Effect of dopamine receptor antagonists on cocaine subjective effects: a naturalistic case study

Schizophrenic patients on neuroleptic medications abuse cocaine and report cocaine-induced euphoria. This study was undertaken to provide better clinical characterization of these phenomena by administering the POMS and a custom-designed questionnaire. A group of heavy cocaine users who were not mentally ill served as the control group. The results clearly suggest that schizophrenic patients report cocaine-induced euphoria and post-use craving despite being treated with therapeutic doses of haloperidol or fluphenazine. The responses of the control group were similar to that of the schizophrenic group except that the latter subjects reported a greater degree of anxiety. These results suggest that blockade of D2 receptors is not sufficient to block cocaine-induced subjective effects in humans.     

D2-family receptor distribution in human postmortem tissue: an autoradiographic study

The distribution throughout the normal human brain of the dopamine D2-family of receptors were investigated autoradiographically. Three ligands were used, [3H]-YM-09151-2 to define the D2, D3, D4 receptors; [3H]raclopride the D2 D3 receptors; and [3H](+)-7-OH-DPAT, in the presence of GTP, demonstrates D3 distribution. [3H]-YM-09151-2 and [3H]raclopride binding were highest in caudate (121 vs 130 fmol mg(-1)), putamen (96 vs 136 fmol mg(-1)), and nucleus accumbens (113 vs 120 fmol mg(-1)). [3H]-YM-09151-2 also displayed significant binding in several cortical areas (56-39 fmol mg(-1)) and hippocampus (27 fmol mg-1). [3H](+)-7-OH-DPAT was highest in the nucleus accumbens. Based upon the ligands properties it is inferred that D2 distribution is highest in putamen, caudate and nucleus accumbens; D3 in the nucleus accumbens; D4 receptor in cortical areas and hippocampus.     

Synaptic organization of the human striatum: a postmortem ultrastructural study

Converging with psycho-social research findings, animal and human laboratory studies indicate that behavioral alternatives are important determinants of drug-taking. To investigate associations between how early adolescents spend their time, i.e. their behavioral repertoire and drug use (use of marijuana, crack/cocaine or inhalants), we analyzed data from an epidemiological sample of 1516 urban middle-school students who had completed private interviews in spring 1993. The interview included a 36-item questionnaire to assess how frequently the youth engaged in different activities; history of drug-taking was assessed separately. Multiple logistic regression was used to estimate associations between drug use and each of seven behavioral domains as well as sex, age and racial-ethnic status. Youths spending a great deal of time working for pay and assuming other adult-like roles were more likely to have initiated drug use (estimated odds ratio, OR = 3.49; p = 0.002). Those who spent much time in religious activities were less likely (OR = 0.2, p <0.001). An exploratory search for interactions disclosed other associations that merit attention in future research. These results corroborate evidence on the potential etiological significance of behavioral repertoire in relation to risk of drug use.     

Effects of in utero cocaine exposure on the expression of mRNAS encoding the dopamine transporter and the D1, D2 and D5 dopamine receptor subtypes in fetal rhesus monkey

The effects of in utero cocaine exposure on the development of the mRNAs encoding the dopamine transporter (DAT) and the D1, D2 and D5 dopamine receptor subtypes were determined in fetal monkey brains at day 45 and day 60 of gestation. Pregnant monkeys were treated with cocaine 3 mg/kg or saline i.m., four times a day from day 18 of gestation until the pregnancy was terminated at day 45 or day 60. The fetal brains were dissected, and tissue RNA extracted and quantified using ribonuclease protection assay analysis. In day 45 fetal monkeys, dopamine D1 and D2 receptor subtype mRNAs and DAT mRNA were found in low quantities both in control and cocaine-treated subjects. In day 60 fetal monkeys, D1 receptor mRNA levels were highest in the frontal cortex/striatal area, and low to moderate quantities were found in diencephalic and mesencephalic fetal brain regions. Dopamine D2 receptor mRNA levels were highest in the frontal cortex/striatal area, diencephalon and the midbrain, moderate in the brainstem and low in the caudal temporal lobe and surrounding cortical areas. Dopamine D5 receptor mRNA was expressed in low quantities throughout the day 60 fetal monkey brain, whereas DAT mRNA was found in the midbrain only. In utero cocaine exposure caused a significant increase in dopamine D1, D2 and D5 receptor subtype mRNAs in the frontal cortex/striatal area of day 60 fetal monkeys. These results support the hypothesis that dopamine synthesis and release may be reduced in cocaine-treated fetuses, which results in dopamine receptor up-regulation.     

Effects of phencyclidine on immediate early gene expression in the brain

An enzyme-linked immunosorbent assay (ELISA) was developed for sensitive and specific determination of pravastatin (PS) sodium, a HMG-CoA reductase inhibitor. Preparation of immunogens to obtain antisera was carried out using chemically modified PS; beta-alanine derivative of PS (for ELISA-1) and 5-deoxy- PS (for ELISA-2) were linked to bovine serum albumin via its terminal carboxylic acid by the N-succinimidyl ester method, to avoid intramolecular lactonization of PS. Enzyme-labeled antigens were prepared similarly by coupling with horseradish peroxidase, and were used by homogeneous combination of antisera. The enzymic activity was determined using a microtiter plate coated with second antibody and tetramethylbenzidine as a chromogenic substrate. Both of the ELISA systems enabled the determination of PS in a range of 5 to 500 pg/well, with an IC50 of 36 to 130 pg/well. Cross-reactivties with main metabolites in plasma, which differed from PS in decaline moiety, were less than a few percent. When ELISA-1 was applied to the determination of PS in human plasma directly after dilution with the ELISA buffer, the detection limit and the intra-assay coefficient (5 ng/ml of PS) were 500 pg/ml and 4.5%, respectively. Further, ELISA-1 was validated by gas chromatography-mass spectrometry with the determination of PS in human plasma after oral administration at a dose of 10 mg/body.     

In vivo amygdala dopamine levels modulate cocaine self-administration behaviour in the rat: D1 dopamine receptor involvement

Nucleus accumbens dopamine is often hypothesized as the critical factor for modulating cocaine self-administration. In the current study we examined the extent to which dopamine in the amygdala could contribute to cocaine intake behaviour and modify nucleus accumbens dopamine levels. Rats were trained to self-administer intravenous cocaine (1.5 mg/kg/injection) under a fixed-ratio reinforcement schedule in daily 3 h operant training sessions. In the first in vivo microdialysis experiment, extracellular dopamine levels were found to be increased 200% of baseline in the amygdala and by 400% in the nucleus accumbens. Although cocaine induced similar profiles of dopamine overflow in the two mesolimbic areas, in the nucleus accumbens the latency of the dopaminergic response was shorter (three- to four-fold) during both initiation and termination of the cocaine self-administration session than in the amygdala. Despite achieving a stable self-regulated pattern of cocaine intake and high dopamine concentrations in the nucleus accumbens, a unilateral injection of the D1 receptor antagonist SCH 23390 (0.5 or 1.5 microg) into the amygdala was still able to increase the rate of cocaine intake. This behavioural effect was accompanied by a dose-dependent increase in nucleus accumbens dopamine levels; at the highest SCH 23390 concentration cocaine intake was increased by 400% and dopamine levels were potentiated by an additional 400%. In vivo autoradiography using [3H]SCH 23390 showed that D1 receptor sites contributing to the behavioural and subsequent neurochemical effects were predominantly localized to the amygdala and not the nucleus accumbens. Altogether these results point to a significant contribution of in vivo amygdala D1 dopamine transmission to cocaine self-administration behaviour.     

Effects of veratridine and cocaine on the kinetics of synaptosomal dopamine release

The clinical and histological features of 16 patients with a primary cutaneous immunocytoma and 10 patients with a secondary cutaneous immunocytoma are reported. In all cases the diagnosis was based on the presence of monotypic plasma cells or lymphoplasmacytoid cells. Our data show that primary cutaneous immunocytomas are a distinct type of cutaneous lymphoma, characterized by (a) the presence of solitary or localized skin lesions (13 of 16 cases); (b) preferential localization on arms and legs (15 of 16 cases); (c) excellent response to local treatment (15 of 16 cases) and (d) a favourable prognosis. Histologically, these primary cutaneous immunocytomas are characterized by the presence of nodular or diffuse infiltrates with monotypic lymphoplasmacytoid/plasma cells located at the periphery of the infiltrates. Important clinical and histological differences were noted between primary and secondary immunocytomas. In the latter group more widespread skin disease was seen, often in the presence of paraproteins and/or autoimmune diseases. In contrast with the peripheral localization of the monotypic cells in primary cutaneous immunocytomas the monotypic lymphoplasmacytoid/plasma cells in secondary immunocytomas formed diffuse infiltrates or these cells were found dispersed throughout the infiltrate. There were no differences in clinical presentation or course between the different subtypes of cutaneous immunocytomas (lymphoplasmacytic, lymphoplasmacytoid and polymorphic immunocytomas). The differential diagnosis between primary cutaneous immunocytomas and cutaneous plasmacytomas, primary follicular centre cell lymphomas and cutaneous 'pseudolymphomas' is discussed.     

Visualization of the dopamine transporter in the human brain postmortem with the new selective ligand [125I]PE2I

In a genetic screen aimed at the identification of trans-acting factors involved in mRNA 3'-end processing of budding yeast, we have previously isolated two temperature-sensitive mutants with an apparent defect in the 3'-end formation of a plasmid-derived pre-mRNA. Surprisingly, both mutants were rescued by the essential gene ESS1/PTF1 that encoded a putative peptidylprolyl-cis/trans-isomerase (PPIase) (Hani, J., Stumpf, G., and Domdey, H. (1995) FEBS Lett. 365, 198-202). Such enzymes, which catalyze the cis/trans-interconversion of peptide bonds N-terminal of prolines, are suggested to play a role in protein folding or trafficking. Here we report that Ptf1p shows PPIase activity in vitro, displaying an unusual substrate specificity for peptides with phosphorylated serine and threonine residues preceding proline. Both mutations were found to result in amino acid substitutions of highly conserved residues within the PPIase domain, causing a marked decrease in PPIase activity of the mutant enzymes. Our results are suggestive of a so far unknown involvement of a PPIase in mRNA 3'-end formation in Saccharomyces cerevisiae.     

Interferon-gamma inhibition of human thyrotropin receptor gene expression

To evaluate the role of interferon-gamma (IFN gamma) on human thyroid-specific gene expression, the effect of IFN gamma on TSH- and cAMP-induced TSH receptor gene expression was studied using cultured thyroid cells obtained from normal thyroid glands and those from patients with Graves' disease. Incubation of Graves' thyroid cells with 1.0 U/L bovine TSH or 1.0 mM 8-bromo-cAMP resulted in a 2-fold increase in TSH receptor mRNA expression, which was markedly inhibited in the presence of IFN gamma in a dose- and time-dependent manner. This inhibitory effect was completely neutralized by monoclonal antibody against IFN gamma. IFN alpha and -beta had no influence on TSH- and cAMP-stimulated TSH receptor mRNA expression. Paranodular normal thyroid cells showed the same results as those obtained using Graves' thyroid cells. Scatchard analysis of the [125I]TSH binding study showed that IFN gamma inhibited the number of TSH receptors up-regulated by TSH on the cell surface at the low affinity binding site (4.1 vs. 8.2 x 10(5)/cell). These results indicate that IFN gamma suppresses TSH- and cAMP stimulated human TSH receptor gene expression, resulting in a decrease in the number of TSH receptors. In conclusion, IFN gamma interacts via an intermediate pathway of TSH signal transduction and attenuates TSH receptor synthesis in normal and Graves' thyroid cells.     

3H]Neurotensin receptor densities in human postmortem brain tissue obtained from normal and schizophrenic persons. An autoradiographic study

[3H]Neurotensin binding and autoradiographic techniques were used to determine the distribution and density of neurotensin receptors in normal and schizophrenic postmortem brain tissue. Coronal hemi-brain blocks of tissue were cut at the level of the caudate and hippocampus from frozen brain tissue obtained from normal individuals with no known psychiatric or neurologic illnesses and from schizophrenic subjects off- or on-antipsychotic drugs at the time of death. Each hemi-block was further divided, sectioned, thaw mounted on to slides, incubated with [3H]neurotensin and apposed to film. Digitized images were analyzed for binding densities. Areas of intense binding include the substantia nigra, the entorhinal cortex, superficial layers of the cingulate, middle frontal, and insular cortices; and with moderate binding in nucleus accumbens, and caudate. Schizophrenic patients off- (3 months or more) or on-antipsychotic drugs at the time of death were tested; all patients showed a reduced level of neurotensin receptors in the caudate (68% of normals), cingulate (34%) and prefrontal cortices (25%).     

Identification of two novel polymorphisms and a rare deletion variant in the human dopamine D4 receptor gene

PURPOSE: To compare turning by an oscillating bed to standard 2-hour turning. Outcomes were survival, length of stay (LOS), duration of mechanical ventilation, and incidence of pneumonia. METHODS: One hundred and three intensive care patients were randomly assigned to standard turning or turning by an oscillating bed. Data, collected at baseline, daily for 7 days, and then three times weekly until study discharge, included demographics, initial Acute Physiology and Chronic Health Evaluation (APACHE II) score, ventilatory/gas exchange parameters, indicators of pneumonia, nursing measures, and chest roentgenograph. RESULTS: There were no significant differences for LOS, duration of ventilation, nor incidence of pneumonia. Higher survival for subjects on the oscillating bed reached borderline significance (P = .056) for subjects with APACHE II greater than or equal to 20. Longitudinal data were analyzed using the random effects model. No differences in ventilatory or gas exchange parameters were identified. Among subjects who developed pneumonia there was a significantly higher respiratory score (nursing acuity scale) for subjects on the oscillating bed. CONCLUSIONS: In selected critically ill patients oscillating therapy may improve survival and improve airway clearance. The frequency and degree of turning needed to prevent complications and improve outcome remains unclear. These newer beds should be used with discrimination so as to not increase hospital costs unnecessarily.     

Increased sensitivity to the locomotor depressant effect of a dopamine receptor antagonist during cocaine withdrawal in the rat

The effect of a dopamine receptor antagonist on locomotor activity was examined during withdrawal from either self-administered or experimenter-administered cocaine. In the self-administration experiment, the locomotor response to a challenge injection of cis-flupenthixol was assessed in photocell cages at 4 h after the cessation of a 12-h cocaine self-administration session. Rats which had self-administered cocaine, and were challenged with cis-flupenthixol (0.05 mg/kg), were found to be hypoactive relative to controls. In the experimenter-administered cocaine experiment, animals were given eight IP injections of 15 mg/kg cocaine over a 9.5-h period, for a total of 120 mg/kg. At 4, 8, and 24 h (tested in three separate groups of rats) after cessation of the eight injections, the locomotor response to a challenge injection of saline or cis-flupenthixol was tested. Cocaine-treated animals displayed a dose-dependent, heightened sensitivity to the locomotor depressant effects of 0.05 mg/kg and 0.2 mg/kg cis-flupenthixol 4 h post-cocaine, whereas they did not show increased sensitivity to 0.05 mg/kg cis-flupenthixol 8 or 24 h post-cocaine. However, cocaine-treated animals displayed a mild hypoactivity 8 h post-cocaine. In a separate group of animals, a dose-response experiment was performed which indicated that a dose of cis-flupenthixol as high as 0.2 mg/kg was required to produce locomotor depression in cocaine-naive rats. The results of this study support clinical observations of dopamine antagonist-precipitated motor dysfunction in abstinent cocaine abusers, and lend further support to the hypothesis that alterations in dopaminergic neurotransmission consequent to prolonged cocaine exposure are partly responsible for some of the symptoms of cocaine withdrawal.     

Direct determination of dopamine D4 receptors in normal and schizophrenic postmortem brain tissue: a [3H]NGD-94-1 study

Normal speed videography was used to determine the angular parameters of 28 Spanish Thoroughbreds at trot. Horses were divided into 3 groups: Group UT, comprising 9 animals (provided by the VII National Stud, Cordoba, Spain) which had undergone no specific training programme and which were hand led at the trot; Group T, formed by 19 horses considered to be highly bred and trained, and which were also hand led; and Group RT, comprising the same horses as the latter group but this time trotted by a rider. Each animal was filmed 6 times from the right-hand side, using a Hi8 (25 Hz) video camera. Angular parameters for fore- and hindlimb joints were measured in each stride from computer-grabbed frames and entered into a spreadsheet for calculation; parameters included maximum and minimum angles, range of motion, and angles at landing, lift off and maximum hoof height; the times at which maximum angle, minimum angle, lift off and maximum hoof height occurred were calculated as percentages of total stride duration. Stride velocity (mean [s.d.]) was 4.01 (0.62), 3.60 (0.34) and 3.07 (0.36) m/s for Groups UT, T and RT, respectively. Data were then compared between Groups UT-T and Groups T-RT. Compared with Group UT, horses from Group T featured a shorter stance percentage (P<0.001) in both fore- and hindlimbs. The range of motion in forelimbs was smaller (P<0.05), due to lower retraction (P<0.001); moreover, maximum retraction appeared earlier (P<0.05). Greater scapular inclination was in evidence (P<0.05) and the shoulder joint extended further (P<0.05). Fore- and hind fetlock joints revealed a relatively shorter hyperextension period during the stance phase (P<0.01). Compared with Group T, horses from Group RT had a longer stance percentage, with belated maximum retraction of the fore- and hindlimbs. The range of movement in scapular inclination was greater (P<0.05), due to a smaller minimum angle (P<0.01), and the shoulder joint flexed more (P<0.05). The elbow joint extended more and for longer during the stance phase. Initial extension of the hip joint (P<0.05) and tarsus (P<0.001) lasted longer. The carpal and fore and hind fetlock joints recorded relatively longer hyperextension times, in addition to greater hyperextension during the stance phase. The results from the present study suggest that rider-effect must be taken in consideration when well gaited horses are selected for dressage purposes.     

A comparative study of postmortem MR imaging and pathological examination of human brain specimens

OBJECTIVE: To determine typical outcome "benchmarks" for 18 functional tasks in patients undergoing stroke rehabilitation. The benchmarks are intended to serve as points of reference to which the outcomes of patients with similar impairments and degrees of disability can be compared. SUBJECTS: Records from 26,339 stroke patients discharged from 252 inpatient facilities across the United States that submitted 1992 data to the Uniform Data System for Medical Rehabilitation. METHODS: Stroke impairment was detailed as the presence or absence of hemiparesis resulting from stroke and the side(s) of involvement. Within each of five stroke impairment categories, patients were further classified by the Functional Independence Measure-Function-Related Groups (FIM-FRGs) into nine syndromes by degree of disability (admission motor and cognitive FIM scores) and by age. Outcomes were determined for each stroke syndrome at patients' discharge from medical rehabilitation. MAIN OUTCOME MEASURES: Patients' median performance levels on each of the 18 items making up the FIM, length of stay, and community discharge rates. RESULTS: The majority of patients whose admission motor FIM scores were above 37 were able to eat, groom, dress the upper body, and manage bladder and bowel functions independently by discharge. In addition to these tasks, most of those whose motor FIM scores were above 55 were able to dress the lower body, bathe, and transfer onto a chair/bed or toilet. The majority of patients whose initial motor FIM scores were above 62 points and whose cognitive FIM scores were above 30 gained independence in most tasks, including stair climbing and tub transfers. Community discharge rates ranged from 51.6% for the group of patients with the most severe disabilities to 99.2% for the group with the least severe disabilities. CONCLUSION: The clinician can apply these benchmarks to guideline development and quality improvement, and in establishing patient goals.     

Association study between schizophrenia and dopamine D3 receptor gene polymorphism

Crocq et al. [1992: J Med Genet 29:858-860] reported the existence of an association between schizophrenia and homozygosity of a BalI polymorphism in the first exon of the dopamine D3 receptor (DRD3) gene. In response to this report, further studies were conducted; however, these studies yielded conflicting results. In the present study, we examined 100 unrelated Japanese schizophrenics and 100 normal controls to determine any association between this polymorphism and schizophrenia. Results suggest that neither allele nor genotype frequencies of the DRD3 gene in the schizophrenics as a whole are significantly different from those of the controls. Further, we found no association between any allele or genotype and any clinical subtype based on family history of schizophrenia and age-at-onset. A significantly high frequency of homozygosity of a dopamine D3 receptor gene allele was not observed in the schizophrenics as a whole, or in clinical subtypes. Our results suggest that an association between the dopamine D3 receptor gene and schizophrenia is unlikely to exist.     

Acute effects of cocaine on human brain activity and emotion

We investigated brain circuitry mediating cocaine-induced euphoria and craving using functional MRI (fMRI). During double-blind cocaine (0.6 mg/kg) and saline infusions in cocaine-dependent subjects, the entire brain was imaged for 5 min before and 13 min after infusion while subjects rated scales for rush, high, low, and craving. Cocaine induced focal signal increases in nucleus accumbens/subcallosal cortex (NAc/SCC), caudate, putamen, basal forebrain, thalamus, insula, hippocampus, parahippocampal gyrus, cingulate, lateral prefrontal and temporal cortices, parietal cortex, striate/extrastriate cortices, ventral tegmentum, and pons and produced signal decreases in amygdala, temporal pole, and medial frontal cortex. Saline produced few positive or negative activations, which were localized to lateral prefrontal cortex and temporo-occipital cortex. Subjects who underwent repeat studies showed good replication of the regional fMRI activation pattern following cocaine and saline infusions, with activations on saline retest that might reflect expectancy. Brain regions that exhibited early and short duration signal maxima showed a higher correlation with rush ratings. These included the ventral tegmentum, pons, basal forebrain, caudate, cingulate, and most regions of lateral prefrontal cortex. In contrast, regions that demonstrated early but sustained signal maxima were more correlated with craving than with rush ratings; such regions included the NAc/SCC, right parahippocampal gyrus, and some regions of lateral prefrontal cortex. Sustained negative signal change was noted in the amygdala, which correlated with craving ratings. Our data demonstrate the ability of fMRI to map dynamic patterns of brain activation following cocaine infusion in cocaine-dependent subjects and provide evidence of dynamically changing brain networks associated with cocaine-induced euphoria and cocaine-induced craving.