Acute Cocaine Withdrawal Research Articles

Parallel changes in brain GABA levels, sleep and mood state during acute cocaine withdrawal: Predictors of “readiness for treatment”?

Parallel changes in brain GABA levels, sleep and mood state during acute cocaine withdrawal: Predictors of “readiness for treatment”?

Relationship between central behavioral effects and peripheral sympathetic neurotransmission functionality during acute cocaine withdrawal syndrome in adult rats

ABSTRACTBackground: Acute cocaine withdrawal syndrome (ACWS) is characterized as a set of organic alterations triggered by abrupt discontinuation of chronic cocaine consumption, usually occurring at 24–40 hours after withdrawal. However, little is known about the relationship between central and peripheral sympathetic neurotransmission during ACWS. Objective and Methods: We investigated the mechanisms involved in central and peripheral sympathetic neurotransmission and how ACWS affects the sympathetic functionality. Cocaine was administered twice daily for 5 days in Wistar rats (at least 5 in each group): on the first and second day, 15 mg/kg/i.p.; third day, 20 mg/kg/i.p.; and finally in the last two days, 30 mg/kg/i.p. Subsequently, at 1, 24, 48 and 120 h after cocaine administration the following experiments were done: (i) at the central level, behavioral tests of open-field and elevated plus maze; and (ii) at the peripheral level, tests of catecholamine release, function of α2-adrenergic receptors (α2-ARs), imidazoline receptors (I1,2-Rs), L-type voltage-gated (Cav1.2) Ca2+ channels and α1-ARs. Results: During ACWS, rats showed hypolocomotion and exacerbation of anxiogenic-effects 24 h after cocaine withdrawal. Likewise, a decrease in the catecholamine release and activity of α2-ARs/I1,2-Rs at 24–48 h after cocaine withdrawal was observed. A decrease in Cav1.2 channels and α1-ARs function at 48 h after cocaine withdrawal was observed. Conclusions: The relationship of central and peripheral sympathetic neurotransmission during ACWS possibly due to a failure in activation and/or inactivation of presynaptic α2-ARs/I1,2-Rs, may offer a potential target for attenuating ACWS.

Accumbal and pallidal dopamine, glutamate and GABA overflow during cocaine self‐administration and its extinction in rats

We investigated the changes in dopamine (DA), glutamate and γ-aminobutyric acid (GABA) during cocaine self-administration in rats implanted with guide cannulae into the nucleus accumbens and ventral pallidum. After stabilized cocaine self-administration, separate groups of rats underwent extinction (10 days) procedure in which cocaine infusion was replaced by saline injections. With using a 'yoked' procedure, the effects of cocaine or its withdrawal on the level of neurotransmitters were evaluated by dual-probe microdialysis. Repeated cocaine administration reduced basal glutamate levels in the nucleus accumbens and ventral pallidum, whereas it did not affect basal accumbal DA levels. Only rats that self-administered cocaine had increased basal GABA overflow in both examined brain structures. Active or passive cocaine administration elevated extracellular accumbal DA, however, the extent of cocaine-evoked DA level was significantly higher in rats that self-administered cocaine while both groups of animals showed also an attenuation of GABA level in the nucleus accumbens. On day 10 of extinction training, rats previously given cocaine revealed decreases in the basal accumbal concentration of glutamate while the basal GABA levels were significantly enhanced as compared with baseline of saline-yoked controls. Potassium depolarization delayed the reduction of the accumbal and pallidal extracellular glutamate levels in the active and passive cocaine groups. The present data indicate that changes in DA and GABA neurotransmission during maintenance phase mirror the motivational aspects of cocaine intake. Depending on acute (24 hours) or late (10 days) cocaine withdrawal, different neurotransmitter systems (i.e. glutamate or GABA) seem to be involved.

Functional connectivity during language processing in acute cocaine withdrawal: A pilot study

Recent research revealed decreased access to semantic and associative networks in acute cocaine withdrawal. In autism, such behavioral outcomes are associated with decreased functional connectivity using functional magnetic resonance imaging. Therefore, we wished to determine whether connectivity is also decreased in acute cocaine withdrawal. Eight subjects in acute cocaine withdrawal were compared to controls for connectivity in language areas while performing a task involving categorization of words according to semantic and phonological relatedness. Acute withdrawal subjects had significantly less overall connectivity during semantic relatedness, and a trend towards less connectivity during phonological relatedness. Of potential future interest is whether this might serve as an imaging marker for treatment in patients.

Involvement of tissue plasminogen activator in stress responsivity during acute cocaine withdrawal in mice

There is evidence that increased release of corticotropin-releasing factor (CRF) in the central nucleus of the amygdala (CeA) contributes to stress responsivity during cocaine withdrawal (WD). Recent studies suggest that tissue plasminogen activator (tPA) in the CeA is a downstream effector protein for CRF after acute “binge” cocaine administration. The purpose of this study was to determine if tPA modulates cocaine WD-induced stress responsivity. Wild-type (WT) and tPA-deficient (tPA − / − ) mice were subjected to chronic (14 days) “binge” cocaine (45 mg/kg per day) or its acute (1 day) WD. Extracellular tPA activity, CRF mRNA levels, and plasma corticosterone (CORT) levels were measured in tPA − / − and WT mice. Extracellular tPA activity was reduced by 50% in the CeA and medial amygdala of WT mice after chronic cocaine and returned to basal levels after acute WD. Unlike WT mice, tPA − / − mice did not display elevated amygdalar CRF mRNA levels during cocaine WD. In comparison to WT mice, tPA − / − mice showed a blunted plasma CORT response during acute WD. These results demonstrate that tPA activity in the amygdala (Amy) is altered by chronic cocaine exposure, and further suggest an involvement of tPA in modulating amygdalar CRF stress responsive system and hypothalamic–pituitary–adrenal axis in response to acute cocaine WD.

Effects of ginseng saponin on acute cocaine-induced alterations in evoked dopamine release and uptake in rat brain nucleus accumbens

In traditional medicine, Panax ginseng has been used to treat various behavioral effects of psychostimulants (e.g., cocaine) and other drugs of abuse and to ameliorate withdrawal symptoms. The neurochemical bases for this efficacy, however, remain to be elucidated. We previously used the real-time fast-scan cyclic voltammetry in rat nucleus accumbens slices to demonstrate that cocaine not only enhances DA release evoked by single-pulse electrical stimulation and inhibits DA uptake during application but also further increases the release upon washout (termed a “rebound” release enhancement). In the present study, we determined whether co-application and washout of ginseng total saponin (GTS), the active ingredient of Panax ginseng, with cocaine attenuate cocaine-induced enhancement of evoked DA release, DA uptake inhibition and/or withdrawal-associated rebound enhancement. Cocaine rapidly potentiated the DA release within the first 10 min of application, and acute cocaine withdrawal caused a rebound increase. Co-application of GTS with cocaine inhibited the release enhancement and subsequently prevented the rebound increase during acute withdrawal. The effect of GTS was concentration-dependent. In contrast, GTS had no significant effects on the cocaine-mediated DA uptake inhibition. These results suggest that the attenuation of the cocaine-induced enhancement of impulse-dependent DA release, rather than uptake inhibition, might be one of the pharmacological bases for attenuation of behavioral effects of cocaine and amelioration of acute withdrawal symptoms by ginseng.

Cocaine withdrawal enhances pentobarbital-induced sleep in rats: Evidence of GABAergic modulation

We intended to clarify whether pentobarbital-induced sleep in rats is affected during cocaine withdrawal and whether GABAergic systems are involved in this sleep. Cocaine (20 mg/kg) was administered subcutaneously (s.c.) to rats once per day for 6 days. Pentobarbital (42 mg/kg) was administered intraperitoneally (i.p.) to the rats 1 day (acute withdrawal), 8 days (subacute withdrawal), or 14 days (subchronic withdrawal) after withdrawal from cocaine. All rats were fasted for 24 h prior to the pentobarbital injection. Pentobarbital-induced sleeping time was significantly increased during both acute and subacute withdrawal, while sleeping onset latency was not affected. However, sleeping time recovered to normal 14 days after withdrawal. Protein levels of GABA A receptor γ-subunits and glutamic acid decarboxylase (GAD) were increased in both acute and subacute cocaine withdrawal in the hypothalamus, but were normal after 14 days of withdrawal. These results indicate that pentobarbital-induced sleeping time in cocaine withdrawal is transiently increased. Hypersomnia in cocaine withdrawal might be influenced by functional changes in the GABAergic systems.

The Effect of Propranolol on Cognitive Flexibility and Memory in Acute Cocaine Withdrawal

Upregulated noradrenergic activity occurs early in cocaine withdrawal. Our previous work revealed impaired cognitive flexibility in acute cocaine withdrawal, a cognitive domain that appears to be modulated by noradrenergic activity. Therefore, we wished to determine the effect of beta-adrenergic antagonists on cognitive performance in acute cocaine withdrawal. Eleven subjects acutely withdrawing from cocaine were tested in this pilot study on tasks of cognitive flexibility as well as word fluency, attention, verbal memory, and spatial memory, off and on propranolol in a double-blinded manner. Propranolol significantly benefited certain aspects of cognitive flexibility in acute cocaine withdrawal, and improved some measures of verbal fluency and verbal recall. Cocaine withdrawal treatment is characterized by high failure rates. Further research is needed to determine the role this finding of a reversible cognitive impairment in cocaine withdrawal has in treatment.

Effect of illicit recreational drugs upon sleep: Cocaine, ecstasy and marijuana

The illicit recreational drugs cocaine, ecstasy and marijuana have pronounced effects upon sleep. Administration of cocaine increases wakefulness and suppresses REM sleep. Acute cocaine withdrawal is often associated with sleep disturbances and unpleasant dreams. Studies have revealed that polysomnographically assessed sleep parameters deteriorate even further during sustained abstinence, although patients report that sleep quality remains unchanged or improves. This deterioration of objective sleep measures is associated with a worsening in sleep-related cognitive performance. Like cocaine, 3,4-methylenedioxymethamphetamine (MDMA; "ecstasy") is a substance with arousing properties. Heavy MDMA consumption is often associated with persistent sleep disturbances. Polysomnography (PSG) studies have demonstrated altered sleep architecture in abstinent heavy MDMA users. Smoked marijuana and oral Delta-9-tetrahydrocannabinol (THC) reduce REM sleep. Moreover, acute administration of cannabis appears to facilitate falling asleep and to increase Stage 4 sleep. Difficulty sleeping and strange dreams are among the most consistently reported symptoms of acute and subacute cannabis withdrawal. Longer sleep onset latency, reduced slow wave sleep and a REM rebound can be observed. Prospective studies are needed in order to verify whether sleep disturbances during cocaine and cannabis withdrawal predict treatment outcome.

Cognitive impairment in acute cocaine withdrawal.

To perform a pilot study to examine a range of cognitive flexibility tasks early in cocaine withdrawal. Previous neuropsychological investigations of cocaine withdrawal have conflicted regarding whether impaired cognitive flexibility occurs. However, most studies have examined patients later in withdrawal. Anxiety and yohimbine-induced panic are greatest early in withdrawal, and both anxiety and increased noradrenergic tone can impair cognitive flexibility. Twelve patients acutely withdrawing from cocaine were compared with gender-, age-, and estimated premorbid intelligence-matched control subjects on tests of cognitive flexibility as well as verbal fluency, verbal memory, spatial memory, and attention. As predicted, impairments were found on the cognitive flexibility tasks. Impairments also were present in verbal fluency and verbal memory but not spatial memory or attention. We propose that the cognitive flexibility impairment may relate to the increased noradrenergic activation recently described in cocaine withdrawal. Impairments on verbal tasks may also relate to an impaired flexibility in the search of semantic networks. Further research will explore the effects of pharmacologic manipulation of the noradrenergic system on cognition in acute withdrawal. Recently, propranolol has been shown to benefit patients in cocaine withdrawal. Further research will explore whether impaired cognitive flexibility related to altered noradrenergic tone could serve as a mechanism for this treatment response.

Amygdalar vasopressin mRNA increases in acute cocaine withdrawal: Evidence for opioid receptor modulation

In humans, stress is recognized as a major factor contributing to relapse to drug abuse in abstinent individuals; drugs of abuse themselves or withdrawal from such drugs act as stressors. In the animals, evidence suggests that centrally released arginine vasopressin in both amygdala and hypothalamus plays an important role in stress-related anxiogenic behaviors. The stress responsive hypothalamic–pituitary–adrenal axis is under tonic inhibition via endogenous opioids, and cocaine withdrawal stimulates hypothalamic–pituitary–adrenal activity. The present studies were undertaken to determine whether: (1) 14-day (chronic) “binge” pattern cocaine administration (45mg/kg/day) or its withdrawal for 3 h (acute), 1 day (subacute) or 10 days (chronic) alters arginine vasopressin mRNA levels in amygdala or hypothalamus; (2) the opioid receptor antagonist naloxone (1mg/kg) alters arginine vasopressin mRNA or hypothalamic–pituitary–adrenal hormonal responses in acute cocaine withdrawal; and (3) there are associated changes of mu opioid receptor or proopiomelanocortin mRNA levels. In amygdala, arginine vasopressin mRNA levels were unchanged after chronic “binge” cocaine, but were increased during acute cocaine withdrawal. Naloxone completely blocked this increase. Neither chronic cocaine nor its acute withdrawal altered amygdalar mu opioid receptor mRNA levels. The increase in amygdalar arginine vasopressin mRNA levels was still observed after subacute withdrawal, but not after chronic withdrawal. Although hypothalamic–pituitary–adrenal tolerance developed with chronic “binge” cocaine, there were modestly elevated plasma adrenocorticotropin hormone levels during acute withdrawal. While naloxone produced modest adrenocorticotropin hormone elevations in cocaine-naïve rats, naloxone failed to elicit an adrenocorticotropin hormone response in cocaine-withdrawn rats. In hypothalamus, neither chronic cocaine nor acute withdrawal altered arginine vasopressin, proopiomelanocortin or mu opioid receptor mRNA levels. These results show that: (1) opioid receptors mediate increased amygdalar arginine vasopressin gene expression during acute cocaine withdrawal, and (2) cocaine withdrawal renders the hypothalamic–pituitary–adrenal axis insensitive to naloxone. Our findings suggest a potential role for amygdalar arginine vasopressin in the aversive consequences of early cocaine withdrawal.

Ondansetron, given during the acute cocaine withdrawal, attenuates oral cocaine self-administration

We have previously shown that ondansetron, given 3.5 h after intravenous cocaine self-administration, can attenuate self-administration the following day. Here we tested ondansetron given either before or after a 14-h oral cocaine session in rats. Ondansetron (0.2 mg/kg sc) given 30 min before the cocaine session had no effect. However, when given 3.5 h after, ondansetron attenuated cocaine intake the following day while having no effect on water intake. Taken with our previous data in intravenous cocaine self-administration, we suggest that the acute cocaine withdrawal period may be an important treatment window and that ondansetron may be an effective cocaine abuse therapy.

κ-Opioid withdrawal in Planaria

Many drug-abusers engage in poly-drug abuse, but there has been relatively little quantification of withdrawal from poly-drug use. Planarians are an advantageous model for these studies due to mammalian-relevant neurotransmitter systems (e.g. dopamine, opioid, and 5-HT). We recently developed a metric that quantified an acute cocaine withdrawal phenomenon in planarians. However, despite much indirect evidence, we lacked direct evidence of a receptor- or carrier-mediated effect. We now report dose-related, naloxone- and nor-binaltorphine-sensitive acute abstinence-induced withdrawal and naloxone-precipitated withdrawal from the κ-opioid agonist U-50,488H ( trans-(±)-3,4-dichloro- N-methyl- N-(2-[1-pyrrolidinyl]cyclohexyl)-benzeneacetamide). The less active enantiomer [ 1R, 2R]U-50,488 produced significantly less withdrawal and U-50,488H withdrawal was not due to pH or osmolarity. These data provide pharmacologic evidence of a κ-opioid receptor-mediated withdrawal phenomenon and neuroadaptation to a pharmacologic stimulus (adaptations in transduction mechanisms) in this model.

Alterations in hypothalamic–pituitary–adrenal axis activity and in levels of proopiomelanocortin and corticotropin-releasing hormone-receptor 1 mRNAs in the pituitary and hypothalamus of the rat during chronic ‘binge’ cocaine and withdrawal

Tolerance to the stimulatory effects of cocaine on the hypothalamic–pituitary–adrenal (HPA) axis develops after chronic ‘binge’ cocaine exposure in the rat. This blunting of HPA axis activity in response to cocaine is associated with a cocaine-induced reduction of corticotropin-releasing hormone (CRH) mRNA level in the hypothalamus. There is limited information about the effects of withdrawal from chronic cocaine on HPA activity. The present studies were undertaken to determine levels of the HPA hormones adrenocorticotropic hormone (ACTH) and corticosterone across 10 days of withdrawal following chronic ‘binge’ pattern cocaine administration (3×15 mg/kg/day at hourly intervals) for 14 days. Male Fischer rats showed a significantly attenuated HPA axis response to chronic ‘binge’ pattern cocaine administration 30 min after the last injection on the 14th day, as measured by both plasma ACTH and corticosterone levels at the nadir time point. Twenty-four hours following the final administration of ‘binge’ cocaine (the 1st day of withdrawal), a significant elevation of plasma ACTH levels and a modest, but significant, elevation of plasma corticosterone levels were found at the nadir time point. This acute withdrawal-related activation of the hormones of the HPA axis was no longer found on the 10th day of withdrawal. In the anterior pituitary, levels of both proopiomelanocortin (POMC) and CRH-receptor 1 (R1) mRNAs were significantly higher than saline controls on the 14th day of chronic ‘binge’ cocaine and were at control levels on the 4th day of withdrawal. In the neurointermediate lobe of the pituitary, a sustained reduction in POMC mRNA levels was observed on the 3rd, 7th and 14th day of chronic ‘binge’ cocaine, but POMC mRNA was at control levels by the 4th day of withdrawal. In the hypothalamus, POMC mRNA levels showed a transient decrease on the 1st day of ‘binge’ cocaine with no change during chronic ‘binge’ cocaine or its withdrawal. CRH mRNA levels in the hypothalamus were not different from saline controls on the 1st and 4th days of withdrawal. Taken together, the present results show that after development of adaptation or tolerance to chronic ‘binge’ cocaine there is an increase in HPA activity during acute cocaine withdrawal. In addition to being associated with CRH input from the hypothalamus, the activation of the HPA axis by cocaine withdrawal may be, at least in part, due to the increased POMC and/or CRH-R1 gene expression observed in the anterior pituitary after chronic ‘binge’ cocaine.

Physiological and Subjective Effects of Acute Cocaine Withdrawal (Crash) in Rats

The physiological and subjective effects of high acute doses of cocaine and the subsequent homeostatic acute withdrawal syndrome were measured in rats. Radiotelemetry recordings of body temperature and activity were monitored in rats for 48 h after 32 mg/kg cocaine (COC) and saline (SAL) were administered by both intraperitoneal and subcutaneous (SC) routes. COC initially produced hypothermia and hyperactivity, followed by a prolonged hyperthermic and hypoactive rebound that seemed to peak around 12 h after injections. The SC route of administration produced the greatest rebound effect. Eight additional rats were monitored for EEG activity by telemetry for 48 h after SC administration of SAL or 32 mg/kg COC. COC produced an initial decrease in alpha and beta wavelength bands, with a trend toward increases in alpha and beta power demonstrated from the 10th through 14th h after injections. Using a three-choice haloperidol (HDL), saline, and COC drug discrimination task, we demonstrated a COC-like subjective state produced during the 10th through 12th h after a 32-mg/kg SC COC injection with no HDL-like responding engendered during any tested period of the acute or rebound effects of COC. These data provide evidence for an acute COC withdrawal syndrome (crash) in rats occurring 10–14 h after a high-dose COC treatment.

Changes in Immunologic Cell Surface Markers during Cocaine Withdrawal in Pregnant Women

To evaluate the effects of acute cocaine withdrawal on the immune system of pregnant women, we analyzed changes in a panel of cell surface markers and plasma proteins that have immunological importance. The cell surface markers included complement receptors [CR1 (CD35), CR2 (CD21), CR3 (CD11b, CD18)], immunoglobulin Fc receptors [FcγRII (CD32), FcγRIII (CD16)], proteins important for lymphocyte function [CD3, CD4, CD8, CD19, CD25, CD45RA], and the framework antigen HLA-ABC. We also measured levels of the plasma proteins C3, C4, IgG, IgM, and IgA, along with the cytokine interleukin-2, soluble lymphocyte markers sCD25, sCD4, sCD8, IL-2, and soluble immune complexes. While no significant changes were seen in the levels of plasma proteins, changes paralleling the course of acute withdrawal were seen in complement receptors and immunoglobulin Fc receptors on leukocyte subpopulations. By contrast, proteins important for lymphocyte function were relatively unperturbed. There was an increase in receptor expression at the onset of withdrawal that peaked 3–5 days after last cocaine use, followed by a decrease in expression to initial (pre-withdrawal) levels. These changes in cell surface receptors may reflect altered immune function in the women who were withdrawing from cocaine.