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PubMed2001

Evaluation of dopamine D-2 receptor occupancy by clozapine, risperidone, and haloperidol in vivo in the rodent and nonhuman primate brain using 18F-fallypride.

We have used the high-affinity dopamine D-2 receptor radioligand, 18F-fallypride for evaluating receptor occupancy by the antipsychotic drugs, clozapine, risperidone, and haloperidol in rodents and nonhuman primates. In rodents, clozapine (0.1 mg/kg to 100 mg/kg) competed with 18F-fallypride at all the doses administered. At doses over 40 mg/kg, clozapine was able to displace all the administered 18F-fallypride. A pseudobiphasic profile of receptor occupancy by clozapine was observed. This behavior was compared with such other neuroleptics as risperidone and haloperidol that exhibited over 90% receptor occupancy at doses over 0.1 mg/kg and did not exhibit a biphasic nature. Dopamine D-2 receptor occupancy in the monkeys was studied using positron emission tomography (PET) after acute subcutaneous doses of the various drugs. At therapeutically relevant doses, clozapine, risperidone, and haloperidol were able to compete significantly with the binding of 18F-fallypride in all brain regions in rhesus monkeys, and our analyses indicate that these drugs (clozapine, risperidone, and haloperidol) do not discriminate between the striatal (caudate and putamen) and the extrastriatal (thalamus and cortical regions) dopamine receptors. The following extent of D-2 receptor occupancies were measured in the monkey brain using PET: clozapine approximately 70% (dose of 9.7 mg/kg), risperidone approximately 75% (0.05 mg/kg), and haloperidol approximately 90% (0.05 mg/kg).

Animals↗
PubMedDate not supplied

Studies of hypercholesterolemia in the nonhuman primate. I. Changes that lead to fatty streak formation.

Morphologic studies resulting from events that occur during the development of the lesions of atherosclerosis were studied in chronic, diet-induced hypercholesterolemia in a series of nonhuman primates. Within 12 days of hypercholesterolemia in Macaca nemestrina, monocytes became adherent to the surface of the endothelium. These monocytes appeared to migrate subendothelially, accumulate lipid, and become lipid-laden macrophages (foam cells). Within a month, a "serofibrinous insudate" formed together with variable numbers of subendothelial lipid-laden macrophages. By the second month, foam cells increased in number, often in multilayers, to form a fatty streak. Concomitantly, the luminal surface of the arteries became increasingly irregular due to the subendothelial accumulation of foam cells. Numerous monocytes continued to attach to the endothelial surface over the fatty streaks, and many of them appeared to enter the intima and participate in the growth of the fatty streaks. Lipid-laden smooth muscle cells appeared in small numbers and formed two to four layers between the macrophages and the internal elastic lamella at 2 to 3 months. During the third month of hypercholesterolemia, endothelial cell continuity over the lipid-laden macrophages became interrupted, exposing the underlying foam cells to circulating blood. Foam cells were then readily observed in whole blood smears, suggesting that many of the lipid-laden macrophages leave the intima and enter the circulation. After 4 months, significant endothelial denudation was found in the iliac artery and many exposed macrophages were covered by adherent platelets in the form of a mural thrombus. Thus, the early components of atherosclerosis induced by chronic hypercholesterolemia centered around the monocyte-macrophage and its interaction with endothelium in the induction of the fatty streak. Subsequent changes that lead to macrophage-smooth muscle interactions, platelet-macrophage interactions, and platelet-endothelial interactions appeared to set the stage for the development of more advanced proliferative lesions.

Animals↗
PubMed2004

Fetal immune suppression as adjunctive therapy for in utero hematopoietic stem cell transplantation in nonhuman primates.

In utero hematopoietic stem cell transplantation could potentially be used to treat many genetic diseases but rarely has been successful except in severe immunodeficiency syndromes. We explored two ways to potentially increase chimerism in a nonhuman primate model: (a) fetal immune suppression at the time of transplantation and (b) postnatal donor stem cell infusion. Fetal Macaca nemestrina treated with a combination of the corticosteroid betamethasone (0.9 mg/kg) and rabbit thymoglobulin (ATG; 50 mg/kg) were given haploidentical, marrow-derived, CD34+ -enriched donor cells. Animals treated postnatally received either donor-derived T cell-depleted or CD34+ -enriched marrow cells. Chimerism was determined by traditional and real-time polymerase chain reaction from marrow, marrow progenitors, peripheral blood, and mature peripheral blood progeny. After birth, the level of chimerism in the progenitor population was higher in the immune-suppressed animals relative to controls (11.3% +/- 2.7% and 5.1% +/- 1.5%, respectively; p = .057). Chimerism remained significantly elevated in both marrow (p = .02) and fluorescence-activated cell sorted and purified CD34+ cells (p = .01) relative to control animals at > or = 14 months of age. Peripheral blood chimerism, both at birth and long term, was similar in immune-suppressed and control animals. In the animals receiving postnatal donor cell infusions, there was an initial increase in progenitor chimerism; however, at 6-month follow-up, the level of chimerism was unchanged from the preinfusion values. Although fetal immune suppression was associated with an increase in the level of progenitor and marrow chimerism, the total contribution to marrow and the levels of mature donor progeny in the peripheral blood remained low. The level of long-term chimerism also was not improved with postnatal donor cell infusion.

Animals↗
PubMed1991

Extrapyramidal syndromes in nonhuman primates: typical and atypical neuroleptics.

The traditional (typical) neuroleptic drugs produce acute extrapyramidal symptoms (EPS) in the majority of patients, whereas the atypical neuroleptics produce only minimal motor system side effects. Studies of acute dystonia in nonhuman primates with typical (haloperidol, fluphenazine), atypical (clozapine), and putative novel antipsychotic compounds with low EPS (remoxipride, melperone) were conducted across a wide dose range in double-blind, placebo-controlled trials. Haloperidol and fluphenazine caused dystonia, and clozapine did not. Remoxipride and melperone also produced dystonia, but remoxipride only did so at doses that were higher than needed for antipsychotic efficacy. Melperone produced dystonia in doses that are in the antipsychotic dose range. The clinical relevance of the findings is discussed.

Animals↗
PubMed1990

Histologic, morphometric, and biochemical evolution of vein bypass grafts in a nonhuman primate model. I. Sequential changes within the first three months.

The objective of this study was to define the histologic and morphometric evolution that accompanies the increase in cholesterol content of vein bypass grafts in a nonhuman primate model. Cephalic vein grafts were interposed bilaterally in the femoral arteries of 15 stump-tailed macaque monkeys (Macaca arctoides), which were fed a diet that sustains plasma cholesterol levels of approximately 225 mg/dl. Grafts were excised from five animals for analysis on each of postoperative days 3, 7, 14, 30, 60, and 90. Cholesterol content increased from 69 +/- 24 micrograms/100 mg (mean +/- standard deviation) in ungrafted vein to 473 +/- 122 micrograms/100 mg in grafts 90 days after implantation (p less than 0.05). By stepwise regression analysis, cholesterol content was best predicted by abundance of foam cells (r2 = 0.82). Intima comprised 13% +/- 5% of the total cross-sectional area of the wall in ungrafted vein and 59% +/- 11% at day 90 (p less than 0.001). With cholesterol content excluded from the stepwise regression, intimal area was best predicted by the presence of foam cells (r2 = 0.39). There was consistently an increase in the prevalence of polymorphonuclear leukocytes on the luminal surface and in both the intima and media during the first 14 days after grafting. Vasa vasorum, which were always present in ungrafted vein, were sparse at 3 days but reappeared by day 7. Medial fibrosis occurred in grafts, and in the 30- to 90-day interval it was directly correlated with the number of adventitial vasa vasorum present (r = 0.64, p less than 0.05). Immunohistochemistry revealed prominent staining for both platelet factor VIII and fibronectin during the first month, with a gradual decline in staining intensity thereafter. The evolution of changes in vein bypass grafts documented in this report are in general agreement with graft changes observed in humans and support the validity of our model in evaluating the histologic correlates of increased graft cholesterol content.

Animals↗
PubMed2002

Molecular evolution of IgG subclass among nonhuman primates: implication of differences in antigenic determinants among Apes.

The cross-reactivity of five different rabbit polyclonal antibodies to human IgG and IgG subclass (IgG1, IgG2, IgG3, and IgG4) was determined by competitive ELISA with nine nonhuman primate species including five apes, three Old World monkeys, and one New World monkey. As similar to those previously reported, the reactivity of anti-human IgG antibody with plasma from different primate species was closely related with phylogenic distance from human. Every anti-human IgG subclass antibody showed low cross-reactivity with plasma from Old World and New World monkeys. The plasma from all apes except for gibbons (Hylobates spp.) showed 60 to 100% of cross-reactivity with anti-human IgG2 and IgG3 antibodies. On the other hand, chimpanzee (Pan troglodytes and Pan paniscus) and orangutan (Pongo pygmaeus) plasma showed 100% cross-reactivity with anti-human IgG1 antibody, but gorilla (Gorilla gorilla) and gibbon plasma showed no cross-reactivity. The chimpanzee and gorilla plasma cross-reacted with anti-human IgG4 antibody at different reactivity, 100% in chimpanzee and 50% in gorilla, but no cross-reactivity was observed in orangutan and gibbon plasma. These results suggest the possibilities that the divergence of "human-type" IgG subclasses might occur at the time of divergence of Homo sapience from Hylobatidae, and that the molecular evolution of IgG1 as well as IgG4 is different from that of IgG2 and IgG3 in great apes, this is probably caused by different in development of immune function in apes during the course of evolution.

Animals↗
PubMed1990

Detection of the ovulatory-luteinizing hormone surge with an enzyme-linked immunospecific human urinary luteinizing hormone assay: applicability to nonhuman primates.

Heterologous antibodies have frequently been used to develop assays in other species. Human urinary LH kits, widely available for predicting the LH surge, offer a unique opportunity to determine the timing of ovulation and mating in nonhuman primates. We tested three commercially available ovulation predictor kits for utility in two macaque species. Midfollicular, midcycle, and castrate urines and their corresponding serum samples were assessed for LH activity using established RIAs as well as urinary ovulation kits. Macaque LH did not sufficiently cross-react with the human urinary anti-LH antibodies in any of the predictor test kits. Although these kits offer excellent results in predicting ovulation by measurement of urinary LH in humans, they appear not to be applicable for urinary LH detection in rhesus nor cynomolgus macaques.

Animals↗
PubMed1992

Cognitive and behavioral deficits in nonhuman primates associated with very early embryonic binge exposures to ethanol.

This study was undertaken to evaluate teratogenesis associated with early weekly ethanol exposure followed by later gestational abstinence. Ethanol, 1.8 gm/kg, was orally administered weekly to gravid nonhuman primates (Macaca nemestrina) for the first 3, 6, or the entire 24 weeks of pregnancy. Control animals received weekly sucrose solution as did the 3- and 6-week cohort animals in subsequent weeks. Thirty-five viable infants were assessed for growth, malformations, and behavioral and cognitive dysfunction. Animals in the 6-week and 24-week cohorts were uniformly abnormal in behavior and inconsistently abnormal in physical development relative to the control animals. Animals in the 3-week cohort were equivocally normal. These results demonstrate ethanol's capacity to produce behavioral teratogenesis (brain dysfunction) in isolation from physical anomalies in the rest of the body. The results strongly suggest that binge drinking in the first 6 to 8 weeks of pregnancy (a period when women may not know that they are pregnant), followed by later gestational abstinence, is as dangerous to the fetus as exposure throughout gestation.

Abnormalities, Drug-Induced↗
PubMed2002

Porcine endogenous retrovirus infects but does not replicate in nonhuman primate primary cells and cell lines.

Porcine endogenous retroviruses (PERV) can infect human cell lines in vitro; hence, there is a presumed risk of viral exposure to a recipient when pig cells are transplanted into humans (xenotransplantation). Nonhuman primates (NHP) are considered a potential permissive animal model to study the risk of in vivo infection of PERV after xenotransplantation. We set out to determine whether PERV can infect and replicate in NHP primary cells or established cell lines from African green monkey, rhesus macaque, and baboon. We confirm that the NHP cell lines under investigation were infected with PERV as measured by detection of viral DNA and RNA by PCR and reverse transcription (RT)-PCR, respectively, indicating that a functional receptor must be present on the cell surface. However, the load of detectable viral DNA in infected NHP cells declined over time, and the cells never had detectable reverse transcriptase activity. Utilizing quantitative real-time TaqMan PCR we found detectable levels of unintegrated DNA intermediates, but the levels were approximately 100-fold lower compared to HEK 293 cells infected with PERV. Virions released from infected NHP cells could productively infect naïve human cell lines, HEK 293 and HeLa, as shown by RT-PCR and RT assay. However, naïve NHP cells remained negative in RT-PCR and RT assay after exposure to virions from infected NHP cells. Together our data demonstrate that NHP cells are not permissive to productive replication by PERV, presumably due to inefficient cell entry and replication. In light of these observations, the appropriateness of NHP as suitable animal models to study PERV infection in vivo needs to be reevaluated.

Animals↗
PubMed1995

Inoculation of nonhuman primates with the N40 strain of Borrelia burgdorferi leads to a model of Lyme neuroborreliosis faithful to the human disease.

We injected rhesus macaques with a highly infective strain of Borrelia burgdorferi to assess whether experimentally inoculated nonhuman primates (NHPs) could serve as models of human Lyme neuroborreliosis (LNB). The animals developed biopsy-confirmed erythema migrans in the area of the inoculations. ELISA testing of sera revealed strong antibody reactivity to B burgdorferi antigens, and Western blotting showed that 16-, 22-, 31-, 34-, and 41-kd proteins of the spirochete were major antigens recognized by antibody. Culture and polymerase chain reaction (PCR) testing of serial CSF specimens revealed that chronic infection of the CNS occurred in all NHPs injected. CSF pleocytosis occurred concurrently with CNS infection. Brain MRI revealed intense meningeal inflammation in one NHP as manifested by gadolinium uptake by the dura at the base of the temporal lobes. All animals had measurable antibody in the CSF after invasion. These studies are the first to demonstrate that experimental LNB in NHPs is a reliable model faithful to the human disease, with spirochetal invasion of the subarachnoid space. This also is the first report of CSF samples positive by culture in experimental LNB. Inflammation in the CNS as manifested by CSF pleocytosis and MRI findings was also correlated with the presence of spirochetal DNA detected by PCR. These data support the hypothesis that the pathogenesis of LNB is associated with direct spirochetal invasion, and provide evidence that CNS involvement is more common than heretofore thought.

Animals↗
PubMed1983

1H NMR studies of lymph chylomicra and very low density lipoproteins from nonhuman primates.

1H NMR spectroscopy at 200 MHz was used to study triglyceride crystalline leads to liquid transitions which occurred on heating between 10 and 50 degrees C in very low density lipoprotein and subfractionated chylomicron particles from nonhuman primates fed a saturated fat (butter fat) diet. Model system studies of pure triglycerides (triolein, tripalmitin and a 1:1 mixture) and emulsion particles consisting of these triglycerides with a surface of egg phosphatidylcholine showed that high resolution spectra were obtained only from liquid triglycerides. In lipoprotein spectra, changes in 1H NMR peak intensities and line widths accompanied the solid leads to liquid transition of the constituent triglycerides. Peak areas of fatty acyl resonances were proportional to the percentage of melted triglyceride determined by differential scanning calorimetry. NMR peak area measurements showed that the calorimetric transition involved the melting of relatively greater numbers of saturated fatty acyl chains than unsaturated chains; at temperatures well below the solid leads to liquid transition, the lipoproteins contained a significant fraction (approximately 33%) of liquid triglycerides which were relatively enriched in unsaturated fatty acyl chains. For model systems containing mixtures of solid and liquid triglycerides, the temperature dependence of line widths of fatty acyl resonances demonstrated that solid triglycerides decreased the mobility of the liquid triglycerides. A similar temperature dependence for the lipoprotein resonances suggested that solid and liquid species are co-mixed in individual lipoprotein particles within a purified subfraction. Temperature-dependent line width and intensity changes were observed for the phospholipid-choline methyl resonance in lipoprotein spectra and were apparently independent of the core transition.

Animals↗
PubMed2001

Treatment with the humanized CD154-specific monoclonal antibody, hu5C8, prevents acute rejection of primary skin allografts in nonhuman primates.

BACKGROUND: Allogeneic skin transplantation remains a rigorous test of any immune intervention designed to prevent allograft rejection. To date, no single, clinically available immunosuppressant has been reported to induce long-term primary skin allograft survival in primates. We have previously shown that treatment with the humanized CD154-specific monoclonal antibody, humanized 5C8 (hu5C8), induces long-term renal allograft survival in nonhuman primates. In this study, we evaluated the efficacy of hu5C8 in preventing primary skin allograft rejection in rhesus monkeys. METHODS: Ten rhesus monkeys were transplanted with full-thickness skin allografts mismatched at both class I and class II major histocompatibility loci. Of these, two were given no treatment, five were treated with hu5C8 alone, and three received hu5C8 combined with whole blood donor-specific transfusion (DST). All recipients also received skin autografts for comparison. Animals were followed by inspection, serial biopsy, mixed lymphocyte culture, and alloantibody determination. RESULTS: Treatment with hu5C8 alone or hu5C8 plus DST greatly prolonged allograft survival. Rejection occurred in the untreated group within 7 days. Mean allograft survival in the monotherapy hu5C8 group was >236 days and in the DST group was >202 days; these differences were not significant. Rejection eventually occurred in most animals. Allograft survival was not correlated with the development of T cell hyporesponsiveness in mixed lymphocyte culture. Rejection was not predicted by the development of donor-specific alloantibody. CONCLUSION: These results show that treatment with the CD154-specific monoclonal antibody, hu5C8, greatly delays the onset of acute skin allograft rejection.

Acute Disease↗
PubMed1992

Amphetamine-stimulated dopamine release competes in vivo for [123I]IBZM binding to the D2 receptor in nonhuman primates.

We used the reversibly binding D2 dopamine receptor radioligand [123I]IBZM (iodobenzamide) to test whether the endogenous neurotransmitter dopamine competes in vivo for radiotracer binding measured with single photon emission computed tomography (SPECT). In a series of nonhuman primate experiments (n = 27), the effects of temperature, amphetamine, haloperidol, and reserpine on brain uptake of [123I]IBZM were measured. Specific brain uptake of [123I]IBZM reached a peak by 100 min postinjection of radioligand and demonstrated a gradual, apparent "steady-state" washout over the next 2 hr. Brain uptake was temperature dependent, with rates of washout of specifically bound radioligand greater under normothermic conditions (26%/hr: core body temperature 35-37 degrees C) than under conditions of controlled hypothermia (11%/hr; 32-34 degrees C). Given the greater retention of radioactivity, low-temperature conditions were used in all other experiments. Administration of haloperidol (0.02 mg/kg IV) during the period of apparent steady state resulted in a dramatic increase in washout (60%/hr; p less than 0.0001), consistent with its potent D2 receptor antagonist properties. d-Amphetamine (1.0 mg/kg IV), which has negligible affinity for the D2 receptor but mediates the release of endogenous stores of dopamine, also enhanced washout (34%/hr; p less than 0.0005). Reserpine pretreatment at doses (1.0 mg/kg) sufficient to cause greater than 90% depletion of striatal dopamine levels blocked this amphetamine-enhanced washout (10%/hr; p less than 0.05). Reserpine did not block the increased washout induced by the direct-acting D2 receptor antagonist haloperidol. These results are consistent with the hypothesis that endogenous dopamine may effectively compete for radioligand binding in vivo in neuroreceptor imaging studies using PET and SPECT.

Animals↗
PubMed1979

Transmission of Sarcocystis suihominis from humans to swine to nonhuman primates (Pan troglodytes, Macaca mulatta, Macaca irus).

Sporocysts of Sarcocystis suihominis obtained from human feces were used to infect swine. Heart, tongue, and skeletal muscle from experimentally infected and noninfected control swine were fed via stomach tube to nonhuman primates including chimpanzees (Pan troglodytes), rhesus monkeys (Macaca mulatta), and cynomolgus monkeys (Macaca irus). All primates fed infected swine tissues shed sporocysts beginning 13 to 15 days postinfection and were still shedding sporocysts at the conclusion of the experiment, 30 days postinfection. Rhesus and cynomolgus monkeys were fed infected swine tissues a second time and shed sporocysts. All primates remained in good health throughout both experiments and exhibited no unusual clinical signs as a result of infection.

Animals↗
PubMed2006

Old world nonhuman primate models of type 2 diabetes mellitus.

Type 2 diabetes mellitus is a major health problem of increasing incidence. To better study the pathogenesis and potential therapeutic agents for this disease, appropriate animal models are needed. Old World nonhuman primates (NHPs) are a useful animal model of type 2 diabetes; like humans, the disease is most common in older, obese animals. Before developing overt diabetes, NHPs have a period of obesity-associated insulin resistance that is initially met with compensatory insulin secretion. When either a relative or absolute deficiency in pancreatic insulin production occurs, fasting glucose concentrations begin to increase and diabetic signs become apparent. Pathological changes in pancreatic islets are also similar to those seen in human diabetics. Initially there is hyperplasia of the islets with abundant insulin production typically followed by replacement of islets with islet-associated amyloid. Diabetic NHPs have detrimental changes in plasma lipid and lipoprotein concentrations, lipoprotein composition, and glycation, which may contribute to progression of atherosclerosis. As both the prediabetic condition (similar to metabolic syndrome in humans) and overt diabetes become better defined in monkeys, their use in pharmacological studies is increasing. Likely due to their genetic similarity to humans and the similar characteristics of the disease in NHPs, NHPs have been used to study recently developed agonists of the peroxisome proliferators-activated receptors. Importantly, agonists of the different receptor subclasses elicit similar responses in both humans and NHPs. Thus, Old World NHPs are a valuable animal model of type 2 diabetes to study disease progression, associated risk factors, and potential new treatments.

Animals↗
PubMed1991

Transmission of retroviral infection by transfusion of seronegative blood in nonhuman primates.

Techniques such as polyclonal B cell activation with pokeweed mitogen (PWM) and polymerase chain reaction (PCR) analysis have documented the existence of simian immunodeficiency virus (SIV)-and human immunodeficiency virus type 1-seronegative but infected humans and nonhuman primates. To establish whether blood from such seronegative but PWM- and PCR-positive monkeys can transmit infection, naive macaques were transfused with whole blood (n = 2) or cultured cells and supernatant fluid (n = 2) from two seronegative but PWM- and PCR-positive sooty mangabeys. After transfusion, three of the four recipients seroconverted, and peripheral blood mononuclear cells from all four recipients secreted SIV-reactive antibodies upon polyclonal activation in vitro and were SIV-positive by PCR that used highly specific gag primer pairs and probe. In addition, CD8+ cells from all four recipients markedly inhibited replication of SIV in autologous cells in vitro. These data suggest caution in the sole use of serologic tests for the detection of retroviral infection and document the ability of such blood samples to transmit infection.

Animals↗
PubMed2006

Noninvasive molecular imaging to detect transgene expression of lentiviral vector in nonhuman primates.

UNLABELLED: Noninvasive imaging of a reporter gene is a new and promising technique to quantify transgene expression after gene therapy. This study was performed to demonstrate visualization of lentiviral-marked cells by PET. METHODS: We transduced nonhuman primate CD34+ hematopoietic cells with a lentiviral vector expressing a PET reporter gene, the mutant viral herpes simplex virus type 1-thymidine kinase (HSV1-sr39tk) gene. 1-(2-Fluoro-2-deoxy-beta-D-arabinofuranosyl)-76Br-5-bromouracil (76Br-FBAU) was used as the substrate for the viral tk enzyme. Upon phosphorylation, 76Br-FBAU was retained by cells and imaged by PET. The long half-life of 76Br, 16.2 h, permitted us to perform extended pharmacokinetic and imaging studies. RESULTS: 76Br-FBAU was retained in vascular tissues of the animals with transplanted tk lentiviral vector-transduced CD34+ cells. Elimination of 76Br-FBAU was through renal and hepatic excretion. CONCLUSION: Noninvasive molecular imaging using PET will help us, in the future, to define the contribution and distribution of cells and their progeny to tissue repair and development.

Animals↗
PubMed2004

The expanding effects of cocaine: studies in a nonhuman primate model of cocaine self-administration.

Although neuroimaging investigations in human cocaine abusers have provided important insights into the brain changes that accompany drug use, the interpretation of reports in human abusers can be very difficult. Studies in nonhuman primates provide a way to systematically evaluate the structural and functional adaptations engendered by cocaine self-administration without the confounds of human research. Functional activity, measured with metabolic mapping methods, and markers of the dopamine system, assessed autoradiographically, were evaluated over the course of chronic cocaine self-administration (5 days, 3.3 months, and 15-22 months). Within the striatum the topography of these responses shifts dramatically over time. Changes in functional activity and alterations in the dopamine system occupy larger and larger portions of dorsal and ventral striatum with increasing durations of cocaine exposure. The growing impact of cocaine suggests that the elements of the behavioral repertoire outside of the influence of cocaine become smaller and smaller with increasing durations of exposure to drug use resulting in cocaine's dominance over all aspects of the addict's life.

Anesthetics, Local↗