Discriminative stimulus properties of ethanol in the rat: differential effects of selective and nonselective benzodiazepine receptor agonists

Rats were trained to discriminate between ethanol (1.0 g/kg; 10% v/v) and saline under a fixed ratio 10 schedule of sweetened milk reinforcement. Both diazepam [nonselective, full benzodiazepine (BZ) receptors agonist] and bretazenil (nonselective, partial BZ receptor agonist) produced dose-dependent ethanol-appropriate responding (>75%). Neither diazepam nor bretazenil affected the response rate at the doses producing maximal generalisation from ethanol. In contrast, zolpidem (full BZ1 receptor agonist) and abecarnil (full BZ1/full or partial BZ2 receptor agonist) produced only moderate (<50%) ethanol-appropriate responding when tested up to doses that markedly decreased the overall response rate. These results suggest that: 1) there are no major differences between full and partial, nonselective BZ receptor agonists in their ability to substitute for 1.0 g/kg dose of ethanol; 2) stimulation of BZ1 receptors alone is not sufficient to produce ethanol-like discriminative stimulus effects in the rat.     

Long-term treatment with abecarnil does not induce diazepam-like dependence in mice

Abecarnil (isopropyl-6-benzyloxy-4-methoxymethyl-beta-carboline-3-carboxylate) is a metabolically stable anxiolytic and anticonvulsant beta-carboline derivative with few sedative and muscle relaxant effects in rodents. Abecamil binds with high affinity to benzodiazepine receptors. Because long-term treatment with benzodiazepines leads to development of dependence, we evaluated in mice whether abecarnil also possesses a potential for producing dependence, using electroencephalographic and electromyographic monitoring, and behavioral assessment of anxiety to detect withdrawal responses after chronic treatment. Diazepam was used as a reference. Mice withdrawn from chronic treatment with diazepam (15 mg/kg/day for 12 days) showed a time-related evolution of anxiety, muscle rigidity and seizures between days 4 and 21 after discontinuation of the treatment. A period between withdrawal days 1 and 3 was symptom free. Mice withdrawn from chronic administration of abecarnil (6 mg/kg/day for 12 days) showed no anxiety and no changes in seizure susceptibility and muscle tone. The doses of diazepam and abecarnil used for chronic treatment were equivalent in terms of kinetics and binding to benzodiazepine receptors. These data indicate that long-term treatment with abecarnil does not induce benzodiazepine-like dependence in mice. Thus, it may be predicted that chronic treatment with abecarnil in humans may offer an important alternative to benzodiazepines in the treatment of anxiety.     

Pharmacological characterization of the novel anxiolytic beta-carboline abecarnil in rodents and primates

beta-Carboline abecarnil was behaviorally and biochemically characterized as a new anxiolytic agent in rodents and primates in comparison with the benzodiazepine (BZ) anxiolytics. Oral treatment with abecarnil (0.5-10 mg/kg) showed a potent anticonflict activity in the water-lick test in rats. The minimal effective dose was lower than those of BZ anxiolytics, such as etizolam, diazepam, clotiazepam and tofisopam. Abecarnil also showed taming effects to suppress fighting and aggressive behaviors in mice and monkeys with little sedative and ataxic effects, in contrast to the BZ anxiolytics producing marked sedative and ataxic effects. Furthermore, abecarnil suppressed both the sedative and ataxic effects induced by diazepam. Abecarnil bound to rat cerebellar BZ1 receptors (Ki = 0.24 nM) with higher affinity than to rat spinal cord BZ2 receptors (Ki = 1.3 nM), whereas BZ derivatives bound to both the receptors with a low and equal affinity. GABA-ratios of abecarnil were 1.9 for the BZ1 receptors and 2.8 for the BZ2 receptors, and they were smaller than those of diazepam and flunitrazepam. Thus, in contrast to the BZ derivatives, abecarnil may act as a selective partial agonist at central BZ1 receptors, resulting in its potent anticonflict and taming effects with little sedative and ataxic effects.     

Pharmacotherapies for alcohol abuse. Withdrawal and treatment

Pharmacologic management of alcoholism is only one part of the management of both alcohol dependence and withdrawal, which also includes the provision of a calm, quiet environment; reassurance; ongoing reassessment; attention to fluid and electrolyte disorders; treatment of coexisting addictions and common medical, surgical, and psychiatric comorbidities; and referral for ongoing psychosocial and medical treatment. For further discussion of these topics, the reader is referred to previously published sources. A survey of alcoholism treatment programs revealed that although benzodiazepines were the most commonly used drugs, standardized monitoring of patients' withdrawal severity was not common practice, and a significant minority of clinicians were using a variety of other drugs, some not known to prevent or treat the complications of withdrawal. Treatment should be based on the available evidence (Working Group on Pharmacological Management of Alcohol Withdrawal: American Society of Addiction Medicine Committee on Practice Guidelines: Pharmacological management of alcohol withdrawal: An evidence-based practice guideline. Unpublished draft, 1997). Patients with significant symptoms, patients with complications such as seizures or delirium tremens, and patients at higher risk for complications of alcohol withdrawal should receive benzodiazepines, particularly chlordiazepoxide, diazepam, or lorazepam, because of their safety and documented efficacy in preventing and treating the most serious complications of alcohol withdrawal. These drugs may be dosed on a fixed schedule for a predetermined number of doses on a tapering schedule over several days, or they may be administered by front-loading. An alternative approach for selected patients without seizures or acute comorbidity is symptom-triggered therapy, which individualizes treatment and decreases the duration and dose of medication administration. With either of the regimens, patients should have their withdrawal severity monitored until symptoms are resolving. Once withdrawal from alcohol is safely completed, the focus should turn to helping to prevent relapse. Disulfiram may be useful in highly motivated subsets of patients and when compliance-enhancing strategies are used. Naltrexone is useful in the broader population of patients entering treatment for alcohol dependence. These pharmacologic interventions should be given in the context of ongoing psychosocial support. There is substantial evidence that pharmacologic management of alcohol abuse and dependence is effective. As would be predicted from alcohol's myriad cellular effects, no panacea exists for alcoholism. For alcohol withdrawal, however, although treatment regimens have only recently been refined, evidence for effective treatment of symptoms and prevention of complications with benzodiazepines has been available for decades. Within the last decade, effective treatments, including naltrexone, have been shown to reduce alcohol intake in alcohol-dependent persons. Given the prevalence and cost of alcohol-related problems, all effective therapies (including pharmacologic treatments) should be considered to treat alcohol abuse and dependence.     

Further evidence for differences between non-selective and BZ-1 (omega 1) selective, benzodiazepine receptor ligands in murine models of "state" and "trait" anxiety

The behavioural effects of several BZ (omega) receptor ligands were compared in mice using the light/dark choice task, an animal model of "state" anxiety, and the free-exploration test, which has been proposed as an experimental model of "trait" anxiety. The drugs used included non-selective full (alprazolam, clorazepate, chlordiazepoxide and diazepam), partial agonists (bretazenil, imidazenil and Ro 19-8022) and BZ-1 (omega 1) selective receptor ligands (abecarnil, CL 218,872 and zolpidem). In the light/dark choice task, non-selective full agonists elicited clear anxiolytic-like effects increasing time spent in the lit box and simultaneously reducing attempts at entry into the illuminated cage followed by withdrawal responses, a measure of risk assessment. With the exception of abecarnil, both non-selective partial agonists and BZ-1 (omega 1) selective receptor ligands displayed reduced efficacy compared to the full agonists as they decreased risk assessment responses without altering time in the lit box. In addition, the weak anxiolytic-like actions displayed by selective BZ-1 (omega 1) agents were evident only at doses which reduced locomotor activity, indicating that this effect may be non-specific. In the free-exploration test, non-selective BZ (omega) receptor agonists markedly increased the percentage of time spent in the novel compartment and reduced the number of attempts to enter whereas selective BZ-1 (omega 1) receptor ligands displayed a weaker neophobia-reducing effect as they reduced risk assessment responses only. As was the case in the light/dark choice task, this latter effect was observed at locomotor depressant doses. These findings indicate that while both full and partial BZ (omega) receptor agonists are equally effective against "trait" anxiety, full agonists may be superior in reducing "state" anxiety. In addition, the lack of specific effects of selective BZ-1 (omega 1) receptor ligands in reducing both types of anxiety suggests that the BZ-1 (omega 1) receptor subtype cannot be considered as the primary target mediating the anxiolytic action of drugs interacting with the GABAA benzodiazepine receptor complex.     

Comparison of several benzodiazepine receptor ligands in two models of anxiolytic activity in the mouse: an analysis based on fractional receptor occupancies

This study compared the effects of the beta-carboline anxiolytic, abecarnil, with other benzodiazepine receptor (BZR) ligands, including the full agonists diazepam and alprazolam, and the partial agonists ZK 95962 and bretazenil (Ro 16-6028), and alpidem, in the mouse four-plate test and plus-maze. The efficacy and potency of each compound was related to the fraction of BZR occupied by the drug. Abecarnil was efficacious in both tests and showed anxiolytic effects comparable with alprazolam and diazepam. In the four-plate test, abecarnil, bretazenil, and ZK 95962 had selective effects on releasing exploratory locomotor activity suppressed by footshock (punished crossings). None of these compounds significantly altered non-punished crossings. In contrast, diazepam and alprazolam increased both unpunished and punished crossings at low to medium doses (receptor occupancies of approximately 20-60%). The number of punished and unpunished crossings fell to control levels or below at higher, more sedative doses (approximately 80% receptor occupancy). Alpidem had very weak anxiolytic-like effects in this test and markedly reduced unpunished crossings at relatively low receptor occupancies (> 15%). In the plus-maze, abecarnil increased the time spent in the open arms and the percentage open arm entries to an extent equal to that observed following diazepam or alprazolam administration. Bretazenil and ZK 95962 had weak effects on the measures of anxiolytic activity in this test. Alpidem also had little anxiolytic-like activity in the plus-maze but markedly reduced the total number of arm entries.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacological modulation of the diazepam-insensitive recombinant gamma-aminobutyric acidA receptors alpha 4 beta 2 gamma 2 and alpha 6 beta 2 gamma 2

We characterized modulation of the gamma-aminobutyric acid (GABA)-evoked responses of the diazepam-insensitive alpha 4 beta 2 gamma2 and alpha 6 beta 2 gamma 2 recombinant GABAA receptors. The partial agonist bretazenil potentiated the responses of both receptors with similar dose dependence but with a higher maximal enhancement at the alpha 4 beta 2 gamma 2 receptor. The bretazenil-induced potentiation was reduced by the benzodiazepine antagonist flumazenil. At a high concentration (10 microM), flumazenil was a weak potentiator of the GABA response. The partial agonist imidazenil was inactive. The imidazobenzodiazepine inverse agonist Ro 15-4513, which is known to bind with high affinity to the alpha 6 beta 2 gamma 2 receptor, potentiated the GABA responses of the alpha 4 beta 2 gamma 2 and alpha 6 beta 2 gamma 2 receptor subtypes with similar dose dependence over the concentration range of 0.1-10 microM. Methyl-6, 7-dimethoxy-4-ethyl-beta-carboline, a beta-carboline inverse agonist, had a similar potentiating effect when tested at a concentration of 10 microM. The alpha 4 beta 2 gamma 2 and alpha 6 beta 2 gamma 2 receptor-mediated currents had equal sensitivities to furosemide and Zn2+ ions, both of which reduced the GABA-evoked responses. The alpha 6 beta 2 gamma 2 receptor but not the alpha 4 beta 2 gamma 2 receptor exhibited a low level of spontaneous activity in the absence of GABA; this resting current could be directly potentiated by Ro 15-4513, methyl-6,7-dimethoxy-4-ethyl-beta-carboline, bretazenil and flumazenil and was blocked by picrotoxin. Thus, although the alpha 4 beta 2 gamma 2 receptors are insensitive to benzodiazepine binding site full agonists, such as diazepam, they can be modulated by certain ligands acting as partial and inverse agonists at diazepam-sensitive receptors and thereby contribute to the respective pharmacological profiles.     

Characterization of benzodiazepine receptors in primary cultures of fetal mouse brain and spinal cord neurons

Primary cultures of fetal mouse brain and spinal cord were examined for the presence of binding sites for [3H]diazepam. Both brain and spinal cord cultures contain high affinity binding sites which resemble benzodiazepine receptors found in mammalian CNS with respect to both pharmacologic profile and response to exogenously applied GABA. These observations, coupled with the electrophysiologic properties of these cells suggest that primary cultures of fetal mouse brain and spinal cord may be valid models for studying the role and regulation of the benzodiazepine receptor.     

Epidemiological study of myasthenia gravis in the province of Reggio Emilia, Italy

In vitro binding profiles were determined for selected benzodiazepine receptor (BZR) ligands by quantitative radioautography in rat brain. The ligands represent subtype-selective agonists (zolpidem) or nonselective BZR agonists (diazepam), as well as BZR partial agonists (bretazenil, Ro 43-9624, and Ro 19-8022). In addition, these compounds were evaluated in a precipitated withdrawal paradigm in monkeys. The physical dependence liability was not clearly related to the in vitro brain BZR binding profiles of these compounds. Therefore, diazepam, bretazenil, Ro 19-8022, and Ro 43-9624 had regional affinities for the 13 selected rat brain regions that were close to the mean values across regions, despite the clearly greater physical dependence potential of diazepam. Zolpidem, on the other hand, had regional affinities for the 13 rat brain regions that diverged significantly from the mean value across regions and exhibited a lower physical dependence potential than diazepam. These results raise the possibility that a combination of BZR subtype selectivity with partial agonism could yield a marked reduction of physical dependence liability.     

Interactions of cholinergic and glutamatergic neuronal systems in the functional activation of cerebral blood flow response: a PET study in unanesthetized monkeys

The present study investigated the effects of the NMDA receptor antagonists dizocilpine (MK-801) and ifenprodil on the appearance of diazepam withdrawal signs caused by discontinuation of long-term diazepam treatment using a drug-admixed food (DAF) method in Fischer 344 rats. The total withdrawal score was significantly decreased by after-withdrawal treatment with dizocilpine or ifenprodil. Dizocilpine, in particular, markedly suppressed the motor withdrawal signs and body weight loss, while ifenprodil suppressed the motor and emotional withdrawal signs. Furthermore, the decrease in the food intake during withdrawal (anorexia) was significantly reduced by dizocilpine, but not by ifenprodil. These behavioral results indicated that the activation of NMDA receptors during withdrawal may play an important role in the appearance of withdrawal signs (in particular motor withdrawal signs) caused by discontinuation of chronic diazepam treatment, and that inhibitory agents for NMDA receptors may be effective in alleviation of the appearance of benzodiazepine withdrawal signs.     

Benzodiazepine receptor ligands are elevated in an animal model of hepatic encephalopathy: relationship between brain concentration and severity of encephalopathy

Elevated levels of benzodiazepine receptor agonists are found in both animal models of hepatic encephalopathy and in humans with this syndrome. The present study investigated the relationship between agonist levels and the severity of the encephalopathy, as well as the potential reversibility of the syndrome by benzodiazepine receptor antagonists. The concentrations of benzodiazepine receptor ligands in rat brains were measured at several intervals during the induction of liver failure with thioacetamide. Six hours after the first dose of thioacetamide, brain concentrations of benzodiazepine receptor ligands were increased and open field activity decreased compared to control rats. However, the brain concentrations of benzodiazepine receptor ligands correlated better with the stage of hepatic encephalopathy than time after initiation of thioacetamide treatment. The benzodiazepine receptor ligands Ro 15-3505, Ro 15-4513 and CGS-8216 ameliorated motor abnormalities in rats with stage 3 hepatic encephalopathy. Only Ro 15-3505 improved motor activity in rats in stage 2 encephalopathy to levels observed in rats with stage 1 encephalopathy. Furthermore, although Ro 15-4513 and CGS 8216 significantly increased motor activity in stage 4 hepatic encephalopathy, this may reflect their partial inverse agonist properties. These findings support the hypothesis that increased brain levels of benzodiazepine receptor agonists contribute to the severity of hepatic encephalopathy and suggest that high-affinity benzodiazepine receptor antagonists are efficacious in reversing this syndrome.     

Effect of kainate on the membrane conductance of hilar glial precursor cells recorded in the perforated-patch configuration

OBJECTIVE: To determine discontinuation effects of ipsapirone, a novel azapirone and partial 5-HTIA agonist that has anxiolytic effects clinically and has not caused dependence or withdrawal symptoms in animals, and to compare these effects with those of the benzodiazepine lorazepam, owing to concern about dependence or withdrawal symptoms following use of these drugs. DESIGN: Prospective, randomized, double-blind, placebo-controlled trial. SETTING: Outpatient and inpatient treatment. PARTICIPANTS: Sixty-five healthy male volunteers who had experience with sedative-hypnotics or anxiolytics and did not meet DSM-III-R criteria for abuse or dependence. INTERVENTIONS: Participants were randomized to receive ipsapirone 15 mg per day (n = 17), ipsapirone 22.5 mg per day (n = 16), lorazepam 3 mg per day (n = 16), or placebo (n = 16) as outpatients for 36 days (treatment) followed by single-blind placebo as inpatients for 3 days and as outpatients for 6 days (withdrawal). OUTCOME MEASURES: Hamilton Anxiety Rating Scale (HAM-A), Hamilton Depression Scale (HAM-D), Spielberger State Anxiety Scale, Sleep Quality Questionnaire, General Symptom Checklist, self-rated intoxication, Clinical Institute Withdrawal Assessment--Benzodiazepines (CIWA-Benzo), psychomotor testing and urine drug screen. RESULTS: Only 45 subjects completed the study; discontinuation rates did not significantly differ among treatment groups. At day 39, fewer and less severe symptoms (e.g., insomnia and fatigue) were found on the CIWA-Benzo scale after treatment with ipsapirone or placebo than after treatment with lorazepam (p < 0.05). Subjects reported longer sleep latency and poorer sleep quality after receiving lorazepam than after receiving ipsapirone or placebo. Scores on the HAM-D, Spielberger State Anxiety and HAM-A scales did not change from baseline. CONCLUSIONS: Withdrawal symptoms were detected after discontinuation of therapeutic doses of lorazepam. Significantly fewer symptoms were observed after withdrawal from anxiolytic doses of ipsapirone.     

Impact of age on the severity, course, and complications of alcohol withdrawal

BACKGROUND: Early identification of alcohol-dependent patients at increased risk for severe or complicated alcohol withdrawal would improve triage and treatment. However, the role of age in predicting alcohol withdrawal outcomes has not been well studied. OBJECTIVE: To assess the impact of age on the severity, course, and complications of alcohol withdrawal. METHODS: We performed a retrospective cohort study of 284 inpatients admitted for alcohol withdrawal between September 1992 and August 1994. Outcomes included alcohol withdrawal severity measured by the revised Clinical Institute Withdrawal Assessment for Alcohol scale, quantity and duration of benzodiazepine therapy, and complications during withdrawal. RESULTS: Initial and maximal withdrawal severity scores, amount of benzodiazepine administered, and duration of benzodiazepine treatment for elevated withdrawal severity scores did not change significantly with age. However, patients aged 60 years and older had increased risk for delirium (adjusted odds ratio [OR], 4.7; 95% confidence interval [CI], 1.5-15.0; P = .008), falls (OR, 3.1; 95% CI, 0.9-11.2; P = .08), and transient dependency in 2 or more activities of daily living (OR, 5.8; 95% CI, 2.9-11.7; P < .001). As age increased, there were significant increases in length of stay (P < .001) and frequency of discharge to an extended care facility (P < .001). CONCLUSIONS: Although alcohol withdrawal severity scores and benzodiazepine requirements were similar across age groups, patients aged 60 years and older were at increased risk for cognitive and functional impairment during withdrawal. These findings support recommendations that older patients with alcohol withdrawal are best treated in closely supervised settings.     

Drinking water health advisory program

A 67-year-old woman with a history of psychotropic drug abuse developed confusion. EEG was consistent with absence status epilepticus (AS). Intravenous (i.v.) flumazenil 1 mg, a benzodiazepine antagonist with anticonvulsant properties, increased both confusion and paroxysmal activity. Complete resolution was obtained after diazepam was administered i.v., and the patient then admitted that she had abruptly discontinued long-standing treatment with carpipramine, amitriptyline, bromazepam, and flunitrazepam. The aggravating effect of flumazenil indicates that benzodiazepine withdrawal was probably the elective triggering factor of this de novo absence status epilepticus.     

Dexmedetomidine, diazepam, and propranolol in the treatment of ethanol withdrawal symptoms in the rat

In this study, the effects of dexmedetomidine, a selective alpha 2-adrenoceptor agonist, on ethanol withdrawal symptoms, were compared with those of diazepam and propranolol. The rats were given highly intoxicating doses of ethanol for 4 days. After the intoxication period, rats were divided into four equal groups: a dexmedetomidine-treated group (30 micrograms/kg, sc), a diazepam-treated group (2 mg/kg, sc), a propranolol-treated group (5 mg/kg, sc), and a control group with no medication. Medication was given in the withdrawal phase-2, 8, 14, and 20 hr after the onset of the withdrawal symptoms. The severity of the ethanol withdrawal symptoms (rigidity, tremor, irritability, and hypoactivity) was observed up to 33 hr after the onset of the ethanol withdrawal symptoms. Both dexmedetomidine and diazepam significantly relieved tremor compared with the control group. Diazepam reduced irritability significantly, compared with the control group. When measured as the sum score of the three most specific withdrawal signs (rigidity, tremor, and irritability), dexmedetomidine and diazepam significantly relieved the ethanol withdrawal reaction. Propranolol attenuated tremor, but was inefficient against other withdrawal symptoms. Dexmedetomidine may thus represent a new effective drug in the treatment of the ethanol withdrawal syndrome.     

Behavioral pharmacology of zolpidem relative to benzodiazepines: a review

Zolpidem, an imidazopyridine that purportedly binds selectively to certain GABA(A) receptor subtypes, is the most commonly prescribed hypnotic. The present article critically reviewed the extant experimental literature to determine whether the behavioral pharmacologic profile of zolpidem also differs from that of benzodiazepines. Specific topics that are reviewed include: 1) reinforcing effects and abuse potential, 2) discriminative-stimulus effects, 3) subject-rated drug effects, 4) performance-impairing effects, 5) tolerance-producing effects, and 6) physiological dependence-producing effects. Studies that employed both nonhumans and humans are reviewed. Based on the available literature, the most parsimonious conclusion is that despite its unique neuropharmacological profile, the behavioral effects of zolpidem are generally similar to those of benzodiazepines. However, it is important to note the dearth of perspective, experimental studies that directly compared zolpidem and a benzodiazepine. Because of the clinical relevance and paucity of published studies, future research should focus explicitly on assessing the reinforcing effects, abuse potential, performance-impairing effects, tolerance-producing effects, and dependence-producing effects of zolpidem relative to a benzodiazepine. Important issues such as the selection of an appropriate comparison drug and subject population, and the doses tested needed to be considered in these future studies.     

Active site structure and stability of the thiol protease papain studied by electron paramagnetic resonance employing a methanethiosulfonate spin label

The benzodiazepine receptor antagonist flumazenil (2.5-20 mg/kg i.p.) increased acetylcholine (ACh) release by up to 85% in the hippocampus of freely moving rats. In contrast, the benzodiazepine receptor full agonist diazepam (2.5-10 mg/kg i.p.) decreased ACh release up to a maximum of 45% in the same brain area. Injection of flumazenil (10 pmol) or diazepam (10 pmol) into the medial septum increased (95%) or reduced (50%), respectively, ACh release in the hippocampus. The maximum effect produced by those drugs was of the same magnitude as that observed after systemic injection. The changes in hippocampal cholinergic function elicited by activation and blockade of benzodiazepine receptors in the medial septum may thus play a crucial role in the alterations of the cognitive processes elicited by benzodiazepine receptor ligands.     

Pharmacological treatment of alcoholism

1. Pharmacological treatments are effective as part of a treatment plan that includes substantial education, psychological therapy and social support. This paper reviews recent literature on animal models of and treatment for alcohol abuse under seven categories: agents to block craving or reduce alcohol intake, agents to induce aversion to alcohol, agents to treat acute alcohol withdrawal, agents to treat protracted alcohol withdrawal, agents to diminish drinking by treating associated psychiatric pathology, agents to decrease drinking by treating associated drug abuse, and agents to induce sobriety in intoxicated individuals. 2. The benzodiazepines provide safe and effective treatment for detoxification, although current research focuses on finding drugs with a smaller likelihood of dependence. As yet, there are no drugs that effectively reverse the intoxicating effects of alcohol. 3. Currently, only two major groups of drugs that are relatively safe have shown any effect at reducing alcohol consumption: aversives such as disulfiram, and opioid antagonists such as naltrexone. 4. Finally, it is important to customize therapy for each patient rather than putting everyone through a standard treatment plan, especially in regards to the use of antidepressant or antipsychotic medications. Tailoring the program to the patient's needs dramatically improves the outcome of therapy and reduces the risk of adverse effects.     

Alprazolam and DN-2327 (Pazinaclone) in humans: Psychomotor, memory, subjective, and reinforcing effects.

The psychomotor, memory, subjective, and reinforcing effects of DN-2327 (DN), a novel partial agonist at benzodiazepine receptors, were compared with those of alprazolam (AL) in 14 men with histories of sedative drug abuse. Placebo, DN (8, 16, and 32 mg), and AL (0.5, 1.0, and 2.0 mg) were administered orally in a randomized, double-blind, cross-over design. DN and AL produced similar maximal impairment on psychomotor and memory performance. AL produced greater increases in participant ratings of sedation and a variety of somatic symptoms that were absent following DN. Abuse liability measures showed both drugs increased liking and good effects and were categorized by participants as sedative-hypnotics; however, 2 of 3 indirect and 1 direct measure of drug reinforcement were greater with AL than with DN. The dissociation between psychomotor-memory performance effects and various subjective effects demonstrates a novel pharmacological profile of DN. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Long-term neuroprotection by benzodiazepine full versus partial agonists after transient cerebral ischemia in the gerbil [corrected

The ability of diazepam, a benzodiazepine full agonist, and imidazenil, a benzodiazepine partial agonist, to protect hippocampal area CA1 neurons from death for at least 35 days after cerebral ischemia was investigated. Diazepam (10 mg/kg) administered to gerbils 30 and 90 minutes after forebrain ischemia produced significant protection of hippocampal area CA1 pyramidal neurons 7 days later. In gerbils surviving for 35 days, diazepam produced the same degree of neuroprotection (70% +/- 30%) in the hippocampus compared with 7 days after ischemia. The therapeutic window for diazepam was short; there was no significant neuroprotection when the administration of diazepam was delayed to 4 hours after ischemia. The neuroprotective dose of diazepam also produced hypothermia (approximately 32 degrees C) for several hours after injection. To assess the role of hypothermia in neuroprotection by diazepam, hypothermia depth and duration was simulated using a cold-water spray in separate gerbils. Seven days after ischemia, neuroprotection by hypothermia was similar to that produced by diazepam. However, 35 days after ischemia, there was no significant protection by hypothermia, suggesting that hypothermia does not play a significant role in long-term diazepam neuroprotection. Imidazenil (3 mg/kg), which produced only minimal hypothermia, protected area CA1 of hippocampus to the same degree as that by diazepam 7 days after ischemia. At 35 days after ischemia, significant protection remained, but it was considerably reduced compared with 7 days. Like diazepam, the therapeutic window for imidazenil was short. Imidazenil neuroprotection was lost when the drug was administered as early as 2 hours after ischemia. The ability of ischemia to produce deficits in working memory and of benzodiazepines to prevent the deficits also was investigated. Gerbils trained on an eight-arm radial maze before ischemia demonstrated a significant increase in the number of working errors 1 month after ischemia. The ischemia-induced deficits in working memory were completely prevented by diazepam but not by imidazenil. There was a significant, but weak, negative correlation between the degree of CA1 pyramidal cell survival and the number of working errors in both the diazepam and imidazenil groups. Thus, if given early enough during reperfusion, both benzodiazepine full and partial agonists are neuroprotective for at least 35 days, but the lack of sedating side effects of imidazenil must be weighed against its reduced efficacy.