minocycline and Substance-Withdrawal-Syndrome

In recent preclinical studies, the role of nitric oxide (NO) in nicotine dependence has become increasingly evident. Inhibition of NO synthesis blocks acquisition of conditioned place preference, and attenuates the nicotine abstinence syndrome in rodents. These findings have not been followed up in human studies. In order to obtain preliminary data on NO inhibition in human smokers, we conducted a randomized, double-blind, crossover study (N=12) of minocycline, a tetracycline derivative antibiotic, that inhibits the neuronal nitric oxide (NO) synthase enzyme with resultant inhibition of NO production. Medication effects were assessed through a smoking choice procedure as well as subjective and physiological responses to nicotine administered via the intravenous route (IV). Minocycline treatment did not affect smoking self-administration in our choice procedure and did not affect most of the subjective responses to IV nicotine or sample smoking. Following IV nicotine administration, there was a greater reduction in craving for cigarettes under minocycline, compared to placebo. Similarly, smokers had greater reduction in their craving for cigarettes following sample smoking under minocycline treatment. These findings provide limited support for the potential use of minocycline as a treatment of nicotine dependence.

Topics: Adult; Affect; Anti-Infective Agents; Attention; Cotinine; Cross-Over Studies; Double-Blind Method; Female; Humans; Injections, Intravenous; Male; Minocycline; Nicotine; Nicotinic Agonists; Psychomotor Performance; Smoking; Substance Withdrawal Syndrome; Surveys and Questionnaires

Topics: Amphetamine-Related Disorders; Animals; Central Nervous System Stimulants; Male; Methamphetamine; Mice; Minocycline; Substance Withdrawal Syndrome

To investigate the effect of minocycline on morphine withdrawal symptoms.. We established a rat model of morphine dependence, then injected the animals with naloxone to induce withdrawal symptoms. Minocycline was injected into the midbrain periaqueductal gray and its effect on withdrawal symptoms and Ca. Minocycline inhibited withdrawal symptoms such as "wet dog" shakes, teeth chatter, and ptosis, perhaps by inhibiting the activation of microglia and the expression of CaMKII, Ras, and p-ERK. Minocycline had no effect on the behavior of control rats or on CaMKII, Ras, or p-ERK expression.. Minocycline alleviates morphine withdrawal symptoms by inhibiting the activation of microglia and downregulating the expression of CaMKII, Ras, and p-ERK.

Topics: Animals; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Disease Models, Animal; Down-Regulation; Humans; Male; MAP Kinase Signaling System; Microglia; Minocycline; Morphine; Naloxone; Periaqueductal Gray; ras Proteins; Rats; Substance Withdrawal Syndrome

This study investigated the effects of minocycline microinjections, into the midbrain periaqueductal gray (PAG), on morphine withdrawal and the expression of pannexin-1 (panx1), phosphorylated mammalian target of rapamycin (p-mTOR), protein kinase A (PKA), and cAMP response element-binding protein (CREB). Rats were injected with morphine, intraperitoneally, at increasing doses, twice per day, to establish animal models of morphine exposure. Minocycline was administered into the PAG before the first intraperitoneal (i.p.) injection of morphine each day, on days 1-4. On the last day of the experiment, all rats were injected with naloxone, and morphine withdrawal was observed, and then changes in the expression levels of ionized calcium-binding adaptor molecule 1 (Iba1) and its downstream factors, panx1, p-mTOR, PKA, and CREB were evaluated by western blot and immunohistochemistry analyses. Morphine withdrawal increased microglial activation, whereas minocycline could inhibit microglial activation and withdrawal and the downregulation of panx1, p-mTOR, PKA, and CREB expression, reducing the effects of morphine withdrawal.

Topics: Animals; Calcium-Binding Proteins; Connexins; Cyclic AMP Response Element-Binding Protein; Male; Microfilament Proteins; Microglia; Microinjections; Minocycline; Morphine; Naloxone; Narcotic Antagonists; Narcotics; Nerve Tissue Proteins; Periaqueductal Gray; Phosphorylation; Rats; Rats, Wistar; Substance Withdrawal Syndrome; TOR Serine-Threonine Kinases

Opioids are the most powerful analgesics available to date. However, they may also induce adverse effects including paradoxical opioid-induced hyperalgesia. A mechanism that might underlie opioid-induced hyperalgesia is the amplification of synaptic strength at spinal C-fibre synapses after withdrawal from systemic opioids such as remifentanil ("opioid-withdrawal long-term potentiation [LTP]"). Here, we show that both the induction as well as the maintenance of opioid-withdrawal LTP were abolished by pharmacological blockade of spinal glial cells. By contrast, the blockade of TLR4 had no effect on the induction of opioid-withdrawal LTP. D-serine, which may be released upon glial cell activation, was necessary for withdrawal LTP. D-serine is the dominant coagonist for neuronal NMDA receptors, which are required for the amplification of synaptic strength on remifentanil withdrawal. Unexpectedly, opioid-withdrawal LTP was transferable through the cerebrospinal fluid between animals. This suggests that glial-cell-derived mediators accumulate in the extracellular space and reach the cerebrospinal fluid at biologically active concentrations, thereby creating a soluble memory trace that is transferable to another animal ("transfer LTP"). When we enzymatically degraded D-serine in the superfusate, LTP could no longer be transferred. Transfer LTP was insensitive to pharmacological blockade of glial cells in the recipient animal, thus representing a rare form of glial cell-independent LTP in the spinal cord.

Topics: Analgesics, Opioid; Animals; Long-Term Potentiation; Male; Memory; Microglia; Minocycline; Rats; Rats, Sprague-Dawley; Remifentanil; Substance Withdrawal Syndrome

Anxiety and negative sensations due to alcohol withdrawal are factors leading to alcohol relapse and addiction. Minocycline, an antibiotic, can decrease alcohol consumption in rats, however, its effects on alcohol withdrawal anxiety and relapse have not been studied.. Part 1: Forced alcohol drinking in gradually increasing concentration was administered till day 22 in rats. Effect of drugs on anxiety was assessed using elevated plus maze (EPM) and two-chambered box apparatus, after removal of alcohol. Part 2: For relapse, an alcohol deprivation effect model was used, rats were continuously offered alcohol and water for 4 consecutive weeks in a two-bottle choice paradigm, followed by 2 weeks of alcohol deprivation. Effect of drugs on alcohol consumption during the first hour of alcohol reintroduction was assessed. Animals were sacrificed and whole brain Tumor Necrosis Factor (TNF) α was estimated.. Part 1: Anxiety at 3 hours was significantly lower following minocycline (20 mg/kg i.p.) or diazepam compared to vehicle control. Part 2: Acute administration of minocycline (5,10 and 20 mg/kg, i.p.) suppressed alcohol consumption significantly (p value<0.05) as compared to vehicle control. A significant decrease in whole brain TNF α was observed in animals treated with minocycline compared to untreated animals.. Minocycline attenuates alcohol withdrawal anxiety and disrupts alcohol relapse.

Topics: Alcohol Drinking; Alcoholism; Animals; Anti-Bacterial Agents; Anxiety; Diazepam; Disease Models, Animal; Dose-Response Relationship, Drug; Male; Maze Learning; Minocycline; Rats; Rats, Wistar; Recurrence; Substance Withdrawal Syndrome; Tumor Necrosis Factor-alpha

Neuroimmune cytokines are increased with alcohol withdrawal and may mediate clinical responses associated with alcoholism. Because minocycline regulates the level of cytokines, it has been suggested as a therapeutic for disorders associated with alcohol. Male Wistar rats were exposed to chronic intermittent alcohol (CIA) comprising three 5-day cycles of ethanol liquid diet separated by 2 days of withdrawal. Rats were tested on social interaction, a measure of anxiety-like behavior, followed immediately by collection of amygdala tissue to measure CCL2 and TNFα or collection of the blood to measure corticosterone (CORT). One group received a single minocycline injection 3 h into the final CIA withdrawal and was tested 2 h later. A second group received injections during each of the three withdrawals and was similarly tested during the final acute withdrawal. A third group received a single injection at 23 h into withdrawal (extended withdrawal) and was tested 6 h later. Results showed that CIA withdrawal increased anxiety-like behavior. A single injection of minocycline during the final acute withdrawal increased anxiety-like behavior in rats that consumed liquid diet with or without alcohol, but this effect disappeared with repeated injections of minocycline. Differences in alcohol intake, blood alcohol level, and plasma CORT levels did not explain results. Only repeated injections of minocycline decreased TNFα mRNA levels in rats that consumed liquid diet with or without alcohol. When a single injection of minocycline was given during extended withdrawal, it decreased CCL2 mRNA levels, but did not reverse the elevation of CCL2 protein. These results suggest that minocycline has actions in brain and on behavior, but minocycline does not significantly impact these actions in relation to alcohol withdrawal.

Topics: Alcoholism; Amygdala; Animals; Anti-Bacterial Agents; Anxiety; Chemokine CCL2; Corticosterone; Drug Administration Schedule; Drug Interactions; Male; Minocycline; Rats, Wistar; RNA, Messenger; Substance Withdrawal Syndrome; Tumor Necrosis Factor-alpha

Nicotine withdrawal (NTW) has been shown to increase pain sensitivity. However, the pathogenesis of NTW-induced hyperalgesia syndrome is unknown. Microglial activation, with increased expression of the P2X4 receptor (P2X4R) and brain-derived neurotrophic factor (BDNF) as important markers, is associated with hyperalgesia; therefore, these markers may represent an unprecedented target to prevent hyperalgesia. In this study, we explored the contributions of spinal microglial P2X4R-BDNF signaling in NTW-induced hyperalgesia. Immunohistochemical analysis showed that spinal microglia were activated and that the P2X4R level was increased and colocalized with ionized calcium-binding adapter molecule 1 in NTW-induced hyperalgesia. Furthermore, we showed that microglial activation with NTW resulted in an increased expression of spinal P2X4R and an elevated release of BDNF. Intrathecal minocycline (a specific inhibitor of microglial activation) reversed thermal hyperalgesia as well as increased the spinal microglial P2X4R and BDNF levels induced by NTW. To the best of our knowledge, the present study provides evidence that spinal microglial P2X4R-BDNF signaling is critical for the development of NTW-induced hyperalgesia.

Topics: Analgesics, Non-Narcotic; Animals; Brain-Derived Neurotrophic Factor; Calcium-Binding Proteins; Disease Models, Animal; Hot Temperature; Hyperalgesia; Male; Microfilament Proteins; Microglia; Minocycline; Nicotine; Nicotinic Agonists; Pain Threshold; Rats, Sprague-Dawley; Receptors, Purinergic P2X4; Spinal Cord; Substance Withdrawal Syndrome

Alcohol use disorder (AUD) is a spectrum disorder characterized by mild to severe symptoms, including potential withdrawal signs upon cessation of consumption. Approximately five hundred thousand patients with AUD undergo clinically relevant episodes of withdrawal annually (New Engl J Med, 2003, 348, 1786). Recent evidence indicates potential for drugs that alter neuroimmune pathways as new AUD therapies. We have previously shown the immunomodulatory drugs, minocycline and tigecycline, were effective in reducing ethanol (EtOH) consumption in both the 2-bottle choice and drinking-in-the-dark paradigms. Here, we test the hypothesis that tigecycline, a tetracycline derivative, will reduce the severity of EtOH withdrawal symptoms in a common acute model of alcohol withdrawal (AWD) using a single anesthetic dose of EtOH in seizure sensitive DBA/2J (DBA) mice.. Naïve adult female and male DBA mice were given separate injections of 4 g/kg i.p. EtOH with vehicle or tigecycline (0, 20, 40, or 80 mg/kg i.p.). The 80 mg/kg dose was tested at 3 time points (0, 4, and 7 hours) post EtOH treatment. Handling-induced convulsions (HICs) were measured before and then over 12 hours following EtOH injection. HIC scores and areas under the curve were tabulated. In separate mice, blood EtOH concentrations (BECs) were measured at 2, 4, and 7 hours postinjection of 4 g/kg i.p. EtOH in mice treated with 0 and 80 mg/kg i.p. tigecycline.. AWD symptom onset, peak magnitude, and overall HIC severity were reduced by tigecycline drug treatment compared to controls. Tigecycline treatment was effective regardless of timing throughout AWD, with earlier treatment showing greater efficacy. Tigecycline showed a dose-responsive reduction in acute AWD convulsions, with no sex differences in efficacy. Importantly, tigecycline did not affect BECs over a time course of elimination.. Tigecycline effectively reduced AWD symptoms in DBA mice at all times and dosages tested, making it a promising lead compound for development of a novel pharmacotherapy for AWD. Further studies are needed to determine the mechanism of tigecycline action.

Topics: Animals; Dose-Response Relationship, Drug; Ethanol; Female; Male; Mice; Mice, Inbred DBA; Minocycline; Seizures; Substance Withdrawal Syndrome; Tigecycline

Evidence has emerged demonstrating that ethanol (EtOH) influences cytokine expression within the central nervous system, although most studies have examined long-term exposure. Thus, the cytokine response to an acute EtOH challenge was investigated, in order to characterize profiles of cytokine changes following acute exposure.. Rats pups were injected intraperitoneally (i.p.) with 2-g/kg EtOH, and IL-1 mRNA and protein were assessed 0, 60, 120, 180, and 240 minutes post injection (Experiment 1). In Experiments 2 to 5, the expression of several cytokines was examined in adult male rats during acute intoxication (3 hours after 4-g/kg EtOH), as well as withdrawal (18 hours post injection), after i.p. or intragastric (i.g.) EtOH administration.. Early in ontogeny, acute EtOH significantly decreased brain IL-1 mRNA and protein. Subsequently, when adult rats were examined, significant and temporally dynamic alterations in central and peripheral cytokines were observed following acute i.p. EtOH exposure (4 g/kg). Although cytokine- and region-dependent central IL-6 expression was generally increased and tumor necrosis factor alpha decreased during intoxication, IL-1 expression exhibited increases during withdrawal. In the periphery, acute i.p. EtOH elevated expression of all cytokines, with the response growing in magnitude as the time post injection increased. Following acute i.g. EtOH (4 g/kg), intoxication-related increases in IL-6 expression were again observed in the paraventricular nucleus of the hypothalamus (PVN), although to a lesser extent. Long-term, voluntary, intermittent EtOH consumption resulted in tolerance to the effects of an i.g. EtOH challenge (4 g/kg) on PVN IL-6 expression, whereas these same elevations in IL-6 expression were still seen in the amygdala in rats with a history of moderate EtOH intake. Treatment with minocycline did not significantly attenuate i.p. or i.g. EtOH-induced changes in central cytokine expression.. Together, these studies provide a foundation for understanding fluctuations in central and peripheral cytokines following acute EtOH as potential contributors to the constellation of neural and behavioral alterations observed during EtOH intoxication and withdrawal.

Topics: Age Factors; Alcoholic Intoxication; Animals; Brain; Corticosterone; Drug Tolerance; Ethanol; Interleukin-1; Interleukin-6; Liver; Male; Minocycline; Rats; Spleen; Substance Withdrawal Syndrome; Time Factors; Tumor Necrosis Factor-alpha

Morphine-induced glial proinflammatory responses have been documented to contribute to tolerance to opioid analgesia. Here, we examined whether drugs previously shown to suppress glial proinflammatory responses can alter other clinically relevant opioid effects; namely, withdrawal or acute analgesia. AV411 (ibudilast) and minocycline, drugs with distinct mechanisms of action that result in attenuation of glial proinflammatory responses, each reduced naloxone-precipitated withdrawal. Analysis of brain nuclei associated with opioid withdrawal revealed that morphine altered expression of glial activation markers, cytokines, chemokines, and a neurotrophic factor. AV411 attenuated many of these morphine-induced effects. AV411 also protected against spontaneous withdrawal-induced hyperactivity and weight loss recorded across a 12-day timecourse. Notably, in the spontaneous withdrawal study, AV411 treatment was delayed relative to the start of the morphine regimen so to also test whether AV411 could still be effective in the face of established morphine dependence, which it was. AV411 did not simply attenuate all opioid effects, as co-administering AV411 with morphine or oxycodone caused three-to-five-fold increases in acute analgesic potency, as revealed by leftward shifts in the analgesic dose response curves. Timecourse analyses revealed that plasma morphine levels were not altered by AV411, suggestive that potentiated analgesia was not simply due to prolongation of morphine exposure or increased plasma concentrations. These data support and extend similar potentiation of acute opioid analgesia by minocycline, again providing converging lines of evidence of glial involvement. Hence, suppression of glial proinflammatory responses can significantly reduce opioid withdrawal, while improving analgesia.

Topics: Analgesia; Analgesics, Opioid; Animals; Anti-Bacterial Agents; Brain; Bronchodilator Agents; Dose-Response Relationship, Drug; Glial Fibrillary Acidic Protein; Immunohistochemistry; Injections, Intraperitoneal; Male; Minocycline; Morphine; Naloxone; Opioid-Related Disorders; Oxycodone; Pain; Pain Measurement; Pyridines; Rats; Rats, Sprague-Dawley; Substance Withdrawal Syndrome; Weight Loss