) on the elevated plus maze (EPM; trial 1 at postnatal day (PND) 46, trial 2 at PND 63), amphetamine (AMPH) (0.5mg/kg, IP)-induced locomotor behavior, basal and post anxiogenic stimuli changes in (1) plasma corticosterone, (2) blood pressure and (3) core body temperature. Initially, animals showed consistent trait differences on EPM with HAn showing more ALB but after 40 days in select housing, HAn rats reared in an EE showed less ALB and diminished AMPH-induced activity compared to HAn animals housed in IE and SE. In the physiological tests, animals housed in EE showed elevated adrenocortical responses to forced novel object exposure but decreased body temperature and blood pressure changes after an air puff stressor. All animals reared in EE and SE had elevated brain-derived neurotrophic factor (BDNF)-positive cells in the central amygdala (CeA), CA1 and CA2 hippocampal regions and the caudate putamen, but these differences were most pronounced in HAn rats for CeA, CA1 and CA2. Overall, these findings suggest that environmental enrichment offers benefits for trait anxiety rats including a reduction in behavioral and physiological responses to anxiogenic stimuli and AMPH sensitivity, and these responses correlate with changes in BDNF expression in the central amygdala, hippocampus and the caudate putamen.

The impact of exposure to addictive drugs on future generations: Physiological and behavioral effects.

It is clear that both genetic and environmental factors contribute to drug addiction. Recent evidence indicating trans-generational influences of drug abuse highlight potential epigenetic factors as well. Specifically, mounting evidence suggests that parental ingestion of abused drugs influence the physiology and behavior of future generations even in the absence of prenatal exposure. The goal of this review is to describe the trans-generational consequences of preconception exposure to drugs of abuse for five major classes of drugs: alcohol, nicotine, marijuana, opioids, and cocaine. The potential epigenetic mechanisms underlying the transmission of these phenotypes across generations also are detailed. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'.

Reproductive experience alters neural and behavioural responses to acute oestrogen receptor α activation.

Reproductive experience (i.e. parturition and lactation) leads to persistent alterations in anxiety-like behaviour that are influenced by the oestrous cycle. We recently found that repeated administration of the selective oestrogen receptors (ER)α agonist propyl-pyrazole triol (PPT) results in anxiolytic-like behaviours on the elevated plus maze (EPM) in primiparous (but not nulliparous) female rats. The present study examined the effects of the acute administration of PPT on EPM behaviour in primiparous and aged-matched, nulliparous female rats. In addition, corticosterone secretion, corticotrophin-releasing hormone (CRH) gene expression and expression of the immediate early gene product Fos in the paraventricular nucleus (PVN) and amygdala were measured either after EPM testing or in home cage controls. Acute PPT administration significantly modified EPM behaviour as a function of reproductive experience, with nulliparous females tending toward increased anxiety-like behaviours and primiparous females tending toward decreased anxiety-like behaviours. In home cage controls, PPT increased corticosterone secretion in all females; however, both vehicle- and PPT-treated, primiparous females had reduced corticosterone levels compared to their nulliparous counterparts. Significant effects of PPT on CRH mRNA within the PVN were observed after the administration of PPT but only in primiparous females tested on the EPM. PPT also increased Fos expression within the PVN of EPM-exposed females; however, both vehicle- and PPT-treated primiparous females had reduced Fos expression compared to nulliparous females. In the amygdala, PPT increased Fos immunoreactivity in the central but not the medial or basolateral amygdala, although these effects were only observed in home cage females. Additionally, both vehicle- and PPT-treated home cage, primiparous females had increased Fos in the central nucleus of the amygdala compared to nulliparous controls. Overall, these data demonstrate that reproductive experience alters the behavioural response to acute ERα activation. Moreover, the findings suggest that central regulation of the hypothalamic-adrenal-pituitary axis is modified as a consequence of reproductive experience.

Isavuconazole activity against Aspergillus lentulus, Neosartorya udagawae, and Cryptococcus gattii, emerging fungal pathogens with reduced azole susceptibility.

Isavuconazole is an extended-spectrum triazole with in vitro activity against a wide variety of fungal pathogens. Clinical isolates of molds Aspergillus lentulus and Neosartorya udagawae and yeast Cryptococcus gattii VGII (implicated in the outbreak in the Pacific Northwest, North America) exhibit reduced susceptibilities to several azoles but higher susceptibilities to isavuconazole.

Differential expression of oestrogen receptor alpha following reproductive experience in young and middle-aged female rats.

Reproductive experience (i.e. pregnancy and lactation) alters a number of physiological and behavioural endpoints, many of which are related to reproductive function and are regulated by oestrogen. For example, reproductive experience significantly attenuates the oestradiol-induced prolactin surge on the afternoon of pro-oestrous and circulating oestradiol levels are reduced at this time. Although parity-related effects on oestrogen receptor (ER) alpha have been observed within the anterior pituitary, there are currently no data regarding possible parity-induced alterations in ERalpha in the brain. Thus, the present study aimed to examine the effect of parity on the expression of ERalpha in reproductively relevant brain regions. Moreover, because previous findings have demonstrated that the long-term effects of reproductive experience are often oestrous cycle-dependent, ERalpha was examined at two stages of the oestrous cycle (i.e. dioestrous and pro-oestrous). Finally, because the expression of ERalpha is significantly influenced by age, both young and middle-aged females were included in the present study. ERalpha status was determined using immunohistochemistry in select brain regions involved in the regulation of reproductive behaviour in age-matched, cycling primiparous (i.e. one pregnancy and lactation) and nulliparous females as well as in age-matched, noncycling (i.e. persistent oestrous) 12 month-old primiparous and nulliparous females. Significant shifts in ERalpha cell numbers were observed in the medial preoptic area and medial amygdala as a consequence of reproductive experience in an oestrous-dependent manner. These findings indicate that significant changes in ERalpha activity occur in the brain as a function of reproductive experience.

Association of paediatric mastocytosis with a polymorphism resulting in an amino acid substitution (M541L) in the transmembrane domain of c-KIT.

BACKGROUND: The receptor tyrosine kinase c-KIT plays a key role in normal mast cell development. Point mutations in c-KIT have been associated with sporadic or familial mastocytosis. OBJECTIVES: Two unrelated pairs of apparently identical twins affected by cutaneous mastocytosis attending the Mastocytosis Clinic at the Royal Children's Hospital, Melbourne, provided an opportunity to assess the possible contribution of c-KIT germline mutations or polymorphisms in this disease. METHODS: Tissue biopsy, blood and/or buccal swab specimens were collected from 10 children with mastocytosis. To detect germline mutations/polymorphisms in c-KIT, we studied all coding exons by denaturing high pressure liquid chromatography. Exons showing mismatches were examined by direct sequencing. The influence of the substitution identified was further examined by expressing the variant form of c-KIT in factor-dependent FDC-P1 cells. RESULTS: In both pairs of twins, a heterozygous ATG to CTG transition in codon 541 was observed, resulting in the substitution of a methionine residue in the transmembrane domain by leucine (M541L). In each case, one parent was also heterozygous for this allele. Expression of M541L KIT in FDC-P1 cells enabled them to grow in human KIT ligand (stem cell factor, SCF) but did not confer factor independence. Compared with cells expressing wild-type KIT at a similar level, M541L KIT-expressing cells displayed enhanced growth at low levels of SCF, and heightened sensitivity to the KIT inhibitor, imatinib mesylate. CONCLUSIONS: The data suggest that the single nucleotide polymorphism resulting in the substitution M541L may predispose to paediatric mastocytosis.

Reproductive experience and expression of dopamine D(2) receptor mRNA: a possible mechanism for reduced prolactin secretion in primiparous rats.

Reproductive experience (i.e. pregnancy and lactation) leads to reduced levels of circulating prolactin in both women and rats. Stimulation of prolactin secretion by dopamine antagonists is also blunted following reproductive experience in both species. Whereas a parity-induced reduction in haloperidol-stimulated prolactin secretion is evident in ovariectomised rats, it is unknown whether a similar attenuation of prolactin secretion is present in reproductively experienced, cycling pro-oestrous rats. The present study examined this possibility. Moreover, to determine possible mechanisms involved in parity-mediated changes in prolactin secretion, both dopamine utilisation within the arcuate nucleus/median eminence and expression of dopamine D(2) receptor mRNA (short and long forms) in the anterior pituitary were measured across the afternoon of pro-oestrous in reproductively experience and inexperienced females. Prolactin secretion was lower on the afternoon of pro-oestrous in primiparous females compared to age-matched, nulliparous controls. In addition, haloperidol-stimulated prolactin secretion was reduced in ovariectomised, reproductively experienced females. Although no differences in dopamine utilisation were observed as a function of reproductive experience, parity did affect the expression of both forms of D(2) receptor mRNA in the anterior pituitary. Compared with nulliparous controls, primiparous females had increased D(2 long) mRNA expression at 12.00 h on pro-oestrous as well as increased D(2 short) mRNA expression at 14.00 h. Because the ratio of D(2 long)/D(2 short) can significantly effect lactotroph proliferation and prolactin secretion, a shift in relative expression of the two D(2) receptor isoforms within the anterior pituitary of parous females may help account for the reduction in prolactin secretion that occurs following reproductive experience.

Increased sensitivity of dopamine systems following reproductive experience in rats.

Several studies have suggested that alterations in forebrain dopamine activity during the postpartum period may result in the onset of postpartum psychosis in women [J. Psychosom. Obstet. Gynecol. 19 (1998) 104; Prog. Neuro-Psychopharmacol. Biol. Psychiatry 17 (1993) 571; J. Clin. Psychiatry 51 (1990) 365.]. The present study investigated whether increased dopamine activity in these forebrain regions is a normal consequence of reproductive experience in rodents. Both intact and ovariectomized parous and nulliparous females were tested for their responses to the dopamine agonist apomorphine using two behavioral measures, prepulse inhibition (PPI) and oral stereotypy. In addition, dopamine and DOPAC levels were measured in tissue from the striatum and nucleus accumbens together with circulating plasma prolactin levels. The results of the behavioral studies demonstrate an increased response to apomorphine in parous females. Parous subjects also had increased levels of dopamine and DOPAC in striatal tissue and lower levels of circulating prolactin. Ovariectomy in nulliparous females resulted in a potentiated response to apomorphine with regard to the disruption of PPI, as well as a significant decrease in the plasma prolactin levels, as compared with intact nulliparous females. These data suggest that increased dopamine activity in forebrain regions occurs as a consequence of parity, which persists for a minimum of several weeks postpartum. These findings support the hypothesis that increased dopamine sensitivity in forebrain dopamine regions may be one potential mechanism underlying the development of postpartum psychosis in women.

Central infusions of the recombinant human prolactin receptor antagonist, S179D-PRL, delay the onset of maternal behavior in steroid-primed, nulliparous female rats.

The expression of maternal behavior in the newly parturient rat is under endocrine regulation. Blocking endogenous PRL secretion with bromocriptine delays the normal rapid expression of maternal care shown toward foster young in steroid-primed virgin female rats. The recent development of the PRL receptor antagonist S179D-PRL, a mutant of human PRL in which the serine residue at the 179 position is replaced with aspartate, provides a potentially useful tool to examine the role of PRL in neural processing. In the present report, three experiments were conducted that examined the effects of this PRL antagonist on the induction of maternal behavior. In each experiment, ovariectomized, nulliparous rats were treated sequentially with SILASTIC capsules implanted sc with progesterone (days 1-11) and estradiol (days 11-17), a treatment that stimulates a rapid onset of maternal behavior in virgin rats. On day 11, females were implanted with Alzet miniosmotic pumps connected to cannulae directed unilaterally at the lateral ventricle (Exp 1) or bilaterally at the medial preoptic area (MPOA; Exp 2 and 3). Pumps contained either doses of S179D-PRL (0.115 or 1.15 mg/ml; Exp 1 and 2), wild-type human PRL (1.15 mg/ml; Exp 3), or the saline vehicle (Exp 1-3). Testing for maternal behavior began on day 12, a day after pump insertion, and animals were tested daily for 6 days. Latencies to contact, retrieve, and group foster test young were recorded. Administration of both the high and low doses of S179D-PRL infused into the lateral ventricle (Exp 1) or MPOA (Exp 2) significantly delayed the onset of maternal behavior. In contrast, MPOA infusions of the control hormone, wild-type human PRL, in Exp 3 did not delay the onset of maternal behavior. These findings support the concept that the effects of S179D-PRL are caused by its actions as a PRL receptor antagonist rather than by a nonspecific effect of the protein. Overall, these results demonstrate the effectiveness of S179D-PRL acting at the level of the central nervous system (and, more specifically, within the MPOA) to regulate maternal behavior, a PRL-mediated response.

Opioid receptor antagonism during early lactation results in the increased duration of nursing bouts.

High levels of mu opioid receptor activation during the postpartum period result in the disruption of ongoing maternal behavior. The role of physiological levels of endogenous opioids on the mediation of maternal behavior in postpartum females, however, has not been closely examined. The purpose of the present experiments was to examine the function of endogenous opioids during early and mid-lactation by treating postpartum females with the opioid antagonist naloxone and monitoring their behavioral interactions with pups. Although this treatment did not lead to any qualitative differences in the maternal behaviors measured (pup retrieval and grooming, nest building, grouping of pups, or crouching over pups), there was a quantitative difference in the amount of time the females spent with pups on the nest and actively nursing pups. Naloxone, given either systemically or centrally (intracerebroventricularly), resulted in prolonged nursing and nesting bouts. This effect, however, was only observed during the early lactation time point (postpartum days 5-7). Females tested later in lactation (postpartum days 10-12 or 12-14) did not display the increased nursing or nesting bouts in response to the antagonist. These data indicate that central opioids play a role in the duration of nursing bouts during early lactation.

Endogenous opioid facilitation of maternal memory in rats.

In rats, contact with pups at parturition establishes a form of maternal memory that enables female rats to respond rapidly to pups in the future. Treatment of pregnant female rats with the long-lasting micro opioid receptor antagonist, beta-funaltrexamine (beta-FNA), prior to parturition interfered with the establishment of maternal memory. Similar treatment 3 hr postpartum resulted in disrupted retention of maternal memory that appeared nonspecific, with both drug- and vehicle-treated rats displaying a deficit. However, infusion of the opioid antagonist 24 hr postpartum had no effect on the retention of maternal memory tested 7 days later. These findings indicate that the establishment of maternal memory is mediated by endogenous opioid activity around the time of parturition.

Reductions in criminality subsequent to group, individual, and family therapy in adolescent residential and day treatment settings.

The complete population of adolescents in a residential and day-treatment program over a 4-year period, 532 youths, served in two studies. Along with residential and day-treatment settings, predictive variables of interest were the number of hours spent in group, individual, and family therapy. A total of 227 adolescents qualified for Study 1 which found a reduction of rates of criminal charges from pre- to posttreatment. Study 1 also found that hours in group therapy explained the most variance in the reduction in rates of criminal charges, followed closely by hours in individual therapy. Hours in family therapy was not a significant predictor. A total of 430 adolescents qualified for Study 2, which found that residential treatment was associated with greater reductions in adult correctional commitments than day treatment. Implications stress the need for further research examining the relationships between therapeutic components of residential treatment and behavioral outcomes.

Effects of AMPA and D1 receptor activation on striatal and nigral GABA efflux.

The ability of locally-administered AMPA and D1 receptor ligands to modulate in vivo striatal and nigral GABA efflux was determined in awake, intact male rats using a dual-probe microdialysis technique. Intrastriatal perfusion of AMPA (100 microM) produced a 50-100% increase in striatal GABA efflux that was totally blocked by co-perfusion with TTX (10.0 microM). This AMPA-stimulated, TTX-sensitive GABA efflux was similar across repeated dialsysis perfusions. The effects of intrastriatal perfusion of the full D1-like agonist SKF 81297 were complex. Perfusion of the higher dose (100 microM) of SKF 81297 enhanced GABA efflux, whereas perfusion of the lower dose (10 microM) decreased GABA efflux. Both of these effects were blocked by co-perfusion with the D1-like antagonist SCH 23390 (10 microM). Intrastriatal perfusion of AMPA (100 microM), SKF 81297 (100 microM), or AMPA + SKF 81297 did not stimulate GABA efflux in the substantia nigra. These bidirectional effects of D1 agonists and the apparent dissociation, under certain conditions, between striatal and nigral GABA efflux highlight the complexities of DA- and Glu-modulated striatonigral activity in situ.

Developmental plasticity in the D1- and D2-mediation of motor behavior in rats depleted of dopamine as neonates.

D1- and D2-like antagonist-induced catalepsy and dorsal immobility were studied in pups (Day 10) and weanlings (Days 20, 28, or 35) that received intraventricular injection of 6-OHDA (50 micrograms/hemisphere) or its vehicle solution or postnatal Day 3. The ability of the D1 of D2 antagonists to induce immobility differed as a function of the lesion condition and the age at the time of testing. Moreover, the two behavioral measures exhibited differences in their specific D1 and D2 receptor modulation. Administration of the D1 antagonist SCH 23390 (0.2 or 1.0 mg/kg) or the D2 antagonist clebopride (1.0, 10.0, or 20.0 mg/kg) led to catalepsy and dorsal immobility in intact rats, regardless of test age. Both antagonists induced catalepsy and dorsal immobility in rats depleted of DA when tested on Day 10. However, the effects of each antagonist in DA-depleted rats were ether negligible or significantly less than in controls when animals were tested as weanlings. These data suggest lesion-induced changes in the DA receptor modulation of motor behavior and that this plasticity requires more than a week to become apparent.