Gastrin releasing peptide (GRP) receptor targeted radiopharmaceuticals: a concise update.

The gastrin releasing peptide (GRP) receptor is becoming an increasingly attractive target for development of new radiolabeled peptides with diagnostic and therapeutic potential. The attractiveness of the GRP receptor as a target is based upon the functional expression of GRP receptors in several tumors of neuroendocrine origin including prostate, breast, and small cell lung cancer. This concise review outlines some of the efforts currently underway to develop new GRP receptor specific radiopharmaceuticals by employing a variety of radiometal chelation systems.

Syntheses, in vitro and in vivo characterization of a 99mTc-(I)-tricarbonyl-benzylamino-dihydroxymethyl phosphine (NP(2)) chelate.

Studies were performed to study the complexation chemistry of 99mTc(CO)(+)(3) with a new tridentate amino-dihydroxymethyl phosphine (NP(2)) ligand with the 99mTc(CO)(3)(OH(2))(+)(3) synthon at tracer levels. A single, well-defined 99mTc(CO)(3)NP(2) complex is formed at pH 7.5 within 10 min at 60 degrees C that exhibits high in vitro and in vivo stability.

Synthesis and characterization of (99m)Tc- and (188)Re-complexes with a diamido-dihydroxymethylenephosphine-based bifunctional chelating agent (N(2)P(2)-BFCA).

A diamido-dihydroxymethylenephosphine (N(2)P(2)) bifunction chelating agent (BFCA) was shown to form well-defined (99m)Tc- and (188)Re-chelate structures. The 4, 4-bis [bis-hydroxymethyl-phosphonyl-propylcarbonmoyl]-butyric acid bifunctional chelating agent (N(2)P(2)-BFCA) formed stable complexes with (99m)Tc and (188)Re in >95% yield with high radiochemical purity (RCP). The biodistribution of the (99m)Tc- and (188)Re-N(2)P(2)-BFCAs after intravenous injection studied in normal mice showed the activity was excreted primarily via renal-urinary pathway indicating their use for labeling peptides with (99m)Tc and (188)Re.

Evaluation of an (111)In-DOTA-rhenium cyclized alpha-MSH analog: a novel cyclic-peptide analog with improved tumor-targeting properties.

UNLABELLED: The aim of this study was to examine the effect of rhenium-mediated peptide cyclization on melanoma targeting, biodistribution, and clearance kinetics of the alpha-melanocyte-stimulating hormone (alpha-MSH) analog 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) coupled ReO-cyclized [Cys(3,4,10),D-Phe(7)]alpha-MSH(3-13) (DOTA-ReCCMSH). METHODS: DOTA-ReCCMSH was compared with its reduced nonmetalated linear homolog, DOTA-CCMSH, and an analog in which rhenium cyclization was replaced by disulfide bond cyclization, DOTA-[Cys(4,10),D-Phe(7)]alpha-MSH(4-13) (CMSH). DOTA was also conjugated to the amino terminus of one of the highest-affinity alpha-MSH receptor-binding peptides, [Nle(4),D-Phe(7)]alpha-MSH (NDP), as a linear peptide standard. The DOTA-conjugated alpha-MSH analogs were radiolabeled with (111)In and examined for their in vitro receptor-binding affinity with B16/F1 murine melanoma cells, and their in vivo biodistribution properties were evaluated and compared in melanoma tumor-bearing C57 mice. RESULTS: The tumor uptake values of (111)In-DOTA-ReCCMSH were significantly higher than those of the other closely related (111)In-DOTA-alpha-MSH conjugates. Even at 24 h after injection, a comparison of the tumor uptake values for (111)In-DOTA-coupled ReCCMSH (4.86 +/- 1.52 percentage injected dose [%ID]/g), CCMSH (1.91 +/- 0.56 %ID/g), CMSH (3.09 +/- 0.32 %ID/g), and NDP (2.47 +/- 0.79 %ID/g) highlighted the high tumor retention property of ReCCMSH. Rhenium-coordinated cyclization resulted in less renal radioactivity accumulation of (111)In-DOTA-ReCCMSH (8.98 +/- 0.82 %ID/g) than of (111)In-DOTA-CCMSH (63.2 +/- 15.6 %ID/g), (111)In-DOTA-CMSH (38.4 +/- 3.6 %ID/g), and (111)In-DOTA-NDP (12.0 +/- 1.96 %ID/g) at 2 h after injection and significantly increased its clearance into the urine (92 %ID at 2 h after injection). A high radioactivity uptake ratio of tumor to normal tissue was obtained for (111)In-DOTA-ReCCMSH (e.g., 489, 159, 100, and 49 for blood, muscle, lung, and liver, respectively, at 4 h after injection). CONCLUSION: The novel ReO-coordinated cyclic structure of DOTA-ReCCMSH contributes significantly to its enhanced tumor-targeting and renal clearance properties and makes DOTAReCCMSH an excellent candidate for melanoma radiodetection and radiotherapy.

Synthesis and in vitro evaluation of an 111In-labeled ST-peptide enterotoxin (ST) analogue for specific targeting of guanylin receptors on human colonic cancers.

BACKGROUND: Human colonic cancer cells are known to express guanylate cyclase C (GC-C) receptors for guanylin and uroguanylin. E. coli ST is a peptide with high metabolic stability that specifically binds to GC-C receptors. An in vitro evaluation of a new synthetic indium-111 labeled ST conjugate for specific targeting of human colonic cancers that express GC-C receptors was performed. MATERIALS AND METHODS: A DOTA conjugated ST analogue DOTA-NCS-6-Ahx-Phe19-ST[1-19] (DOTA-NCS-ST) was synthesized and labeled with indium-111. The non-radioactive indium analogue (In-DOTA-NCS-ST) was also prepared in macroscopic quantities. 111In-DOTA-NCS-ST was produced as a single species (>80% RCP) and purified by HPLC. Human colon cancer CaCO-2 and T-84 cells were used to evaluate the in vitro IC50 values for GC-C receptor binding and determine the cell uptake and retention of radioactivity. RESULTS: The DOTA-NCS-ST and In-DOTA-NCS-ST conjugates exhibit high in vitro binding affinity for GC-C receptors with IC50 values <10 nM. The in vitro cell binding studies with the 111In-DOTA-NCS-ST conjugate demonstrated that 111In-label ST internalizes in human colon cancer cells and exhibits long-term retention. CONCLUSION: The combination of radiolabeling efficacy and specific in vitro cell uptake and retention suggests that the DOTA-NCS-ST construct holds potential for the development of diagnostic or therapeutic radiopharmaceuticals labeled with trivalent radiometals for specific targeting of human colonic cancers.

In vivo evaluation of an 111In-labeled ST-peptide analog for specific-targeting of human colon cancers.

In vitro competitive binding studies of In-DOTA-NCS-6-Ahx-Phe(19)-ST[1-19] vs. 125I-Tyr(5)-6-Ahx-Phe(19)-ST[1-19] with guanylate cyclase -C (GC-C) receptors on human colon cancer LS-180 cells revealed an IC(50) value of 7.7 +/- 0.1.6 nM. The in vitro cellular residualization studies of the 111In-DOTA-NCS-ST peptide and GC-C receptor mediated stimulated cGMP production with LS-180 cells demonstrates that this peptide selectively binds to LS-180 cells in an agonistic fashion. In vivo biodistribution studies in LS-180 tumor bearing SCID mice demonstrates that the 111In-DOTA-NCS-ST peptide targets the tumor with a specific uptake of 0.94 +/- 0.31%ID/g at 1 hr p.i. and approximately 23% was retained by the tumor at 4 hrs p.i. The radioactivity cleared rapidly from the blood stream with 84.5 +/- 3.4%ID at 1h p.i. found in the urine. High activity in urine and kidney, and minimal activity in liver and intestines, demonstrates preferential clearance of the radioactivity through the renal/urinary pathway. The specific in vitro and in vivo accumulation of the radioactivity by LS-180 human colonic cancer cells highlights the potential of radiometallated-DOTA-ST analogs as diagnostic/therapeutic radiopharmaceuticals.

Radiometallated receptor-avid peptide conjugates for specific in vivo targeting of cancer cells.

New receptor-avid radiotracers are being developed for site-specific in vivo targeting of a myriad of receptors expressed on cancer cells. This review exemplifies strategies being used to design radiometallated peptide conjugates that maximize uptake in tumors and optimize their in vivo pharmacokinetic properties. Efforts to produce synthetic peptide analogues that target the following three receptor systems are highlighted: Gastrin releasing peptide (GRP), alpha-melanocyte stimulating hormone (alpha-MSH), and guanylate cyclase-C (GC-C) receptors.

Synthesis, characterization, and labeling with 99mTc/188Re of peptide conjugates containing a dithia-bisphosphine chelating agent.

Radiolabeling of small receptor-avid peptides at specific predetermined chelation sites with radioactive metals has been an effective approach for production of target-specific radiopharmaceuticals for diagnosis and therapy of diseases. Among various electron-donating groups found on chelator frameworks, phosphines are unique because they display versatile coordination chemistry with a wide range of transition metals. We have recently reported the utility of a dithia-bis(hydroxymethyl)phosphine-based (P2S2) bifunctional chelating agent (BFCA) containing air-stable primary phosphine groups to form 99mTc-labeled receptor-avid peptides by the preconjugation approach. Here we report a novel strategy for labeling small peptides with both 99mTc and 188Re using the P2S2-COOH (6,8-bis[3-(bis(hydroxymethyl)phosphanyl)propylsulfanyl]octanoic acid) BFCA by a postconjugation radiolabeling approach. The first step in this approach involves the coupling of the corresponding (PH2)2S2-COOH intermediate to the N-terminus of the peptide(s). Formylation of P-H bonds with aqueous formaldehyde in the presence of HCl in ethanol affords the corresponding (hydroxymethyl)phosphine-P2S2-peptide conjugates in the form of an oxidatively stable phosphonium salt. The P2S2-peptide conjugates are generated (where the PH2 groups are converted to P(CH2OH)2 groups) by treatment of the P2S2-peptide phosphonium salt(s) with 1 M sodium bicarbonate solution at pH 8.5. Complexation of BFCA conjugates with 99mTc is achieved by direct reduction with Sn(II) tartarate to yield the 99mTc-P2S2-peptide conjugate in near quantitative yields. Complexation of the BFCA conjugates with 188Re is achieved by transchelation with 188Re citrate in yields of >/=90%. In this study, (PH2)2S2-COOH BFCA was conjugated to model peptides. The glycineglycine ethyl ester (GlyGlyOEt)-(PH2)2S2-COOH BFCA conjugate was converted to the hydroxymethylene phosphine form and complexed with 99mTc to produce the 99mTcO2-P2S2-GlyGlyOEt conjugate 8 in RCPs of >/=95%. This singular 99mTc product is stable over 24 h in aqueous solution as confirmed by HPLC. Identical retention times of the 99mTcO2-P2S2-GlyGlyOEt complex and its cold rhenium analogue (ReO2-P2S2-GlyGlyOEt) on HPLC indicates similarity in structures at the macroscopic and the tracer levels. The utility of this postconjugation strategy was further demonstrated by synthesizing a P2S2-D-Lys6-LHRH conjugate and producing its corresponding 99mTc complex in RCPs of >/=88%. Finally, the P2S2-5-Ava-BBN[7-14]NH2 bombesin (BBN) analogue was synthesized, the PH2 groups converted to P(CH2OH)2 groups and subsequently labeled with 188Re to yield a 188Re-labeled bombesin analogue with a RCP of >/=90%. The biological integrity of this conjugate was demonstrated in both in vitro and in vivo. The results of this investigation demonstrate that the (PH2)2S2-COOH BFCA can be conveniently used as a precursor for labeling small receptor-avid peptides with diagnostic (99mTc) and therapeutic (188Re) radionuclides via the postconjugation approach in high yields.

Melanoma-targeting properties of (99m)technetium-labeled cyclic alpha-melanocyte-stimulating hormone peptide analogues.

Preliminary reports have demonstrated that (99m)technetium (Tc)-labeled cyclic [Cys(3,4,10), D-Phe7]alpha-MSH(3-13) (CCMSH) exhibits high tumor uptake and retention values in a murine melanoma mouse model. In this report, the tumor targeting mechanism of 99mTc-CCMSH was studied and compared with four other radiolabeled alpha-melanocyte stimulating hormone (alpha-MSH) peptide analogues: 125I-(Tyr2)-[Nle4, D-Phe7]alpha-MSH [125I-(Tyr2)-NDP]; 99mTc-CGCG-NDP; 99mTc-Gly11-CCMSH; and 99mTc-Nle11-CCMSH. In vitro receptor binding, internalization, and cellular retention of radiolabeled alpha-MSH analogues in B16/F1 murine cell line demonstrated that >70% of the receptor-bound radiolabeled analogues were internalized together with the receptor. Ninety % of the internalized 125I-(Tyr2)-NDP, whereas only 36% of internalized 99mTc-CCMSH, was released from the cells into the medium during a 4-h incubation at 37 degrees C. Two mouse models, C57 mice and severe combined immunodeficient (Scid) mice, inoculated s.c. with B16/F1 murine and TXM-13 human melanoma cells were used for the in vivo studies. Tumor uptake values of 11.32 and 2.39 [% injected dose (ID)/g] for 99mTc-CCMSH at 4 h after injection, resulted in an uptake ratio of tumor:blood of 39.0 and 11.5 in murine melanoma-C57 and human melanoma-Scid mouse models, respectively. Two strategies for decreasing the nonspecific kidney uptake of 99mTc-CCMSH, substitution of Lys11 in CCMSH with Gly11 or Nle11, and lysine coinjection, were evaluated. The biodistribution data for the modified peptides showed that Lys11 replacement dramatically decreased the kidney uptake, whereas the tumor uptakes of 99mTc-Nle11- and 99mTc-Gly11-CCMSH were significantly lower than that of 99mTc-CCMSH. Lysine coinjection significantly decreased the kidney uptake (e.g., from 14.6% ID/g to 4.5% ID/g at 4 h after injection in murine melanoma-C57 mice) without significantly changing the value of tumor uptake of 99mTc-CCMSH. In conclusion, the compact cyclic structure of 99mTc-CCMSH, its resistance to degradation, and its enhanced intracellular retention are the major contributing factors to the superior in vivo tumor targeting properties of 99mTc-CCMSH. Lys11 residue in 99mTc-CCMSH is critical to the tumor targeting in vivo, and lysine coinjection rather than lysine replacement can significantly decrease the nonspecific renal radioactivity accumulation without impeding the high melanoma-targeting properties of 99Tc-CCMSH. The metal-cyclized CCMSH molecule displays excellent potential for the development of melanoma-specific diagnostic and therapeutic agents.

Psychosocial predictors of satisfaction among orthognathic surgery patients.

This study assessed the usefulness of selected psychosocial tests and demographic measures in identifying satisfied versus dissatisfied patients who received orthognathic surgery. Data were collected prior to placement of orthodontic appliances, 1 to 2 weeks presurgery, and at 1 week, 8 weeks, 6 months, 12 months and and 2 years postsurgery. The Revised Symptom Checklist-90 (SCL-90-R) scales, the Eysenck Personality Inventory (EPI), the Sickness Impact Profile (SIP), and the Oral Health Status Questionnaire (OHSQ) were used as independent variables. Indicators from the Post-Surgical Patient Satisfaction Questionnaire (PSPSQ), which assesses patient satisfaction regarding psychosocial issues, oral functioning, and esthetics, served as a postsurgical dependent measure of patient satisfaction. Thirty-one male and 86 female subjects participated in the multisite randomized trial comparing rigid and wire fixation. Patient age was significantly correlated with patient satisfaction from 8 weeks postsurgery through 2 years postsurgery. Older patients appear to report greater postsurgical satisfaction in comparison to younger patients. The postsurgical OHSQ (esthetics subscale) and postsurgical PSPSQ (satisfaction) were significantly related at 8 weeks, 6 months, 12 months, and 2 years postsurgery. Additionally, PSPSQ (satisfaction) and postsurgical OHSQ (general oral health scale) were correlated at 12 months. The EPI, SIP, and SCL-90-R were not significantly associated with postsurgical satisfaction when assessing the entire study sample. Postsurgical qualitative data from the PSPSQ indicated that 50% of the patients reported positive outcomes in oral functioning. Sixty-five percent reported esthetic improvements, and 37% reported neurosensory loss.

Early sexual experiences among pregnant and parenting adolescents.

One hundred sixty-six pregnant or parenting adolescent females completed a survey regarding early sexual experiences (wanted and unwanted), family dysfunction and violence, and health-risky behaviors occurring prior to age 18. Fifty-three percent had at least one unwanted sexual experience. Younger age at first unwanted sexual experience was associated with younger age at first wanted sexual experience. Adolescent females with an unwanted sexual experience, as compared to those without, were more likely to be victims of physical violence, to have run away, to be substance abusers, and to have family members with drug or alcohol problems. Four factors explained 39% of the variance in age at first pregnancy: presence of a family member with a drinking problem, age first got hit with a belt or other object by a family member, age first got drunk, and age at first wanted sexual experience. It was concluded that the prevention of teenage pregnancy entails a multifaceted approach that addresses family life, early sexual experiences, and health-risky behaviors.

99mTc-labeling and in vivo studies of a bombesin analogue with a novel water-soluble dithiadiphosphine-based bifunctional chelating agent.

Recent progress in the synthesis of water-soluble phosphine ligand systems and their corresponding 99mTc complexes prompted the development of a new bifunctional chelating agent (BFCA) based on a tetradentate dithiadiphosphine framework (P2S2-COOH). The detailed synthesis of this new BFCA is described here. The corresponding 99mTc complex, 99mTc-P2S2-COOH, can be formed in >95% yield. To demonstrate the potential of this chelate to efficiently label peptides, 99mTc-P2S2-COOH was coupled to the N-terminal region of the truncated nine-amino acid bombesin analogue, 5-Ava-Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH2 [BBN(7-14)], to form 99mTc-P2S2-BBN(7-14). Conjugation to the peptide was performed in borate buffer (pH 8.5) by applying the prelabeling approach in yields of >60%. In competitive binding assays, using Swiss 3T3 mouse fibroblast cells against [125I-Tyr4]bombesin, Re-P2S2-BBN(7-14) exhibited an IC50 value of 0.8 +/- 0.4 nM. The pharmacokinetic studies of 99mTc-P2S2-BBN(7-14) and its ability to target tissue expressing gastrin-releasing peptide (GRP) receptors were performed in normal mice. The 99mTc-P2S2-BBN(7-14) exhibited fast and efficient clearance from the blood pool (0.6 +/- 0.1% ID, 4 h postinjection) and excretion through the renal and hepatobiliary pathways (56.4 +/- 8.2 and 28.1 +/- 7.9% ID, 4 h postinjection, respectively). Significant uptake in the pancreas was observed (pancreatic acini cells express bombesin/GRP receptors), producing pancreas:blood and pancreas:muscle ratios of ca. 22 and 80, respectively, at 4 h postinjection.

Psychosocial predictors of high-risk patients undergoing orthognathic surgery.

The purpose of this analysis was to identify a set of predictor variables that are prospectively related to postsurgical outcomes. Specifically, psychosocial characteristics were sought to predict postsurgical outcomes. The 5 Revised Symptom Checklist-90 (SCL-90-R) scales, the neuroticism score of the Eysenck Personality Inventory (EPI), the psychosocial domain score from the Sickness Impact Profile (SIP), and 4 scales from the Oral Health Status Questionnaire (OHSQ) were used as the predictors. A total of 31 male and 86 female subjects participated in this multicenter randomized trial, which compared rigid and wire fixation. Data were collected prior to placement of orthodontic appliances, 1 to 2 weeks presurgery, and at 1 week, 8 weeks, 6 months, and 2 years after surgery. Baseline oral health was used as an indicator of postsurgical oral health functioning. A path analytic model of influences on presurgical oral health was estimated (R2 = 0.43). The results suggest that presurgical screening of demographic characteristics (age, sex, and ethnicity), oral health (the OHSQ), quality of life issues (SIP), and personality features (SCL-90-R), accounts for 23% to 39% of the variance in postsurgical oral health outcomes. The path analysis conducted suggests that a patient's age, ethnicity, gender, and elevated scores on the EPI have indirect effects on postsurgical health. As determined by a 2-stage least squares regression model, 3 variables--the patient's presurgical oral health (per the OHSQ), pre- and postsurgical Global Severity Index (GSI) score from the SCL-90-R, and the psychosocial scale score from the SIP--were found to have a statistically significant impact on postsurgical outcomes. Additionally, the GSI, SIP, and OHSQ are reliable measures in predicting oral health outcomes.

Design and characterization of alpha-melanotropin peptide analogs cyclized through rhenium and technetium metal coordination.

alpha-Melanocyte stimulating hormone (alpha-MSH) analogs, cyclized through site-specific rhenium (Re) and technetium (Tc) metal coordination, were structurally characterized and analyzed for their abilities to bind alpha-MSH receptors present on melanoma cells and in tumor-bearing mice. Results from receptor-binding assays conducted with B16 F1 murine melanoma cells indicated that receptor-binding affinity was reduced to approximately 1% of its original levels after Re incorporation into the cyclic Cys4,10, D-Phe7-alpha-MSH4-13 analog. Structural analysis of the Re-peptide complex showed that the disulfide bond of the original peptide was replaced by thiolate-metal-thiolate cyclization. A comparison of the metal-bound and metal-free structures indicated that metal complexation dramatically altered the structure of the receptor-binding core sequence. Redesign of the metal binding site resulted in a second-generation Re-peptide complex (ReCCMSH) that displayed a receptor-binding affinity of 2.9 nM, 25-fold higher than the initial Re-alpha-MSH analog. Characterization of the second-generation Re-peptide complex indicated that the peptide was still cyclized through Re coordination, but the structure of the receptor-binding sequence was no longer constrained. The corresponding 99mTc- and 188ReCCMSH complexes were synthesized and shown to be stable in phosphate-buffered saline and to challenges from diethylenetriaminepentaacetic acid (DTPA) and free cysteine. In vivo, the 99mTcCCMSH complex exhibited significant tumor uptake and retention and was effective in imaging melanoma in a murine-tumor model system. Cyclization of alpha-MSH analogs via 99mTc and 188Re yields chemically stable and biologically active molecules with potential melanoma-imaging and therapeutic properties.

Child sexual revictimization by multiple perpetrators.

OBJECTIVE: The objectives of this study were to describe feelings, disclosure characteristics, family dysfunction, and health risky behaviors in those adolescents having unwanted sexual experiences (USE; any kind of sexual touching that was bad, uncomfortable, or forced) with multiple perpetrators and to compare these parameters with those adolescents having USE(s) with single perpetrators. METHOD: A cross-sectional survey of consecutive waiting room patients from four clinic sites was done in 538 adolescents and young adults; 76% of the study population were Hispanic and over half were poor. One hundred sixty-one subjects with single perpetrator USE(s) were compared with 97 subjects who had USE(s) with more than one perpetrator. RESULTS: Victims of multiple perpetrators were more likely than victims of single perpetrators to react with self-blame and delay disclosure of USE due to shame. When compared with victims of single perpetrators, those with multiple perpetrators were more likely to disclose their USE to protect self or others or because they became weary or intolerant of the abuse. Although family violence and substance abuse were common in both victims of single and multiple perpetrators of USE, these factors appeared to potentiate the likelihood of repeated victimization in childhood. Prevalence of health risky behaviors did not differ between the two groups. CONCLUSIONS: The findings indicated that sexual revictimization by multiple perpetrators is not uncommon and suggest that abused children should be questioned about this possibility. Children and teenagers who have USE(s) with more than one perpetrator may have more difficulties with psychological recovery due to increased shame and self-blame.

Unwanted and illegal sexual experiences in childhood and adolescence.

Three hundred forty-two anonymous surveys regarding unwanted sexual experiences (USE) were filled out in three clinic sites: a pediatric sexual abuse clinic, family practice clinic, and family planning clinic. In the latter two clinics, 40% of females and 16% of males had at least one unwanted sexual experience prior to turning 18 years old. Only 91% of the sexual abuse clinic patients indicated their experience was unwanted. In addition, 27% of the subjects had wanted sexual experiences that were illegal and underreported: These experiences involved a partner at least 4 years older or younger. While feelings of victimization were most common, self-blame and naivete about the abuse were also frequently reported, especially in those who had an USE with a peer. Ambivalence, self-blame, and peer pressure were associated with a lower tendency to disclose one's USE. Although unwanted and illegal sexual experiences were less common in Hispanic females, feelings of self-blame and ambivalence regarding their USE were more frequent in comparison with White females. These findings have important investigative and therapeutic implications for professionals who encounter victims of sexual abuse.

Child sexual abuse: An undermining of the polis.

This paper explores the sexual abuse literature and the political participation literature for possible linkages. Research on political participation indicates low levels of political trust and damaged self-esteem have important impacts on style and level of political involvement. The literature on child sexual abuse indicates potential root causes for lowered trust and self-esteem which have implications for adult participation in the civic arena. Sexual abuse has negative effects on individual victims and also undermines the foundations of democratic societies.

Decrease in locus coeruleus [3H]idazoxan binding site density in genetically epilepsy-prone (GEPR) rats.

Deficits in norepinephrine synthesis, transmitter level, turnover and reuptake have been reported in the brain of genetically epilepsy-prone (GEPR) rats. We investigated the hypothesis that these alterations may trigger a compensatory downregulation of locus coeruleus alpha 2-adrenergic receptors and an upregulation of postsynaptic alpha 2-adrenergic receptor density in forebrain regions of GEPR rat brain. alpha 2-adrenergic receptor density was measured in the locus coeruleus and 7 forebrain regions of control and GEPR rats by in vitro [3H]idazoxan autoradiography. Specific [3H]idazoxan binding site density was decreased significantly in the locus coeruleus of both GEPR-3 and GEPR-9 rats compared to controls. No significant differences in specific [3H]idazoxan binding were observed in the 7 forebrain regions of GEPR-9 rats compared to control. Reduced locus coeruleus alpha 2-adrenergic receptor density in GEPR rats may produce a net increase in locus coeruleus noradrenergic cell firing, an effect which could, in part, offset the impact of reduced noradrenergic influence in GEPR rat forebrain. Additionally, decreased norepinephrine levels in GEPR rat brain may be a long-term consequence of reduced alpha 2-adrenergic receptor-mediated inhibition of locus coeruleus firing activity.