Clonidine and yohimbine in opioid-dependent humans responding under a naloxone novel-response discrimination procedure.

Opioid-maintained volunteers were trained to distinguish between a low dose of the opioid antagonist naloxone (0.15 mg/70 kg, i.m.; i.e. Drug A) and placebo (i.e. Drug B), under an instructed novel-response drug discrimination procedure in which subjects identify the drug condition as 'A', 'B', or 'N' (neither A nor B - 'novel'). Once the discrimination was acquired, doses of naloxone, the alpha2-adrenergic antagonist yohimbine, the alpha2-adrenergic agonist clonidine, and the training dose of naloxone in combination with clonidine were tested. Naloxone and yohimbine each produced a dose-related increase and decrease in naloxone- and 'novel'-appropriate responding, respectively, with the naloxone stimulus partially generalizing to yohimbine. Clonidine produced primarily placebo-appropriate responding. Naloxone produced expected changes in self-reports, but effects of yohimbine and clonidine were unremarkable, and yohimbine was never identified as an opioid antagonist. Clonidine partially attenuated naloxone-occasioned responding in a non-dose-related manner, and attenuated some, but not all, naloxone-induced changes in self-report measures. Naloxone attenuated or enhanced several clonidine-induced changes in self-report and physiological measures. These findings indicate that adrenergic mechanisms are involved in the expression of opioid withdrawal, but the involvement is indirect.

Activity of pallidal and striatal tonically active neurons is correlated in mptp-treated monkeys but not in normal monkeys.

The goal of this study is to assess the function of tonically active neurons (TANs) of the striatum and their malfunction in the parkinsonian state. We recorded multiple spike trains of striatal TANs and pallidal neurons, which are the main target of striatal projections. Recordings were performed in two vervet monkeys before and after the induction of tremulous parkinsonism by systemic injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP). We then calculated cross-correlograms between TANs and pallidal neurons to evaluate the interactions between them. In the normal monkeys, only 1.3% (2/152) of the cross-correlograms displayed significant peaks, and 8.6% (13/152) displayed significant oscillations. After MPTP treatment, 42.8% (83/194) of the cross-correlograms displayed significant peaks or troughs, or both, and 58.8% (114/194) displayed significant 3-19 Hz periodic oscillations. The frequency content of the coherent oscillations matched the frequency content of the activity of individual TANs, but was only weakly related to that of individual pallidal cells. These results confirm the notion that in the normal state neurons in the basal ganglia tend to fire independently, whereas in the parkinsonian state they exhibit synchronized oscillatory activity. The low level of correlated activity in the normal state demonstrates that TANs have only a slight effect on pallidal activity during execution of familiar behavior. The high level of oscillatory correlated activity in the parkinsonian state further suggests that coherent oscillations of the whole basal ganglia circuitry underlie the clinical features of Parkinson's disease.

Nicotine transdermal patch and atypical antipsychotic medications for smoking cessation in schizophrenia.

OBJECTIVE: Schizophrenic patients have high rates of cigarette smoking. The authors compared the outcomes of two group psychotherapy programs for smoking cessation in patients with schizophrenia or schizoaffective disorder who were also treated with the nicotine transdermal patch and with either atypical or typical antipsychotic medications. METHOD: Forty-five subjects were randomly assigned to 1) the group therapy program of the American Lung Association (N=17) or 2) a specialized group therapy program for smokers with schizophrenia (N=28) that emphasized motivational enhancement, relapse prevention, social skills training, and psychoeducation. All subjects participated in 10 weeks of treatment with the nicotine transdermal patch (21 mg/day) and 10 weekly group therapy sessions and continued to receive their prestudy atypical (N=18) or typical (N=27) antipsychotic medications. Outcome variables included treatment retention, rate of smoking abstinence, and expired-breath carbon monoxide level. RESULTS: Smoking abstinence rates did not differ in the two group therapy programs. However, atypical antipsychotic agents, in combination with the nicotine transdermal patch, significantly enhanced the rate of smoking cessation (55.6% in the atypical agent group versus 22.2% in the typical group), which was reflected by a significant effect of atypical versus typical agents on carbon monoxide levels. Risperidone and olanzapine were associated with the highest quit rates. CONCLUSIONS: The results suggest that 1) smoking cessation rates with the nicotine transdermal patch are modest in schizophrenia, 2) specialized group therapy for schizophrenic patients is not significantly different from American Lung Association group therapy in its effect on smoking cessation, and 3) atypical agents may be superior to typical agents in combination with the nicotine transdermal patch for smoking cessation in schizophrenia.

Protease inhibitor therapy in HIV-infected children.

We reviewed the short-term response to and safety of protease inhibitor (PI) therapy in HIV-infected children by performing a retrospective chart review of open-label PI containing combination therapy at two urban pediatric HIV centers. Seventy HIV-infected children received 101 PI containing antiretroviral therapy (ART) combinations. Main outcome measures were follow-up CD4 counts, viral loads, and patient or caregiver reported compliance. During follow-up, treatment with PI ART was associated with a mean maximal increase in CD4+ lymphocyte count of 454 x 10(6)/L and a mean maximal decrease in viral load of 1.76 log units. Of the 32 patients who achieved undetectable viral loads, 28 (87.5%) remained undetectable through a mean follow-up of 8.9 months. Patients who reported good compliance achieved a higher rate of response (92.6%) than those who reported poor compliance (61.5%). Of 14 changes made to a second PI because of treatment failure, 11 (78.6%) resulted in a positive response to the second regimen. Nineteen of 101 courses of PI therapy resulted in significant side effects, including renal complications in 8 of 21 patients treated with indinavir. PI ART was associated with substantial short-term improvement in immunological and virological parameters in this heavily pretreated cohort, with 40% of patients maintaining an undetectable viral load after 9 months of therapy. Patients who failed one PI regimen usually responded to a second regimen. There was a significant rate of side effects from PI treatment.

Desipramine in opioid-dependent cocaine abusers maintained on buprenorphine vs methadone.

BACKGROUND: Cocaine abuse occurs in 40% to 60% of patients entering opioid maintenance treatment, and effective pharmacotherapies are needed for this combined dependence. METHODS: This 13-week, randomized, double-blind, placebo-controlled trial evaluated the efficacy of desipramine hydrochloride (0 or 150 mg/d) plus buprenorphine hydrochloride (12 mg/d) or methadone hydrochloride (65 mg/d) in 180 opioid-dependent cocaine abusers (124 men, 56 women). Supervised urine samples were obtained thrice weekly, and self-reported cocaine and heroin use was reported once weekly. Desipramine plasma levels were determined at weeks 4 and 10. RESULTS: In men, opioid abstinence was increased more rapidly over time when treated with methadone than with buprenorphine, whereas cocaine abstinence was increased more with buprenorphine than with methadone. In women, opioid abstinence was increased the least rapidly when treated with buprenorphine plus placebo, while cocaine abstinence was increased more rapidly over time when treated with methadone than with buprenorphine. Regardless of sex or opioid medication, desipramine increased opioid and cocaine abstinence more rapidly over time than placebo. Self-reported opioid use confirmed these findings. Desipramine plasma levels were higher in women than in men, particularly those on buprenorphine maintenance. Higher desipramine plasma levels were associated with greater opioid, but not cocaine, abstinence. CONCLUSIONS: Desipramine may be a useful adjunctive medication in facilitating opioid and cocaine abstinence in opioid-maintained patients. The efficacy of opioid medications to treat opioid or cocaine dependence may differ by sex. These findings highlight the importance of including sex as a factor when examining treatment outcome in these types of trials.

Physiology of MPTP tremor.

Rhesus and vervet monkeys respond differently to treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride neurotoxin (MPTP). Both species develop akinesia, rigidity, and severe postural instability. However, rhesus monkeys only develop infrequent, short episodes of high-frequency tremor, whereas vervet monkeys have many prolonged episodes of low-frequency tremor. After MPTP treatment, the spiking activity of many pallidal neurons became oscillatory and highly correlated. Oscillatory autocorrelation functions were dominated by lower frequencies, cross-correlograms by higher frequencies. The phase shift distribution of the oscillatory cross-correlograms of pallidal cells in MPTP-treated vervet monkey were clustered around 0 phase shift, unlike the oscillatory correlograms in the MPTP-treated rhesus monkey, which were widely distributed between 0 degrees and 180 degrees. Analysis of the instantaneous phase differences between tremors of two limbs in the MPTP monkeys and human parkinsonian patients showed short periods of tremor synchronization. We thus concluded that the rhesus and the vervet models of MPTP-induced parkinsonism may represent the tremulous and nontremulous variants of human parkinsonism. We suggest that the tremor phenomena of Parkinson's disease (PD) are related to the emergence of synchronous neuronal oscillations in the basal ganglia. Finally, the oscillating neuronal assemblies in the pallidum of tremulous parkinsonian primates are more stable (in time and in space) than those of parkinsonian primates without overt tremor.

Gender stereotyping for sociability, dominance, character, and mental health: a meta-analysis of findings from the bogus stranger paradigm.

A meta-analysis was conducted of target gender effects on trait attributions from 18 bogus stranger studies that had manipulated target gender and target physical attractiveness. Collapsed over sex of perceivers, female targets were seen as more sociable, happier, and possessing greater character than male targets. However, these effects were small and were often moderated by the perceivers' sex. Male perceivers viewed female targets as more sociable and happier than male targets, whereas female perceivers viewed male targets as more dominant than female targets. There was no moderation of the gender effect on attributions of character, as both sexes viewed females more favorably than males and the effect size was very small for perceivers of both sexes.

Physiological aspects of information processing in the basal ganglia of normal and parkinsonian primates.

There are two views as to the character of basal-ganglia processing - processing by segregated parallel circuits or by information sharing. To distinguish between these views, we studied the simultaneous activity of neurons in the output stage of the basal ganglia with cross-correlation techniques. The firing of neurons in the globus pallidus of normal monkeys is almost always uncorrelated. However, after dopamine depletion and induction of parkinsonism by treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), oscillatory activity appeared and the firing of many neurons became correlated. We conclude that the normal dopaminergic system supports segregation of the functional subcircuits of the basal ganglia, and that a breakdown of this independent processing is a hallmark of Parkinson's disease.

Protease inhibitor therapy in children with perinatally acquired HIV infection.

OBJECTIVE: To review the short-term response and safety of protease inhibitor therapy in HIV-infected children. DESIGN: Retrospective chart review of open-label protease inhibitor-containing combination therapy. SETTING: Two urban pediatric HIV centers. PATIENTS: Twenty-eight HIV-infected children were prescribed 30 protease inhibitor-containing antiretroviral therapy combinations. The median age at initiation of protease inhibitor antiretroviral therapy was 79 months. Patients had been on previous antiretroviral therapy for a mean of 45.5 months. RESULTS: Of the 28 children who completed at least 1 month of therapy, 26 experienced marked virologic and immunologic improvement (mean maximal decrease in viral load 1.90 log10 copies/ml; SD, 0.8; mean maximal rise in CD4+ lymphocytes of 279 x 10(6)/l; SD, 300 x 10(6)/l). Eleven patients achieved a viral nadir of < 400 copies/ml, and seven sustained this level of viral suppression for a mean of 6 months. Indinavir use was associated with a high incidence of renal side-effects, including two patients who developed interstitial nephritis. Two patients on ritonavir experienced a significant elevation of liver enzymes. CONCLUSIONS: Protease inhibitor therapy was associated with substantial short-term virologic and immunologic improvement in this primarily heavily pretreated cohort, with 25% maintaining a viral load of < 400 copies/ml after 6 months of therapy. There was a significant rate of adverse events. Pharmacokinetic and safety data are needed to guide aggressive antiretroviral therapy in HIV-infected children, and further treatment options are required for those failing or intolerant to the available protease inhibitors.

Neuronal synchronization of tonically active neurons in the striatum of normal and parkinsonian primates.

1. Previous studies indicate that tonically active neurons (TANs) are the cholinergic interneurons of the striatum and predict that their activity is synchronized. To test whether TANs do fire synchronously, and whether dopamine depletion affects their synchronization, we recorded the simultaneous activity of several TANs in the putamens of two vervet monkeys before and after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment. 2. Cross-correlation analysis revealed that most pairs of TANS (33 of 54; 61.1%) fire synchronously at +/- 60-ms delay. Correlated activity was more common between neurons with characteristic response to reward (17 of 19 pairs; 89.5%). 3. Cross-correlation study of 24 triplets of TANS showed synchronization of spiking activity of all 3 TANS in only 29.2% of cases (7 of 24 triplets). Correlated activity of two of three possible pairs was found in 25% of the cases. 4. After MPTP treatment and the development of parkinsonian symptoms, most TANS' auto- and cross-correlograms (22 of 28 units; 78.6%; and 23 of 28 pairs; 82.1%) became oscillatory. The number of correlated pairs was slightly increased (24 of 28; 85.7%). The strength of the synchronization was not significantly different from the normal values. 5. These findings support the notion that TANs function as distributed, partially overlapping synchronized networks. However, a normal dopaminergic system is not essential for synchronization of TANs; on the contrary, dopaminergic activity may even have a desynchronizing effect on the basal ganglia's system.

Generalizability of the type A/type B distinction across different psychoactive substances.

Previous research using cluster analysis has found that abusers of both alcohol and cocaine can be categorized into more severe (Type B) and less severe (Type A) subgroups. This article sought to replicate and extend these findings in a sample of 521 inpatients, outpatients, and nontreatment-seeking abusers of alcohol, cocaine, marijuana, and opiates. Cluster analyses of subsamples that met the DSM-IV criteria for dependence or abuse for alcohol, cocaine, marijuana, and opiates found that the Type A/Type B distinction was largely generalizable across drugs. Type As--who consistently accounted for about 60% of all substance abuse and about half of abusers in treatment-scored lower than Type Bs on a variety of substance abuse and psychiatric measures that were administered both at intake and at a 6-month follow-up.

Construct validity of the dependence syndrome as measured by DSM-IV for different psychoactive substances.

The Diagnosis of Drug Dependence in the Official Psychiatric Nomenclatures (DSM-III-R, DSM-IV, and ICD 10) are based on the Drug Dependence Syndrome construct. Although the validity and utility of the dependence syndrome has been widely documented for alcohol, the generalizability of the dependence syndrome to other psychoactive substances is still not clear. Thus, this article examines the construct validity of the drug dependence syndrome, as measured by diagnostic criteria for DSM-IV, using both internal consistency analyses and confirmatory factor analyses. Data were obtained from non-mutually exclusive groups of abusers for five drugs (alcohol, cocaine, marijuana, opioids, sedatives, stimulants) drawn from a pool of 521 subjects obtained from drug treatment, general psychiatric and community samples. As predicted by the theory, drug dependence items were found to be unidimensional and factorially distinct from measures of the consequences of substance abuse (e.g. legal problems) for all drug groups. Moreover, the drug dependence items yielded internally consistent scales that produced a distribution of scores reflecting a continuum from low to high severity of abuse for all drugs.

Neurons in the globus pallidus do not show correlated activity in the normal monkey, but phase-locked oscillations appear in the MPTP model of parkinsonism.

1. To test the mode of functional connectivity in the basal ganglia circuitry, we studied the activity of simultaneously recorded neurons in the globus pallidus (GP) of a behaving rhesus monkey. The cross-correlograms of pairs of neurons in the GP were compared with those of neurons in the thalamus and frontal cortex and to the cross-correlograms of pallidal pairs after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment. 2. In contrast with cortical and thalamic neuronal activity, almost all pairs (n = 76/81 pairs; 93.8%, 1,629/1,651 histograms; 98.7%) of GP neurons in the normal monkey were not driven by a common input. 3. The monkey was systemically treated with MPTP until the appearance of parkinsonian signs and an intermittent 7- to 11-Hz action/postural tremor. After the MPTP treatment, many pallidal neurons (49/140; 35%) became oscillatory, and 19% (n = 31/162) of pallidal pairs had oscillatory cross-correlograms. 4. These results support the model of parallel processing in the basal ganglia of normal monkeys and suggest a breakdown of the independent activity in the parkinsonian state.

Construct validity of the abuse-dependence distinction as measured by DSM-IV criteria for different psychoactive substances.

This article used the diagnostic criteria of the Diagnostic and Statistical Manual-Fourth Edition (DSM-IV) to compare the validity of a qualitative and a quantitative model of the abuse-dependence distinction for different psychoactive substances in samples of drug users drawn from drug treatment inpatients, general psychiatric patients, and the community. The hypothesis that DSM-IV abuse criteria differ from dependence criteria in kind rather than degree (a qualitative model) was only occasionally supported by confirmatory factor analyses of DSM-IV diagnostic criteria, by patterns of correlations of the two kinds of criteria with Addiction Severity Score (ASI) composites and measures of frequency of substance abuse, and by concurrent/prognostic validity analyses. However, the findings were consistent with a quantitative model of the abuse-dependence distinction that posits that abuse is a mild form of dependence. Whether abuse and dependence categories of users were established from separate DSM-IV criteria for abuse and dependence or from scores from a severity-of-dependence scale based on the pooled DSM-IV dependence and abuse criteria, abusers generally used drugs less than users in the dependence category and reported less problems associated with substance abuse on the ASI.

Gender differences in personality: a meta-analysis.

Four meta-analyses were conducted to examine gender differences in personality in the literature (1958-1992) and in normative data for well-known personality inventories (1940-1992). Males were found to be more assertive and had slightly higher self-esteem than females. Females were higher than males in extraversion, anxiety, trust, and, especially, tender-mindedness (e.g., nurturance). There were no noteworthy sex differences in social anxiety, impulsiveness, activity, ideas (e.g., reflectiveness), locus of control, and orderliness. Gender differences in personality traits were generally constant across ages, years of data collection, educational levels, and nations.

A model integrating mental health and primary care services for families with HIV.

The need to integrate mental health and primary care service delivery for individuals and families living with human immunodeficiency virus (HIV) and acquired immune deficiency syndrome (AIDS) has been well documented. Accessibility, flexibility, and cultural specificity are qualities necessary, but generally lacking, in existing models of integrated care. In this paper, NOAH (No One Alone with HIV), an innovative, hospital-based program of family-focused HIV mental health services, will be described. NOAH is designed to meet the needs of primary care providers, allied professionals/paraprofessionals, and the diversity of inner-city patients they serve. Central to the model are population-specific "family health facilitators," who collaborate with providers by offering mental health interventions at one or more levels along a continuum of service intensity. Whenever possible, primary care team members are empowered to manage mental health problems directly. When more intensive services are required, responsibility for direct intervention transfers to the family health facilitator. With the locus of inner-city HIV primary care shifting from hospitals to neighborhood health centers, this hospital-based program has been extended into the community to support the early integration of mental health and primary care services at the community level.