Effects Of Psychoactive Drugs Research Articles

Education did not interact with major depression on performance of memory tests in acute southern Brazilian in patients.

The relationship of cognitive function to depression in older adults has become a topic of extensive clinical interest and research.ObjectiveTo analyze association between cognitive/memory performance,Major Depression, and education in 206 inpatients from the Psychiatry and Internal Medicine Departments.MethodsPatients were evaluated by the Mini Mental State Examination, a battery of memory tests, and the Montgomery-Åsberg Depression Rating Scale. Depression patients comprised 45 severe and 42 mild/moderate, according to the Montgomery-Asberg scale. The effect of psychoactive drugs was recorded (30% drug-free). Education was measured in years. Cognitive/memory tests assessed five domains: general mental functioning, attention, sustained attention/working memory, learning memory (verbal), and remote memory. An index for memory impairment was created (positivity: 50% of tests below cutoff).ResultsThe chief effect on worse performance was Major Depression for the domains (age and education adjusted) of attention, learning, remote memory, and general functioning. For the domain “sustained attention and working memory”, only severely depressed patients differed from the medical controls (p=.008). Education showed an independent effect on test performances. No interaction between depression and educational status was observed.We also observed an independent effect of psychoactive drugs on some cognitive/memory domains. Logistic Regression showed Major Depression as the main risk for cognitive impairment.ConclusionsThese data demonstrated association of Major Depression with impaired cognitive performance independent of educational attainment or psychiatric medications.

Bipolar disorders and dementia: fortuitous association or filiation? A case-report and review of the literature

The prevalence of bipolar disorders is about 4% of the population. Among the patients the emergence of cognitive disorders has been identified. These disorders can sometimes result in authentic dementia-like syndromes. The neuropsychological characteristics of the cognitive impairment include disorders of the steady attention, executive functions, memory and language. This group of cognitive disorders leads to a subcorticofrontal syndrome. Different neuroanatomical bases have been suggested. The most common etiopathogenic hypothesis retains a cumulative neurological toxicity of the thymic episodes (depression or mania). The role of psychoactive treatments must be taken into account. The secondary cognitive effects of psychoactive drugs usually used in bipolar disorder (lithium, antiepileptics, antidepressants, antipsychotics or tranquillizers) are similar to the cognitive impairment associated with the disease. Differentiation between cognitive disorders related to the pathology and those related to its treatment is difficult. The optimal use of the therapeutic drug classes, preferring antipsychotics of second generation and avoiding products with anticholinergic effect, is essential. There is no specific pharmacological treatment for this dementia syndrome. Psychological approaches offer an alternative way of care, which remains to be investigated and validated. Prevention of iatrogenic effects of drugs constitutes, presently, the main therapeutic intervention.

Sertraline and fluoxetine: Safe treatments for children and adolescents with epilepsy and depression

Objective Depression is frequent, underdiagnosed, and untreated in people with epilepsy. The lack of treatment is partially explained by the concerns over the proconvulsive effects of psychoactive drugs. There are few studies on the effects of selective serotonin reuptake inhibitors (SSRIs) in adults with epilepsy and none in children. The main purpose of the present study was to analyze the impact of SSRIs on the severity and frequency of seizures in children and adolescents with epilepsy and major depressive disorders. In addition, we also evaluated the efficacy of SSRIs in the treatment of depressive symptoms and side effects other than seizure aggravation. Methods Monthly frequency of seizures was recorded in the 3–6 months preceding the introduction of SSRIs. According to the criteria proposed by A.M. Kanner, A.M. Kozak and M. Frey (Epilepsy Behav 2000;1:100–5), a positive correlation between introduction of SSRIs and seizure worsening should be considered in the following circumstances: (1) occurrence of de novo generalized tonic–clonic (GTC) seizures; (2) recurrence of GTC seizures following a period of at least 1 year without such episodes; and (3) increase in monthly seizure frequency compared with that reported before introduction of SSRIs. Seizure worsening was considered as probably caused by an SSRI when the increase in monthly frequency occurred in a period up to 3 months after the beginning of SSRI use. Results Thirty-six children with epilepsy had a depressive disorder. Seizures worsened in two patients. Among this group of patients with depression, all had an improvement in their depressive symptoms. One patient taking fluoxetine had a facial rash and one patient taking sertraline had gastrointestinal disorders. These conditions improved, with total remission, when fluoxetine was replaced with sertraline and vice versa. Conclusion In this sample of children and adolescents with epilepsy and depressive disorders, we observed that SSRIs are a good therapeutic option, considering their efficacy in remission of depressive symptoms, their few adverse effects, and their maintenance of satisfactory seizure control. Treatment of depression should be considered relevant in the treatment of patients with epilepsy.

Alexey Kondratyevich Savrasov (1830–1897): the muse and the bottle

The Russian landscape painter Alexey Savrasov lived in the middle of the 19th century. He was overwhelmed with grief at the loss of several of his children and he used alcohol to blunt the pain and anguish. The effects of psychoactive substances and especially alcohol have been linked closely to creativity. His life story demonstrates the bitter relationship between the bottle and the muse. He became dependent on alcohol, his family broke up and he was fired from work, his creativity declined and his health deteriorated. At death, he was a lonely and a forgotten man and only two persons attended his funeral.

Using drug-discrimination techniques to study the abuse-related effects of psychoactive drugs in rats

Drug-discrimination (DD) techniques can be used to study abuse-related effects by establishing the interoceptive effects of a training drug (e.g., cocaine) as a cue for performing a specific operant response (e.g., lever pressing reinforced by food). During training with this protocol, pressing one lever is reinforced when the training drug is injected before the start of the session, and responding on a second lever is reinforced when vehicle is injected before the session. Lever choice during test sessions can then be used as an indication of whether a novel drug has effects similar to the training drug, or whether a potential therapeutic alters the effects of the training drug. Although training can be lengthy (up to several months), the pharmacological specificity of DD procedures make them a perfect complement to other techniques used to study drug-abuse phenomena, such as intravenous self-administration and conditioned place-preference procedures.

Clock genes: influencing and being influenced by psychoactive drugs

Although clock genes are the hallmark of circadian rhythms, they are also currently considered as transcription factors that have a prominent role in the pharmacology of the CNS. The expression of these transcription factors in the mammalian brain is not only intrinsically rhythmic but is also modulated by external inputs and hormones. An altered expression of clock genes, as evidenced in transgenic mice, has a profound influence on the behavioral effects of psychoactive drugs. Focusing on clock genes expressed in the brain might lead to the discovery of novel drug-target pathways.

Understanding how the brain perceives alcohol: neurobiological basis of ethanol discrimination.

Understanding the neurobiological mechanisms that regulate how the brain perceives the intoxicating effects of alcohol is highly relevant to understanding the development and maintenance of alcohol addiction. The basis for the subjective effects of intoxication can be studied in drug discrimination procedures in which animals are trained to differentiate the presence of internal stimulus effects of a given dose of ethanol (EtOH) from its absence. Research on the discriminative stimulus effects of psychoactive drugs has shown that these effects are mediated by specific receptor systems. In the case of alcohol, action mediated through ionotropic glutamate, gamma-aminobutyric acid, and serotonergic receptors concurrently produce complex, or multiple, basis for the discriminative stimulus effects of EtOH. These receptor systems may contribute differentially to the discriminative stimulus effects of EtOH based on the EtOH dose, species differences, physiological states, and genetic composition of the individual. An understanding of the receptor mechanisms that mediate the discriminative stimulus effects of EtOH can be used to develop medications aimed at decreasing the subjective effects associated with repeated intoxication. The goal of this symposium was to present an overview of recent findings that highlight the neurobiological mechanisms of EtOH's subjective effects and to suggest the relevance of these discoveries to both basic and clinical alcohol research.

Behavioral and psychiatric consequences of sleep-wake schedule disorders

Circadian rhythm sleep disorders (CRSDs) arise when an individual's sleep-wake rhythm mismatches the environmental 24-h schedule. Physiological data and genetic studies in patients with CRSDs suggest that these disorders result from abnormal functioning of the circadian timing system. Diagnosis involves recognition of the characteristics of CRSDs, which can be achieved by clinical interview and actigraphic monitoring of rest-activity patterns. Bright-light therapy and melatonin administration have proved to be the most effective treatment modalities of CRSDs. In psychiatric practice, CRSDs can be encountered on various occasions. Some evidence indicates that a deviant sleep-wake schedule might be a predisposing factor to personality disorders. CRSDs can emerge as an iatrogenic effect of certain psychoactive drugs, such as haloperidol and fluvoxamine. It is not uncommon that the daytime functional difficulties that accompany CRSDs are misinterpreted as symptoms of psychopathology. Recognition and awareness of these disorders should prevent years of erroneous diagnosis and treatment in these patients.

Sex- and gender-related differences in the neurobiology of drug abuse

Sex-related responses to drugs of abuse add an important dimension to the larger issue of gender-related differences in epidemiology, prevention strategies and treatment. One of the most important factors in collecting such data is controlling for the many demographic, behavioral, physiological, and hormonal differences that exist between males and females as these may influence the direct effects of a drug and contribute to a progression from use to abuse to dependence. There are a number of factors that make studying female subjects more challenging. Aside from the obvious hormonal and menstrual cycle differences, there are a variety of gender-related issues that are unique to women and alter the drug abuse profile of certain drugs, regardless of the pharmacological effect. Studies have revealed that the pharmacokinetic profiles (secondary to route of administration) may alter the responses to cocaine and may help explain some of the male/female differences that have been observed, especially via the intranasal route. Sex differences appear to be minimal when cocaine is administered i.v. or by inhalation suggesting that rate of absorption may play an important role in the acute effects of cocaine. In summary, difficulties in conducting studies with females can be overcome with careful planning, time and additional expense. Using controlled laboratory studies, important pharmacokinetic and pharmacodynamic differences in drug effects may modulate male/female expectations about psychoactive drug effects and ultimately play a role in the etiology of drug abuse, dependence and how treatment programs should be structured. Finally, the application of new brain imaging techniques has the potential to reveal the mechanism of these sex-related differences.

Differential effects of dopamine and psychoactive drugs on dopamine transporter phosphorylation and regulation

The dopamine transporter (DAT) is a phosphoprotein whose activity and phosphorylation state are acutely regulated by both protein kinase C (PKC) and substrate transport. DAT is a major site of action for psychostimulant and therapeutic drugs that either block transport or are transported substrates, but the effects of such drugs on DAT phosphorylation and regulation are not well understood. To examine these issues we subjected rDAT LLC-PK 1 cells to acute in vitro pretreatments with the endogenous, psychostimulant, and therapeutic compounds dopamine (DA), (−)-cocaine, 2β-carbomethoxy-3β-(4-fluorophenyl)tropane (β-CFT), GBR 12909, mazindol, and methylphenidate (MPH), in the presence or absence of the PKC activator phorbol 12 myristate 13 acetate (PMA), followed by analysis of DAT metabolic phosphorylation and transport activity. Basal phosphorylation of DAT was not affected by any of the uptake blockers tested, and PMA-stimulated phosphorylation was not affected by cocaine, β-CFT, mazindol or MPH, but was strongly suppressed by GBR 12909. Pretreatment of cells with cocaine or MPH had no effect on subsequent DA transport activity or the extent of PMA-induced transport down-regulation, whereas GBR 12909 inhibited PMA-induced DAT internalization. These findings indicate that these DAT phosphorylation and down-regulation properties are unaffected by some classes of uptake blocking drugs, but that differential regulatory effects may be exerted by GBR compounds. Pretreatment of cells with DA had no obvious effect on basal or PMA-stimulated DAT phosphorylation but led to cocaine-blockable transport down-regulation. DA-induced down-regulation was blocked by the PKC inhibitor bisindoylmaleimide I and was not additive with down-regulation induced by PMA, consistent with PKC serving as a common step and point of integration for these DA and PMA induced processes. The results of this study provide information on the potential for endogenous and psychoactive compounds to modulate or be modulated by DAT phosphorylation-mediated regulatory mechanisms that may contribute to drug behavioral or therapeutic properties.

Editorial???Behavioural Pharmacology of Cannabinoids

Editorial???Behavioural Pharmacology of Cannabinoids

Neurosteroids: endogenous regulators of the GABAA receptor

GABA(A) (gamma-aminobutyric acid type A) receptors mediate most of the 'fast' synaptic inhibition in the mammalian brain and are targeted by many clinically important drugs. Certain naturally occurring pregnane steroids can potently and specifically enhance GABA(A) receptor function in a nongenomic (direct) manner, and consequently have anxiolytic, analgesic, anticonvulsant, sedative, hypnotic and anaesthetic properties. These steroids not only act as remote endocrine messengers, but also can be synthesized in the brain, where they modify neuronal activity locally by modulating GABA(A) receptor function. Such 'neurosteroids' can influence mood and behaviour in various physiological and pathophysiological situations, and might contribute to the behavioural effects of psychoactive drugs.

Effect of fluoxetine and cocaine on the expression of clock genes in the mouse hippocampus and striatum

Long-term drug-induced alterations in CNS gene expression may be responsible for some therapeutic effects, such as antidepressant action, as well as for psychopathological conditions, such as drug addiction and abuse. Transcription factors called “clock” genes can be affected by psychotropic drugs and may modify the expression pattern of other genes. In this study in mice, we investigated the delayed effects of single and repeated (i.e. 14 days) administration of the antidepressant fluoxetine and the psychostimulant cocaine on the brain expression of clock genes Period1, Period2, Period3, Clock, Bmal1, Cryptochrome1, Cryptochrome2, and NPAS2 (neuronal PAS domain protein 2), and their putative target gene, serotonin N-acetyltransferase. Mice were treated at ZT05 (lights on at 5:00 am; ZT00). Brain samples (i.e. hippocampus, striatum, and prefrontal cortex) were processed for a semi-quantitative mRNA assay. Repeated but not single treatment with either drug increased serotonin N-acetyltransferase expression in all areas tested. On the other hand, the expression of clock genes was differentially affected depending on the drug (i.e. fluoxetine and cocaine), treatment schedule (i.e. single and repeated), and brain area (i.e. hippocampus and striatum) tested. More pronounced changes were induced by repeated rather than single administrations of fluoxetine or cocaine. We propose that the effects of psychoactive drugs on clock transcription factors may mediate long-term drug-induced changes, possibly by regulating the expression of a second set of genes (i.e. clock-controlled genes).

Differential Effects of Psychoactive Drugs in Adolescents and Adults

It is well known that most people who use psychoactive drugs started as teenagers. In spite of this, there has been little preclinical research on the effects of psychostimulants during adolescence. Recently, however, a number of laboratories have begun to focus on drug effects in adolescents as compared with adults. The data show that there are unique responses to drugs during this period of development. This review will focus on our current understanding of neurochemical and behavioral drug effects during adolescence.

Synthetic cannabinoid WIN55,212-2 inhibits generation of inflammatory mediators by IL-1beta-stimulated human astrocytes.

Activated glial cells have been implicated in the neuropathogenesis of many infectious and inflammatory diseases of the brain. A number of inflammatory mediators have been proposed to play a role in glial cell-related brain damage; e.g., free radicals such as nitric oxide (NO), cytokines, and chemokines. Our laboratory has been interested in the effect of psychoactive drugs and their derivatives on the production of these mediators. Cannabinoids have been shown to possess immunomodulatory as well as psychoactive properties. We previously have shown that interleukin (IL)-1beta-stimulated human astrocytes, but not microglia, produce NO. In this study, we investigated the effects of the synthetic cannabinoid WIN55,212-2 on the production of several key inflammatory mediators by human fetal astrocytes activated by IL-1beta. Expression of the cannabinoid receptors CB1 and CB2 was detected on human astrocytes. WIN55,212-2 (10(-5) M) potently inhibited inducible NO synthase (iNOS) and corresponding NO production by IL-1beta-stimulated astrocytes. The CB1 and CB2 receptor-specific antagonists SR141716A and SR144528, respectively, partially blocked this suppressive effect. In addition, treatment of astrocytes with WIN55,212-2 downregulated in a concentration-dependent manner IL-1beta-induced tumor necrosis factor (TNF)-alpha release. Treatment with WIN55,212-2 also inhibited production of the chemokines CXCL10, CCL2 and CCL5 by IL-1beta-activated astrocytes. These findings indicate that WIN55,212-2 inhibits the production of inflammatory mediators by IL-1beta-stimulated human astrocytes and suggest that comparable agents may have therapeutic potential for the management of brain inflammation.

Drugs, Environment, Brain, and Behavior

The effects of psychoactive drugs are not just a function of their pharmacological actions, but are due to complex interactions among pharmacological, psychological, and environmental factors. We discuss here how drug-environment interactions determine the likelihood that addictive drugs produce a persistent form of neurobehavioral plasticity (sensitization) thought to be involved in the pathophysiology of addiction and relapse.

Drugs and human memory (part 2). Clinical, theoretical, and methodologic issues.

Drugs and human memory (part 2). Clinical, theoretical, and methodologic issues.

Use of psychoactive and antiepileptic drugs: guidelines for pediatricians

To review the guidelines for the use of psychoactive and antiepileptic drugs in childhood and adolescence. Literature review. The clinical indications, dosage and side effects of psychoactive and antiepileptic drugs are presented. The use of psychoactive drugs is increasing due to the release of new drugs and to the better understanding of emotional disorders in children and adolescents. The use of antiepileptic and psychoactive drugs in childhood requires extensive knowledge concerning pharmacokinetics and deleterious side effects. An adequate choice of drugs is essential to ensure a successful treatment.

Is the onset of psychoactive drug effects compatible with a protein-synthesis mechanism?

While many have suggested that protein synthesis may mediate the action of antipsychotic drugs, it is difficult to test. In this math modeling study it is found that the time course of action of the drugs are compatible with a protein-synthesis model and, furthermore, that the half-lives required by the model are indeed found in relevant proteins in the brain.

Stress-induced hyperthermia and anxiety: pharmacological validation

When mammals, including man, are confronted with a stressful event, their core body temperature rises, stress-induced hyperthermia. In mice, the stress-induced hyperthermia procedure has been developed to measure antistress or anxiolytic-like effects of psychoactive drugs. Group-housed and singly housed versions of the stress-induced hyperthermia generate comparable results. Because the number of animals needed to perform an experiment is much lower in the singly housed versus the group-housed procedure, the former is the test of choice for pharmacological testing. A typical stress-induced hyperthermia test starts with an injection 60 min before the first rectal temperature measurement ( T 1), followed by a second temperature measurement ( T 2) 10–15 min later. The difference Δ T (= T 2− T 1) is the stress-induced hyperthermia. The procedure also measures the intrinsic activity of drugs on the basal body temperature and Δ T is relatively independent from the intrinsic temperature effects of drugs. Anxiolytic drugs (benzodiazepines, 5-HT 1A receptor agonists, alcohol) reduce Δ T suggestive of anxiolytic-like effects. Because the parameter measured for anxiety in the stress-induced hyperthermia procedure is not dependent on locomotor activity, like in almost all other anxiety tests, the stress-induced hyperthermia procedure is an attractive addition to tests in the anxiety field. Because the stress-induced hyperthermia is also present with a comparable pharmacological profile in females, this procedure has a wide species and gender validity. The procedure was applied in various genetically modified mice [5-HT 1A and 5-HT 1B receptor knockout (KO) mice and corticotropin-releasing hormone overexpressing (CRH-OE) mice] to study phenotypic influences of the various mutations on aspects of anxiety. The stress-induced hyperthermia test in singly housed male and female mice appears a useful and extremely simple test to measure effects of drugs on certain aspects of anxiety or to help to determine phenotypic differences in mutant mice.