Adult and in utero exposure to cocaine alters sensitivity to the Parkinsonian toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

Cocaine abuse is a significant problem in the United States, including its use by approximately 1% of pregnant women. Cocaine acts as an indirect agonist of dopamine at the dopamine transporter, resulting in the presence of excess dopamine in the synapse. Since synaptic dopamine can rapidly oxidize to form free radicals, it was hypothesized that exposure to this drug might produce damage in dopaminergic systems such as the substantia nigra pars compacta, damage to which is a hallmark of Parkinson's disease. To test this hypothesis we exposed mice both in utero and as adults to cocaine and examined its effects on the nigrostriatal system. We found that exposure to cocaine both in utero or as adults did not affect substantia nigra cell number, but did make these neurons more susceptible to the parkinsonian toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. We also found long-lasting changes in D2 receptor mRNA levels as well as changes in the monoamine transport system and several growth factors. This work suggests that use of cocaine might be a predisposing factor for development of Parkinson's disease in both adults exposed chronically as well as in individuals exposed prenatally.     

Reproductive risks of cocaine

Cocaine use during pregnancy in the USA has increased dramaticallyin the past decade, and has resulted in an associated increasein a variety of maternal and perinatal complications. However,a number of confounding factors make it difficult to determinethe direct impact of perinatal cocaine use on maternal and fetaloutcome. Many substance-abusing women use multiple drugs whilepregnant, receive inadequate prenatal care and are predisposedto other health problems that impact on perinatal outcome. Asa result of the rapid clearance of cocaine and limitations ofavailable screening methods, the identification of individualusers can be difficult. Furthermore, the determination of accurateprevalence rates of cocaine use during pregnancy has been frustratedby sampling bias. Cocaine has profound systemic and cardiovasculareffects in both the mother and the fetus, and as a rsult a numberof complications (i.e. fetal malformations, preterm labour,placental abruption) have been attributed to perinatal cocaineexposure. In addition, maternal cocaine use has been associatedwith a number of neonatal abnormalities, including cardio-pulmonaryeffects, somatic changes and neuro-behavioural sequelae. Itis estimated that US $500 million dollars in additional healthexpenditure resulted from increased neonatal hospital costsand longer lengths of stay for cocaine-exposed neonates. Thisarticle reviews the reproductive risks associated with prenatalcocaine use. The pharmacology and physiology of cocaine in relationto pregnancy is discussed, and the impact of this substanceon the growth and development of the fetus and infant is reviewed.     

Dissection of the aorta and coronary arteries associated with acute cocaine intoxication.

Acute myocardial ischemia, cardiac arrhythmias, and conduction disturbances are the most common cardiovascular complications of cocaine and its alkaloidal freebase "crack." Cocaine abuse-related acute aortic dissection has been reported only rarely: three cases in the last 5 years. Described herein, to our knowledge, is the first case of cocaine intoxication-associated acute aortic dissection that also involved the coronary arteries, causing sudden death.     

Cocaine sensitization inhibits the hyperpolarization-activated cation current Ih and reduces cell size in dopamine neurons of the ventral tegmental area

The progressive augmentation of motor activity that results from repeated cocaine administration is termed behavioral sensitization. This phenomenon is thought to be a critical component in compulsive drug taking and relapse. Still, the cellular mechanisms that underlie sensitization remain elusive. Cocaine abuse, nonetheless, is known to evoke neuroplastic adaptations in dopamine (DA) neurotransmission originating from the midbrain's ventral tegmental area (VTA). Here, we report that concomitant with the development of locomotor sensitization to cocaine the hyperpolarization-activated cation current (I(h)) amplitude is depressed by ～40% in VTA DA cells. Such effect did not result from a negative shift in I(h) voltage dependence. Nonstationary fluctuation analysis indicates that this inhibition was caused by an ～45% reduction in the number of h-channels with no change in their unitary properties. The cocaine-induced I(h) depression was accompanied by a reduction in cell capacitance of similar magnitude (～33%), leaving h-current density unaltered. Two implications follow from these data. First, I(h) inhibition may contribute to cocaine addiction by increasing bursting probability in DA cells and this effect could be intensified by the decrease in cell capacitance. Second, the cocaine-induced diminution of DA cell capacitance may also lead to reward tolerance promoting drug-seeking behaviors.     

Allocentrically implied target locations are updated in an eye-centred reference frame

Cocaine is a psychotropic drug with a high potential for abuse due to its euphoric effects. Efforts to develop medications for the treatment of cocaine dependence have not been clinically successful. Some studies using animal models have shown positive effects of dopaminergic agents such as partial agonists of the dopamine D1 receptor. Thus, this study aimed to examine the effect of the dopamine D1 receptor partial agonist SKF 38393 on cocaine craving. Adult male C57BL/6J mice were injected with cocaine for 10 days in a conditioned place preference apparatus using a biased procedure and subsequently treated for three consecutive days with SKF 38393. The results showed that SKF 38393 was able to block the preference of cocaine-conditioned animals for the compartment paired with the drug without showing effects on locomotor activity. The results of this study suggest that partial activation of D1 dopamine receptors may be necessary for the development of pharmacotherapies for cocaine addiction.     

Phasic inhibition of dopamine uptake in nucleus accumbens induced by intravenous cocaine in freely behaving rats

A new approach combining fast-scan cyclic voltammetry with iontophoretic dopamine delivery was used in freely behaving rats to evaluate the time-course of dopamine uptake inhibition in nucleus accumbens induced by intravenous cocaine at a dose (1.0mg/kg) known to maintain self-administration behavior. Cocaine significantly increased the decay time of the dopamine response without altering its magnitude or time to peak. An increase in decay time was evident at 2 min, peaked at 6 min (+87%), and decreased to baseline at 18 min after a single cocaine injection. The change in decay time was similar in all rats and remained essentially the same, albeit slightly larger, for subsequent cocaine injections both within a session and over repeated sessions. The change in dopamine decay time did not correlate with cocaine-induced motor activation, which was maximal during the first minute after injection and decreased slowly over the next 20 min. Our data provide direct evidence for a phasic change in dopamine uptake induced by intravenous cocaine under behaviorally relevant conditions. The relatively slow and gradual development of dopamine uptake inhibition, which peaks at times when behaving rats self-inject cocaine, is inconsistent with the suggested role of this mechanism in the acute rewarding (euphoric) effects of self-injected cocaine, but supports its role in the activational and motivational aspects of drug-seeking and drug-taking behavior. Because intravenous cocaine enters the brain rapidly and peaks in neural tissue (1-2 min) long before it effectively inhibits dopamine uptake (6 min), it appears that some of the acute psychoemotional ("rush"), behavioral, autonomic, and neuronal effects of this drug, which are apparently resistant to dopamine receptor blockade, are mediated via rapid central or peripheral mechanisms independent of monoamine uptake.     

Acute and chronic cocaine differentially alter the subcellular distribution of AMPA GluR1 subunits in region-specific neurons within the mouse ventral tegmental area

Cocaine administration increases AMPA GluR1 expression and receptor-mediated activation of the ventral tegmental area (VTA). Functionality is determined, however, by surface availability of these receptors in transmitter- and VTA-region-specific neurons, which may also be affected by cocaine. To test this hypothesis, we used electron microscopic immunolabeling of AMPA GluR1 subunits and tyrosine hydroxylase (TH), the enzyme needed for dopamine synthesis, in the cortical-associated parabrachial (PB) and in the limbic-associated paranigral (PN) VTA of adult male C57BL/6 mice receiving either a single injection (acute) or repeated escalating-doses for 14 days (chronic) of cocaine. Acute cocaine resulted in opposing VTA-region-specific changes in TH-containing dopaminergic dendrites. TH-labeled dendrites within the PB VTA showed increased cytoplasmic GluR1 immunogold particle density consistent with decreased AMPA receptor-mediated glutamatergic transmission. Conversely, TH-labeled dendrites within the PN VTA showed greater surface expression of GluR1 with increases in both synaptic and plasmalemmal GluR1 immunogold density after a single injection of cocaine. These changes diminished in both VTA subregions after chronic cocaine administration. In contrast, non-TH-containing, presumably GABAergic dendrites showed VTA-region-specific changes only after repeated cocaine administration such that synaptic GluR1 decreased in the PB, but increased in the PN VTA. Taken together, these findings provide ultrastructural evidence suggesting that chronic cocaine not only reverses the respective depression and facilitation of mesocortical (PB) and mesolimbic (PN) dopaminergic neurons elicited by acute cocaine, but also differentially affects synaptic availability of these receptors in non-dopaminergic neurons of each region. These adaptations may contribute to increased cocaine seeking/relapse and decreased reward that is reported with chronic cocaine use.     

可卡因对多巴胺能神经元的作用及机制

可卡因主要作用于单胺类转运体,包括多巴胺转运体(DAT)、5-HT转运体(SERT)和去甲肾上腺素转运体(NET),阻止这些转运体将突触前释放的神经递质转运回突触前膜神经末梢,从而增强单胺能神经递质的作用而产生精神兴奋效应,其中DAT是可卡因作用的主要环节。可卡因也能够增加突触前末梢神经递质的释放,对突触后神经元的基因和蛋白水平的调节在可卡因成瘾中的作用也是不可忽视的。本文就可卡因成瘾分子机制的最新研究进展作一综述。     

CaMKII: a biochemical bridge linking accumbens dopamine and glutamate systems in cocaine seeking

Increases in dopamine and glutamate transmission in the nucleus accumbens independently promote the reinstatement of cocaine seeking, an animal model of relapse. Here we have tested whether cocaine reinstatement in rats depends on interactions between accumbal dopamine and glutamate systems that are mediated by Ca(2+)/calmodulin-mediated kinase II (CaMKII). We show that stimulation of D1-like dopamine receptors in the nucleus accumbens shell reinstates cocaine seeking by activating L-type Ca(2+) channels and CaMKII. Cocaine reinstatement is associated with D1-like dopamine receptor-dependent increases in accumbens shell CaMKII phosphorylated on Thr286 and glutamate receptor 1 (GluR1) phosphorylated on Ser831 (a known CaMKII phosphorylation site), in addition to increases in cell-surface expression of GluR1-containing AMPA receptors in the shell. Consistent with these findings, cocaine reinstatement is attenuated by intra-shell administration of AAV10-GluR1-C99, a vector that impairs the transport of GluR1-containing AMPA receptors. Thus, CaMKII may be an essential link between accumbens shell dopamine and glutamate systems involved in the neuronal plasticity underlying cocaine craving and relapse.     

Cocaine self-administration in dopamine-transporter knockout mice

The plasma membrane dopamine transporter (DAT) is responsible for clearing dopamine from the synapse. Cocaine blockade of DAT leads to increased extracellular dopamine, an effect widely considered to be the primary cause of the reinforcing and addictive properties of cocaine. In this study we tested whether these properties are limited to the dopaminergic system in mice lacking DAT. In the absence of DAT, these mice exhibit high levels of extracellular dopamine, but paradoxically still self-administer cocaine. Mapping of the sites of cocaine binding and neuronal activation suggests an involvement of serotonergic brain regions in this response. These results demonstrate that the interaction of cocaine with targets other than DAT, possibly the serotonin transporter, can initiate and sustain cocaine self-administration in these mice.     

The binding sites for cocaine and dopamine in the dopamine transporter overlap

Cocaine is a widely abused substance with psychostimulant effects that are attributed to inhibition of the dopamine transporter (DAT). We present molecular models for DAT binding of cocaine and cocaine analogs constructed from the high-resolution structure of the bacterial transporter homolog LeuT. Our models suggest that the binding site for cocaine and cocaine analogs is deeply buried between transmembrane segments 1, 3, 6 and 8, and overlaps with the binding sites for the substrates dopamine and amphetamine, as well as for benztropine-like DAT inhibitors. We validated our models by detailed mutagenesis and by trapping the radiolabeled cocaine analog [3H]CFT in the transporter, either by cross-linking engineered cysteines or with an engineered Zn2+-binding site that was situated extracellularly to the predicted common binding pocket. Our data demonstrate the molecular basis for the competitive inhibition of dopamine transport by cocaine.     

Cocaine and apoptosis in myocardial cells

Toxic effects of cocaine on the heart muscle have been known for many years. Cardiovascular complications related to cocaine abuse include myocardial ischemia and infarction, inflammation, and disease of the heart muscle, rhythm disturbances, and sudden cardiac death. Cocaine toxicity-related cardiac morbidity and mortality are often due to several interacting mechanisms. Cocaine also has a potent pharmacological effect, indirectly stimulating the sympathetic nervous system, and it has a direct toxic effect on the heart. Although apoptosis (also called programmed cell death) has been shown to play an important role in the pathogenesis of several diseases in the heart, including heart failure and ischemic myocardial infarction, the role of apoptosis in the toxic effect of cocaine on the heart has not been explored. Recent studies indicated that cocaine causes apoptotic cell death in both adult and fetal heart muscles. Increased oxidative stress and reactive oxygen species, and the subsequent activation of a "stress responsive" enzyme (p38-mitogen-activated protein kinase) in the heart may play an important role in cocaine-induced apoptosis in the heart muscle. These findings suggest a new way to understand the cardiotoxic effects of cocaine, and may have potential clinical implications in the better management of cocaine-induced heart diseases. Anat Rec (New Anat): 257:208-216, 1999.     

Acute cocaine induces endothelin-1-dependent constriction of rabbit basilar artery.

It has been postulated that ischemic stroke due to acute cocaine usage involves constriction of the cerebral vasculature. However, the mechanism underlying the constriction remains unclear. This study tested whether cocaine constriction was mediated via endothelin-1. Cocaine suffusion induced maintained constriction in the rabbit basilar artery in situ. The constriction was relaxed by PD145065, an endothelin A and B receptor antagonist. These results support the hypothesis that constriction of the cerebral vasculature due to acute cocaine exposure is via endothelin-1 release. Endothelin receptor antagonists may be of therapeutic benefit in cerebrovascular pathophysiologies involving cocaine constriction.     

Error-processing deficits in patients with cocaine dependence

Cocaine abuse and addiction can be characterized by a persisting use of cocaine in the face of adverse consequences. In the present study we focus on one specific element of adverse consequences: the making of errors. The aim of this study was to determine whether cocaine-dependent persons have error-processing deficits as measured using error-related negativity (ERN) and error positivity (Pe). Event-related potentials (ERPs) during an Eriksen flanker task were recorded from cocaine-dependent patients and a control group. Cocaine-addicted patients showed reduced ERN and Pe components as compared to a control group. On the behavioral level, patients showed reduced post-error accuracy improvement. The present findings reveal that cocaine addiction is associated with reduced error processing and impaired behavioral correction of errors after an error is made. These deficits may be associated with a compromised dopamine system. It is argued that these cognitive deficits may contribute to the maintenance of the cocaine addiction.     

The Effects of Cocaine and Stress on Lymphocyte Proliferation in Rats1

The effects of cocaine, stress, and the combination of cocaine and stress on proliferative responses to mitogens in vitro were examined in rats. In this paradigm, hypothalamic dopamine and norepinephrine were measured to examine whether catecholamine levels relate to changes in immune function. Cocaine, stress, and cocaine plus stress decreased cellular immune function to Con A mitogen compared with a control group. Hypothalamic dopamine levels were inversely related to immune proliferation to lipopolysaccharide (LPS) mitogen. The results are discussed in terms of the deleterious effects of cocaine and stress and possible mechanisms for cocaine and stress induced immune suppression.     

Serotonin transporters upregulate with chronic cocaine use

Cocaine potently inhibits serotonin (5-HT) reuptake in cell bodies and at nerve terminals and 5-HT has been implicated as a modulator of dopaminergic neurotransmission. Chronic use of cocaine may lead to a ‘serotonin-deficit’ form of 5-HT dysregulation. We have examined the status of the 5-HT transporter (SERT) using ligand binding and autoradiographic methods in subgroups of cocaine overdose deaths. Quantitative autoradiography of [¹²⁵I]RTI-55 was used to map and measure the effect of chronic cocaine use on SERT densities in the striatum, substantia nigra, amygdala, and adjacent paralimbic cortical areas of cocaine overdose (CO) victims with and without preterminal evidence of excited delirium (ED). SERT densities were elevated in the nucleus accumbens and throughout the anterior and posterior sectors of striatum in CO victims compared with age-matched and drug-free control subjects. In contrast, SERT densities were increased significantly in the anterior striatum, but not the posterior sectors in ED victims. Significant elevations in SERT were measured in the orbitofrontal gyrus (Brodmann area 11), the anterior portion of the insular cortex and the cingulate gyrus (Brodmann area 24) in CO and ED victims. Saturation binding site analysis demonstrated an increase in the density of RTI-55 binding sites with no change in the affinity of the radioligand for the SERT. Chronic cocaine exposure upregulated SERT densities in the substantia nigra of the CO, but not ED victims. The lack of SERT upregulation in the substania nigra and posterior striatum suggests the possibility of a distinct phenotype for fatal ED victims that exhibited an acute onset of bizarre and violent behavior prior to death. Adaptive changes in the SERT densities may contribute to depressed mood and drug craving associated with acute cocaine abstinence.     

Kappa-opioid receptor activation prevents alterations in mesocortical dopamine neurotransmission that occur during abstinence from cocaine

In vivo microdialysis was used to characterize basal dopamine dynamics and cocaine-evoked dopamine levels in the medial prefrontal cortex of male Sprague-Dawley rats that had previously received once daily injections of cocaine (days 1-5; 20mg/kg, i.p.) in combination with the selective kappa-opioid receptor agonist U-69593 (days 3-5; 0.32mg/kg, s.c.) or its vehicle. The influence of these treatments on [3H]dopamine uptake in medial prefrontal cortex synaptosomes was also determined. Three days following the cessation of drug treatment, animals with prior history of cocaine administration exhibited enhanced psychomotor stimulation in response to a subsequent cocaine challenge. This effect was not apparent in animals that had previously received the cocaine treatment regimen in combination with the kappa-opioid receptor agonist U-69593. Cocaine challenge increased prefrontal dopamine levels in all pretreatment groups, but cocaine-pre-exposed animals had lower cocaine-evoked dopamine levels and higher basal in vivo extraction fraction, indicative of an increase in basal dopamine uptake relative to controls. Pretreatment with U-69593 prevented these effects of cocaine. Measurement of [3H]dopamine uptake in synaptosomes revealed a significant increase in uptake three days after the cessation of cocaine treatment. No increase in uptake was observed in animals that had received the cocaine treatment regimen in combination with U-69593.These results demonstrate that the early phase of abstinence from cocaine is associated with marked alterations in medial prefrontal cortex dopamine neurotransmission and that these neuroadaptations are prevented by the activation of kappa-opioid receptors. Furthermore, they raise the possibility that mesocortical dopamine neurons may be an important neural substrate upon which kappa-opioid agonists act to prevent the development of cocaine-induced behavioral sensitization.     

Thrombotic microangiopathy in cocaine abuse-associated malignant hypertension: report of 2 cases with review of the literature

Cocaine is one of the most commonly used illicit drugs. Acute renal failure is an emergent complication in patients with acute cocaine intoxication. It is well known that rhabdomyolysis and vasoconstriction can be important pathogenetic mechanisms resulting in acute renal failure in these patients. Clinically, although cocaine abuse is associated with elevated blood pressure, persistent accelerated hypertension reaching levels diagnostic of malignant hypertension is uncommon. Cocaine-induced malignant hypertension associated with morphologic features of thrombotic macroangiopathy has been rarely mentioned in the literature. We report 2 cases of cocaine abuse-associated malignant hypertension with renal failure. Kidney biopsies revealed thrombotic microangiopathy with fibrinoid necrosis of arterioles and glomerular tufts. Cocaine-mediated endothelial injury and platelet activation may play important pathogenetic roles in cocaine abusers who develop acute renal failure and malignant hypertension.     

Cocaine mechanisms: enhanced cocaine,fluoxetine and nisoxetine place preferences following monoamine transporter deletions

Cocaine blocks uptake by neuronal plasma membrane transporters for dopamine, serotonin and norepinephrine, producing subjective effects in humans that are both euphoric/rewarding and also fearful, jittery and aversive. Mice with gene knockouts of each of these transporters display cocaine reward, manifest by cocaine place preferences that are at least as great as wildtype values. Norepinephrine and serotonin receptor knockouts even display enhanced cocaine reward. One explanation for these observations could be that cocaine produces aversive or anhedonic effects by serotonin or norepinephrine receptor blockade in wildtype mice that are removed in serotonin or norepinephrine receptor knockouts, increasing net cocaine reward. Adaptations to removing one transporter could also change the rewarding valence of blocking the remaining transporters. To test these ideas, drugs that block serotonin transporter (fluoxetine), norepinephrine transporter (nisoxetine) or all three transporters (cocaine) were examined in single- or multiple-transporter knockout mice. Fluoxetine and nisoxetine acquire rewarding properties in several knockouts that are not observed in wildtype mice. Adding serotonin transporter knockout to norepinephrine transporter knockouts dramatically potentiates cocaine reward.These and previous data provide evidence that serotonin and norepinephrine transporter blockade can contribute to the net rewarding valence of cocaine. They identify neuroadaptations that may help to explain the retention of cocaine reward by dopamine and serotonin transporter knockout mice. They are consistent with emerging hypotheses that actions at the three primary brain molecular targets for cocaine each provide distinct contributions to cocaine reward and cocaine aversion in wildtype mice, and that this balance changes in mice that develop without dopamine, norepinephrine or serotonin transporters.