Absence of 5-HT3 and cholinergic mechanisms in improgan antinociception

Improgan, an analgesic derived from histamine antagonists, acts in the brain stem to activate descending non-opioid, pain-relieving circuits, but the mechanism of action of this drug remains elusive. Because improgan has a moderate affinity for 5-HT(3) receptors, and, since cholinergic and serotonergic drugs can modulate descending analgesic circuits, roles for 5-HT(3), nicotinic and muscarinic receptors in improgan antinociception were presently investigated in rats. Improgan (80 microg, icv) induced nearly maximal inhibition of hot plate and tail flick nociceptive responses, and these actions we unaffected by antagonists of muscarinic (atropine, 5.9 mg/kg, i.p.) and nicotinic (mecamylamine, 2 mg/kg, i.p.) receptors. Control experiments verified that these antagonist treatments were maximally effective against muscarinic and nicotinic antinociception in both tests. In addition, improgan antinociception was unaffected by icv pretreatment with a 5-HT(3) antagonist (ondansetron, 20 microg). When given alone, icv treatment with neither this antagonist nor a 5-HT(3) agonist (m-chlorophenylbiguanide, 1000 nmol, icv) modified thermal nociceptive latencies. These results show no role for supraspinal cholinergic and 5-HT(3) receptors in improgan antinociception. The findings help to narrow the search for the relevant mediators of the action of this novel analgesic agent.     

The paradoxical effects of SKF83959, a novel dopamine D1-like receptor agonist, in the rat acoustic startle reflex paradigm

While the benzazepine SKF83959 elicits classical behavioral responses associated with dopamine D1 receptors, it also acts as a D1 receptor antagonist biochemically. The paradoxical properties of this agent remain an enigma. In the present study, we sought to determine the behavioral effects of SKF83959 in the rat acoustic startle reflex test. Systemic administration of SKF83959 produced a dose-related increase in the startle amplitude with a stimulus of 105 dB, and a significant group difference was observed between animals treated with 1 mg/kg SKF83959 and vehicle controls. SKF83959 also significantly reduced the latency to startle response to stimuli of 95 dB and 105 dB in a dose-dependent manner. However, unlike classical dopamine D1-like receptor agonists, SKF83959 failed to disrupt prepulse inhibition (PPI) of either the startle amplitude or the latency to startle response; rather, the agent dose-dependently increased the PPI latency to startle response of 105 dB stimulus. These results suggest that the behavioral effects of SKF83959 in the rat acoustic startle reflex paradigm are paradoxical, and these paradoxical effects may be associated with its distinct pharmacological properties.     

Attention on inattention: the differential effect of caregiver education on endorsement of ADHD symptoms

The impact of caregiver education level on endorsement of attention-deficit hyperactivity disorder (ADHD) symptoms for inattention (IA) and hyperactivity-compulsivity (HA) in a sample of high-risk youths was examined. Participants were 1347 caregivers of varying educational backgrounds who completed the ADHD module of the Diagnostic Interview Schedule for Children IV. The relationship of caregiver education to ADHD symptom endorsement was examined in three sets of analyses in which IA and HA symptoms were simultaneously regressed on caregiver years of education. Both multivariate analysis of covariance and logistic regression analyses revealed significantly lower rates of IA symptom endorsement by caregivers with less education, while there was no effect for HA symptoms. A multiple indicator multiple cause (MIMIC) model analysis also revealed that caregiver years of education was significantly positively associated with IA but not with HA symptoms, even when other demographic factors were controlled. There is a clear effect of caregiver education on ADHD symptom endorsement patterns, raising concerns that demographic factors related to symptom measurement may contribute to discrepancies in the assessment and treatment of ADHD.     

Racial and ethnic differences in utilization of mental health services among high-risk youths

OBJECTIVE: Racial and ethnic disparities in mental health service use have been identified as a major public health problem. However, the extent to which these disparities may be accounted for by other confounding sociodemographic or clinical predictors of service use (e.g., family income, functional impairment, caregiver strain) is relatively unexplored, especially for youth services. The goal of this study was to test for racial/ethnic disparities in use of a variety of outpatient, inpatient, and informal mental health services among high-risk youths, with the effects of other predictive factors controlled. METHOD: Participants were 1,256 youths ages 6-18 years who received services in a large, publicly funded system of care (including the child welfare, juvenile justice, special education, alcohol and drug abuse, and mental health service sectors). Youths and caregivers were interviewed with established measures of mental health service use, psychiatric diagnoses, functional impairment, caregiver strain, and parental depression. RESULTS: Significant racial/ethnic group differences in likelihood of receiving any mental health service and, specifically, formal outpatient services were found after the effects of potentially confounding variables were controlled. Race/ethnicity did not exert a significant effect on the use of informal or 24-hour-care services. CONCLUSIONS: Racial/ethnic disparities in service use remain a public health problem.     

Tri-ethnic variations of co-morbid substance and alcohol use disorders in schizophrenia

OBJECTIVES: This study examined the differential prevalence of substance and alcohol use disorders among European Americans, African Americans, and Latinos with schizophrenia (n = 6424) who received public mental health services in San Diego County during fiscal year 2002-2003. METHODS: Data were obtained from the public mental health database used by the San Diego County Mental Health System. Chi-Square analyses and stepwise logistic regression analyses were used to examine differences regarding the prevalence of substance and alcohol use among clients with schizophrenia and schizoaffective disorder, and to analyze the sociodemographic variables associated with this co-morbidity. RESULTS: Significant differences in the prevalence of diagnosed co-morbidity were found across the ethnic groups. Rates of co-morbid diagnosis among African Americans (25%) were significantly higher than those among European Americans (22%) and Latinos (19%). Logistic regression results revealed ethnicity was a significant predictor of co-morbid substance and alcohol use, as was being homeless and male. Among Latinos, language preference was also a significant predictor. Latinos who denoted English as their primary language were 1.7 times more likely to be diagnosed with co-morbid substance or alcohol use disorders than Latinos who denoted Spanish. CONCLUSIONS: Among people with schizophrenia, there were significant differences in prevalence rates and predictors of diagnosed co-morbid substance and alcohol use disorders. Future research is needed to examine the relationship among language preference, level of acculturation, and subsequent diagnosing barriers for Latinos. Among African Americans, the reasons behind increased co-morbidity rates need to be examined, and homelessness should be carefully addressed among all three ethnic groups.     

Gender differences in childhood onset conduct disorder

The present study tested several predictions related to the theory that girls with conduct disorder (CD) follow a single delayed onset pathway. The following hypotheses were tested among a high-risk, stratified random sample of youth who used public services during a 6-month period: boys will be more likely to have childhood onset CD (COCD) than girls; girls with COCD will be less common than girls with adolescent onset CD (AOCD); COCD girls. AOCD girls, and COCD boys will be similar in terms of risk profiles and AOCD boys will have a less severe risk profile than COCD girls; and risk factors that differentiate between COCD and AOCD among males will not differentiate between COCD and AOCD among females. Among those youth who met the criteria for CD, males were significantly more likely to have COCD than females. However, close to half of females with CD met the criteria for the COCD subtype. Of the seven risk factors that were examined, girls with COCD scored higher than COCD boys on three factors and higher than AOCD girls on four factors; however, only one significant difference was found between AOCD girls and COCD boys. Finally, risk factors appeared to differentiate between COCD and AOCD groups in a similar way among males and females. These findings suggest that COCD is not rare among females in public service sectors, COCD girls can be distinguished from AOCD girls in terms of risk factors, and risk factors for COCD among males are also relevant to females.     

Activation of brain stem nuclei by improgan, a non-opioid analgesic

Improgan is a compound developed from histamine antagonists which shows the pre-clinical profile of a highly effective, non-opioid analgesic when administered into the rodent CNS. Pharmacological studies suggest that improgan activates descending pain-relieving circuits, but the brain and spinal sites of action of this drug have not been previously studied. Presently, the effects of intracerebral and intrathecal microinjections of improgan were evaluated on thermal nociceptive responses in rats. Improgan produced large, dose- and time-related reductions in nociceptive responses following administration into the ventrolateral periaqueductal gray (PAG), the dorsal PAG, and the rostral ventromedial medulla (RVM). The drug had no measurable effects after injections into the caudate nucleus, basolateral amygdala, hippocampus, ventromedial hypothalamus, superior colliculi, ventrolateral medulla, or the spinal subarachnoid space. Inactivation of the RVM by muscimol microinjections completely attenuated antincociceptive responses produced by intraventricular improgan. These findings, taken with earlier results, show that, like opioids and cannabinoids, improgan acts in the PAG and RVM to activate descending analgesic systems. Unlike these other analgesics, improgan does not act in the spinal cord or in CNS areas outside of the brain stem.     

Brain environment interactions: stress, posttraumatic stress disorder, and the need for a postmortem brain collection

Stress, especially the extreme stress of traumatic events, can alter both neurobiology and behavior. Such extreme environmental situations provide a useful model for understanding environmental influences on human biology and behavior. This paper will review some of the evidence of brain alterations that occur with exposure to environmental stress. This will include recent studies using neuroimaging and will address the need for histological confirmation of imaging study results. We will review the current scientific approaches to understanding brain environment interactions, and then make the case for the collection and study of postmortem brain tissue for the advancement of our understanding of the effects of environment on the brain. Creating a brain tissue collection specifically for the investigation of the effects of extreme environmental stressors fills a gap in the current research; it will provide another of the important pieces to the puzzle that constitutes the scientific investigation of negative effects of environmental exposures. Such a resource will facilitate new discoveries related to the psychiatric illnesses of acute stress disorder and posttraumatic stress disorder, and can enable scientists to correlate structural and functional imaging findings with tissue abnormalities, which is essential to validate the results of recent imaging studies.     

M-mode ultrasound: a reliable measure of transversus abdominis thickness?

OBJECTIVE: The purpose of this study was to establish a reliable method for measuring transversus abdominis thickness in asymptomatic human subjects in supine lying, standing and walking. DESIGN AND METHODS: This was a single operator reliability study using ultrasound imaging to measure 22 subjects on three separate occasions. A purpose built high-density foam reinforced belt was used to house and position the transducer over the mid-point of the transversus abdominis. Each subject was imaged in supine, standing, and treadmill walking at 3 kph. Intraclass correlation coefficients and standard error of measurement analysis were used to measure the data. RESULTS: The correlation coefficient data analysis resulted in intraclass correlation coefficients of 0.94 (standard error of measurement 0.35) in supine lying, 0.88 (0.66) in standing and 0.88 (0.56) in walking. CONCLUSION: The method described is a reliable tool for measuring changes in thickness of transversus abdominis in supine lying, standing and walking. RELEVANCE: This procedure has the potential to detect dysfunctional changes in abdominal muscle activity for patients with low back pain in a functional setting.