BDNF receptor antagonism during the induction of morphine dependence exacerbates the severity of physical dependence and ameliorates psychological dependence in rats.

This study examined the effects of systemic administration of the TrkB receptor antagonist (ANA-12) during induction of morphine dependence on the severity of physical and psychological dependence and the cerebrospinal fluid (CSF) BDNF levels in morphine-dependent and withdrawn rats. Rats became morphine-dependent by increasing daily doses of morphine for 7 days, along with ANA-12 injection. Then, rats were tested for the severity of physical dependence on morphine (spontaneous withdrawal signs), anxiety-like (the elevated plus maze), depressive-like (sucrose preference test) behaviors after spontaneous morphine withdrawal. Also, the CSF BDNF levels were assessed 2 h after the last dose of morphine and day 13 after morphine withdrawal in morphine-dependent and withdrawn rats. We found that the morphine withdrawal signs were significantly higher in morphine dependent rats receiving ANA-12 on days of 5-7 after morphine withdrawal, also ANA-12 exacerbated overall dependence severity. While, the percentage of time spent in the open arms and sucrose preference were higher in morphine-dependent rats receiving ANA-12 than morphine-dependent rats receiving saline. Also, the ANA-12 injection decreased the CSF BDNF levels following morphine dependence, while increased it after morphine withdrawal. We conclude that the ANA-12 exacerbated the severity of physical morphine dependence but attenuated the anxiety/depressive-like behaviors in morphine-dependent and withdrawn rats. Also, ANA-12 injection was able to reverse the changes in the CSF BDNF levels. Therefore, ANA-12 is not more likely to complete treatment for opiate addiction.

Withdrawal from an opioid induces a transferable memory trace in the cerebrospinal fluid.

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.

Cerebrospinal fluid lactate concentration after withdrawal of metabolic suppressive therapy in subarachnoid hemorrhage.

Hyperglycolysis is a known phenomenon after severe subarachnoid hemorrhage (SAH) and after brain injury. It is characterized by decreased oxidative metabolism and relatively increased anaerobic glycolysis. Metabolic suppressive therapy reduces the cerebral metabolic rate of oxygen (CMRO(2)) and the cerebral metabolic rate of glucose (CMRGluc). If CMRO(2) is suppressed after SAH, withdrawal of metabolic suppressive therapy could lead to the accumulation of lactate. In this project, we assessed the relationship between the withdrawal of metabolic suppressive therapy and cerebrospinal fluid (CSF) lactate concentration. A prospective observational database containing 262 patients with SAH was retrospectively analyzed. CSF lactate levels were compared with the daily dose of metabolic suppressive therapy. Outcome was assessed with the Glasgow Outcome Scale (GOS). In 56% of patients an increase in CSF lactate (mean: 3.2 ± 0.9 mmol/L) after withdrawal of metabolic suppressive therapy was observed. Mean Glasgow Outcome Score (GOS) was lower in patients with an increase in CSF lactate concentration (>0.5 mmol/L) after withdrawal of metabolic suppressive therapy (p = 0.095). In 88% of patients who died during the first 30 days after SAH, a CSF lactate elevation of more than 0.5 mmol/L after withdrawal of metabolic suppressive therapy was found (p = 0.071).

CSF CRH in abstinent cocaine-dependent patients.

Alterations in stress responsivity may be important in the vulnerability to become cocaine dependent. Thus, an index of hypothalamic-pituitary-adrenal (HPA) axis function was examined in abstinent cocaine-dependent patients. Cerebrospinal fluid (CSF) concentrations of corticotropin releasing factor (CRH) were determined in 29 abstinent cocaine-dependent patients and 66 normal controls. The results showed that there was no significant difference between the abstinent cocaine-dependent patients and normal controls for CSF CRH. Also, CSF CRH concentrations were not related to cocaine-craving scores in a cue-elicited cocaine-craving procedure. Thus, these data suggest that after protracted abstinence from cocaine there is no marked dysregulation of CRH systems as measured by CSF CRH concentrations.

Cerebrospinal fluid monoamine metabolites in cocaine patients: no relationship to cue-induced craving.

We aimed to examine the relationship between central monoamine metabolites and craving cocaine in cocaine-dependent patients. Cerebrospinal fluid (CSF) monoamine metabolite concentrations were determined in 20 withdrawn cocaine-dependent patients. Patients also participated in a cue-elicited cocaine craving procedure. There were no significant relationships between cocaine craving scores and CSF concentrations of the dopamine metabolite, homovanillic acid, the serotonin metabolite, 5-hydroxyindoleacetic acid, or the norepinephrine metabolite, 3-methoxy-4-hydroxyphenylethylglycol. CSF monoamine metabolite concentrations were not related to cocaine craving in withdrawn cocaine-dependent patients.

Relationship between cortisol and serotonin metabolites and transporters in alcoholism [correction of alcolholism].

BACKGROUND: Stress hormone activation may induce clinical depression via an interference with central serotonergic neurotransmission. In alcoholics, a reduction in serotonin transporters was associated with clinical depression, and an activation of cortisol secretion is frequently found during detoxification. We assessed the interaction between stress hormone activation, serotonin transporters, monoamine metabolites in the cerebrospinal fluid (CSF), and mood states in male and female alcoholics and healthy control subjects. METHODS: The availability of serotonin transporters was measured with [I-123]beta-CIT and SPECT in the raphe area of the brainstem in 31 alcoholics after four weeks of abstinence and in 25 age-matched healthy volunteers. Concentrations of plasma cortisol were measured on the day of the SPECT scan. Within one week after the SPECT scan, we assessed monoamine metabolites and corticotropin-releasing factor (CRF) in the CSF. RESULTS: Clinical depression was associated with a reduction in serotonin transporter availability among male alcoholics. Among male alcoholics and healthy volunteers, CSF 5-HIAA and plasma cortisol concentrations were inversely correlated with the availability of raphe serotonin transporters and positively correlated with the severity of clinical depression. No significant correlations were observed between raphe serotonin transporters and HVA, MHPG and CRF concentrations in the CSF. CONCLUSION: Our findings support the hypothesis of an interaction between reduced serotonin transporters, stress hormone activation and clinical depression. They confirm the hypothesis that serotonergic neurotransmission dysfunction in alcoholism is limited to male alcoholics. The observed interactions between high cortisol concentrations and reduced serotonin transporter availability warrant further studies in major depression and other neuropsychiatric diseases with implied cortisol activation and serotonergic dysfunction.

Biochemical alterations during medication withdrawal in Parkinson's disease with and without neuroleptic malignant-like syndrome.

The object was to assess alterations in CSF concentrations of monoamine metabolites during withdrawal of medication in patients with Parkinson's disease in relation to the presence or absence of episodes resembling neuroleptic malignant syndrome (NMS). This syndrome is a fatal condition developing after neuroleptic therapy, and a neuroleptic malignant-like syndrome (NMLS) may also occur after withdrawal of antiparkinsonian drugs in patients with Parkinson's disease. Previous biochemical assays showed that the CSF concentration of the dopamine metabolite homovanillic acid (HVA) is an independent prognostic factor for development of NMLS in patients with Parkinson's disease. In the present study, CSF concentrations of HVA, the noradrenaline (norepinephrine) metabolite 3-methoxy-4-hydroxyphenylethylene glycol, and the serotonin metabolite 5-hydroxyindole acetic acid were assayed using high performance liquid chromatography with electrochemical detection. The study population consisted of nine patients with Parkinson's disease with NMLS and 12 without NMLS, in whom metabolites were assayed during both withdrawal and remedicated periods. Concentrations of HVA in the CSF were significantly lower during the withdrawal period than the medicated period regardless of whether patients developed NMLS, and HVA concentrations were comparably increased after remedication in both groups. However, HVA concentrations were significantly lower in patients with NMLS than in those without NMLS during both withdrawal and medicated periods. Other metabolites showed no significant differences. The present data provide further biochemical evidence for extremely suppressed central dopaminergic activity during NMLS, which may indicate a narrow safety margin for medication withdrawal in patients with Parkinson's disease.

CSF monoamine metabolite and beta endorphin levels in recently detoxified alcoholics and healthy controls: prediction of alcohol cue-induced craving?

BACKGROUND: Abnormalities in central neurotransmitter systems have been described in alcohol-dependent individuals and may contribute to alcohol craving. This study compared cerebrospinal fluid (CSF) levels of monoamine metabolites and beta endorphin levels in samples from early-onset alcohol-dependent patients (n = 20), late-onset alcohol-dependent patients (n = 14), and healthy controls (n = 23). It also evaluated whether these CSF measures levels predicted the degree of craving experienced in response to an alcohol cue. METHODS: Individuals meeting DSM-III and -IV R-criteria for alcohol dependence, 1 to 3 months postdetoxification, and healthy controls underwent a lumbar puncture. Patients also completed a cue exposure test day between 3 and 15 days later. RESULTS: Alcohol-dependent patients had lower CSF levels of the norepinephrine metabolite MHPG compared with the healthy subjects, but this difference disappeared when differences in age between the groups were accounted for. No other group comparisons between patients and healthy subjects reached significance. CSF levels of the dopamine metabolite HVA were significantly higher in the early-onset patients compared with the late-onset patients and controls. The CSF measures did not predict the precue levels of craving, or the increase in craving after alcohol cue exposure. CONCLUSIONS: These results are inconclusive about the role of monoaminergic dysregulation in recovering alcoholics. They also question the utility of these CSF measures to predict alcohol cue reactivity in patients who have been sober at least 1 month.

Severity of depression in abstinent alcoholics is associated with monoamine metabolites and dehydroepiandrosterone-sulfate concentrations.

Depressed mood increases the relapse risk of abstinent alcoholics; its neurobiological correlates may include reduced serotonin and norepinephrine turnover rates and increased cortisol concentrations during detoxification stress. Neurosteroids such as dehydroepiandrosterone and its sulfate (DHEA and DHEA-S) may antagonize cortisol action and may have mood-elevating effects on their own. We measured severity of depression with Beck's Depression Inventory (BDI) and Hamilton's Depression Rating Scale (HDRS), plasma concentrations of cortisol, DHEA and DHEA-S, and CSF concentrations of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA), the norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) and the dopamine metabolite homovanillic acid (HVA) in 21 abstinent alcoholics after 4 weeks of abstinence and in 11 age-matched healthy control subjects. Only CSF MHPG concentrations were reduced in alcoholics compared to control subjects (41.4 +/- 6.6 vs. 53.3 +/- 8.6 pmol/ml). Self-rated depression was significantly correlated with CSF MHPG (Spearman's R = +0.57, P < 0.01), CSF 5-HIAA (R = +0.51, P < 0.05) and plasma cortisol concentrations (R = +0.50, P < 0.05). Negative correlations were found between DHEA-S concentrations and both self-rated depression (R = -0.45, P < 0.05) and observer-rated depression (R = -0.55, P < 0.05). The ratio of DHEA-S to cortisol serum concentrations was also negatively correlated with depression (BDI: R = -0.55, P < 0.01; HDRS: R = -0.63, P < 0.005). Anxiety (Spielberger's State Anxiety Scale) was only associated with CSF MHPG concentrations (R = +0.58, P < 0.01). Our findings point to the importance of noradrenergic dysfunction in the pathogenesis of depression among abstinent alcoholics and indicate that their mood states may also be modulated by a low DHEA-S to cortisol ratio, hypothetically indicative of low stress protection capacities.

Cerebrospinal fluid concentrations of corticotropin-releasing hormone (CRH) and diazepam-binding inhibitor (DBI) during alcohol withdrawal and abstinence.

The neuropeptides diazepam binding inhibitor (DBI) and corticotropin-releasing hormone (CRH) elicit anxietylike symptoms when administered intracerebroventricularly to laboratory animals. Because of the similarities between the symptoms of certain anxiety states and the alcohol withdrawal syndrome, we hypothesized that increased secretion of either of these endogenous neuropeptides may, at least in part, be responsible for the symptoms of alcohol withdrawal. We therefore measured DBI and CRH concentrations in cerebrospinal fluid (CSF) of 15 alcohol-dependent patients during acute withdrawal (Day 1) and again at 3 week's abstinence (Day 21). In addition, plasma concentrations of cortisol were measured to evaluate the relationship between pituitary-adrenal axis activation and CSF CRH concentrations. CSF CRH (p < .04), but not CSF DBI, was significantly higher on Day 1 than on Day 21. Although there was a significant decrease in plasma cortisol from Day 1 to Day 21 (p < .001), a significant correlation between CSF CRH and plasma cortisol concentrations was not observed at either time point. Neither CSF neuropeptide correlated with clinical measures of withdrawal severity. These tentative findings may implicate CRH, but not DBI, in the pathogenesis of alcohol withdrawal. Alternately, the central release of CRH and DBI may not be adequately reflected in lumbar CSF.

Cerebrospinal fluid corticotropin-releasing factor increases following haloperidol withdrawal in chronic schizophrenia.

Corticotropin-releasing factor (CRF), an endogenous neuropeptide, has been shown to coordinate endocrine, behavioral and autonomic responses to stress. However, while previous studies of cerebrospinal fluid (CSF) CRF in schizophrenia have not demonstrated significant differences compared to control groups, these studies have not examined the effects of symptom severity or antipsychotic medication. CSF CRF concentrations increased in 18 of 21 male schizophrenic (DSM-III-R) patients after maintenance haloperidol was replaced by placebo (P < 0.0001); there was also a trend for relatively greater increases in relapsers. CRF concentrations were not significantly related to severity of psychosis, depression, anxiety or negative symptoms. During haloperidol treatment, but not after medication withdrawal, worse childhood premorbid adjustment was associated with higher CSF CRF levels. Finally, in contrast to the positive correlation between CSF CRF and norepinephrine concentrations reported in depression, a negative trend was seen in this schizophrenic sample.

Noradrenergic activity and prediction of psychotic relapse following haloperidol withdrawal in schizophrenia.

OBJECTIVE: The purpose of this study was to develop a model based on the authors' previous studies to identify which neuroleptic-treated schizophrenic patients are at risk of early relapse following drug withdrawal. METHOD: Clinical and CSF monoamine-related variables obtained for 50 male haloperidol-treated, schizophrenic patients were used in a logistic regression model to identify those who relapsed (N = 24) within 6 weeks after placebo substitution and those who did not (N = 26). RESULTS: The oral dose of haloperidol, weight, CSF norepinephrine, 3-methoxy-4-hydroxyphenylglycol and chromogranin A-like immunoreactivity, and the anxiety and paranoia subscale ratings of the Brief Psychiatric Rating Scale produced a model that correctly predicted 18 relapsers and 21 nonrelapsers. By including the interactions of paranoia subscale by CSF norepinephrine and anxiety by CSF norepinephrine, the model correctly identified 20 relapsers and 23 nonrelapsers with a sensitivity and specificity of 83% and 88%, respectively. CONCLUSIONS: Increased noradrenergic activity during chronic dopamine blockade may be an episode marker and may predict relapse within 6 weeks following haloperidol withdrawal in schizophrenia. Effective relapse prediction models have important practical implications for the treatment of schizophrenia and the understanding of the psychotic relapse process.

Cerebrospinal fluid oxytocin concentration in schizophrenic patients does not differ from control subjects and is not changed by neuroleptic medication.

Cerebrospinal fluid (CSF) oxytocin concentrations in 20 neuroleptic-treated schizophrenic patients, 31 neuroleptic-withdrawn schizophrenic patients, and 15 normal control subjects were compared. Neither within-subject comparisons of CSF oxytocin concentration measurements made during neuroleptic treatment and withdrawal (n = 11), nor comparison of the combined neuroleptic-withdrawn and neuroleptic-treated patient group (n = 40) with control subjects (n = 15) differed significantly, suggesting that CSF oxytocin concentration is not altered in schizophrenia.

CSF diazepam binding inhibitor and schizophrenia: clinical and biochemical relationships.

Diazepam-binding inhibitor (DBI) is a 9-kD neuropeptide that interacts with the benzodiazepine (BZD) binding sites of the neuronal gamma-aminobutyric acid type A (GABAA) receptor and with the glial mitochondrial BZD receptor (MBR). We explored the involvement of CSF DBI-LI in schizophrenia, based on the potential role of GABA in the negative symptoms associated with schizophrenia, the relationship of its receptors with dopamine and norepinephrine release, and the proposed therapeutic efficacy of BZDs in schizophrenia. Clinical data, CSF DBI-LI and CSF monoamine measures were obtained in 65 drug-free male chronic (DSM-IIIR) schizophrenic patients, 53 of whom were also tested prior to haloperidol withdrawal. Following haloperidol withdrawal, CSF DBI-LI increased significantly. Drug-free CSF DBI-LI did not correlate with CSF monoamines. CSF DBI-LI was significantly higher in paranoid compared to chronic undifferentiated schizophrenic patients. The data suggest that DBI may have a symptom modulatory rather than an etiological role in schizophrenia.

CSF gamma-aminobutyric acid in alcoholics and control subjects.

Alcohol has widespread effects on the gamma-aminobutyric acid (GABA) system in the brain. This system in the brain is also postulated to have a role in anxiety, and alcoholics have been reported to have more anxiety disorders. Therefore, the authors undertook a study to compare CSF levels of GABA in abstinent alcoholic patients and normal control subjects. There was no significant difference between groups in CSF levels of GABA. Also, there was no significant difference in GABA level between alcoholic patients with histories of withdrawal seizures and those without such a history.

CSF norepinephrine in schizophrenia is elevated prior to relapse after haloperidol withdrawal.

Thirty-two male DSM-III diagnosed schizophrenic patients received a lumbar puncture (LP) during chronic haloperidol treatment that was followed by replacement with placebo for up to 6 weeks. Fourteen patients relapsed on placebo within 6 weeks. Patients received a second LP at the time of relapse or at the end of 6 weeks if they had not relapsed. Bunney-Hamburg Global Psychosis Ratings of the day and the hours of sleep of the night before the LP were obtained, as were the Brief Psychiatric Ratings Scale (BPRS) ratings during the week of the LPs. CSF norepinephrine (NE), 3-methoxy-4-hydroxyphenylglycol (MHPG), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5 HIAA) concentrations were measured with high-pressure liquid chromatography (HPLC). Patients who relapsed had significantly higher CSF NE levels on and off haloperidol than patients who did not relapse. CSF MHPG was higher in the relapsers in the drug-free condition only, but CSF HVA and 5-HIAA were not significantly different in either condition. In the drug-free relapsed patients, CSF NE correlated significantly with the psychosis ratings of the day and hours of sleep the night prior to the LP. Our data indicate that elevated CSF NE levels during neuroleptic treatment may predict behavioral decompensation after discontinuing the medication.

Endogenous opioids in cerebrospinal fluid of opioid-dependent humans.

Endogenous opioid systems may be altered as a consequence of addiction, but evidence to support this idea is meager so far. We obtained 136 cerebrospinal fluid (CSF) samples from 72 opioid addicts during four distinct states: methadone maintenance, detoxification from methadone, opioid antagonist treatment, and drug-free status. CSF endorphins were measured in 86 patients samples using a radioreceptor assay (RRA), and beta-endorphin levels were measured in 85 patient samples using a radioimmuno assay (RIA). During detoxification, both RRA fraction I and beta-endorphin showed a generally similar pattern of changes. Both were lowest when measured 40-50 hr after the last opioid dose, and both showed an apparent rebound to higher than methadone maintenance values at 60-70 hr following the last dose. During methadone maintenance and drug-free states, the addicts' levels of fraction I RRA endorphins in the CSF were higher than levels found in a normal control group. Fraction II endorphins were also elevated in the addicts who were drug free. In contrast, CSF beta-endorphin during both methadone maintenance and drug-free states was lower in the addicts as compared to the normal, drug-naive group. Except for the pattern found during detoxification, there were no consistent changes in endorphin levels across different states of addiction.

Elevated cerebrospinal fluid histidine in alcohol withdrawal.

Cerebrospinal fluid (CSF) histidine concentration was significantly elevated in seven patients early in the alcohol withdrawal syndrome (206.3 +/- 74.4 (SEM) nanomols/ml CSF). When these same patients were restudied an average of six days later when alcohol withdrawal was clinically resolved, their mean CSF histidine concentration continued to be significantly elevated (164.7 +/- 24.7) when compared to normal (12.0 +/- 0.5 nanomols/ml CSF). Other amino acids (aspartic acid, serine, alanine, methionine, leucine, tyrosine, phenylalanine, lysine and arginine) showed no definite changes from normal, and no change during the course of alcohol withdrawal. Possible reasons for these high concentrations and the extreme variability (especially early in alcohol withdrawal) are discussed.