Dopamine Reuptake Inhibitor Bupropion Research Articles

Physiologically Based Pharmacokinetic Modeling of Bupropion and Its Metabolites in a CYP2B6 Drug-Drug-Gene Interaction Network.

The noradrenaline and dopamine reuptake inhibitor bupropion is metabolized by CYP2B6 and recommended by the FDA as the only sensitive substrate for clinical CYP2B6 drug–drug interaction (DDI) studies. The aim of this study was to build a whole-body physiologically based pharmacokinetic (PBPK) model of bupropion including its DDI-relevant metabolites, and to qualify the model using clinical drug–gene interaction (DGI) and DDI data. The model was built in PK-Sim® applying clinical data of 67 studies. It incorporates CYP2B6-mediated hydroxylation of bupropion, metabolism via CYP2C19 and 11β-HSD, as well as binding to pharmacological targets. The impact of CYP2B6 polymorphisms is described for normal, poor, intermediate, and rapid metabolizers, with various allele combinations of the genetic variants CYP2B6*1, *4, *5 and *6. DDI model performance was evaluated by prediction of clinical studies with rifampicin (CYP2B6 and CYP2C19 inducer), fluvoxamine (CYP2C19 inhibitor) and voriconazole (CYP2B6 and CYP2C19 inhibitor). Model performance quantification showed 20/20 DGI ratios of hydroxybupropion to bupropion AUC ratios (DGI AUCHBup/Bup ratios), 12/13 DDI AUCHBup/Bup ratios, and 7/7 DDGI AUCHBup/Bup ratios within 2-fold of observed values. The developed model is freely available in the Open Systems Pharmacology model repository.

Dopamine mediates life-history responses to food abundance in Daphnia

Expression of adaptive reaction norms of life-history traits to spatio-temporal variation in food availability is crucial for individual fitness. Yet little is known about the neural signalling mechanisms underlying these reaction norms. Previous studies suggest a role for the dopamine system in regulating behavioural and morphological responses to food across a wide range of taxa. We tested whether this neural signalling system also regulates life-history reaction norms by exposing the zooplankton Daphnia magna to both dopamine and the dopamine reuptake inhibitor bupropion, an antidepressant that enters aquatic environments via various pathways. We recorded a range of life-history traits across two food levels. Both treatments induced changes to the life-history reaction norm slopes. These were due to the effects of the treatments being more pronounced at restricted food ration, where controls had lower somatic growth rates, higher age and larger size at maturation. This translated into a higher population growth rate (r) of dopamine and bupropion treatments when food was restricted. Our findings show that the dopamine system is an important regulatory mechanism underlying life-history trait responses to food abundance and that bupropion can strongly influence the life history of aquatic species such as D. magna. We discuss why D. magna do not evolve towards higher endogenous dopamine levels despite the apparent fitness benefits.

Hyperactive behavioral phenotypes and an altered brain monoaminergic state in male offspring mice with perinatal hypothyroidism.

Thyroid hormone (TH) is essential for normal brain development. TH insufficiency during early stages of development may increase the risk for attention deficit/hyperactivity disorder, in which malfunction of brain monoaminergic systems is likely involved. However, little is known about the effects of perinatal hypothyroidism on behaviors and brain monoaminergic systems in offspring mice. The present study examined in mice (1) whether perinatal hypothyroidism causes hyperactive behavioral phenotypes, (2) how perinatal hypothyroidism influences brain monoaminergic systems, and (3) whether hyperactive behavioral phenotypes are associated with the state of brain monoaminergic systems. When dams were exposed to propylthiouracil, offspring mice developed hypothyroidism during the perinatal period. Offspring mice with perinatal hypothyroidism exhibited hyperactive behavioral phenotypes such as hyper-ambulatory activity and an increased response rate in the two-way active avoidance test in a male-specific manner. Significant decreases in dopamine (DA) and serotonin turnover were observed in the striatum (ST), nucleus accumbens, hypothalamus, and hippocampus in male mice with perinatal hypothyroidism. A significant correlation between ambulatory activity and DA turnover in the ST and an augmented ambulatory response to the DA reuptake inhibitor bupropion suggested that DA in the ST was involved in the hyper-ambulatory activity in mice with perinatal hypothyroidism.

Mechanisms underlying the endogenous dopaminergic inhibition of spinal locomotor circuit function in Xenopus tadpoles.

Dopamine plays important roles in the development and modulation of motor control circuits. Here we show that dopamine exerts potent effects on the central pattern generator circuit controlling locomotory swimming in post-embryonic Xenopus tadpoles. Dopamine (0.5–100 μM) reduced fictive swim bout occurrence and caused both spontaneous and evoked episodes to become shorter, slower and weaker. The D2-like receptor agonist quinpirole mimicked this repertoire of inhibitory effects on swimming, whilst the D4 receptor antagonist, L745,870, had the opposite effects. The dopamine reuptake inhibitor bupropion potently inhibited fictive swimming, demonstrating that dopamine constitutes an endogenous modulatory system. Both dopamine and quinpirole also inhibited swimming in spinalised preparations, suggesting spinally located dopamine receptors. Dopamine and quinpirole hyperpolarised identified rhythmically active spinal neurons, increased rheobase and reduced spike probability both during swimming and in response to current injection. The hyperpolarisation was TTX-resistant and was accompanied by decreased input resistance, suggesting that dopamine opens a K+ channel. The K+ channel blocker barium chloride (but not TEA, glybenclamide or tertiapin-Q) significantly occluded the hyperpolarisation. Overall, we show that endogenously released dopamine acts upon spinally located D2-like receptors, leading to a rapid inhibitory modulation of swimming via the opening of a K+ channel.

A dopamine and noradrenaline reuptake inhibitor (bupropion) does not alter exercise performance of bank voles

Physical performance is determined both by biophysical and physiological limitations and behavioral characteristic, specifically motivation. We applied an experimental evolution approach combined with pharmacological manipulation to test the hypothesis that evolution of increased aerobic exercise performance can be triggered by evolution of motivation to undertake physical activity. We used a unique model system: bank voles from A lines, selected for high swim-induced aerobic metabolism (VO2swim), which achieved a 61% higher mass-adjusted VO2swim than those from unselected C lines. Because the voles could float on the water surface with only a minimum activity, the maximum rate of metabolism achieved in that test depended not only on their aerobic capacity, but also on motivation to undertake intensive activity. Therefore, we hypothesized that signaling of neurotransmitters putatively involved in regulating physical activity (dopamine and noradrenaline) had changed in response to selection. We measured VO2swim after intraperitoneal injections of saline or the norepinephrine and dopamine reuptake inhibitor bupropion (20 mg/kg or 30 mg/kg). Additionally, we measured forced-exercise VO2 (VO2max). In C lines, VO2swim (mass-adjusted mean ± standard error (SE): 4.0 ± 0.1 mLO2/min) was lower than VO2max (5.0 ± 0.1 mLO2/min), but in A lines VO2swim (6.0 ± 0.1 mLO2/min) was as high as VO2max (6.0 ± 0.1 mLO2/min). Thus, the selection effectively changed both the physiological–physical performance limit and mechanisms responsible for the willingness to undertake vigorous locomotor activity. Surprisingly, the drug had no effect on the achieved level of VO2swim. Thus, the results did not allow firm conclusions concerning involvement of these neurotransmitters in evolution of increased aerobic exercise performance in the experimental evolution model system.

Effects of Bupropion and Pramipexole on Cell Proliferation in the Hippocampus of Adrenocorticotropic Hormone-Treated Rats

The dopamine reuptake inhibitor bupropion and dopamine D2/3 receptor agonist pramipexole have been clinically proven to improve both depression and treatment-resistant depression. We examined its influence on the duration of immobility during the forced swim test in adrenocorticotropic hormone (ACTH)-treated rats and further analyzed the possible role of the dopamine nerve system in this effect. Bupropion and pramipexole significantly decreased the duration of immobility in normal and ACTH-treated rats. We previously demonstrated that the chronic administration of ACTH caused a significant decrease in hippocampal cell proliferation and neurogenesis. In this study, we used the mitotic marker 5-bromo-2'-deoxyridine to investigate the effects of bupropion and pramipexole on cell proliferation in the subgranular zone of the hippocampal dentate gyrus following chronic treatment with ACTH. The ACTH treatment for 14 d decreased adult hippocampal cell proliferation. The chronic administration of bupropion for 14 d blocked the loss of cell proliferation resulting from the chronic treatment with ACTH, whereas pramipexole did not. The administration of bupropion may have treatment-resistant antidepressive properties, which may be partly attributed to the normalization of hippocampal cell proliferation.

Effects of bupropion on the forced swim test and release of dopamine in the nucleus accumbens in ACTH-treated rats

The dopamine reuptake inhibitor bupropion has clinically been proven to improve depression and treatment-resistant depression. We examined its influence on the duration of immobility during the forced swim test in adrenocorticotropic hormone (ACTH)-treated rats and further analyzed the possible role of dopamine receptors in this effect. Additionally, the mechanism by which bupropion acts in this model was explored specifically in relation to the site of action through the use of microinjections into the medial prefrontal cortex and nucleus accumbens. Bupropion significantly decreased the duration of immobility in normal and ACTH-treated rats. This effect was blocked by D2 and D3 receptor antagonists in normal rats. Furthermore, infusions of bupropion into the nucleus accumbens, but not medial prefrontal cortex, decreased the immobility of normal and ACTH-treated rats during the forced swim test. Bupropion treatment plus repeated ACTH treatment significantly increased the extracellular dopamine concentration. These findings suggest the antidepressant-like effect of bupropion to be related to levels of dopamine in the rat nucleus accumbens.

Repetitive transcranial magnetic stimulation for tinnitus treatment: No enhancement by the dopamine and noradrenaline reuptake inhibitor bupropion

Repetitive transcranial magnetic stimulation (rTMS) of the temporal cortex has shown beneficial effects in patients with chronic tinnitus. Recent preclinical data in healthy controls suggest that the effects of low-frequency rTMS can be enhanced by dopaminergic drugs. We investigated whether application of the dopamine reuptake inhibitor bupropion increases the clinical effects of low-frequency rTMS over the auditory cortex in tinnitus patients. Eighteen subjects with chronic tinnitus received 10 sessions of 1 Hz rTMS (2000 pulses/day, 110% motor threshold) applied to the left temporal cortex. In addition, these subjects received one dosage of 150 mg bupropion (Wellbutrin XL/Elontril) 4 hours before each TMS session. Treatment outcome was assessed with a tinnitus questionnaire over a 3-month period. Treatment effects were compared with a control group of 100 tinnitus patients matched for age, tinnitus duration, and tinnitus questionnaire baseline scores, who received the same rTMS treatment without prior bupropion application. For the whole sample, there was a significant effect of rTMS treatment over time. There were no significant differences between the bupropion and the control group. Our data suggest that 150 mg bupropion administration does not enhance the effect of rTMS in the treatment of tinnitus.

Seksuelle bivirkninger av antidepressive legemidler

Sexual dysfunction is often concurrent with depressive disorders. Antidepressants may induce or augment sexual dysfunction as an adverse effect. About 40% of all patients treated with selective serotonin reuptake inhibitors, or other serotonergic agents, report such effects. If sexual dysfunction is not adequately dealt with it may contribute to noncompliance and thus compromise treatment. For the norepinephrine and dopamine reuptake inhibitor bupropion, the incidence of sexual adverse effects is equal to that for placebo. Additional treatment with bupropion, or switching to mirtazapin or bupropion, may be effective. Studies in men have documented positive effects of concomitant treatment with sildenafil or tadalafil.

Efficacy of Bupropion and the Selective Serotonin Reuptake Inhibitors in the Treatment of Major Depressive Disorder With High Levels of Anxiety (Anxious Depression)

The goal of this work was to compare the efficacy of the norepinephrine and dopamine reuptake inhibitor bupropion with the selective serotonin reuptake inhibitors (SSRIs) in the treatment of major depressive disorder with high levels of anxiety (anxious depression). Ten double-blind, randomized studies from 1991 through 2006 were combined (N = 2122). Anxious depression was defined as a 17-item Hamilton Rating Scale for Depression (HAM-D-17) anxiety-somatization factor score >or= 7. Among patients with anxious depression (N = 1275), response rates were greater following SSRI than bupropion treatment according to the HAM-D-17 (65.4% vs. 59.4%, p = .03) and the Hamilton Rating Scale for Anxiety (61.5% vs. 54.5%, p = .03). There was also a greater reduction in HAM-D-17 mean +/- SD scores (-14.1 +/- 7.6 vs. -13.2 +/- 7.9, p = .03) and a trend toward statistical significance for a greater reduction in HAM-A mean +/- SD scores (-10.5 +/- 7.4 vs. -9.6 +/- 7.6, p = .05) in favor of SSRI treatment among patients with anxious depression. There was no statistically significant difference in efficacy between bupropion and the SSRIs among patients with moderate/low levels of anxiety. There appears to be a modest advantage for the SSRIs compared to bupropion in the treatment of anxious depression (6% difference in response rates). Using the number-needed-to-treat (NNT) statistic as 1 indicator of clinical significance, nearly 17 patients would need to be treated with an SSRI than with bupropion in order to obtain 1 additional responder. This difference falls well above the limit of NNT = 10, which was suggested by the United Kingdom's National Institute of Clinical Excellence. Nevertheless, the present work is of theoretical interest because it provides preliminary evidence suggesting a central role for serotonin in the regulation of symptoms of negative affect such as anxiety.

Efficacy of bupropion and the selective serotonin reuptake inhibitors in the treatment of anxiety symptoms in major depressive disorder: A meta-analysis of individual patient data from 10 double-blind, randomized clinical trials

The goal of this work was to compare the efficacy of the norepinephrine–dopamine reuptake inhibitor bupropion with the selective serotonin reuptake inhibitors (SSRIs) in the treatment of anxiety symptoms in major depressive disorder (MDD). Ten double-blind, randomized studies, involving a total of 2890 bupropion-, SSRI- or placebo- treated patients were pooled. Anxiety symptoms of depression were defined using the Hamilton depression rating scale (HDRS) Anxiety-Somatization factor (HDRS-AS) score, as well as the Hamilton anxiety scale (HAM-A) score. Both bupropion and the SSRIs led to a comparable degree of improvement in anxiety symptoms, defined using the HDRS-AS score (−3.8 ± 2.8 vs. −3.9 ± 2.8, p = 0.130) or HAM-A score (−8.8 ± 7.2 vs. −9.1 ± 7.0, p = 0.177). There was no consistent difference in the time to anxiolysis between the two treatment groups. In addition, there was no difference in the proportion of bupropion- and SSRI- remitters who continued to experience residual anxiety, defined as a HDRS-AS score >0 at endpoint (69.2% vs. 74.7%, p = 0.081) or a HAM-A score >7 at endpoint (9.5% vs. 8.4%, p = 0.284). Finally, there was no statistically significant difference in the severity of residual anxiety symptoms between bupropion- or SSRI- treated patients with remitted depression, defined using the HDRS-AS (1.15 ± 1.14 vs. 1.25 ± 1.09, p = 0.569), or HAM-A scores at endpoint (3.30 ± 2.89 vs. 3.31 ± 2.89, p = 0.552). Contrary to clinician impression, there does not appear to be any difference in the anxiolytic efficacy of bupropion and the SSRIs when used to treat MDD.

The other face of depression, reduced positive affect: the role of catecholamines in causation and cure

Despite significant advances in pharmacologic therapy of depression over the past two decades, a substantial proportion of patients fail to respond or experience only partial response to serotonin re-uptake inhibitor antidepressants, resulting in chronic functional impairment. There appears to be a pattern of symptoms that are inadequately addressed by serotonergic antidepressants - loss of pleasure, loss of interest, fatigue and loss of energy. These symptoms are key to the maintenance of drive and motivation. Although these symptoms are variously defined, they are consistent with the concept of ;decreased positive affect'. Positive affect subsumes a broad range of positive mood states, including feelings of happiness (joy), interest, energy, enthusiasm, alertness and self-confidence. Although preliminary, there is evidence to suggest that antidepressants that enhance noradrenergic and dopaminergic activity may afford a therapeutic advantage over serotonergic antidepressants in the treatment of symptoms associated with a reduction in positive affect. Dopaminergic and noradrenergic agents, including the dual acting norepinephrine and dopamine re-uptake inhibitors, have demonstrated antidepressant activity in the absence of serotonergic function, showing similar efficacy to both tricyclic and serotonin re-uptake inhibitor antidepressants. Moreover, the norepinephrine and dopamine re-uptake inhibitor bupropion has been shown to significantly improve symptoms of energy, pleasure and interest in patients with depression with predominant baseline symptoms of decreased pleasure, interest and energy. Focusing treatment on the predominant or driving symptomatology for an individual patient with major depression could potentially improve rates of response and remission.

Direct evidence of facilitative actions of dopamine in the medial preoptic area on reflexive and noncontact erections in male rats.

We examined the effects of alterations of the extracellular dopamine level in the medial preoptic area on 2 erectile contexts, namely reflexive and noncontact erections, in male rats. The extracellular dopamine level was measured in the medial preoptic area after administering the dopamine reuptake inhibitor bupropion hydrochloride (Sigma Chemical Co., St. Louis, Missouri) into the same area through a micro-dialysis tube. We measured the frequency and latency of reflexive erections, and the frequency of noncontact erection during infusion of bupropion. Administration of 10 mM. bupropion was associated with significant elevation in the extracellular dopamine level in the medial preoptic area. Bupropion (1 mM.) and Ringer's solution did not induce significant alterations in dopamine in the medial preoptic area. The number of reflexive erections significantly increased and erection latency decreased during infusion of 10 mM. bupropion into the medial preoptic area. The number of noncontact erections was also increased by administering 10 mM. of drug. The altered dopamine level in the medial preoptic area affected 2 distinct penile erectile contexts, suggesting that the dopamine levels in the medial preoptic area may be involved in the regulation of erection. These results may have important implications for the central regulation of penile erection.

Antidepressant-like effects in various mice strains in the tail suspension test

Several studies have reported rodent strain differences in the response to antidepressants in animal models of depression. The aim of the present study was to investigate the potential contribution of genetic factors to antidepressant response in an animal model of depression: the tail suspension test (TST). For this study four mice strains (Swiss and NMRI, two outbred strains and DBA/2 and C57BL/6J Rj, two inbred strains) were submitted to the TST after acute administration of five antidepressants: the tricyclic antidepressants (TCAs) imipramine and desipramine, the selective serotonin (5-HT) reuptake inhibitors (SSRIs) paroxetine and citalopram and the dopamine reuptake inhibitor bupropion. The C57BL/6J Rj strain had a longer baseline immobility time in comparison to the other strains. All antidepressants studied in this work decreased immobility time in the Swiss and C57BL/6J Rj strains. However, the Swiss strain displayed greater sensitivity to citalopram (from 2 mg/kg) and C57BL/6J Rj to paroxetine (from 0.5 mg/kg). This latter presented a greater size-effect with citalopram than with other strains and reached more than 60% from 8 mg/kg. Moreover the size-effect of desipramine, paroxetine and bupropion in Swiss mice was greater than in the other strains in the TST. The NMRI and DBA/2 mice only responded to 5-HT reuptake inhibitors, both selective (paroxetine, citalopram) or non-selective (imipramine). The NMRI strain was more sensitive to imipramine and presented a size-effect (43% at 8 mg/kg) superior to those of other strains. DBA/2 strain was more sensitive to citalopram than paroxetine and imipramine. Our results suggest that response to an antidepressant treatment is under control of genetic factors and that the strain of mouse is an important parameter to consider.

Direct Evidence of Facilitative Actions of Dopamine in the Medial Preoptic Area on Reflexive and Noncontact Erections in Male Rats

We examined the effects of alterations of the extracellular dopamine level in the medial preoptic area on 2 erectile contexts, namely reflexive and noncontact erections, in male rats. The extracellular dopamine level was measured in the medial preoptic area after administering the dopamine reuptake inhibitor bupropion hydrochloride (Sigma Chemical Co., St. Louis, Missouri) into the same area through a micro-dialysis tube. We measured the frequency and latency of reflexive erections, and the frequency of noncontact erection during infusion of bupropion. Administration of 10 mM. bupropion was associated with significant elevation in the extracellular dopamine level in the medial preoptic area. Bupropion (1 mM.) and Ringer's solution did not induce significant alterations in dopamine in the medial preoptic area. The number of reflexive erections significantly increased and erection latency decreased during infusion of 10 mM. bupropion into the medial preoptic area. The number of noncontact erections was also increased by administering 10 mM. of drug. The altered dopamine level in the medial preoptic area affected 2 distinct penile erectile contexts, suggesting that the dopamine levels in the medial preoptic area may be involved in the regulation of erection. These results may have important implications for the central regulation of penile erection.

Interaction of dopamine D1 and NMDA receptors mediates acute clozapine potentiation of glutamate EPSPs in rat prefrontal cortex.

The atypical antipsychotic drug clozapine effectively alleviates both negative and positive symptoms of schizophrenia via unclear cellular mechanisms. Clozapine may modulate both glutamatergic and dopaminergic transmission in the prefrontal cortex (PFC) to achieve part of its therapeutic actions. Using whole cell patch-clamp techniques, current-clamp recordings in layers V-VI pyramidal neurons from rat PFC slices showed that stimulation of local afferents (in 2 microM bicuculline) evoked mixed [AMPA/kainate and N-methyl-D-aspartate (NMDA) receptors] glutamate receptor-mediated excitatory postsynaptic potentials (EPSPs). Clozapine (1 microM) potentiated polysynaptically mediated evoked EPSPs (V(Hold) = -65 mV), or reversed EPSPs (rEPSP, V(Hold) = +20 mV) for >30 min. The potentiated EPSPs or rEPSPs were attenuated by elevating [Ca(2+)](O) (7 mM), by application of NMDA receptor antagonist 2-amino5-phosphonovaleric acid (50 microM), or by pretreatment with dopamine D1/D5 receptor antagonist SCH23390 (1 microM) but could be further enhanced by a dopamine reuptake inhibitor bupropion (1 microM). Clozapine had no significant effect on pharmacologically isolated evoked NMDA-rEPSP or AMPA-rEPSPs but increased spontaneous EPSPs without changing the steady-state resting membrane potential. Under voltage clamp, clozapine (1 microM) enhanced the frequency, and the number of low-amplitude (5-10 pA) AMPA receptor-mediated spontaneous EPSCs, while there was no such changes with the mini-EPSCs (in 1 microM TTX). Taken together these data suggest that acute clozapine can increase spike-dependent presynaptic release of glutamate and dopamine. The glutamate stimulates distal dendritic AMPA receptors to increase spontaneous EPSCs and enabled a voltage-dependent activation of neuronal NMDA receptors. The dopamine released stimulates postsynaptic D1 receptor to modulate a lasting potentiation of the NMDA receptor component of the glutamatergic synaptic responses in the PFC neuronal network. This sequence of early synaptic events induced by acute clozapine may comprise part of the activity that leads to later cognitive improvement in schizophrenia.

A catalytic antibody against cocaine prevents cocaine's reinforcing and toxic effects in rats.

Cocaine addiction and overdose have long defied specific treatment. To provide a new approach, the high-activity catalytic antibody mAb 15A10 was elicited using a transition-state analog for the hydrolysis of cocaine to nontoxic, nonaddictive products. In a model of cocaine overdose, mAb 15A10 protected rats from cocaine-induced seizures and sudden death in a dose-dependent fashion; a noncatalytic anticocaine antibody did not reduce toxicity. Consistent with accelerated catalysis, the hydrolysis product ecgonine methyl ester was increased >10-fold in plasma of rats receiving mAb 15A10 and lethal amounts of cocaine. In a model of cocaine addiction, mAb 15A10 blocked completely the reinforcing effect of cocaine in rats. mAb 15A10 blocked cocaine specifically and did not affect behavior maintained by milk or by the dopamine reuptake inhibitor bupropion. This artificial cocaine esterase is a rationally designed cocaine antagonist and a catalytic antibody with potential for medicinal use.

Cocaine toxicity: concurrent influence of dopaminergic, muscarinic and sigma receptors in mediating cocaine-induced lethality.

The concurrent influence of dopaminergic, sigma and muscarinic neurotransmitter systems in mediating cocaine-induced lethality is predicted by previous receptor binding results from our laboratories. The present results demonstrate that pharmacological manipulations of these predicted neurotransmitter systems alter the occurrence of cocaine-induced lethality in C57BL/6J mice. The dopamine reuptake inhibitor bupropion increased the number of occurrences of lethality produced by (-) cocaine, while the dopaminergic D1 antagonist SCH 23390, the muscarinic M1 antagonist pirenzepine, and the sigma ligand (+) SKF 10047 all significantly, but only partially, antagonized (-) cocaine-induced lethality. In addition, the protective effects against lethality of the drug combinations SCH 23390 + pirenzepine or SCH 23390 + SKF 10047 were greater than any of these drugs used alone. These results are consistent with those from the previous receptor binding studies, and provide converging supportive evidence that the lethal effects of cocaine depend upon concurrent interactions with dopaminergic, muscarinic M1 and sigma receptor sites.