Abstract:
RATIONALE:Cortical gamma-aminobutyric acid (GABA)ergic neurons contribute to the orchestration of pyramidal neuron population firing as follows: (1) by releasing GABA on GABA(A) and GABA(B) receptors, (2) by releasing reelin in the proximity of integrin receptors located on cortical pyramidal neuron dendritic spines, and (3) through reelin contributing to the regulation of dendritic spine plasticity by modulating dendritic resident mRNA translation. In schizophrenia (SZ) and bipolar (BP) postmortem brains, the downregulation of mRNAs encoding glutamic acid decarboxylase 67 (GAD(67)) and reelin decreases the cognate proteins coexpressed in prefrontal cortex (PFC) GABAergic neurons. This finding has been replicated in several laboratories. Such downregulation suggests that the neuropil hypoplasticity found in the PFC of SZ and BP disorder patients may depend on a downregulation of GABAergic function, which is associated with a decrease in reelin secretion from GABAergic neuron axon terminals on dendrites, somata, or axon initial segments of pyramidal neurons. Indirectly, this GABAergic neuron downregulation may play a key role in the expression of positive and negative symptoms of SZ and BP disorders. OBJECTIVES:The above described GABAergic dysfunction may be addressed by pharmacological interventions to treat SZ and BP disorders using specific benzodiazepines (BZs), which are devoid of intrinsic activity at GABA(A) receptors including alpha(1) subunits but that act as full positive allosteric modulators of GABA action at GABA(A) receptors containing alpha(2), alpha(3), or alpha(5) subunits. These drugs are expected to enhance GABAergic signal transduction without eliciting sedation, amnesia, and tolerance or dependence liabilities. RESULTS AND CONCLUSIONS:BZs, such as diazepam, although they are efficient in equilibrating GABA(A) receptor signal transduction in a manner beneficial in the treatment of positive and negative symptoms of SZ, may not be ideal drugs, because by mediating a full positive allosteric modulation of GABA(A) receptors containing the alpha(1) subunit, they contribute to sedation and to the development of tolerance after even a brief period of treatment. In contrast, other BZ-binding site ligands, such as 6-(2bromophenyl)-8-fluoro-4H-imidazo [1,5-a][1,4] benzodiazepine-3-carboxamide (imidazenil), which fail to allosterically and positively modulate the action of GABA at GABA(A) receptors with alpha(1) subunits but that selectively allosterically modulate cortical GABA(A) receptors containing alpha(5) subunits, contribute to the anxiolytic, antipanic, and anticonvulsant actions of these ligands without producing sedation, amnesia, or tolerance. Strong support for the use of imidazenil in psychosis emerges from experiments with reeler mice or with methionine-treated mice, which express a pronounced reelin and GAD(67) downregulation that is also operative in SZ and BP disorders. In mice that model SZ symptoms, imidazenil increases signal transduction at GABA(A) receptors containing alpha(5) subunits and contributes to the reduction of behavioral deficits without producing sedation or tolerance liability. Hence, we suggest that imidazenil may be considered a prototype for a new generation of positive allosteric modulators of GABA(A) receptors, which, either alone or in combination with neuroleptics, should be evaluated in GABAergic dysfunction operative in the treatment of SZ and BP disorders with psychosis.
journal_name
Psychopharmacology (Berl)journal_title
Psychopharmacologyauthors
Guidotti A,Auta J,Davis JM,Dong E,Grayson DR,Veldic M,Zhang X,Costa Edoi
10.1007/s00213-005-2212-8subject
Has Abstractpub_date
2005-07-01 00:00:00pages
191-205issue
2eissn
0033-3158issn
1432-2072journal_volume
180pub_type
杂志文章,评审abstract:RATIONALE:Low capacity of the central serotonergic system has been associated with impulsive behaviour. Both low platelet monoamine oxidase (MAO) activity and the short (S) allele of the serotonin transporter gene promoter region polymorphism (5-HTTLPR) are proposed to be markers of less efficient serotonergic function...
journal_title:Psychopharmacology
pub_type: 临床试验,杂志文章
doi:10.1007/s00213-007-0867-z
更新日期:2007-11-01 00:00:00
abstract::To analyze the involvement of dopamine (DA) and serotonin (5-HT) release in the stimulus properties of methamphetamine, two amphetamine analogs that selectively release either brain DA (phentermine) or 5-HT (fenfluramine) were tested for their ability to substitute for methamphetamine in rats discriminating methamphet...
journal_title:Psychopharmacology
pub_type: 杂志文章
doi:10.1007/s002130050836
更新日期:1999-01-01 00:00:00
abstract::Pigeons were trained to peck each of two response keys. Periods during which pecks on one key (the food key) produced access to grain according to a random-ratio 80 schedule alternated irregularly with periods during which food-key responses had no scheduled consequences (extinction). Both keys remained amber unless a...
journal_title:Psychopharmacology
pub_type: 杂志文章
doi:10.1007/BF00422418
更新日期:1981-01-01 00:00:00
abstract::The behavioral effects of the benzodiazepine (BZP)-receptor partial inverse agonists, beta-CCE and FG 7142, are reviewed and the claim that these compounds possess "anxiogenic" properties is examined. Results obtained from human studies and global observations in animals, as well as those from experiments on aggressio...
journal_title:Psychopharmacology
pub_type: 杂志文章,评审
doi:10.1007/BF00212837
更新日期:1988-01-01 00:00:00
abstract::Primiparous rats received 0.05, 0.25, 0.50, or 1.50 mg d-amphetamine/kg body weight, injected IP, when offspring reached 3-4 and 10-11 days of age. A multidimensional analysis of their maternal behavior revealed that at doses as low as 0.25 mg/kg, amphetamine had a disruptive effect on mother-pup intercontact interval...
journal_title:Psychopharmacology
pub_type: 杂志文章
doi:10.1007/BF00435314
更新日期:1980-01-01 00:00:00
abstract:RATIONALE:Carbon monoxide synthetized by inducible heme oxygenase (HO-1) exerts potent anti-inflammatory and antinociceptive effects during acute and neuropathic pain, but its role in the modulation of chronic inflammatory pain and the possible involvement of nitric oxide in this action remain unknown. OBJECTIVES AND ...
journal_title:Psychopharmacology
pub_type: 杂志文章
doi:10.1007/s00213-013-3302-7
更新日期:2014-03-01 00:00:00
abstract:RATIONALE:The positive modulation of gamma-aminobutyric acid type-A (GABAA) receptors is a putative mechanism via which alcohol escalates aggressive behavior. Broad-spectrum benzodiazepine antagonists block alcohol-heightened aggression in rats and monkeys. However, the degree to which GABAA subunit composition plays a...
journal_title:Psychopharmacology
pub_type: 杂志文章
doi:10.1007/s00213-003-1661-1
更新日期:2004-03-01 00:00:00
abstract::The effect of the dopamine receptor antagonist haloperidol on the development of sensitization to ethanol-induced increases in locomotor activity was examined in DBA/2J mice. In Experiment 1, different groups of mice were given saline or ethanol (2 g/kg) immediately before each of four locomotor activity sessions (48-...
journal_title:Psychopharmacology
pub_type: 杂志文章
doi:10.1007/BF02245821
更新日期:1995-08-01 00:00:00
abstract:RATIONALE:Conditioned behavioral responses to discrete drug-associated cues can be modulated by the environmental context in which those cues are experienced, a process that may facilitate relapse in humans. Rodent models of drug self-administration have been adapted to reveal the capacity of contexts to trigger drug s...
journal_title:Psychopharmacology
pub_type: 杂志文章
doi:10.1007/s00213-009-1657-6
更新日期:2009-12-01 00:00:00
abstract:RATIONALE:The administration of heroin has been shown to inhibit the induction of nitric oxide, a molecule known to play a critical role in immune function. Previous research has shown that this alteration can be conditioned to environmental stimuli that have been associated with drug administration. However, it remain...
journal_title:Psychopharmacology
pub_type: 杂志文章
doi:10.1007/s00213-006-0673-z
更新日期:2007-05-01 00:00:00
abstract:RATIONALE:Animal models aimed to mimic mania have in common the lack of genuine affective parameters. Although rodent amphetamine-induced hyperlocomotion is a frequently used behavioral model of mania, locomotor activity is a rather unspecific target for developing new pharmacological therapies, and does not necessaril...
journal_title:Psychopharmacology
pub_type: 杂志文章
doi:10.1007/s00213-013-3413-1
更新日期:2014-07-01 00:00:00
abstract:RATIONALE:In cell culture systems, agonists can promote the phosphorylation and internalization of receptors coupled to G proteins (GPCR), leading to their desensitization. However, in the CNS opioid agonists promote a profound desensitization of their analgesic effects without diminishing the presence of their recepto...
journal_title:Psychopharmacology
pub_type: 杂志文章,评审
doi:10.1007/s00213-005-2248-9
更新日期:2005-06-01 00:00:00
abstract:RATIONALE:Acute tryptophan depletion (ATD) is a widely used method to study the role of serotonin (5-HT) in affect and cognition. ATD results in a strong but transient decrease in plasma tryptophan and central 5-HT synthesis and availability. Although its use is widespread, the evidence that the numerous functional eff...
journal_title:Psychopharmacology
pub_type: 杂志文章
doi:10.1007/s00213-007-0908-7
更新日期:2007-12-01 00:00:00
abstract::Psychopharmacological studies using caffeinated beverages or caffeine have rarely considered temporal effects on psychological and physiological function or the specific contribution of caffeine, hot water, or beverage type to the observed effects. The effect of 400 ml hot tea, coffee, and water consumption on systoli...
journal_title:Psychopharmacology
pub_type: 临床试验,杂志文章
doi:10.1007/s002130050438
更新日期:1997-11-01 00:00:00
abstract:RATIONALE:Intermittent footshock stress reliably reinstates extinguished alcohol-taking behavior in drug-free rats, but the neurochemical events involved in this effect are not known. OBJECTIVE:We studied here whether two main modulators of stress responses, corticotropin-releasing factor (CRF) and corticosterone, are...
journal_title:Psychopharmacology
pub_type: 杂志文章
doi:10.1007/s002130000411
更新日期:2000-06-01 00:00:00
abstract::Monoamine oxidase inhibitors (MAOIs) are widely accepted as effective antidepressants. Unfortunately their use has been limited by their capacity to potentiate dietary tyramine (the so called "cheese effect") and their interaction with other drugs. The latter poses a particular problem for patients undergoing anaesthe...
journal_title:Psychopharmacology
pub_type: 杂志文章,评审
doi:10.1007/BF02246234
更新日期:1992-01-01 00:00:00
abstract::The topography of stereotyped behaviour produced by apomorphine in rats was studied by using either a scoring system, based on observation in a wire cage, or by quantification of horizontal and vertical activities, and of the total distances run in an open field, using an automatic recording system. The latter design ...
journal_title:Psychopharmacology
pub_type: 杂志文章
doi:10.1007/BF00172869
更新日期:1986-01-01 00:00:00
abstract:RATIONALE:It is important to study age-related differences that may put adolescents at risk for alcohol-related problems. Adolescents seem less sensitive to the aversive effects of ethanol than adults. Less is known of appetitive effects of ethanol and stress modulation of these effects. OBJECTIVES:This study aims to ...
journal_title:Psychopharmacology
pub_type: 杂志文章
doi:10.1007/s00213-013-3163-0
更新日期:2013-12-01 00:00:00
abstract::In the context of Pavlovian conditioning, two types of behaviour may emerge within the population (Flagel et al. Nature, 469(7328): 53-57, 2011). Animals may choose to engage either with the conditioned stimulus (CS), a behaviour known as sign-tracking (ST) which is sensitive to dopamine inhibition for its acquisition...
journal_title:Psychopharmacology
pub_type: 杂志文章
doi:10.1007/s00213-019-05323-y
更新日期:2019-08-01 00:00:00
abstract:RATIONALE:Previous studies indicate that the rewarding effect of D-1 dopamine receptor stimulation in nucleus accumbens (NAc) shell is greater in food-restricted (FR) than in ad libitum fed (AL) rats. The D-1 receptor is positively coupled to adenylyl cyclase and activates protein kinase A (PKA). OBJECTIVES:The purpos...
journal_title:Psychopharmacology
pub_type: 杂志文章
doi:10.1007/s00213-011-2602-z
更新日期:2012-06-01 00:00:00
abstract::The present study compared the acute subject-rated and performance-impairing effects of trazodone and triazolam in seven healthy humans. Trazodone (50, 100 and 200 mg), triazolam (0.125, 0.25, 0.50 mg) and placebo were administered orally in a double-blind, crossover design. Drug effects were measured approximately 30...
journal_title:Psychopharmacology
pub_type: 临床试验,杂志文章,随机对照试验
doi:10.1007/s002130050259
更新日期:1997-05-01 00:00:00
abstract:RATIONALE:Depression is a frequent non-motor symptom in Parkinson's disease (PD) with increasing rates with the progression of the disease. Molecular imaging studies have shown a reduction of dopamine transporter (DAT) density in depressed PD patients (dPD); however, DAT role in the pathophysiology of PD depression is ...
journal_title:Psychopharmacology
pub_type: 杂志文章
doi:10.1007/s00213-010-1867-y
更新日期:2010-07-01 00:00:00
abstract:RATIONALE:Alcohol and nicotine addiction are prevalent conditions that co-occur. Despite the prevalence of co-use, factors that influence the suppression and enhancement of concurrent alcohol and nicotine intake are largely unknown. OBJECTIVES:Our goals were to assess how nicotine abstinence and availability influence...
journal_title:Psychopharmacology
pub_type: 杂志文章
doi:10.1007/s00213-019-05426-6
更新日期:2020-04-01 00:00:00
abstract::This study examined the possibility that amphetamine-induced stereotypy and facilitation of memory consolidation are both mediated by amphetamine's stimulation of dopaminergic activity in the caudate nucleus. In the first experiment, rats were given pairings of a tone and a shock followed by SC amphetamine (2 mg/kg). ...
journal_title:Psychopharmacology
pub_type: 杂志文章
doi:10.1007/BF00427774
更新日期:1984-01-01 00:00:00
abstract::The effects of chronic lithium treatment on methylphenidate-, D1 dopamine receptor agonist (A-77636)-, and tactile stimulation-induced increases in frontal cortical acetylcholine release were studied in the rat using in vivo brain microdialysis. Cortical acetylcholine release in control rats was maximally stimulated b...
journal_title:Psychopharmacology
pub_type: 杂志文章
doi:10.1007/BF02249415
更新日期:1996-05-01 00:00:00
abstract:RATIONALE:Chronic pain is becoming a more common medical diagnosis and is especially prevalent in older individuals. As such, prescribed use of opioids is on the rise, even though the efficacy for pain management in older individuals is unclear. OBJECTIVES:Thus, the present preclinical study assessed the effectiveness...
journal_title:Psychopharmacology
pub_type: 杂志文章
doi:10.1007/s00213-013-3208-4
更新日期:2014-01-01 00:00:00
abstract::The concurrent influence of dopaminergic, sigma and muscarinic neurotransmitter systems in mediating cocaine-induced lethality is predicted by previous receptor binding results from our laboratories. The present results demonstrate that pharmacological manipulations of these predicted neurotransmitter systems alter th...
journal_title:Psychopharmacology
pub_type: 杂志文章
doi:10.1007/s002130050198
更新日期:1997-02-01 00:00:00
abstract:RATIONALE:Nicotine and other agonists of nicotinic cholinergic receptors (nAChR) have been shown to improve performance in specific memory domains in rodents and monkeys. Such beneficial effects are observed in preclinical models of age-related cognitive decline, stimulating interest in nAChR ligands as possible therap...
journal_title:Psychopharmacology
pub_type: 杂志文章
doi:10.1007/s00213-004-1804-z
更新日期:2004-09-01 00:00:00
abstract::Administration of drugs that reduce the influence of dopamine at its receptor site can lead to postsynaptic supersensitivity, whereas treatment with dopamine (DA) agonists can cause postsynaptic subsensitivity. Both unaltered and enhanced postsynaptic responses to DA have been shown after pretreatment with DA agonists...
journal_title:Psychopharmacology
pub_type: 杂志文章
doi:10.1007/BF00428198
更新日期:1985-01-01 00:00:00
abstract::The aim of the present study was to investigate the locomotor stimulant effects of the atypical antipsychotic agent, olanzapine, in mice depleted of their dopamine by reserpine and alpha-methyl-DL-p-tyrosine pretreatment. Olanzapine (0.5, 1 and 2 mg/kg) dose-dependently increased locomotor activity, which was complete...
journal_title:Psychopharmacology
pub_type: 杂志文章
doi:10.1007/s002130050877
更新日期:1999-02-01 00:00:00