Mini review: Promotion of substance abuse in HIV patients: Biological mediation by HIV-1 Tat protein.

Despite successful viral suppression by combinatorial anti-retroviral therapy, HIV infection continues to negatively impact the quality of life of patients by promoting neuropathy and HIV-Associated Neurocognitive Disorders (HAND), where substance use disorder (SUD) is highly comorbid and known to worsen health outcomes. While substance abuse exacerbates the progression of HIV, emerging evidence also suggests the virus may potentiate the rewarding effect of abused substances. As HIV does not infect neurons, these effects are theorized to be mediated by viral proteins. Key among these proteins are HIV-1 Tat, which can continue to be produced under viral suppression in patients. This review will recap the behavioral evidence for HIV-1 Tat mediation of a potentiation of cocaine, opioid and alcohol reward, and explore the neurochemical dysfunction associated by Tat as potential mechanisms underlying changes in reward. Targeting rampant oxidative stress, inflammation and excitotoxicity associated with HIV and Tat protein exposure may prove useful in combating persistent substance abuse comorbid with HIV in the clinic.

Pharmacokinetic and pharmacodynamic analyses of cocaine and its metabolites in behaviorally divergent inbred mouse strains.

Cocaine (COC) is a psychostimulant with a high potential for abuse and addiction. Risk for COC use disorder is driven, in part, by genetic factors. Animal models of addiction-relevant behaviors have proven useful for studying both genetic and nongenetic contributions to drug response. In a previous study, we examined initial locomotor sensitivity to COC in genetically diverse inbred mouse strains. That work highlighted the relevance of pharmacokinetics (PK) in initial locomotor response to COC but was limited by a single dose and two sampling points. The objective of the present study was to characterize the PK and pharmacodynamics of COC and its metabolites (norcocaine and benzoylecgonine) in six inbred mouse strains (I/LnJ, C57BL/6J, FVB/NJ, BTBR T+ tf/J, LG/J and LP/J) that exhibit extreme locomotor responses to cocaine. Mice were administered COC at one of four doses and concentrations of cocaine, norcocaine and benzoylecgonine were analyzed in both plasma and brain tissue at 5 different time points. Initial locomotor sensitivity to COC was used as a pharmacodynamic endpoint. We developed an empirical population PK model that simultaneously characterizes cocaine, norcocaine and benzoylecgonine in plasma and brain tissues. We observed interstrain variability occurring in the brain compartment that may contribute to pharmacodynamic differences among select strains. Our current work paves the way for future studies to explore strain-specific pharmacokinetic differences and identify factors other than PK that are responsible for the diverse behavioral response to COC across these inbred mouse strains.

Drug-Evoked Synaptic Plasticity of Excitatory Transmission in the Ventral Tegmental Area.

Cocaine leads to a strong euphoria, which is at the origin of its recreational use. Past the acute effects, the drug leaves traces in the brain that persist long after it has been cleared from the body. These traces eventually shape behavior such that drug use may become compulsive, and addiction develops. Here, we discuss cocaine-evoked synaptic plasticity of glutamatergic transmission onto dopamine (DA) neurons of the ventral tegmental area (VTA) as one of the earliest traces after a first injection of cocaine. We review the literature that has examined the induction requirements, as well as the expression mechanism of this form of plasticity, and ask the question about its functional significance.

Effects of Cebranopadol on Cocaine-induced Hyperactivity and Cocaine Pharmacokinetics in Rats.

Cebranopadol is known as a highly potent analgesic. Recent studies also demonstrated that administration of cebranopadol significantly decreased cocaine self-administration and significantly reduced cue-induced cocaine-seeking behaviors in rats. However, it was unclear whether these interesting behavioral observations are related to any potential effects of cebranopadol on cocaine pharmacokinetics or cocaine-induced hyperactivity. In principle, a promising therapeutic candidate for cocaine dependence treatment may alter the cocaine pharmacokinetics and/or attenuate cocaine-induced reward and hyperactivity and, thus, decrease cocaine self-administration and reduce cue-induced cocaine-seeking behaviors. In this study, we examined possible effects of cebranopadol on cocaine pharmacokinetics and cocaine-induced hyperactivity for the first time. According to our animal data in rats, cebranopadol did not significantly alter the pharmacokinetics of cocaine. According to our more extensive locomotor activity testing data, cebranopadol itself also dose-dependently induced hyperactivity in rats at doses higher than 50 µg/kg. Cebranopadol at a low dose of 25 µg/kg (p.o.) did not induce significant hyperactivity itself, but significantly potentiated cocaine-induced hyperactivity on Days 4 to 7 after the repeated daily dosing of the drug.

Suppression of cocaine relapse-like behaviors upon pimavanserin and lorcaserin co-administration.

Cocaine use disorder (CUD) is a major public health challenge for which there are no pharmacotherapeutics approved by the United States Food and Drug Administration (FDA). The propensity to relapse in CUD involves several vulnerability factors including sensitivity to cues associated with cocaine-taking. Serotonin (5-hydroxytryptamine, 5-HT) neurotransmission, particularly through the 5-HT2A receptor (5-HT2AR) and 5-HT2C receptor (5-HT2CR), is mechanistically linked to cocaine-seeking in preclinical models. In the present experiments, we employed self-administration assays in male rats to investigate whether acute and/or repeated administration of the FDA-approved selective 5-HT2AR antagonist/inverse agonist pimavanserin, selective 5-HT2CR agonist lorcaserin or their combination would alter cocaine intake and/or cocaine-seeking behavior. We found that acute administration of lorcaserin, but not pimavanserin, attenuated cocaine intake while pimavanserin plus lorcaserin did not impact cocaine self-administration. In contrast, 10-days of repeated administration of pimavanserin, lorcaserin, or pimavanserin plus lorcaserin during forced abstinence from cocaine self-administration, blunted cocaine-seeking, similar to the acute administration of each ligand. Taken together, these data reveal the efficacy of repeated treatment with pimavanserin plus lorcaserin to attenuate factors important to relapse-like behaviors in rodent models of CUD. This article is part of the special issue entitled 'Serotonin Research: Crossing Scales and Boundaries'.

Catalytic activities of cocaine hydrolases against the most toxic cocaine metabolite norcocaethylene.

A majority of cocaine users also consume alcohol. The concurrent use of cocaine and alcohol produces the pharmacologically active metabolites cocaethylene and norcocaethylene, in addition to norcocaine. Both cocaethylene and norcocaethylene are more toxic than cocaine itself. Hence, a truly valuable cocaine-metabolizing enzyme for cocaine abuse/overdose treatment should be effective for the hydrolysis of not only cocaine, but also its metabolites norcocaine, cocaethylene, and norcocaethylene. However, there has been no report on enzymes capable of hydrolyzing norcocaethylene (the most toxic metabolite of cocaine). The catalytic efficiency parameters (kcat and KM) of human butyrylcholinesterase (BChE) and two mutants (known as cocaine hydrolases E14-3 and E12-7) against norcocaethylene have been characterized in the present study for the first time, and they are compared with those against cocaine. According to the obtained kinetic data, wild-type human BChE showed a similar catalytic efficiency against norcocaethylene (kcat = 9.5 min-1, KM = 11.7 µM, and kcat/KM = 8.12 × 105 M-1 min-1) to that against (-)-cocaine (kcat = 4.1 min-1, KM = 4.5 µM, and kcat/KM = 9.1 × 105 M-1 min-1). E14-3 and E12-7 showed an improved catalytic activity against norcocaethylene compared to wild-type BChE. E12-7 showed a 39-fold improved catalytic efficiency against norcocaethylene (kcat = 210 min-1, KM = 6.6 µM, and kcat/KM = 3.18 × 107 M-1 min-1). It has been demonstrated that E12-7 as an exogenous enzyme can efficiently metabolize norcocaethylene in rats.

Testing Unconventional Matrices to Monitor for Prenatal Exposure to Heroin, Cocaine, Amphetamines, Synthetic Cathinones, and Synthetic Opioids.

BACKGROUND: The prevalence of drug use during pregnancy continues to increase despite the associated serious adverse obstetrical outcomes, including increased risk of miscarriage, fetal growth restriction, brain development impairment, neonatal abstinence syndrome, preterm delivery, and stillbirths. Monitoring drug use during pregnancy is crucial to limit prenatal exposure and provide suitable obstetrical health care. The authors reviewed published literature reporting the concentrations of common drugs of abuse and new psychoactive substances (NPS), such as synthetic cathinones and synthetic opioids, NPS, and their metabolites using unconventional matrices to identify drug use during pregnancy and improve data interpretation. METHODS: A literature search was performed from 2010 to July 2019 using PubMed, Scopus, Web of Science scientific databases, and reports from international institutions to review recently published articles on heroin, cocaine, amphetamine, methamphetamine, synthetic cathinone, and synthetic opioid monitoring during pregnancy. RESULTS: Meconium has been tested for decades to document prenatal exposure to drugs, but data regarding drug concentrations in amniotic fluid, the placenta, the umbilical cord, and neonatal hair are still lacking. Data on prenatal exposure to NPS are limited. CONCLUSIONS: Maternal hair testing is the most sensitive alternative matrix for identifying drug use during pregnancy, while drug concentrations in the meconium, placenta, and umbilical cord offer the identification of prenatal drug exposure at birth. Adverse developmental outcomes for the infant make it critical to promptly identify maternal drug use to limit fetal exposure or, if determined at birth, to provide resources to the exposed child and family. Alternative matrices offer choices for monitoring and challenge laboratories to deliver highly sensitive and specific analytical methods for detection.

Acute cocaine administration alters permeability of blood-brain barrier in freely-moving rats- Evidence using miniaturized fluorescence microscopy.

BACKGROUND: Cocaine has a variety of negative effects on the central nervous system, including reports of decreased barrier function of brain microvascular endothelial cells. However, few studies have directly shown the effects of cocaine on blood-brain barrier (BBB) function in vivo. The miniature integrated fluorescence microscope (i.e., miniscope) technology was used to visualize cocaine-induced changes in BBB permeability in awake, freely-moving rats. METHODS: The miniscope was implanted in the prefrontal cortex of adult male rats. After recovery and acclimation, rats received an injection of cocaine (5-20 mg/kg ip) 15 minutes following iv infusion of sodium fluorescein, a low molecular weight tracer. Fluorescence intensity was recordedin vivo via the miniscope for 30 minutes or 24 hours post cocaine administration and served as an indicator of BBB permeability. RESULTS: Results demonstrate that cocaine increased the sodium fluorescein extravasation in brain microcirculation in a dose-dependent manner 30 minutes, but not 24 hours after administration. CONCLUSION: We report for the first time using direct visualization of brain microcirculation with the miniscope technology in awake, freely-moving rats, that acute cocaine administration produced a transient increase in the BBB permeability.

Assessment of Striatal Dopamine Transporter Binding in Individuals With Major Depressive Disorder: In Vivo Positron Emission Tomography and Postmortem Evidence.

Importance: Major depressive disorder (MDD) might involve dopamine (DA) reductions. The DA transporter (DAT) regulates DA clearance and neurotransmission and is sensitive to DA levels, with preclinical studies (including those involving inescapable stressors) showing that DAT density decreases when DA signaling is reduced. Despite preclinical data, evidence of reduced DAT in MDD is inconclusive. Objective: Using a highly selective DAT positron emission tomography (PET) tracer ([11C] altropane), DAT availability was probed in individuals with MDD who were not taking medication. Levels of DAT expression were also evaluated in postmortem tissues from donors with MDD who died by suicide. Design, Setting, and Participants: This cross-sectional PET study was conducted at McLean Hospital (Belmont, Massachusetts) and Massachusetts General Hospital (Boston) and enrolled consecutive individuals with MDD who were not taking medication and demographically matched healthy controls between January 2012 and March 2014. Brain tissues were obtained from the Douglas-Bell Canada Brain Bank. For the PET component, 25 individuals with current MDD who were not taking medication and 23 healthy controls recruited from McLean Hospital were included (all provided usable data). For the postmortem component, 15 individuals with depression and 14 healthy controls were considered. Intervention: PET scan. Main Outcomes and Measures: Striatal and midbrain DAT binding potential was assessed. For the postmortem component, tyrosine hydroxylase and DAT levels were evaluated using Western blots. Results: Compared with 23 healthy controls (13 women [56.5%]; mean [SD] age, 26.49 [7.26] years), 25 individuals with MDD (19 women [76.0%]; mean [SD] age, 26.52 [5.92] years) showed significantly lower in vivo DAT availability in the bilateral putamen and ventral tegmental area (Cohen d range, -0.62 to -0.71), and both reductions were exacerbated with increasing numbers of depressive episodes. Unlike healthy controls, the MDD group failed to show an age-associated reduction in striatal DAT availability, with young individuals with MDD being indistinguishable from older healthy controls. Moreover, DAT availability in the ventral tegmental area was lowest in individuals with MDD who reported feeling trapped in stressful circumstances. Lower DAT levels (and tyrosine hydroxylase) in the putamen of MDD compared with healthy controls were replicated in postmortem analyses (Cohen d range, -0.92 to -1.15). Conclusions and Relevance: Major depressive disorder, particularly with recurring episodes, is characterized by decreased striatal DAT expression, which might reflect a compensatory downregulation due to low DA signaling within mesolimbic pathways.

The transition to cocaine addiction: the importance of pharmacokinetics for preclinical models.

A key question in addiction research concerns how, in some individuals, initial recreational or casual patterns of drug use may change brain and psychological function in ways that promote a transition to the problematic patterns of use that define substance use disorders (addiction). In preclinical studies, this is modeled using self-administration procedures. However, most cocaine self-administration procedures produce continuously high brain concentrations of drug, whereas in people, bouts of use are thought to be more intermittent. Here, we ask whether such temporal pharmacokinetic factors matter, by comparing and contrasting the neuropsychological consequences of intermittent vs. long access cocaine self-administration experience. It turns out, the temporal pattern of cocaine use has profound effects on a number of outcomes. First, despite much less total drug consumption, intermittent access to cocaine is more effective in producing addiction-like behavior. Second, intermittent and long access cocaine self-administration change the brain in very different ways to influence motivated behavior. We argue that intermittent access self-administration procedures might be better suited than traditional self-administration procedures for isolating drug-induced changes in neuropsychological function that contribute to the transition to cocaine addiction.

Is atomised intranasal cocaine systemically absorbed during endoscopic sinus surgery?

BACKGROUND: In order to perform endoscopic sinus surgery (ESS) safely and efficiently, preparation of the nasal mucosa with vasoconstrictor agents is crucial to minimise bleeding. There is no single best method, although traditionally cocaine has been the agent of choice. However, there have been concerns over the potential for systemic side effects when applied topically. With this concern in mind, there exists limited contemporary research looking at cocaine absorption in the context of ESS. This study aims to determine the amount and duration of systemic cocaine absorption after intranasal atomised administration of modified Moffett’s solution prior to ESS. METHODOLOGY: Twelve adults undergoing ESS were enrolled. Modified Moffett's solution containing 100 mg cocaine hydrochloride and 1 mg of adrenaline was administered topically 5 minutes prior to surgery. Serum cocaine and the cocaine degradation product, benzoylecgonine, were measured at specific time points up to 12 hrs post administration. RESULTS: Peak plasma cocaine concentration occurred between 60 and 120 minutes post-administration (range 13-31 micrograms/L). The mean peak plasma concentration was 20.35 micrograms/L occurring at 120 minutes post-administration. Benzoylecgonine was detected in 11 subjects at 60 minutes post-administration and in all subjects 12 hours post-administration of cocaine. CONCLUSIONS: This study demonstrates that there are low levels of systemic absorption of cocaine when administered in an atomised modified Moffett’s formulation prior to endoscopic sinus surgery.

A cholecystokinin B receptor antagonist and cocaine interaction, phase I study.

AIMS: RPR 102681, a cholecystokinin-B antagonist, increased dopamine (DA) release and reduced cocaine self-administration in animals. This pilot study sought to assess the safety and pharmacokinetics (PK) of co-administration of RPR 102681 and cocaine, and to confirm the DA release mechanism of RPR 102681. METHODS: Sixteen cocaine-dependent participants were randomized to either placebo or RPR102681 at 3 ascending doses; cocaine was co-administered at steady state of RPR 102681. [11 C]raclopride positron emission tomography scans were conducted at baseline and at each RPR102681 dose. RESULTS: RPR 102681 was well tolerated, and safe to co-administer with cocaine. RPR 102681 did not alter the PK of either cocaine or its metabolite benzoylecgonine and showed no intrinsic abuse liability. There was a trend toward reduction of cocaine craving scores. In contrast to animal studies, RPR 102681 significantly increased the binding potential of [11 C]raclopride in the ventral striatum (t test, P < .001) and caudate nucleus (t test, P < .0001) in a small subset of patients, suggesting that it may reduce intrasynaptic striatal DA. CONCLUSION: Overall, this pilot study suggests that RPR 102681 would be unlikely candidate, as an agonist medication for the treatment for cocaine addiction but worth investigating further for possible role in reducing craving.

Salt-Assisted Liquid-Liquid Extraction of Meconium for Analysis of Cocaine and Amphetamines by Liquid Chromatography-Tandem Mass Spectrometry.

Meconium, the first stool of a newborn, can be analyzed to identify prenatal exposure to drugs of abuse. Meconium accumulates in a fetus during the second and third trimesters of pregnancy providing a wide window of exposure. Identification of in utero drug exposure is essential for the diagnosis and treatment of infants for dependency/withdrawal caused from the exposure. However, testing of meconium samples is often cumbersome and time-consuming. Unlike liquid samples, meconium is a viscous, semisolid, tar-like substance that needs to be individually weighed prior to extraction. Additionally, the meconium matrix is not homogeneous and not easily mixed or extracted. A method for analyzing cocaine and metabolites as well as amphetamines in meconium utilizing ceramic homogenizers prior to salt-assisted liquid-liquid extraction and liquid chromatography tandem-mass spectrometry (LC-MS/MS) is presented.

Drugs of abuse from a different toxicological perspective: an updated review of cocaine genotoxicity.

Cocaine is one of the most widely consumed psychoactive substances and has been recognized as a major public health concern for many years. While several aspects of the toxicology of cocaine have been thoroughly described in the literature, namely its effects on different target organs, other toxicological features should not be disregarded. In this perspective, the in vitro and in vivo genotoxic effects of cocaine, along with the genotoxicity data from human exposure, especially in the context of "crack" smoking, were reviewed. Some concerns regarding (1) the chronic abuse and forms of cocaine, (2) the role of metabolism and (3) the mode of action of cocaine were discussed. The major limitations of the experimental and human studies available were also addressed and some research gaps in this field identified. Overall, although the genotoxicity of cocaine is still a matter of discussion, this psychoactive substance exhibits a genotoxic potential that should be further considered.

TV-1380 attenuates cocaine-induced changes in cardiodynamic parameters in monkeys and reduces the formation of cocaethylene.

BACKGROUND: TV-1380 is a rationally mutated, human BChE fused to human serum albumin that has high hydrolytic enzymatic activity against cocaine and as well as an extended elimination half-life. OBJECTIVE: The present studies examined the safety of TV-1380 and its protective effect when given to monkeys alone or concomitantly with cocaine and ethanol. METHODS: A set of studies was conducted in monkeys with TV-1380. The parameters tested included telemetric assessment of cardiovascular parameters, clinical pathology, plasma analysis of cardiac troponin I, ex-vivo analyses of cocaethylene and PK analysis of serum concentrations of TV-1380, cocaine and its metabolites, and histopathological examinations. RESULTS: TV-1380 treatment in monkeys was well tolerated. TV-1380 pretreatment prior to cocaine significantly attenuated the cardiac effects of cocaine and reduced cocaine-induced elevations in serum cardiac troponin I. TV-1380 changed the metabolic fate of cocaine resulting in decreased exposure to benzoylecgonine, while increasing the exposure to ecgonine methyl ester in plasma.TV-1380 reduced the plasma levels of the toxic metabolite cocaethylene formed after co-administration of ethanol and cocaine. CONCLUSION: The results of this study demonstrate that TV-1380 not only accelerates the elimination of cocaine, but also protects the treated animal from the cardiac effects of cocaine, and inhibits the formation of the toxic cocaethylene metabolite when cocaine is given together with ethanol, supporting further clinical development of modified BChE products as possible treatments for cocaine abuse.

Ontogeny of cocaine-induced behaviors and cocaine pharmacokinetics in male and female neonatal, preweanling, and adult rats.

RATIONALE: Ontogenetic differences in the behavioral responsiveness to cocaine have often been attributed to the maturation of dopaminergic elements (e.g., dopamine transporters, D2High receptors, receptor coupling, etc.). OBJECTIVE: The purpose of this study was to determine whether ontogenetic changes in cocaine pharmacokinetics might contribute to age-dependent differences in behavioral responsiveness. METHODS: Male and female neonatal (PD 5), preweanling (PD 10 and PD 20), and adult (PD 70) rats were injected (IP) with cocaine or saline and various behaviors (e.g., locomotor activity, forelimb paddle, vertical activity, head-down sniffing, etc.) were measured for 90 min. In a separate experiment, the dorsal striata of young and adult rats were removed at 10 time points (0-210 min) after IP cocaine administration. Peak cocaine values, cocaine half-life, and dopamine levels were determined using HPLC. RESULTS: When converted to percent of saline controls, PD 5 and PD 10 rats were generally more sensitive to cocaine than older rats, but this effect varied according to the behavior being assessed. Peak cocaine values did not differ according to age or sex, but cocaine half-life in brain was approximately 2 times longer in PD 5 and PD 10 rats than adults. Cocaine pharmacokinetics did not differ between PD 20 and PD 70 rats. CONCLUSIONS: Differences in the cocaine-induced behavioral responsiveness of very young rats (PD 5 and PD 10) and adults may be attributable, at least in part, to pharmacokinetic factors; whereas, age-dependent behavioral differences between the late preweanling period and adulthood cannot readily be ascribed to cocaine pharmacokinetics.

[Acute kidney injury and rhabdomyolysis after cocaine overdose: case report and literature review].

Cocaine, a natural alkaloid derived from the coca plant, is one of the most commonly used illicit drugs. Cocaine abuse causes systemic adverse effects like stroke, myocardic infarction, arterial dissection, vascular thrombosis and rhabdomyolysis. Cocaine use is, also, associated with renal complications such as acute kidney injury, vasculitis, acute interstitial nephritis, chronic kidney disease, malignant hypertension with thrombotic microangiopathy. Acute kidney injury may or may be not associated to rhabdomyolysis. Rhabdomyolysis caused by cocaine abuse is multifactorial, involving tissue ischemia secondary to vasoconstriction and cellular damage caused by the drug. We report a 50-year-old man with history of chronic hepatitis C and substance abuse admitted to our unit with severe rhabdomyolysis and acute kidney failure after nasal insufflation of cocaine overdose. Renal function recovered after several treatments of dialysis. We conclude that cocaine adversely impacts kidney function ; in addition cocaine and rhabdomyolysis are the double danger for acute kidney injury. Medical management of cocaine toxicity requires a multisystem approach, with close monitoring cardiac, neurological and renal function.

Membrane cholesterol removal and replenishment affect rat and monkey brain monoamine transporters.

The dopamine transporter (DAT) is abundantly expressed in the striatum where it removes extracellular dopamine into the cytosol of presynaptic nerve terminals. It is the target of drugs of abuse and antidepressants. There is a loss of the DAT in Parkinson's disease affecting release of levodopa implicated in levodopa-induced dyskinesias. This study investigated the effect of cholesterol on DAT, serotonin transporter (SERT) and vesicular monoamine transporter 2 (VMAT2) in monkey and rat brains in vitro. DAT protein levels measured by Western blot remained unchanged with in vitro methyl-ß-cyclodextrin (MCD) incubations to remove membrane cholesterol or with incubations to increase membrane cholesterol content. By contrast, striatal DAT specific binding labelled with [125I]RTI-121 or with [125I]RTI-55 decreased with increasing concentrations of MCD and increased with cholesterol loading. Moreover, [125I]RTI-121 specific binding of striatal membranes depleted of cholesterol with MCD was restored to initial DAT content with addition of cholesterol showing its rapid and reversible effect. By contrast, striatal VMAT2 and SERT specific binding showed no or limited changes by cholesterol manipulations. Similar results were obtained for monkey caudate nucleus, putamen and nucleus accumbens. Membrane microviscosity was assessed by fluorescence polarization spectroscopy, using the probe 1,6-diphenyl-1,3,5-hexatriene. DAT changes positively correlated with changes of membrane microviscosity in rat and monkey brain regions investigated and with membrane cholesterol contents. Similar findings were observed with desmosterol but to a lower extent than with cholesterol. These results show an important effect of cholesterol on the DAT associated with microviscosity changes that should be considered in drug therapies.

Efecto de la cocaína sobre la inhibición por prepulso de la respuesta de sobresalto / Effects of cocaine on prepulse inhibition of the startle response

Introducción. La inhibición por prepulso (IPP) de la respuesta de sobresalto es una medida de sincronización sensitivomotora basada en la respuesta del reflejo de sobresalto. Un déficit en la IPP se ha observado en pacientes psiquiátricos, especialmente con esquizofrenia, así como en sujetos vulnerables a desarrollarla. Asimismo, los consumidores de cocaína presentan un alto índice de patologías psiquiátricas como la esquizofrenia. Objetivo. Conocer las alteraciones que el consumo de cocaína puede producir en la IPP. Desarrollo. Se realiza una revisión exhaustiva de los estudios, tanto clínicos como con modelos animales, que hayan evaluado la IPP tras el consumo o la administración de cocaína. Se sugieren bases neurales y mecanismos de acción subyacentes para explicar los resultados. Conclusiones. La cocaína altera la IPP a través de su acción sobre el sistema dopaminérgico. La administración aguda de cocaína disminuye la IPP al aumentar la dopamina, mientras que con el consumo crónico, dependiendo del tiempo de abstinencia, la IPP puede restablecerse. Sin embargo, los efectos de la cocaína sobre la IPP parecen depender de los niveles basales de la IPP que muestre el individuo. Así, dado que un déficit en la IPP se ha relacionado con una mayor vulnerabilidad a desarrollar patologías mentales como la esquizofrenia, los niveles de la IPP en los sujetos podrían considerarse como un biomarcador de vulnerabilidad psiquiátrica. Por ello, conocer mejor el efecto que drogas como la cocaína ejercen sobre la IPP puede ayudar a comprender el desarrollo de la patología dual (AU)

Introduction. Prepulse inhibition (PPI) of the startle response is an index used to evaluate how the pre-attention system. works. PPI is altered in patients with a mental disorder such as schizophrenia and in subjects who are vulnerable to it. Likewise, cocaine users also frequently exhibit psychiatric disorders as schizophrenia. Aim. To know the alterations that cocaine produces on PPI. Development. A comprehensive review is carried out, covering both clinical and preclinical studies with animal models that have evaluated the effects of cocaine exposure on the PPI paradigm. Underlying neural bases and mechanisms of action are suggested to explain these findings. Conclusions. Cocaine alters PPI through its action on the dopaminergic system. Acute exposure of cocaine decreases PPI by increasing dopamine, while with chronic use, depending on withdrawal time, PPI can be restored. However, the effects of cocaine on PPI appear to depend on the baseline levels of PPI shown by the individual. Thus, since a deficit in PPI has been associated with a greater vulnerability to developing mental pathologies such as schizophrenia, PPI level in subjects could be considered as a biomarker of psychiatric vulnerability. Therefore, a better understanding of the effect of drugs such as cocaine on PPI may help to understand the development of dual pathology (AU)