Neuromolecular imaging, a nanobiotechnology for Parkinson's disease: advancing pharmacotherapy for personalized medicine.

Evaluating each patient and animal as its own control achieves personalized medicine, which honors the hippocratic philosophy, explaining that "it is far more important to know what person has the disease than what disease the person has." Similarly, individualizing molecular signaling directly from the patient's brain in real time is essential for providing prompt, patient-based treatment as dictated by the point of care. Fortunately, nanotechnology effectively treats many neurodegenerative diseases. In particular, the new medicinal frontier for the discovery of therapy for Parkinson's disease is nanotechnology and nanobiotechnology. Indeed, the unique nanotechnology of neuromolecular imaging combined with the series of nanobiosensors enables continuous videotracking of molecular neurotransmitters in both the normal physiologic and disease states with long-term electrochemical operational stability. This nanobiotechnology is able to track a signal in real time with excellent temporal and spatial resolution directly from each patient's brain to a computer as subjects are behaving during movement, normal and/or dysfunctional including prion-like Parkinson's behavioral biometrics. Moreover, the molecular signaling performed by these nanobiosensors live streams directly online and originates from precise neuroanatomic brain sites such as, in this case, the dorsal striatum in basal ganglia. Thus, the nanobiotechnology studies discussed herein imaged neuromolecules with and without L-3,4-dihydroxyphenylalanine (L-DOPA) in dorsal striatal basal ganglia neurons. Parkinsonian and non-Parkinsonian animals were video-tracked, and images were readily seen on a laptop via a potentiostat using a semiderivative electrical circuit. Administered L-DOPA doses were 50 and 100 mg/kg intraperitoneally (ip); the same experimental paradigm was used to image and then contrast data. Results showed that the baseline release of biogenic amine molecules was significantly above detection limits in non-Parkinsonian animals. After administration of L-DOPA, biogenic amines significantly increased in these non-Parkinson's animals. Nevertheless, it is intriguing to see that L-DOPA could not enable synaptic dopamine release in Parkinson's animals, thereby demonstrating that biogenic amines are biomarkers for Parkinson's disease. Biomarkers are biochemical, genetic, or molecular measures of biological reactions. Importantly, there were other significant biomarkers present in Parkinsonian animals and absent in non-Parkinsonian animals; these were peptide neurotransmitters that include dynorphin and somatostatin in the brain with detection limits of 40 nM for dynorphin and 37 nM for somatostatin (see Table 1). Furthermore, L-DOPA significantly increased these peptide biomarkers, dynorphin and somatostatin, in Parkinson's animals. Targeting biomarkers enables new diagnostic devices and treatments for Parkinson's disease through nanotechnology and nanobiotechnology.

Low penetrance susceptibility to glioma is caused by the TP53 variant rs78378222.

BACKGROUND: Most of the heritable risk of glioma is presently unaccounted for by mutations in known genes. In addition to rare inactivating germline mutations in TP53 causing glioma in the context of the Li-Fraumeni syndrome, polymorphic variation in TP53 may also contribute to the risk of developing glioma. METHODS: To comprehensively evaluate the impact of variation in TP53 on risk, we analysed 23 tagSNPs and imputed 2377 unobserved genotypes in four series totaling 4147 glioma cases and 7435 controls. RESULTS: The strongest validated association signal was shown by the imputed single-nucleotide polymorphism (SNP) rs78378222 (P=6.86 × 10(-24), minor allele frequency ~0.013). Confirmatory genotyping confirmed the high quality of the imputation. The association between rs78378222 and risk was seen for both glioblastoma multiforme (GBM) and non-GBM tumours. We comprehensively examined the relationship between rs78378222 and overall survival in two of the case series totaling 1699 individuals. Despite employing statistical tests sensitive to the detection of differences in early survival, no association was shown. CONCLUSION: Our data provided strong validation of rs78378222 as a risk factor for glioma but do not support the tenet that the polymorphism being a clinically useful prognostic marker. Acquired TP53 inactivation is a common feature of glioma. As rs78378222 changes the polyadenylation signal of TP53 leading to impaired 3'-end processing of TP53 mRNA, the SNP has strong plausibility for being directly functional contributing to the aetiological basis of glioma.

The TERT variant rs2736100 is associated with colorectal cancer risk.

BACKGROUND: Polymorphic variation at the 5p15.33 (TERT-CLPTM1L) locus is associated with the risk of many cancers but a relationship with colorectal cancer (CRC) risk has yet to be defined. METHODS: We used data from six genome-wide association studies (GWAS) of CRC, linkage disequilibrium mapping and imputation, to examine the relationship between 73 single-nucleotide polymorphisms at 5p15.33 and CRC risk in detail. RESULTS: rs2736100, which localises to intron 2 of TERT, provided the strongest evidence of an association with CRC (P=2.28 × 10⁻4). The association was also shown in an independent series of 10 047 CRC cases and 6918 controls (P=0.02). A meta-analysis of all seven studies (totalling 16 039 cases, 16 430 controls) provided increased evidence of association (P=2.49 × 10⁻5; per allele odds ratio=1.07). The association of rs2736100 on CRC risk was shown to be independent of 15 low-penetrance variants previously identified. CONCLUSION: The rs2736100 association demonstrates an influence of variation at 5p15.33 on CRC risk and further evidence that the 5p15.33 (TERT-CLPTM1L) locus has pleiotropic effects (reflecting generic or lineage-specific effects) on cancer risk.

Search for inherited susceptibility to radiation-associated meningioma by genomewide SNP linkage disequilibrium mapping.

BACKGROUND: Exposure to ionising radiation is a well-established risk factor for multiple types of tumours, including malignant brain tumours. In the 1950s, radiotherapy was used to treat Tinea Capitis (TC) in thousands of children, mostly of North-African and Middle Eastern origin, during the mass migration to Israel. The over-representation of radiation-associated meningioma (RAM) and other cancers in specific families provide support for inherited genetic susceptibility to radiation-induced cancer. METHODS: To test this hypothesis, we genotyped 15 families segregating RAM using high-density single-nucleotide polymorphism (SNP) arrays. Using the family-based association test (FBAT) programme, we tested each polymorphism and haplotype for an association with RAM. RESULTS: The strongest haplotype associations were attained at 18q21.1 (P=7.5 × 10(-5)), 18q21.31 (P=2.8 × 10(-5)) and 10q21.3 (P=1.6 × 10(-4)). Although associations were not formally statistically significant after adjustment for multiple testing, the 18q21.1 and 10q21.3 associations provide support for a variation in PIAS2, KATNAL2, TCEB3C, TCEB3CL and CTNNA3 genes as risk factors for RAM. CONCLUSION: These findings suggest that any underlying genetic susceptibility to RAM is likely to be mediated through the co-inheritance of multiple risk alleles rather than a single major gene locus determining radiosensitivity.

A large-scale meta-analysis to refine colorectal cancer risk estimates associated with MUTYH variants.

BACKGROUND: defective DNA repair has a causal role in hereditary colorectal cancer (CRC). Defects in the base excision repair gene MUTYH are responsible for MUTYH-associated polyposis and CRC predisposition as an autosomal recessive trait. Numerous reports have suggested MUTYH mono-allelic variants to be low penetrance risk alleles. We report a large collaborative meta-analysis to assess and refine CRC risk estimates associated with bi-allelic and mono-allelic MUTYH variants and investigate age and sex influence on risk. METHODS: MUTYH genotype data were included from 20 565 cases and 15 524 controls. Three logistic regression models were tested: a crude model; adjusted for age and sex; adjusted for age, sex and study. RESULTS: all three models produced very similar results. MUTYH bi-allelic carriers demonstrated a 28-fold increase in risk (95% confidence interval (CI): 6.95-115). Significant bi-allelic effects were also observed for G396D and Y179C/G396D compound heterozygotes and a marginal mono-allelic effect for variant Y179C (odds ratio (OR)=1.34; 95% CI: 1.00-1.80). A pooled meta-analysis of all published and unpublished datasets submitted showed bi-allelic effects for MUTYH, G396D and Y179C (OR=10.8, 95% CI: 5.02-23.2; OR=6.47, 95% CI: 2.33-18.0; OR=3.35, 95% CI: 1.14-9.89) and marginal mono-allelic effect for variants MUTYH (OR=1.16, 95% CI: 1.00-1.34) and Y179C alone (OR=1.34, 95% CI: 1.01-1.77). CONCLUSIONS: overall, this large study refines estimates of disease risk associated with mono-allelic and bi-allelic MUTYH carriers.

Mirror therapy and treadmill training for patients with chronic stroke: a pilot randomized controlled trial.

BACKGROUND: Previous lower-limb mirror therapy research has focused on non-weight bearing interventions. OBJECTIVES: The primary aim of this study was to investigate the effect and feasibility of a combination of mirror therapy and treadmill training on post-stroke lower-limb recovery compared to a placebo intervention. METHODS: All patients (N = 30) walked on a treadmill for 30 min per day, 3 days per week, for 4 weeks. The mirror therapy and treadmill training group (n = 15) walked on the treadmill while viewing a reflection of their non-paretic limb in a mirror positioned in their mid-sagittal plane. The placebo group (n = 15) received no mirror visual feedback due to an altered mirror position. PRIMARY OUTCOME MEASURES: Ten Metre Walk Test (10MWT) and Six Minute Walk Test (6MWT). SECONDARY OUTCOME MEASURES: Modified Ashworth Scale (MAS) and Fugl-Meyer Assessment-Lower Extremity (FMA-LE). Feasibility was appraised by examining participant compliance and any adverse events. RESULTS: No significant between group differences were demonstrated for the 10MWT, 6MWT or FMA-LE at post-training or 3-month follow-up assessment. A significant between group difference on the MAS was demonstrated in the reduction of ankle dorsiflexion muscle tone (p = 0.006) and ankle plantarflexion muscle tone (p = 0.01) in the mirror therapy group compared to the placebo group at post-training assessment but not at 3-month follow-up. CONCLUSION: Our study reveals that in our group of patients with chronic stroke, mirror therapy combined with treadmill training facilitated significant reductions in ankle muscle tone (p < 0.05) compared to a placebo intervention.

Runs of homozygosity and testicular cancer risk.

BACKGROUND: Testicular germ cell tumour (TGCT) is highly heritable but > 50% of the genetic risk remains unexplained. Epidemiological observation of greater relative risk to brothers of men with TGCT compared to sons has long alluded to recessively acting TGCT genetic susceptibility factors, but to date none have been reported. Runs of homozygosity (RoH) are a signature indicating underlying recessively acting alleles and have been associated with increased risk of other cancer types. OBJECTIVE: To examine whether RoH are associated with TGCT risk. METHODS: We performed a genome-wide RoH analysis using GWAS data from 3206 TGCT cases and 7422 controls uniformly genotyped using the OncoArray platform. RESULTS: Global measures of homozygosity were not significantly different between cases and controls, and the frequency of individual consensus RoH was not significantly different between cases and controls, after correction for multiple testing. RoH at three regions, 11p13-11p14.3, 5q14.1-5q22.3 and 13q14.11-13q.14.13, were, however, nominally statistically significant at p < 0.01. Intriguingly, RoH200 at 11p13-11p14.3 encompasses Wilms tumour 1 (WT1), a recognized cancer susceptibility gene with roles in sex determination and developmental transcriptional regulation, processes repeatedly implicated in TGCT aetiology. DISCUSSION AND CONCLUSION: Overall, our data do not support a major role in the risk of TGCT for recessively acting alleles acting through homozygosity, as measured by RoH in outbred populations of cases and controls.

CASP8 variants D302H and -652 6N ins/del do not influence the risk of colorectal cancer in the United Kingdom population.

Polymorphisms in CASP8 at 2q33.1 have been associated with the risk of developing cancer, specifically, the D302H variant (rs1045485) with breast cancer in the European population and the -652 6N ins/del promoter variant (rs3834129) with multiple tumours including colorectal cancer (CRC) in the Chinese population. We evaluated the relationship between -652 6N ins/del and D302H variants and risk of developing CRC in the UK population by genotyping 4016 cases and 3749 controls. Both variants showed no evidence of an association with risk of developing CRC (P=0.42 and 0.22, respectively). In contrast, the recently identified CRC susceptibility allele rs6983267 mapping to 8q24 was significantly associated with disease risk (P=8.94 x 10(-8)). It is thus very unlikely that variation in CASP8 defined by -652 6N ins/del or D302H influences the risk of CRC in European populations. The implications of our findings both in terms of population-specific effects and publication bias are discussed.

Comprehensive analysis of common mitochondrial DNA variants and colorectal cancer risk.

Several lines of evidence implicate mitochondrial dysfunction in the development of cancer. To test the hypothesis that common mtDNA variation influences the risk of colorectal cancer (CRC), we genotyped 132 tagging mtDNA variants in a sample of 2854 CRC cases and 2822 controls. The variants examined capture approximately 80% of mtDNA common variation (excluding the hypervariable D-loop). We first tested for single marker associations; the strongest association detected was with A5657G (P=0.06). Overall the distribution of association P-values was consistent with a null distribution. Next, we classified individuals into the nine common European haplogroups and compared their distribution in cases and controls. This analysis also provided no evidence of an association between mitochondrial variation and CRC risk. In conclusion, our results provide little evidence that mitochondrial genetic background plays a role in modifying an individual's risk of developing CRC.

Mirror therapy for improving lower limb motor function and mobility after stroke: A systematic review and meta-analysis.

BACKGROUND: Mirror therapy has been proposed as an effective intervention for lower limb rehabilitation post stroke. RESEARCH QUESTION: This systematic review with meta-analysis examined if lower limb mirror therapy improved the primary outcome measures of muscle tone and motor function and the secondary outcome measures balance characteristics, functional ambulation, walking velocity, passive range of motion (PROM) for ankle dorsiflexion and gait characteristics in patients with stroke compared to other interventions. METHODS: Standardised mean differences (SMD) and mean differences (MD) were used to assess the effect of mirror therapy on lower limb functioning. RESULTS: Nine studies were included in the review. Among the primary outcome measures there was evidence of a significant effect of mirror therapy on motor function compared with sham and non-sham interventions (SMD 0.54; 95% CI 0.24-0.93). Furthermore, among the secondary outcome measures there was evidence of a significant effect of mirror therapy for balance capacity (SMD -0.55; 95% CI -1.01 to -0.10), walking velocity (SMD 0.71; 95% CI 0.35-1.07), PROM for ankle dorsiflexion (SMD 1.20; 95% CI 0.71-1.69) and step length (SMD 0.56; 95% CI -0.00 to 1.12). SIGNIFICANCE: The results indicate that using mirror therapy for the treatment of certain lower limb deficits in patients with stroke may have a positive effect. Although results are somewhat positive, overly favourable interpretation is cautioned due to methodological issues concerning included studies.

Diabetes-related changes in L-tryptophan-induced release of striatal biogenic amines.

In vivo voltammetry was used to measure the synaptic release of rat striatal dopamine and serotonin after the administration of the amino acid L-tryptophan to streptozocin-induced diabetic rats. Dopamine and serotonin release from rat striatum was studied at a short-term or acute (3-day) interval and a long-term or chronic (3- to 7-wk) interval after the induction of diabetes. The study was also done in age-, sex-, and food-matched controls. The findings show that L-tryptophan decreased dopamine release from rat striatum in nondiabetic rats. The decreased striatal dopamine release, after L-tryptophan administration, was exacerbated in acutely diabetic rats and further exacerbated in chronically diabetic rats. By contrast, rat striatal serotonin release predictably increased after L-tryptophan injection in nondiabetic rats. A further increased striatal serotonin release was seen in acutely diabetic rats. Chronically diabetic rats, however, responded to L-tryptophan with a dramatic and significant decrease in striatal serotonin release. The results show that in acutely diabetic and normal rats, L-tryptophan administration reduced striatal dopamine and increased striatal serotonin release, whereas in chronically diabetic rats, the release of both biogenic amines was decreased. The findings indicate that the progression of diabetes is associated with an impaired ability to release primary neurotransmitter biogenic amines.

I. Serotonin (5-HT) within dopamine reward circuits signals open-field behavior. II. Basis for 5-HT--DA interaction in cocaine dysfunctional behavior.

Light microscopic immunocytochemical studies, using a sensitive silver intensification procedure, show that dopamine (DA) and serotonin (5-HT) axons terminate on neurons in the nucleus accumbens (NAcc) (A10) terminals and also in dorsal striatum (DSTr) (A9) terminals. The data demonstrate a prominent endogenous anatomic interaction at these distal presynaptic sites between the neurotransmitters 5-HT and DA; the pattern of the 5-HT-DA interaction differs between A10 and A9 terminals. Moreover, in distinction to the variance shown anatomically between 5-HT--DA interactions at distal A9 and A10 sites, the 5-HT--DA interactions at the level of DA somatodendrites, the proximal site, are similar, i.e. 5-HT terminals in the midbrain tegmentum are profuse and have a massive overlap with DA neurons in both ventral tegmental area (VTA) and substantia nigra pars compacta (SNpc). We suggest with reference to the DA neurons of A10 and A9 pathways, inclusive of somatodendrites (sites of proximal presynaptic interactions in the midbrain) and axons (sites of distal presynaptic interactions), that 5-HT--DA interactions in A10 terminals are more likely to exceed those in the DStr arrangement. Furthermore, our neuroanatomic data show that axonally released DA at A10 terminals may originate from proximal 5-HT somatodendrites, i.e. dorsal raphe (DR) or the proximal DA somatodendrites, VTA. In vivo microvoltammetric studies were done with highly sensitive temporal and spatial resolution; the studies demonstrate basal (endogenous) real time 5-HT release at distal A10 and distal A9 terminal fields and real time 5-HT release at proximal A10 VTA somatodendrites. In vivo microvoltammetric studies were performed concurrently and on line with studies of DA release, also at distal A10 and distal A9 terminal fields and at proximal A10 somatodendrites. Serotonin release was detected in a separate voltammetric peak from the DA voltammetric peak. The electrochemical signal for 5-HT release was detected within 10-12 s and that for DA release within 12-15 s, after each biogenic amine diffused through the synaptic environment onto the microelectrode surface. The electrochemical signal for 5-HT and a separate electrochemical signal for DA are detected on the same voltammogram within 22-27 s; each electrochemical signal represents current changes in picoamperes, within seconds of detection time. The amplitude of each electrochemical signal reflects the changes in diffusion of each biogenic amine to the microelectrode surface. Each neurotransmitter has a distinct potential at which oxidation occurs; this results in a recording which has a distinct peak for a specific neurotransmitter. The concentration of each neurotransmitter within the synaptic environment is directly related to the electrochemical signal detected via the Cottrell equation. Voltammograms were recorded every 5 min. At the time that basal 5-HT release and basal DA release were recorded within same animal control, open-field behavioral studies were performed, also concurrently, by infrared photocell beams. The frequency of each behavioral parameter was monitored every 100 ms; the number of behavioral events, were summated every 5 min during the time course of study. Thus, the detection of neurotransmitters occurs in real time, while simultaneously monitoring the animal's behavior by infrared photocell beams. The results from the in vivo microvoltammetric and behavioral data from this study show that basal 5-HT release at distal A10 and A9 terminals dramatically increased with DA release. Moreover, each increase in basal 5-HT release, at both A10 and at A9 terminal fields occurred consistently and at the same time as each increase in open-field locomotion and stereotypy occurred naturally during the animal's exploration in a novel chamber. Thus, the terminology 'synchronous and simultaneous' describes aptly the correlation between 5-HT release at distal A10 and A9 terminal fields and open-field locomo

Serotonergic function in diabetic rats: psychotherapeutic implications.

Extracellular serotonin in striatum was studied in untreated streptozotocin-induced diabetic rats and in untreated nondiabetic rats that served as age-, food-, and sex-matched controls. Extracellular serotonin was studied under anesthesia in vivo and dynamically with voltammetry. The results showed that an early and significant increase in extracellular serotonin occurred in striatum in the untreated acutely (3 days) diabetic rat. In untreated long-term (3-7 weeks) diabetic rats, however, the increase in serotonin in extracellular fluid in striatum decreased and returned to normal. The findings show a change in serotonergic function in acutely diabetic rats. The serotonergic alteration may have psychotherapeutic implications.

In vivo electrochemical and behavioral evidence for specific neural substrates modulated differentially by enkephalin in rat stimulant stereotypy and locomotion.

The enkephalinamide, D-Ala2-D-Pro5-enkephalinamide monoacetate (WY 42, 186), when systemically administered to male Sprague-Dawley rats, significantly inhibited sniffing, repetitive head movements, and frequency of rearing, stereotyped behaviors which are often associated with nigrostriatal dopamine activation. On the other hand, the locomotor component of amphetamine-induced stereotyped behavior, which is associated with mesolimbic dopaminergic activation, was not inhibited. In vivo electrochemical analysis showed a significant decrease in striatal dopamine release from striatum after systemic administration of D-Ala2-D-Pro5-enkephalinamide monoacetate in chloral hydrate anesthetized rats, whereas the dopamine signal from the nucleus accumbens, a mesolimbic neuroanatomigic modulation of dopamine both behaviorally and biochemically. Also, the concept of separate neural systems for the stereotypic and locomotor components of amphetamine-induced stereotypy is reinforced.

Behavioral and biochemical changes induced by lithium and L-tryptophan in muricidal rats.

Lithium (0.5--12 meq/kg) and L-tryptophan (100--800 mg/kg) inhibited the muricidal (mouse killing) response in isolated, male, Long Evans rats and did so both in an acute (single dose) and on an longer-term intraperitoneal treatment basis. The response was dose-dependent. There was no concomitant motor impairment at doses effective in inhibiting the muricidal response. Plasma lithium levels were positively correlated with the percentage inhibition of muricidal behavior. When lithium and L-tryptophan were administered in combination in their smallest effective doses, the behavioral interaction was synergistic in the acute and addictive in the longer-term treatment. The effects of pharmacological treatment on the inhibition of muricidal behavior were: lithium and L-tryptophan greater than L-tryptophan greater than - lithium. The results of biochemical assays showed that these compounds fore- and hindbrain serotonin turnover. The biochemical action of lithium and L-tryptophan in combination on brain serotonergic pathways was again clearly more potent than that which occurred after treatment with either lithium or L-tryptophan alone. The magnitude of the biochemical changes paralleled those of psychopharmacological changes. These data show an interaction between lithium and L-tryptophan both in the repression of aggressive behavior in rats and in the alteration of centrally acting serotonergic function. These data further elucidate a mechanism of action through central serotonergic function for a psychotherapeutic agent, lithium, and for aggressive behavior, muricide.

Inspired and expired gas concentrations in man during carbogen breathing.

Capnometer measurements during 46 evaluable treatments in which patients were administered carbogen (95% O2, 5% CO2) have demonstrated that the mean inspired carbon dioxide level was 3.1% (range 0-4.7) and the mean inspired oxygen concentration was 70.6% (range 26.4-94). The explanation for this observation is leakage of air into the breathing system during radiotherapy.

Striatal neurochemistry of dynorphin-(1-13): in vivo electrochemical semidifferential analyses.

The striatal neurochemistry of dynorphin-(1-13) was studied by simultaneously measuring extracellular dopamine and serotonin voltammetrically and in vivo after the injection of dynorphin-(1-13) to male Sprague-Dawley rats. The subcutaneous administration of dynorphin-(1-13), at a dose (1.5 mg/kg), known to exert CNS mediated behavioral effects, caused a statistically significant decrease in extracellular dopamine and a statistically significant increase in extracellular serotonin from rat anterior striatum. These parallel and opposite effects of dynorphin-(1-13) on these biogenic amines occurred gradually during a three hour time course. Maximal effects on dopamine (55%) and on serotonin (62%) occurred at the end of the three hour period of study. Mean effects on dopamine and serotonin (35% and 42% respectively) were averaged from scan results over the three hour period of study; the results were significantly different from control values. Dose response studies showed that a lower dose of dynorphin-(1-13) (0.5 mg/kg sc) had little or no effect on the alteration of these biogenic amines from striatum. The highest dose of dynorphin-(1-13) studied, (3.0 mg/kg sc), predictably and significantly altered extracellular biogenic amines. The dose response, however, was not incremental. The results are consistent with the role of dynorphin-(1-13) as a neuromodulatory peptide. The results further support the concept that the neuromodulatory role of dynorphin-(1-13) may take place through neurotransmitter regulation. The data suggest that the function of dynorphin-(1-13) may be a presynaptic modulation of neurotransmission in striatum.

Opiate regulation of mesolimbic serotonin release: in vivo semiderivative electrochemical analyses.

The effect of a pharmacologically effective dose of d-morphine sulfate on serotonin release from nucleus accumbens of male, Sprague-Dawley rats was studied. In vivo electrochemical evidence showed that the reference exogenous opiate, morphine, after intraperitoneal administration, significantly increased basal nucleus accumbens serotonin release over control values. These data show a mesolimbic opiate-serotonergic interaction in rat brain.

A functional separation of behavioral stereotypy based on naloxone-reversible effects of seryl enkephalinamide: comparison with morphine.

Amphetamine's stereotypic behavioral actions, produced by the stimulant at a moderate dose, were inhibited by the systemic administration of seryl enkephalinamide, D-Ser2-D-Ser5-enkephalinamide, (Wy 42,896). The classical sequelae of stimulatory behavioral events: sniffing, head bobbing, rearing and locomotor activity, were significantly inhibited by the seryl enkephalinamide. Subsequently, pretreatment with the opiate receptor antagonist, naloxone, significantly blocked the inhibitory effects of the seryl enkephalinamide on the stereotypic and locomotor components. Concomitantly, the behavioral stereotypic component, licking, a behavior usually produced by opiates and only high doses of amphetamine, was significantly induced by the seryl enkephalinamide. Pretreatment with naloxone on the stimulatory behavioral effect of licking, produced a significant inhibitory effect. The combination treatment, consisting of both the seryl enkephalinamide and the stimulant amphetamine, caused a naloxone-reversible synergistic effect. These data show that the seryl enkephalinamide, produced concomitant, naloxone-reversible, inhibitory and stimulatory behavioral stereotypic effects. These data are discussed within the context of current neuronal theories which might underly the observed dose-related continuum of behavioral stereotypies produced by morphine and amphetamine.

Characterizing stearate probes in vitro for the electrochemical detection of dopamine and serotonin.

This paper describes an electrochemical method for the detection of dopamine and serotonin in vitro. Dopamine and serotonin can be distinguished from each other without interference from metabolites. 3-4-dihydroxyphenylacetic acid and 5-hydroxyindoleacetic acid. The method also provides selective differentiation of dopamine and serotonin in the presence of other possible interfering chemicals, ascorbic acid and uric acid. Specific details for voltammetric technology, electrode fabrication, electrode conditioning, paste synthesis and experimental protocol are presented. The method uses semidifferential treatment of voltammetric data in conjunction with a graphite stearate indicator electrode. The methodology is relevant to the interpretation of electrochemical signals for dopamine and serotonin in vivo in neuroanatomical substrates, richly innervated by dopaminergic and serotonergic neuronal circuitry.