Numerical study of acoustic focusing using a bianisotropic acoustic lens.

Materials with sub-wavelength asymmetry and long-range order have recently been shown to demonstrate acoustical properties analogous to electromagnetic bianisotropy. One characteristic of bianisotropic acoustic media is the existence of direction-dependent acoustic impedance. Therefore, the magnitude and phase of the acoustic fields transmitted through bianisotropic acoustic media are dependent on the direction of bianisotropic polarization. These materials can therefore be used as acoustic metasurfaces to control acoustic fields. To demonstrate this behavior, a numerical model of bianisotropic acoustic waveguides is utilized to design a lens that focuses an incident plane wave by only manipulating the orientation of the bianisotropic coupling vector.

Parental education and youth suicidal behaviours: a systematic review and meta-analysis.

AIMS: Lower parental education has been linked to adverse youth mental health outcomes. However, the relationship between parental education and youth suicidal behaviours remains unclear. We explored the association between parental education and youth suicidal ideation and attempts, and examined whether sociocultural contexts moderate such associations. METHODS: We conducted a systematic review and meta-analysis with a systematic literature search in PubMed, PsycINFO, Medline and Embase from 1900 to December 2020 for studies with participants aged 0-18, and provided quantitative data on the association between parental education and youth suicidal ideation and attempts (death included). Only articles published in English in peer-reviewed journals were considered. Two authors independently assessed eligibility of the articles. One author extracted data [e.g. number of cases and non-cases in each parental education level, effect sizes in forms of odds ratios (ORs) or beta coefficients]. We then calculated pooled ORs using a random-effects model and used moderator analysis to investigate heterogeneity. RESULTS: We included a total of 59 articles (63 study samples, totalling 2 738 374 subjects) in the meta-analysis. Lower parental education was associated with youth suicidal attempts [OR = 1.12, 95% Confidence Interval (CI) = 1.04-1.21] but not with suicidal ideation (OR = 1.05, 95% CI = 0.98-1.12). Geographical region and country income level moderated the associations. Lower parental education was associated with an increased risk of youth suicidal attempts in Northern America (OR = 1.26, 95% CI = 1.10-1.45), but with a decreased risk in Eastern and South-Eastern Asia (OR = 0.72, 95% CI = 0.54-0.96). An association of lower parental education and increased risk of youth suicidal ideation was present in high- income countries (HICs) (OR = 1.14, 95% CI = 1.05-1.25), and absent in low- and middle-income countries (LMICs) (OR = 0.91, 95% CI = 0.77-1.08). CONCLUSIONS: The association between youth suicidal behaviours and parental education seems to differ across geographical and economical contexts, suggesting that cultural, psychosocial or biological factors may play a role in explaining this association. Although there was high heterogeneity in the studies reviewed, this evidence suggests that the role of familial sociodemographic characteristics in youth suicidality may not be universal. This highlights the need to consider cultural, as well as familial factors in the clinical assessment and management of youth's suicidal behaviours in our increasingly multicultural societies, as well as in developing prevention and intervention strategies for youth suicide.

Thymosin beta 4 sulfoxide is an anti-inflammatory agent generated by monocytes in the presence of glucocorticoids.

The possibility that glucocorticoids upregulate the expression of anti-inflammatory mediators is an exciting prospect for therapy in inflammatory diseases, because these molecules could give the therapeutic benefits of steroids without toxic side effects. Supernatants from monocytes and macrophages cultured in the presence of glucocorticoids increase the dispersion of neutrophils from a cell pellet in the capillary tube migration assay. This supernatant factor, unlike other neutrophil agonists, promotes dispersive locomotion of neutrophils at uniform concentration, lowers their adhesion to endothelial cells, inhibits their chemotactic response to fMLP and induces distinctive morphological changes. Here we show that thymosin beta4 sulfoxide is generated by monocytes in the presence of glucocorticoids and acts as a signal to inhibit an inflammatory response. In vitro, thymosin beta4 sulfoxide inhibited neutrophil chemotaxis, and in vivo, the oxidized peptide, but not the native form, was a potent inhibitor of carrageenin-induced edema in the mouse paw. Thymosin beta4 is unique, because oxidation attenuates its intracellular G-actin sequestering activity, but greatly enhances its extracellular signaling properties. This description of methionine oxidation conferring extracellular function on a cytosolic protein may have far-reaching implications for future strategies of anti-inflammatory therapy.

Bioactivity as an options value of sea cucumbers in the Egyptian Red Sea.

The utility of a species can be divided into its direct, indirect, and options values. In the marine environment, direct consumptive values predominate and often lead to overexploitation at the expense of significant options values derived through bioprospecting for natural products. We surveyed the waters of the Egyptian Red Sea coast (Gulf of Aqaba [north] and the Red Sea [south]) for species of sea cucumbers and analyzed extracts from species for a range of bioactivities with potential biomedical applications. All habitat types were surveyed within these regions. We found 22 species of sea cucumber of which two, Holothuria fuscogilva and Holothuria flavomaculata, were recorded in Egypt for the first time. Although none of the species identified were unique to the Gulf of Aqaba, 10 species were only found in the Red Sea sector. Bioassay results showed that although no species had antibacterial activity, most extracts exhibited activity against Candida and Leishmania but were most active against a LoVo mammalian carcinoma cell line. Our most significant finding was the intraspecific variation in bioactivity in individuals collected from different habitat types and sectors of the coast. This variation may reflect the effect of environment on secondary metabolite production or may indicate significant genetic diversity between populations within a species. Our results indicate a potentially significant options value to sea cucumbers through bioprospecting. Given the importance of economic development in countries such as Egypt and the perceived low conservation value of invertebrates such as sea cucumbers, the linking of these factors to conservation is vital for the maintenance and sustainable exploitation of these animals.

Apertureless near-field/far-field CW two-photon microscope for biological and material imaging and spectroscopic applications.

We present the development of a versatile spectroscopic imaging tool to allow for imaging with single-molecule sensitivity and high spatial resolution. The microscope allows for near-field and subdiffraction-limited far-field imaging by integrating a shear-force microscope on top of a custom inverted microscope design. The instrument has the ability to image in ambient conditions with optical resolutions on the order of tens of nanometers in the near field. A single low-cost computer controls the microscope with a field programmable gate array data acquisition card. High spatial resolution imaging is achieved with an inexpensive CW multiphoton excitation source, using an apertureless probe and simplified optical pathways. The high-resolution, combined with high collection efficiency and single-molecule sensitive optical capabilities of the microscope, are demonstrated with a low-cost CW laser source as well as a mode-locked laser source.

Growth changes after inhalant abuse and toluene exposure: A systematic review and meta-analysis of human and animal studies.

Inhalant abuse is a significant public health issue, particularly for adolescents, the predominant group of inhalant users. Adolescence is a critical growth period, and inhalant abuse has been associated with growth impairments, including reduced body weight and height. However, the extent to which inhalant abuse affects growth remains unquantified, and potential moderators remain unknown. To address this knowledge gap, a systematic review and meta-analysis of clinical human and preclinical animal studies utilizing toluene exposure (the primary solvent in abused products) was conducted. Five-hundred and sixty-nine studies were screened; 31 met inclusion criteria, yielding 64 toluene-control comparisons for body weight and 6 comparisons for height. Toluene exposure was negatively associated with body weight ( d = -0.73) and height ( d = -0.69). Concentration of inhaled toluene, but not duration, moderated the effect of toluene exposure on body weight, with more severe impairments at higher concentrations. Differences in effect size for body weight were observed for study characteristic subgroups including sex, age at first exposure, administration route and species. However, these findings should be interpreted cautiously due to low study numbers. Growth impairments, particularly during adolescence, can cause long-term health consequences. These effects on growth are therefore an important clinical outcome for individuals with a history of inhalant abuse.

Inhalant abuse among adolescents: neurobiological considerations.

Experimentation with volatile substances (inhalants) is common during early adolescence, yet limited work has been conducted examining the neurobiological impact of regular binge use during this key stage of development. Human studies consistently demonstrate that chronic use is associated with significant toxic effects, including neurological and neuropsychological impairment, as well as diffuse and subtle changes in white matter. However, most preclinical research has tended to focus on acute exposure, with limited work examining the neuropharmacological or toxicological mechanisms underpinning these changes or their potential reversibility with abstinence. Nevertheless, there is growing evidence that commonly abused inhalants share common cellular mechanisms, and have similar actions to other drugs of abuse. Indeed, the majority of acute behavioural effects appear to be underpinned by changes in receptor and/or ion channel activity (for example, GABA(A), glycine and 5HT(3) receptor activation, NMDA receptor inhibition), although nonspecific interactions can also arise at high concentrations. Recent studies examining the effects of toluene exposure during the early postnatal period are suggestive of long-term alterations in the function of NMDA and GABA(A) receptors, although limited work has been conducted investigating exposure during adolescence. Given the critical role of neurotransmitter systems in cognitive, emotional and brain development, future studies will need to take account of the substantial neuromaturational changes that are known to occur in the brain during childhood and adolescence, and to specifically investigate the neuropharmacological and toxicological profile of inhalant exposure during this period of development.

Neuropharmacology of addiction--setting the scene.

Addiction is a complex disorder, affecting not only the individual addict, but also their family and the community at large. While therapeutic strategies are available for the treatment of some forms of substance abuse/dependence, these are not without problems and are not universally efficacious. Moreover, in some instances (for example, cocaine addiction), there are still no medications specifically registered as treatment options. In this themed issue of the British Journal of Pharmacology, we highlight a number of addictions from a pharmacological perspective, with an emphasis on both mechanism and potential therapeutic approaches that are either under development or reflect preclinical work. As such, the authors endeavour to describe the latest thinking on the neural theory of addiction and corresponding novel pharmacotherapeutic targets, and in this way to set the stage for future advances in research and drug development. In addition, we have also attempted to draw attention to the clinicians' perspective in terms of the interface between basic science and care provision.

Persistent downregulation of hippocampal CREB mRNA parallels a Y-maze deficit in adolescent rats following semi-chronic amphetamine administration.

BACKGROUND AND PURPOSE: We investigated possible differences in the impact of chronic amphetamine administration during adolescence and adulthood on aspects of behaviour and brain chemistry. EXPERIMENTAL APPROACH: Adult (n=32) and adolescent (n=32) male Sprague-Dawley rats were given either D-amphetamine sulphate (10 mg kg(-1) daily, i.p.) or saline (1 mL kg(-1), i.p.) for 10 days. Rats were subsequently tested for anxiety-like behaviour, learning and memory, and sensorimotor gating. Nine weeks later, rats received saline (1 mL kg(-1)) or acute amphetamine challenge (1.5 mg kg(-1)) and the expression levels of mRNA for tyrosine kinase B (TrkB) or cAMP response element-binding protein (CREB) were measured in the hippocampus. KEY RESULTS: The adolescent amphetamine pretreated group revealed a deficit in exploration on the Y-maze during a 6 h retention test. The frequency of visits to the novel arm was 35% lower for the amphetamine group compared with controls. In parallel, a 43% decrease in hippocampal CREB mRNA, but not TrkB mRNA, was observed in periadolescent rats treated chronically with amphetamine 9 weeks earlier. None of the effects were detected in the adult treated cohort. CONCLUSIONS AND IMPLICATIONS: Chronic amphetamine treatment during periadolescence resulted in altered behaviour on the Y-maze and persistent downregulation of hippocampal CREB mRNA expression. Given that this group had intact spatial learning and reference memory, it would appear that the deficits observed on the Y-maze reflect a dysfunction in response to novelty. Because no effects of amphetamine treatment were observed in the adult cohort, these data suggest idiosyncratic sensitivity of periadolescence to the long-term effects of psychostimulants.

Brain-derived neurotrophic factor in serum as an animal welfare indicator of environmental enrichment in pigs.

Environment enrichment is a rising topic for animal welfare but measures to identify effective enrichment interventions are lacking. In humans and rodent species, environmental enrichment increases brain-derived neurotrophic factor (BDNF), the most abundant neurotrophin in the brain. Higher BDNF concentration is ultimately linked to higher stress resilience, and BDNF in the hippocampus enhances learning and memory. In addition, BDNF concentrations in the brain and blood are correlated, offering the opportunity to use peripheral BDNF as a minimally invasive measure of effective enrichment reflecting neural changes. This study investigated changes in serum BDNF following the provision of environmental enrichment to pigs. Pigs were housed in different environments during lactation (enriched vs barren) and after weaning (enriched vs barren), using a 2 × 2 factorial design and the provision of a foraging block as enrichment. Pigs provided with foraging enrichment during lactation or after weaning tended to have higher serum BDNF concentrations than pigs housed in a barren environment, and this effect was significant for pigs enriched during lactation when sampled 5 wk after weaning. Brain-derived neurotrophic factor concentration reduced as the pigs aged from 3 to 11 wk. The measurement of BDNF in serum brings a practical approach to study the effects of environmental enrichment on neurobiological changes in domestic animals. A better understanding of the factors modulating BDNF and its link to welfare states could bring insight into the benefits of stimulating an animal's life.

Optimisation of anti-psychotic therapeutics: a balancing act?

Schizophrenia is a complex and debilitating disorder. Although effective therapeutic strategies are available, these are not without problems and are not universally efficacious. In this issue of the British Journal of Pharmacology, a trio of papers describe the characterisation of a potential, novel anti-psychotic medication, F15063. This compound combines antagonism of dopamine D(2)-like receptors with agonism at 5-HT(1A) receptors. Based on in vitro and in vivo profiles, the authors suggest that this compound approaches the 'optimal balance' for activity at these receptor systems.

A comparison of acute and chronic toxicity tests used to examine the temporal stability of a gradient in copper tolerance of Hediste diversicolor from the Fal estuary, Cornwall, UK.

The aim of this study was to use two different toxicity tests to verify the existence of a gradient in tolerance along Rostronguet Creek. Hediste diversicolor was collected from five populations in the Fal estuary previously shown to vary in copper tolerance. Exposure to 4 mgL(-1) of copper in an acute assay demonstrated that Mylor Creek worms were sensitive (LT(50) 86 h) and the tolerance of Rostronguet Creek worms increased moving upstream from the mouth of the creek (LT(50)s 100-258 h). There was no significant difference in tolerance between Mylor worms and worms from the mouth of Rostronguet Creek. This is in agreement with a previous study [Grant, A., Hateley, J.G., Jones, N.V., 1989. Mapping the ecological impact of heavy metals on the estuarine polychaete Nereis diversicolor using inherited metal tolerance. Marine Pollution Bulletin 20, 235-238] and demonstrates temporal stability of the gradient. Copper tolerance was also measured using a chronic toxicity test run for 90 d using step-wise increases in challenge concentration. A significant difference in tolerance was shown between populations from Mylor Creek and those at the mouth of Rostronguet Creek, which has not been reported previously. Experimental protocol was therefore an important factor in detecting population variation in tolerance.

Addiction, cognitive decline and therapy: seeking ways to escape a vicious cycle.

Any type of behavioral change is an effortful process. Thus, the process of behavioral therapy, where clients seek to change maladaptive behavioral patterns, requires high-level cognitive engagement. It is unfortunate, then, that cognitive impairment is a feature of substance use disorders (SUDs), and especially because the domains that tend to be impaired are the very ones involved in the process of therapeutic behavioral change. In this review, we compare the cognitive profile that is frequently observed with chronic SUD with the skills that are required to initiate and sustain behavioral change during rehabilitation. Furthermore, we look to new therapeutic developments that seek to improve cognitive function. We propose that the use of these cognitive enhancing agents as adjuncts to behavioral therapy should help to overcome some of the cognitive barriers imposed by the disorder itself, and hence reduce the chance of relapse.

Genetic interdependence of adenosine and dopamine receptors: evidence from receptor knockout mice.

Dopamine and adenosine receptors are known to share a considerable overlap in their regional distribution, being especially rich in the basal ganglia. Dopamine and adenosine receptors have been demonstrated to exhibit a parallel distribution on certain neuronal populations, and even when not directly co-localized, relationships (both antagonistic and synergistic) have been described. This study was designed to investigate dopaminergic and purinergic systems in mice with ablations of individual dopamine or adenosine receptors. In situ hybridization histochemistry and autoradiography was used to examine the level of mRNA and protein expression of specific receptors and transporters in dopaminergic pathways. Expression of the mRNA encoding the dopamine D2 receptor was elevated in the caudate putamen of D1, D3 and A2A receptor knockout mice; this was mirrored by an increase in D2 receptor protein in D1 and D3 receptor knockout mice, but not in A2A knockout mice. Dopamine D1 receptor binding was decreased in the caudate putamen, nucleus accumbens, olfactory tubercle and ventral pallidum of D2 receptor knockout mice. In substantia nigra pars compacta, dopamine transporter mRNA expression was dramatically decreased in D3 receptor knockout mice, but elevated in A2A receptor knockout mice. All dopamine receptor knockout mice examined exhibited increased A2A receptor binding in the caudate putamen, nucleus accumbens and olfactory tubercle. These data are consistent with the existence of functional interactions between dopaminergic and purinergic systems in these reward and motor-related brain regions.

Neurochemical modulation of cardiovascular control in the nucleus tractus solitarius.

The central control of cardiovascular function has been keenly studied for a number of decades. Of particular interest are the homeostatic control mechanisms, such as the baroreceptor heart-rate reflex, the chemoreceptor reflex, the Bezold-Jarisch reflex and the Breuer-Hering reflex. These neurally-mediated reflexes share a common termination point for their respective centrally-projecting sensory afferents, namely the nucleus tractus solitarius (NTS). Thus, the NTS clearly plays a critical role in the integration of peripherally initiated sensory information regarding the status of blood pressure, heart rate and respiratory function. Many endogenous neurochemicals, from simple amino acids through biogenic amines to complex peptides have the ability to modulate blood pressure and heart rate at the level of the NTS. This review will attempt to collate the current knowledge regarding the roles of neuromodulators in the NTS, the receptor types involved in mediating observed responses and the degree of importance of such neurochemicals in the tonic regulation of the cardiovascular system. The neural pathway that controls the baroreceptor heart-rate reflex will be the main focus of attention, including discussion of the identity of the neurotransmitter(s) thought to act at baroafferent terminals within the NTS. In addition, this review will provide a timely update on the use of recently developed molecular biological techniques that have been employed in the study of the NTS, complementing more classical research.

Activation of bee venom phospholipase A2 by oleoyl imidazolide produces a thiol- and proteinase-resistant conformation.

Assay methods for bee venom phospholipase A2 are presented which respond to different aspects of enzymic behaviour and which allow basal activity, fatty acid activation and acyl-group activation to be distinguished. The stability of the enzyme to thiols and proteinases is dramatically increased by activation with the selective acylating agent, oleoyl imidazolide. These results support the model of activation by conformation change. Limited-fixation studies indicate that enzyme conformation is determined by interaction with the substrate. The oleoyl-enzyme is partially inactivated by trypsin, but its electrophoretic mobility is unchanged. This protective effect is highly selective and only one other component of the venom is protected against trypsin by oleoyl imidazolide. Combination of trypsin and thiol treatment produces a large fragment of the activated enzyme which could be used for structural studies of the activation site.

Minocycline treatment attenuates microglia activation and non-angiotensin II [125I] CGP42112 binding in brainstem following nodose ganglionectomy.

We have previously shown that following unilateral nodose ganglionectomy, [125I] CGP42112 binds to a non-angiotensin II (Ang II) related binding site in rat dorsal motor nucleus of the vagus nerve, ambiguus nucleus and nucleus of the solitary tract. Furthermore, this up-regulated binding site localizes with activated microglia. Given that some tetracyclines may inhibit microglia activation in brain, we examined the effect of minocycline treatment on the binding of [125I] CGP42112 and [3H] PK11195 (an established radioligand for microglia), as well as OX-42 immunoreactivity (an immunomarker for activated microglia), following nodose ganglionectomy. Male Wistar Kyoto rats underwent unilateral nodose ganglionectomy or sham operation and were treated with saline or minocycline (50 mg/kg i.p.) 12 h before surgery and twice daily after surgery (each 50mg/kg i.p.) for 3 days. Subsequent to nodose ganglionectomy, [125I] CGP42112 binding (insensitive to PD123319 or Ang II) was increased approximately two-fold in the ipsilateral nucleus of the solitary tract and was also induced in the ipsilateral dorsal motor nucleus of the vagus nerve and ambiguus nucleus of saline-treated rats. Treatment with minocycline reduced this non-angiotensin II [125I] CGP42112 binding (40-50% reduction) in the nucleus of the solitary tract, dorsal motor nucleus of the vagus nerve and ambiguus nucleus. Analogous experiments using [3H] PK11195 also revealed up-regulated binding in the ipsilateral nucleus of the solitary tract ( approximately 205%), dorsal motor nucleus of the vagus nerve (approximately 80%) and ambiguus nucleus (approximately 210%) of saline-treated rats following nodose ganglionectomy, which was reduced by 40-100% with minocycline treatment. Immunoreactivity to OX-42 confirmed an increase in microglia activation and accumulation of macrophages in these brain stem nuclei following nodose ganglionectomy, which was also attenuated following treatment with minocycline. These data demonstrate that non-Ang II [125I] CGP42112 binding following nodose ganglionectomy is attenuated by minocycline treatment. This minocycline-induced effect was associated with reduced activation of microglia and an apparent reduction in the number of macrophages in the abovementioned nuclei. This evidence suggests that a non-Ang II [125I] CGP42112 binding site is located on, or associated with, activated microglia and macrophages, providing a useful tool with which to quantitate the neuroprotective effects of centrally acting anti-inflammatory compounds.

Chronic intermittent toluene inhalation in adolescent rats results in metabolic dysfunction with altered glucose homeostasis.

BACKGROUND AND PURPOSE: Abuse of toluene-containing inhalants is an increasing public health problem, especially among adolescents. Abuse during adolescence is associated with emaciation, while industrial exposure leads to altered glycaemic control suggesting metabolic instability. However, the relationship between adolescent inhalant abuse and metabolic dysfunction remains unknown. EXPERIMENTAL APPROACH: To model human abuse patterns, we exposed male adolescent Wistar rats [postnatal day (PND) 27] to chronic intermittent inhaled toluene (CIT, 10,000 ppm) or air (control) for 1 h·day(-1) , three times a week for 4 weeks. Feeding and body composition were monitored. After 4 weeks, circulating metabolic hormone concentrations and responses to a glucose tolerance test (GTT) were measured. Dietary preference was measured by giving animals access to either a 'western diet' plus standard chow (WC + SC) or standard chow alone during 4 weeks of abstinence. Metabolic hormones and GTT were subsequently measured. KEY RESULTS: Adolescent CIT exposure significantly retarded weight gain, altered body composition, circulating metabolic hormones and responses to a GTT. While reduced body weight persisted, responses to a GTT and circulating hormones appeared to normalize for animals on standard chow following abstinence. In CIT-exposed WC + SC rats, we observed impaired glucose tolerance associated with altered metabolic hormones. Analysis of hypothalamic genes revealed differential expression profiles in CIT-exposed rats following both the exposure period and abstinence, suggesting a central contribution to inhalant-induced metabolic dysfunction. CONCLUSION AND IMPLICATIONS: CIT exposure during adolescence has long-term effects on metabolic function, which may increase the risk of disorders related to energy balance and glycaemic control.

Relaxin-3 receptor (Rxfp3) gene deletion reduces operant sucrose- but not alcohol-responding in mice.

The pervasive use of refined sugars in highly accessible, palatable foods and persistent exposure to reinforcing food-associated cues has contributed to overconsumption of sugar-rich diets and the current obesity epidemic in Western society. We have shown previously that brain relaxin-3 mRNA levels positively correlate with sucrose and alcohol intake, and that central antagonism of relaxin-3 receptors (RXFP3) attenuates alcohol self-administration and alcohol-seeking in rats, but food-seeking behaviour and palatable food consumption in mice. To further examine the relationship between motivated appetitive behaviours and relaxin-3/RXFP3 signalling, we investigated the effect of Rxfp3 gene deletion in C57BL/6J mice on sucrose and alcohol self-administration and cue-induced reinstatement (RNST) of sucrose- and alcohol-seeking. Acquisition and maintenance of sucrose and alcohol self-administration was assessed in male wild-type (WT) and Rxfp3 knockout (KO) (C57BL/6J(RXFP3TM1) (/) (DGen) ) littermate mice using fixed ratio (FR) schedules of reinforcement. Mice were subsequently challenged with a progressive ratio (PR) test to measure motivation and, following extinction training, re-exposed to reward-associated cues to evaluate RNST of active lever-responding. Wild-type and Rxfp3 KO mice displayed similar acquisition of FR1 sucrose self-administration, but Rxfp3 KO mice responded less when the instrumental requirement was increased to FR3. These mice also showed a lower breakpoint for sucrose and attenuated cue-induced RNST of sucrose-seeking. Notably, no marked genotype differences in alcohol-responding were observed. In mice, endogenous relaxin-3/RXFP3 signalling promotes self-administration of sucrose under high response requirements and cue-induced RNST of sucrose-seeking, but does not apparently regulate motivation to consume alcohol or alcohol-seeking behaviour.

Markers of adenosine removal in normotensive and hypertensive rat nervous tissue.

Adenosine mechanisms are altered in brain stem nuclei associated with cardiovascular control in spontaneously hypertensive rats (SHR). Therefore, in the present study we used a number of techniques to compare the binding of the adenosine transport inhibitor [3H]nitrobenzylthioinosine ([3H]NBMPR) as well as adenosine deaminase immunoreactivity (ADA-IR) in brain stems and nodose ganglia of SHR and age-matched normotensive Donryu rats (DRY). Saturation binding revealed a single class of [3H]NBMPR binding sites in the dorsal brain stem of both strains, with Kd and Bmax values of 65 +/- 9 pmol/L and 282 +/- 31 fmol/mg protein, respectively, in SHR and 129 +/- 2 pmol/L and 217 +/- 23 fmol/mg protein in DRY. The Kd for [3H]NBMPR was significantly lower in SHR than in DRY. In competition assays, NBMPR, dilazep, dipyridamole, and adenosine displaced [3H]NBMPR binding, with Kd values of 0.21 +/- 0.04, 57.16 +/- 16.20, 1340 +/- 100, and 87000 +/- 12500 nmol/L, respectively, in DRY and 0.17 +/- 0.04, 28.24 +/- 3.60, 621 +/- 100, and 32000 +/- 6820 in SHR. Kd values for all displacers were lower in SHR; however, only values for dipyridamole and adenosine reached statistical significance. Autoradiography of adenosine transport sites with [3H]NBMPR revealed that unilateral nodose ganglionectomy reduced [3H]NBMPR binding on the denervated side of the nucleus tractus solitarius by 20.6 +/- 1.1% in DRY and 18.7 +/- 2.3% in SHR. The density of [3H]NBMPR binding in nodose ganglia was significantly lower in SHR (0.99 +/- 0.06 Bq/mm2) than in DRY (1.25 +/- 0.08). Immunohistochemical studies demonstrated ADA-IR in the dorsal vagal complex, associated with both nerve cells and fibers. Measurement of ADA-IR in the dorsal vagal complex with an 125I-labeled secondary antibody revealed a significantly higher level of ADA-IR in SHR (122%) than in DRY. In the nodose ganglia, ADA-IR was associated with a population of vagal perikarya. The present study helps provide a molecular explanation for the previously reported impaired cardiovascular responses to intra-nucleus tractus solitarius microinjection of adenosine in hypertensive rats.