Effects Of Chronic Cocaine Exposure Research Articles

Cocaine perturbs mitovesicle biology in the brain.

Cocaine, an addictive psychostimulant, has a broad mechanism of action, including the induction of a wide range of alterations in brain metabolism and mitochondrial homeostasis. Our group recently identified a subpopulation of non-microvesicular, non-exosomal extracellular vesicles of mitochondrial origin (mitovesicles) and developed a method to isolate mitovesicles from brain parenchyma. We hypothesised that the generation and secretion of mitovesicles is affected by mitochondrial abnormalities induced by chronic cocaine exposure. Mitovesicles from the brain extracellular space of cocaine-administered mice were enlarged and more numerous when compared to controls, supporting a model in which mitovesicle biogenesis is enhanced in the presence of mitochondrial alterations. This interrelationship was confirmed in vitro. Moreover, cocaine affected mitovesicle protein composition, causing a functional alteration in mitovesicle ATP production capacity. These data suggest that mitovesicles are previously unidentified players in the biology of cocaine addiction and that target therapies to fine-tune brain mitovesicle functionality may be beneficial to mitigate the effects of chronic cocaine exposure.

Effects of chronic cocaine exposure on the circadian rhythmic expression of the clock genes in reward-related brain areas in rats

Drug addiction is a widespread social problem, which not only brings adverse consequences to the human body, but also causes great burden to the society. However, it's still unclear how the long-term and sustained cocaine exposure will affect clock genes’ expression in the reward related brain areas. We hypothesize that chronic cocaine exposure causes changes in the circadian rhythmic expression of clock genes in brain regions associated with reward, since previous studies have shown that cocaine use causes circadian disorders. Sprague-Dawley male rats were administrated with cocaine 20 mg/kg at ZT4 through intraperitoneal injection for 21 consecutive days. Twenty-four hours after the last cocaine administration brain samples were collected at 4-h intervals for 24 h (every 4h: ZT 0; ZT 4; ZT 8; ZT 12; ZT 16; ZT 20) to examine expression of rPer1, rPer2, rPer3, rCry, rBmal1 and rClock by quantitative real-time reverse-transcription polymerase chain reaction (RT-PCR). We found that chronic cocaine exposure to rats resulted in significantly disturbances in expression of clock genes in reward related brain areas compared to saline - treated rats. In cocaine-treated rats, rPer1 expression in the suprachiasmatic nucleus (SCN), prefrontal cortex (PFC) and ventral tegmental area (VTA); rPer2 expression in the nucleus accumbens (NAc) shell and hippocampus; rPer3 expression in the NAc core; rCry expression in the SCN and PFC; rBmal1 expression in the SCN and NAc core showed robust circadian rhythms that were essentially identical to those in control rats. However, robust circadian rhythm in rPer1 expression in the SCN and rCry expression in the PFC was nearly completely phase - reversed in cocaine-treated rats. A blunting of circadian oscillations of rPer1 expression occurred in the NAc core and shell and hippocampus; of rPer2 expression occurred in the SCN, PFC, NAc core and hippocampus; of rPer3 expression occurred in the SCN, PFC, NAc shell, hippocampus and VTA; of rCry expression occurred in the NAc core and shell, hippocampus and VTA; of rBmal1 expression occurred in the PFC, NAc shell, hippocampus and VTA in cocaine - treated rats. These rhythm changes accompanied by significant increase in rPer1, rPer2, rPer3 and rBmal1 in the PFC, rPer1, rPer2 and rBmal1 in the hippocampus; significant decrease in rPer2, rPer3 and rCry in the SCN, rPer3, rCry, rBmal1 and rClock in the NAc core compared to control rats. rClock expression in cocaine - treated rats showed no rhythmic change, identical to control rats.These results suggest that chronic cocaine exposure results in disturbances in clock genes’ expression in reward related areas.

Chronic cocaine induces HIF-VEGF pathway activation along with angiogenesis in the brain.

Cocaine induces vasoconstriction in cerebral vessels, which with repeated use can result in transient ischemic attacks and cerebral strokes. However, the neuroadaptations that follow cocaine’s vasoconstricting effects are not well understood. Here, we investigated the effects of chronic cocaine exposure (2 and 4 weeks) on markers of vascular function and morphology in the rat brain. For this purpose we measured nitric oxide (NO) concentration in plasma, brain neuronal nitric oxide synthase (nNOS or NOS1), HIF-1α, and VEGF expression in different brain regions, i.e., middle prefrontal cortex, somatosensory cortex, nucleus accumbens, and dorsal striatum, using ELISA or Western blot. Additionally, microvascular density in these brain regions was measured using immunofluorescence microscopy. We showed that chronic cocaine significantly affected NOS1, HIF-1α and VEGF expression, in a region- and cocaine treatment-time- dependent manner. Cerebral microvascular density increased significantly in parallel to these neurochemical changes. Furthermore, significant correlations were detected between VEGF expression and microvascular density in cortical regions (middle prefrontal cortex and somatosensory cortex), but not in striatal regions (nucleus accumbens and dorsal striatum). These results suggest that following chronic cocaine use, as cerebral ischemia developed, NOS1, the regulatory protein to counteract blood vessel constriction, was upregulated; meanwhile, the HIF-VEGF pathway was activated to increase microvascular density (i.e., angiogenesis) and thus restore local blood flow and oxygen supply. These physiological responses were triggered presumably as an adaptation to minimize ischemic injury caused by cocaine. Therefore, effectively promoting such physiological responses may provide novel and effective therapeutic solutions to treat cocaine-induced cerebral ischemia and stroke.

Power spectrum scale invariance as a neural marker of cocaine misuse and altered cognitive control.

BackgroundMagnetic resonance imaging (MRI) has highlighted the effects of chronic cocaine exposure on cerebral structures and functions, and implicated the prefrontal cortices in deficits of cognitive control. Recent investigations suggest power spectrum scale invariance (PSSI) of cerebral blood oxygenation level dependent (BOLD) signals as a neural marker of cerebral activity. We examined here how PSSI is altered in association with cocaine misuse and impaired cognitive control.MethodsEighty-eight healthy (HC) and seventy-five age and gender matched cocaine dependent (CD) adults participated in functional MRI of a stop signal task (SST). BOLD images were preprocessed using standard procedures in SPM, including detrending, band-pass filtering (0.01–0.25 Hz), and correction for head motions. Voxel-wise PSSI measures were estimated by a linear fit of the power spectrum with a log-log scale. In group analyses, we examined differences in PSSI between HC and CD, and its association with clinical and behavioral variables using a multiple regression. A critical component of cognitive control is post-signal behavioral adjustment, which is compromised in cocaine dependence. Therefore, we examined the PSSI changes in association with post-signal slowing (PSS) in the SST.ResultsCompared to HC, CD showed decreased PSS and PSSI in multiple frontoparietal regions. PSSI was positively correlated with PSS in HC in multiple regions, including the left inferior frontal gyrus (IFG) and right supramarginal gyrus (SMG), which showed reduced PSSI in CD.ConclusionsThese findings suggest disrupted connectivity dynamics in the fronto-parietal areas in association with post-signal behavioral adjustment in cocaine addicts. These new findings support PSSI as a neural marker of impaired cognitive control in cocaine addiction.

Long-term effects of chronic cocaine exposure throughout adolescence on anxiety and stress responsivity in a Wistar rat model

Adolescents display increased vulnerability to engage in drug experimentation. This is often considered a risk factor for later drug abuse. In this scenario, the permanent effects of cocaine exposure during adolescence on anxiety levels and stress responsivity, which may result in behavioral phenotypes prone to addiction, are now starting to be unveiled. Thus, the purpose of the present study was to evaluate the long-lasting effects of chronic cocaine administration during adolescence, on anxiety-like behavior and on stress response. Adolescent male Wistar rats were daily administered 45-mg cocaine/kg of body weight in three equal intraperitoneal doses with 1-h interval, from postnatal day (PND) 35 to 50. The effects of cocaine administration on anxiety levels, assessed in the Elevated Plus Maze (EPM), and on social stress response, assessed in the resident–intruder paradigm (R/I), were evaluated 10days after withdrawal, when rats were reaching the adulthood. The underlying dopaminergic activity, and the corticosterone and testosterone levels were determined. Our results showed that cocaine induced long-lasting alterations in the hypothalamus–pituitary–adrenals (HPA) axis function and in testosterone levels. Such alterations resulted in significant and enduring changes in behavioral responses to environmental challenges, such as the EPM and R/I, including the evaluation of potential threats that may lead to high-risk behavior and low-benefit choices. This was further supported by an altered dopaminergic function in the amygdala and hippocampus. The present findings provide new insights into how the use of cocaine during adolescent development may modulate emotional behavior later in life. Compromised ability to recognize and deal with potential threats is an important risk factor to perpetuate compulsive drug seeking and relapse susceptibility.

Chronic cocaine administration causes extensive white matter damage in brain: Diffusion tensor imaging and immunohistochemistry studies

The effect of chronic cocaine exposure on multiple white matter structures in rodent brain was examined using diffusion tensor imaging (DTI), locomotor behavior, and end point histology. The animals received either cocaine at a dose of 100mg/kg (N=19), or saline (N=17) for 28 days through an implanted osmotic minipump. The animals underwent serial DTI scans, locomotor assessment, and end point histology for determining the expressions of myelin basic protein (MBP), neurofilament-heavy protein (NF-H), proteolipid protein (PLP), Nogo-A, aquaporin-4 (AQP-4), and growth associated protein-43 (GAP-43). Differences in the DTI measures were observed in the splenium (scc) and genu (gcc) of the corpus callosum (cc), fimbria (fi), and the internal capsule (ic). A significant increase in the activity in the fine motor movements and a significant decrease in the number of rearing events were observed in the cocaine-treated animals. Reduced MBP and Nogo-A and increased GAP-43 expressions were most consistently observed in these structures. A decrease in the NF-H expression was observed in fi and ic. The reduced expression of Nogo-A and the increased expression of GAP-43 may suggest destabilization of axonal connectivity and increased neurite growth with aberrant connections. Increased GAP-43 suggests drug-induced plasticity or a possible repair mechanism response. The findings indicated that multiple white matter tracts are affected following chronic cocaine exposure.

Perseveration in the presence of punishment: The effects of chronic cocaine exposure and lesions to the prefrontal cortex

Perseveration is the repetition of a previously appropriate response in a manner, or context, which is detrimental to the individual. Although both cocaine exposure and prefrontal cortex (PFC) dysfunctions have been implicated in perseverative-like behaviours, the underlying nature of the impairments has been debated.The current study tested whether chronic cocaine exposure and PFC lesions induce perseverative-like behaviours by causing insensitivity to punishment. Food-restricted male Sprague-Dawley rats were trained to respond for sucrose on concurrent schedules of reinforcement. After initial training, rats received either a sensitizing regimen of cocaine exposure, or excitotoxic lesions to subregions of the PFC. The test of perseveration involved a choice of responding between two levers associated with fixed ratio and progressive ratio (PR) schedules. Responding on the PR lever was punished by a 1min timeout period. It was found that, unlike control subjects, those exposed to chronic cocaine, or with lesions to the medial prefrontal cortex, were significantly slower in adapting their responding to avoid punishment.The current study provides evidence that both cocaine exposure and lesions to the prefrontal cortex can increase perseverative-like responding, although the magnitude and permanence of these effects are contingent on the nature of the task.

Effects of nicotinic acetylcholine receptor agonists on cognition in rhesus monkeys with a chronic cocaine self-administration history

Cocaine use is associated with impaired cognitive function, which may negatively impact treatment outcomes. One pharmacological strategy to improve cognition involves nicotinic acetylcholine receptor (nAChR) stimulation. However, the effects of chronic cocaine exposure on nAChR distribution and function have not been characterized. Thus, one goal of this study was to examine nAChR availability in rhesus monkeys with an extensive cocaine self-administration history (n = 4; ∼6 years, mean intake, 1463 mg/kg) compared to age-matched cocaine-naive control monkeys (n = 5). Using [11C]-nicotine and positron emission tomography (PET) imaging, cocaine-experienced monkeys showed significantly higher receptor availability in the hippocampus compared to cocaine-naive monkeys. A second goal was to examine the effects of nAChR agonists on multiple domains of cognitive performance in these same monkeys. For these studies, working memory was assessed using a delayed match-to-sample (DMS) task, associative learning and behavioral flexibility using stimulus discrimination and reversal learning tasks. When administered acutely, the nonselective high-efficacy agonist nicotine, the low-efficacy α4β2* subtype-selective agonist varenicline and the high-efficacy α7 subtype-selective agonist, PNU-282987 significantly improved DMS performance in both cocaine-naive and cocaine-experienced monkeys. Individual doses of nicotine and varenicline that engendered maximum cognitive enhancing effects on working memory did not affect discrimination or reversal learning, while PNU-282987 disrupted reversal learning in the cocaine-naive monkeys. These findings indicate that a cocaine self-administration history influenced nAChR distribution and the effects of nAChR agonists on cognitive performance, including a reduced sensitivity to the disrupting effects on reversal learning. The cognitive enhancing effects of nAChR agonists may be beneficial in combination with behavioral treatments for cocaine addiction.This article is part of a Special Issue entitled ‘Cognitive Enhancers’.

The endogenous opioid system in cocaine addiction: what lessons have opioid peptide and receptor knockout mice taught us?

Cocaine addiction has become a major concern in the UK as Britain tops the European 'league table' for cocaine abuse. Despite its devastating health and socio-economic consequences, no effective pharmacotherapy for treating cocaine addiction is available. Identifying neurochemical changes induced by repeated drug exposure is critical not only for understanding the transition from recreational drug use towards compulsive drug abuse but also for the development of novel targets for the treatment of the disease and especially for relapse prevention. This article focuses on the effects of chronic cocaine exposure and withdrawal on each of the endogenous opioid peptides and receptors in rodent models. In addition, we review the studies that utilized opioid peptide or receptor knockout mice in order to identify and/or clarify the role of different components of the opioid system in cocaine-addictive behaviours and in cocaine-induced alterations of brain neurochemistry. The review of these studies indicates a region-specific activation of the µ-opioid receptor system following chronic cocaine exposure, which may contribute towards the rewarding effect of the drug and possibly towards cocaine craving during withdrawal followed by relapse. Cocaine also causes a region-specific activation of the κ-opioid receptor/dynorphin system, which may antagonize the rewarding effect of the drug, and at the same time, contribute to the stress-inducing properties of the drug and the triggering of relapse. These conclusions have important implications for the development of effective pharmacotherapy for the treatment of cocaine addiction and the prevention of relapse.

Group II metabotropic glutamate receptors in the striatum of non-human primates: Dysregulation following chronic cocaine self-administration

A growing body of evidence has demonstrated a role for group II metabotropic glutamate receptors (mGluRs) in the reinforcing effects of cocaine. These receptors are important given their location in limbic-related areas, and their ability to control the release of glutamate and other neurotransmitters. They are also potential targets for novel pharmacotherapies for cocaine addiction. The present study investigated the impact of chronic cocaine self-administration (9.0 mg/kg/session for 100 sessions, 900 mg/kg total intake) on the densities of group II mGluRs, as assessed with in vitro receptor autoradiography, in the striatum of adult male rhesus monkeys. Binding of [ 3H]LY341495 to group II mGluRs in control animals was heterogeneous, with a medial to lateral gradient in binding density. Significant elevations in the density of group II mGluRs following chronic cocaine self-administration were measured in the dorsal, central and ventral portions of the caudate nucleus ( P < 0.05), compared to controls. No differences in receptor density were observed between the groups in either the putamen or nucleus accumbens. These data demonstrate that group II mGluRs in the dorsal striatum are more sensitive to the effects of chronic cocaine exposure than those in the ventral striatum. Cocaine-induced dysregulation of the glutamate system, and its consequent impact on plasticity and synaptic remodeling, will likely be an important consideration in the development of novel pharmacotherapies for cocaine addiction.

Glycogen synthase kinase 3β in the nucleus accumbens core mediates cocaine‐induced behavioral sensitization

Glycogen synthase kinase 3beta (GSK-3beta) is a ubiquitous serine/threonine protein kinase involved in a number of signaling pathways. Previous studies have demonstrated a role for GSK-3beta in the synaptic plasticity underlying dopamine-associated behaviors and diseases. Drug sensitization is produced by repeated exposure to the drug and is thought to reflect neuroadaptations that contribute to addiction. However, the role of GSK-3beta in cocaine-induced behavior sensitization has not been examined. The present study investigated the effects of chronic cocaine exposure on GSK-3beta activity in the nucleus accumbens (NAc) and determined whether changes in GSK-3beta activity in the NAc are associated with cocaine-induced locomotor sensitization. We also explored whether blockade of GSK-3beta activity in the NAc inhibits the initiation and expression of cocaine-induced locomotor sensitization in rats using systemic or brain region-specific administration of the GSK-3beta inhibitors lithium chloride (LiCl) and SB216763. GSK-3beta activity in the NAc core, but not NAc shell, increased after chronic cocaine (10 mg/kg, i.p.) administration. The initiation and expression of cocaine-induced locomotor sensitization was attenuated by systemic administration of LiCl (100 mg/kg, i.p.) or direct infusion of SB216763 (1 ng/side) into the NAc core, but not NAc shell. Collectively, these results indicate that GSK-3beta activity in the NAc core, but not NAc shell, mediates the initiation and expression of cocaine-induced locomotor sensitization, suggesting that GSK-3beta may be a potential target for the treatment of cocaine addiction.

The effects of chronic cocaine exposure on impulsivity in rats

Chronic exposure to cocaine increases impulsive behavior, leading to a reduced preference for a larger, delayed reinforcer over a smaller, immediate reinforcer. This study examined the development of impulsivity over multiple days of cocaine exposure and cessation of cocaine. Male Sprague-Dawley rats were trained on a discrete-trials delay-discounting task, during which they chose between a small, immediate reinforcer of one food pellet and a large reinforcer of 3 food pellets after an adjusted delay (0, 10, 20, 40, and 60 s). When stable preferences were established, rats received daily injections of deionized water or cocaine (3, 7.5, 15 mg/kg) 5 min before the delay-discounting task for 9 days. All groups showed an increased preference for the smaller reinforcer as delay to the larger reinforcer increased. Repeated exposure to 7.5 or 15 mg/kg cocaine further decreased preference for the larger reinforcer over the 9 days. When cocaine administration was discontinued, preference for the larger reinforcer returned to baseline levels in the 7.5 mg/kg group, but remained depressed in the 15 mg/kg group. These findings indicate that continuing exposure to cocaine dose-dependently decreases choice for the large reinforcer over time, and that the bias remains when cocaine is no longer administered, and that the recovery after high doses of cocaine occurs slowly.

Long-term effects of chronic cocaine exposure during adolescence in the aggressive and social behaviour of young adult male rats

Event Abstract Back to Event Long-term effects of chronic cocaine exposure during adolescence in the aggressive and social behaviour of young adult male rats Cecilia Juliana Alves1, 2, A. Magalhaes1, L. De-Sousa1, 2, M. A. Tavares1, 3, P. R. Monteiro1, 4 and Teresa Summavielle1, 4* 1 Universidade do Porto, Instituto de Biologia Molecular e Celular (IBMC), Portugal 2 Instituto de Ciencias Biomedicas de Abel Salazar, Portugal 3 University of Porto, Faculty of Medicine, Portugal 4 Escola Superior de Tecnologia da Saúde do Porto do IPP, Portugal This study aimed to evaluate the long-term effects of chronic cocaine exposure during adolescence in the aggressive behaviour of young adult male rats through the social threat provided by the resident-intruder paradigm. The neurochemical and stress-hormone response to the social threat were also evaluated. To achieve this objective it was developed an animal model of chronic cocaine administration during adolescence in Wistar rats. Adolescent males were submitted to a chronic “binge” pattern of cocaine-hydrochloride administration (3x15 mg/kg/day at hourly intervals; intraperitoneal), from postnatal day (PND) 35 to PND 50. Controls were given a 0.9% NaCl solution following the same experimental protocol. Ten days after the last administration of cocaine, rats were tested using the resident-intruder paradigm. Offensive, defensive and social behaviour were registered during 10 min. At the end of the test the substantia nigra and the ventral tegmental area (SN-VTA), the dorsal raphe nucleus, the amygdala, the hippocampus, the prefrontal cortex and the hypothalamus were collected for neurochemical determination. Plasma was also collected for corticosterone levels determination. Cocaine-treated male rats presented no differences in frequency, duration or latency of the offensive behaviours, however, these animals displayed increased duration of the anogenital sniffing behaviour, and increased latency and lower frequency of flight behaviour. Neurochemical data indicated that after the behavioural test cocaine-treated rats displayed lower levels of DOPAC in the hippocampus and lower 5-HT turnover rate in the SN-VTA. The corticosterone response to the resident- intruder paradigm did not differ between cocaine-treated and control animals. The results seem to indicate that although cocaine treatment during adolescence did not affected the aggressive behaviour of young adult rats; it affected social investigation that was increased by pre-exposure to cocaine. Consistently, the observed alterations in the dopaminergic and serotonergic systems were not associated with aggressive behaviour, but may have been relevant to the increased social investigation observed in cocaine-treated rats in response to the challenge provided by the test.Alves CJ was granted by FCT (SFRH/BD/17195/2004) Conference: 11th Meeting of the Portuguese Society for Neuroscience, Braga, Portugal, 4 Jun - 6 Jun, 2009. Presentation Type: Poster Presentation Topic: Neuronal Communication Citation: Juliana Alves C, Magalhaes A, De-Sousa L, Tavares MA, Monteiro PR and Summavielle T (2009). Long-term effects of chronic cocaine exposure during adolescence in the aggressive and social behaviour of young adult male rats. Front. Neurosci. Conference Abstract: 11th Meeting of the Portuguese Society for Neuroscience. doi: 10.3389/conf.neuro.01.2009.11.139 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 11 Aug 2009; Published Online: 11 Aug 2009. * Correspondence: Teresa Summavielle, Universidade do Porto, Instituto de Biologia Molecular e Celular (IBMC), Porto, Portugal, tsummavi@ibmc.up.pt Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Cecilia Juliana Alves A. Magalhaes L. De-Sousa M. A Tavares P. R Monteiro Teresa Summavielle Google Cecilia Juliana Alves A. Magalhaes L. De-Sousa M. A Tavares P. R Monteiro Teresa Summavielle Google Scholar Cecilia Juliana Alves A. Magalhaes L. De-Sousa M. A Tavares P. R Monteiro Teresa Summavielle PubMed Cecilia Juliana Alves A. Magalhaes L. De-Sousa M. A Tavares P. R Monteiro Teresa Summavielle Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Effects of chronic cocaine exposure on corticotropin-releasing hormone binding protein in the central nucleus of the amygdala and bed nucleus of the stria terminalis

The neuropeptide, corticotropin-releasing hormone (CRH), has been shown to play a role in behavioral and neurobiological effects of drugs of abuse. An important modulator of CRH, the CRH binding protein (CRH-BP), has not, on the other hand, been assessed for its role in drug-associated effects. The primary objective of the present experiment was to assess whether prior, chronic exposure to cocaine modulates expression of CRH-BP, and to compare expression of the BP with that of the peptide itself. We assessed CRH-BP and CRH mRNA expression in two brain regions where CRH is known to affect responses to drugs of abuse; namely, the central nucleus of the amygdala (CeA) and bed nucleus of the stria terminalis (BNST). Male Long-Evans rats were given 14 daily injections of cocaine (30 mg/kg, i.p.) or saline. One, 3, 10, 28, or 42 days post-treatment, animals were killed and adjacent brain sections through the CeA and BNST were processed for CRH-BP and CRH by in situ hybridization. In the CeA, cocaine pre-exposure increased both CRH and CRH-BP mRNA expression 1 day post-treatment. In the dorsal BNST, cocaine pre-exposure elevated levels of CRH-BP, but not CRH, mRNA 3 days post-treatment. Taken together, the results suggest that withdrawal-induced changes in the expression of the CRH-BP, and CRH itself, are relatively short-lived and that a dysregulation in basal expression of either gene is not likely responsible for long-lasting behavioral effects noted with cocaine and other drugs of abuse.

Metabolic Mapping of the Effects of Cocaine during the Initial Phases of Self-Administration in the Nonhuman Primate

Because most human studies of the neurobiological substrates of the effects of cocaine have been performed with drug-dependent subjects, little information is available about the effects of cocaine in the initial phases of drug use before neuroadaptations to chronic exposure have developed. The purpose of the present study, therefore, was to define the substrates that mediate the initial effects of cocaine in a nonhuman primate model of cocaine self-administration using the 2-[14C]deoxyglucose method. Rhesus monkeys were trained to self-administer 0.03 mg/kg per injection (N = 4) or 0.3 mg/kg per injection (N = 4) cocaine and compared with monkeys trained to respond under an identical schedule of food reinforcement (N = 4). Monkeys received 30 reinforcers per session, and metabolic mapping was conducted at the end of the fifth self-administration session. Cocaine self-administration reduced glucose utilization in the mesolimbic system, including the ventral tegmental area, ventral striatum, and medial prefrontal cortex. In addition, metabolic activity was increased in the dorsolateral and dorsomedial prefrontal cortex, as well as in the mediodorsal nucleus of the thalamus. These latter effects are distinctly different from those seen after the noncontingent administration of cocaine, suggesting that self-administration engages circuits beyond those engaged merely by the pharmacological actions of cocaine. The involvement of cortical areas subserving working memory suggests that strong associations between cocaine and the internal and external environment are formed from the very outset of cocaine self-administration. The assessment of the effects of cocaine at a time not readily evaluated in humans provides a baseline from which the effects of chronic cocaine exposure can be investigated.

Outcome related electrophysiological subtypes of cocaine dependence.

We previously described the existence of two quantitative EEG (QEEG) subtypes of cocaine dependent males, identified at baseline, displaying differential proneness to relapse. The current study expands the population to include females and enhances the measure set to include both QEEG and somatosensory EP (SEP) features. Fifty-seven cocaine dependent adults (16 F, 41 M) were evaluated 5-14 days after last cocaine use, while in residence at a drug-free therapeutic community. The median length of stay in treatment (continued abstinence) was 25 weeks. Using a small subset of QEEG and SEP baseline features, three subtypes (CLUS) were identified. CLUS 2 (n = 25) and CLUS 3 (n = 23) replicated the published subtypes, while CLUS 1 (n = 9) was previously undescribed. Cluster membership was significantly associated with length of stay in treatment (chi 2 = 13.789, P < 0.001), but not with length of exposure to crack cocaine or to any demographic or clinical features. Seventy-eight percent of CLUS 1 and 65% of CLUS 3 left treatment < or = 25 weeks, whereas 80% of CLUS 2 remained in treatment > 25 weeks. The existence of outcome related subtypes may reflect: [1] differential neurophysiological vulnerability, "traits," predisposing individuals to cocaine addiction; or [2] differential neurosensitivity, "states," due to the effects of chronic cocaine exposure, and associated differences in treatment outcome. Using Variable Resolution Electrical Tomographic Analysis (VARETA), the mathematically most probable neuroanatomical source of the scalp recorded EEG data was localized. Computation of VARETA on the baseline Cluster profiles suggest significant differences in the underlying pathophysiology of these subtypes.

Chronic cocaine alters hemodynamics and leukocyte-endothelial interactions in rat mesenteric venules

We investigated the effects of chronic cocaine exposure on the microcirculation in the rat mesenteric venules under both non-inflammatory and FMLP-induced inflammatory conditions. Chronic cocaine significantly increased WBC rolling flux in both conditions, and potentiated FMLP-induced leukocyte-endothelial cell adhesion (LEA). In cocaine-treated animals, total WBC number increased by 91%, and the ratio of white blood cell to red blood cell velocity was significantly lower, while vessel diameter was unchanged. Chronic cocaine decreased serum levels of tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6), but had no effect on interleukin-1 beta (IL-1β). Expression of intercellular adhesion molecule-1 (ICAM-1) was increased in mesenteric venules following chronic cocaine exposure, and may be one of the mechanisms underlying enhancement of FMLP-induced LEA. The increase in WBC count, WBC flux and LEA, and the change in cell velocity seen in the cocaine-treated animals could cause a decrease in effective vessel diameter and a change in intravascular resistance, and may underlie the progressive vascular damage seen in chronic cocaine-abusing individuals.

Cocaine-induced alterations in the density of monoaminergic receptors in the embryonic guinea pig cerebral wall.

Quantitative receptor autoradiography was used to examine the effect of chronic cocaine exposure on the density of alpha1-, alpha2- and beta-adrenergic, 5-HT1A- and 5-HT2-serotonergic, and D1- and D2-dopaminergic receptors in the fetal guinea pig cerebral wall which contained forming motor area of the cerebral cortex. The pregnant guinea pig received two daily subcutaneous injections of 20 mg/kg cocaine beginning on the 20th day of pregnancy (E20). The control animals received injections of equivalent volume of saline. The receptor densities were examined between days 5-30 of the treatment, which corresponds to E25-E50. By the fifth day of treatment (E25), cocaine produced downregulation of all receptors studied throughout the entire depth of the fetal cerebral wall. More extended treatment, however, resulted in recovery of receptor levels. Finally, from days 20-30 of treatment (E40-E50) there was a significant upregulation of noradrenergic and dopaminergic receptor sites. These findings demonstrate that exposure to cocaine in utero can influence adrenergic, serotonergic, and dopaminergic receptors in the embryonic cerebral wall, which may lead to alteration in corticogenesis. Furthermore, the present study reveals that, in the course of chronic treatment, cocaine may completely reverse its receptor regulatory activity in the fetal brain.

Downregulation of 5-HT1A receptors in rat hypothalamus and dentate gyrus after ?binge? pattern cocaine administration

The effect of chronic cocaine exposure on the central serotonergic system in the rat was investigated using a selective 5-HT1A receptor agonist, [3H]8-hydroxy-2-(di-N-propylamino) tetralin (8-OH-DPAT), and a 5-HT2A receptor antagonist, [3H]ketanserin, as tritiated ligands in a quantitative autoradiography study. Rats were administered cocaine in a "binge" pattern, 15 mg/kg/injection, three times a day, at 1-h intervals for 14 days to mimic the pattern often seen in human cocaine addicts. A significant decrease in the binding of [3H]8-OH-DPAT was found in the ventromedial hypothalamus (P < 0.001) and the dorsal dentate gyrus (P < 0.01) in rats administered cocaine as compared with rats injected with saline. No significant difference in the binding of [3H]ketanserin was found in frontal, parietal, agranular insular, and piriform cortices, caudate-putamen, olfactory tubercle, nucleus accumbens, thalamus, septohippocampal nucleus, and claustrum. Several studies have shown that 5-HT1A receptor agonists have antidepressant properties. Other studies, in animal models, have shown that 5-HT1A receptor agonists stimulate the hypothalamic-pituitary-adrenal axis, which is of interest, since chronic activation of this axis has been related to anxiety and depression. Our data show that the 5-HT1A component of the serotonergic system is altered following chronic "binge" pattern cocaine administration in an animal model and may be related to changes in the HPA axis and behavior.

Downregulation of 5‐HT1A receptors in rat hypothalamus and dentate gyrus after “binge” pattern cocaine administration

The effect of chronic cocaine exposure on the central serotonergic system in the rat was investigated using a selective 5-HT1A receptor agonist, [3H]8-hydroxy-2-(di-N-propylamino) tetralin (8-OH-DPAT), and a 5-HT2A receptor antagonist, [3H]ketanserin, as tritiated ligands in a quantitative autoradiography study. Rats were administered cocaine in a “binge” pattern, 15 mg/kg/injection, three times a day, at 1-h intervals for 14 days to mimic the pattern often seen in human cocaine addicts. A significant decrease in the binding of [3H]8-OH-DPAT was found in the ventromedial hypothalamus (P < 0.001) and the dorsal dentate gyrus (P < 0.01) in rats administered cocaine as compared with rats injected with saline. No significant difference in the binding of [3H]ketanserin was found in frontal, parietal, agranular insular, and piriform cortices, caudate-putamen, olfactory tubercle, nucleus accumbens, thalamus, septohippocampal nucleus, and claustrum. Several studies have shown that 5-HT1A receptor agonists have antidepressant properties. Other studies, in animal models, have shown that 5-HT1A receptor agonists stimulate the hypothalamic–pituitary–adrenal axis, which is of interest, since chronic activation of this axis has been related to anxiety and depression. Our data show that the 5-HT1A component of the serotonergic system is altered following chronic “binge” pattern cocaine administration in an animal model and may be related to changes in the HPA axis and behavior. Synapse 30:166–171, 1998. © 1998 Wiley-Liss, Inc.