The present series of experiments had two main objectives: The first was to determine the conditions under which self-injection of the benzodiazepine diazepam would be optimal; the second was to identify neurochemical substrates which... more
The present series of experiments had two main objectives: The first was to determine the conditions under which self-injection of the benzodiazepine diazepam would be optimal; the second was to identify neurochemical substrates which underlie the maintenance of diazepam selfadministration. Data from the first experiment indicated that rats maintained on an FI-1 (Fixed Interval of 1 min) schedule of food delivery self-injected significantly more diazepam than rats not maintained on this schedule. Results from the second experiment demonstrated that the benzodiazepine antagonist Ro 15-1788, and the GABA antagonist bicuculline, significantly reduced diazepam self-administration, but the opiate antagonist naloxone was without effect. Data from the third experiment showed that the dopamine antagonist haloperidol also significantly reduced the rate of diazepam self-injection. Thus, these findings indicate that the acquisition of diazepam self-injection occurs under an FI-1 schedule of food delivery, which has been shown to be middly stressful, while its maintenance depends upon the functional integrity of benzodiazepine and GABA receptors and upon the activity of deopaminergic pathways.
Aggressive behavior can serve important adaptive functions in social species. However, if it exceeds the species-typical pattern, it may become maladaptive. Very high or escalated levels of aggressive behavior can be induced in laboratory... more
Aggressive behavior can serve important adaptive functions in social species. However, if it exceeds the species-typical pattern, it may become maladaptive. Very high or escalated levels of aggressive behavior can be induced in laboratory rodents by pharmacological (alcohol-heightened aggression), environmental (social instigation), or behavioral (frustration-induced aggression) means. These various forms of escalated aggressive behavior may be useful in further elucidating the neurochemical control over aggression and violence. One neurochemical system most consistently linked with escalated aggression is the GABAergic system, in conjunction with other amines and peptides. Although direct stimulation of GABA receptors generally suppresses aggression, a number of studies have found that positive allosteric modulators of GABAA receptors can cause increases in aggressive behavior. For example, alcohol, benzodiazepines, and many neurosteroids are all positive modulators of the GABAA re...
Disease processes or events that accompany acute alcohol withdrawal (AW) can cause significant illness and death. Some patients experience seizures, which may increase in severity with subsequent AW episodes. Another potential AW... more
Disease processes or events that accompany acute alcohol withdrawal (AW) can cause significant illness and death. Some patients experience seizures, which may increase in severity with subsequent AW episodes. Another potential AW complication is delirium tremens, characterized by hallucinations, mental confusion, and disorientation. Cognitive impairment and delirium may lead to a chronic memory disorder (i.e., Wernicke-Korsakoff syndrome). Psychiatric problems associated with withdrawal include anxiety, depression, and sleep disturbance. In addition, alterations in physiology, mood, and behavior may persist after acute withdrawal has subsided, motivating relapse to heavy drinking. Recent advances in neurobiology may support the development of improved medications to decrease the risk of AW complications and support long-term sobriety.
Progabide inhibited male rat sexual behavior at a dose of 200 mg/kg. This dose had only modest effects on ambulatory activity and no effect at all on motor coordination as evaluated by a rotarod test. The GABAA antagonist bicuculline, at... more
Progabide inhibited male rat sexual behavior at a dose of 200 mg/kg. This dose had only modest effects on ambulatory activity and no effect at all on motor coordination as evaluated by a rotarod test. The GABAA antagonist bicuculline, at a dose of 1 mg/kg, blocked the effects of progabide on sex behavior. In contrast, the GABAB antagonist CGP 35348, at doses of 50 and 100 mg/kg, was ineffective. These doses have previously been shown to block the actions of baclofen on sexual behavior. It was concluded that the GABAA but not the GABAB receptor is important for the inhibitory effects of progabide on that behavior. The actions of progabide on ambulatory activity were not blocked by bicuculline or CGP 35348 at any of the doses used (up to 2 and 200 mg/kg, respectively). Even the combination of both antagonists was ineffective. This suggests that the motor effects of progabide are mediated by either a non-GABAergic receptor or by a subtype of the GABAA or the GABAB receptor that is not sensitive to the antagonists. Present results show that the effects of progabide on motor functions depend on mechanisms different from those involved in its effects on sexual behavior. They further suggest that the GABAA receptor may be important for drug actions on male sexual behavior.
Emotional stress provokes a stereotyped pattern of autonomic and endocrine changes that is highly conserved across diverse mammalian species. Nearly 50 years ago, a specific region of the hypothalamus, the hypothalamic defense area, was... more
Emotional stress provokes a stereotyped pattern of autonomic and endocrine changes that is highly conserved across diverse mammalian species. Nearly 50 years ago, a specific region of the hypothalamus, the hypothalamic defense area, was defined by the discovery that electrical stimulation in this area evoked changes that replicated this pattern. Attention later shifted to the hypothalamic paraventricular nucleus (PVN) owing
In the present study, alterations of the General GABA and GABAA receptors in the hippocampus of pilocarpine-induced temporal lobe epileptic rats and the therapeutic application of Bacopa monnieri and its active component Bacoside-A were... more
In the present study, alterations of the General GABA and GABAA receptors in the hippocampus of pilocarpine-induced temporal lobe epileptic rats and the therapeutic application of Bacopa monnieri and its active component Bacoside-A were investigated. Bacopa monnieri (Linn.) is a herbaceous plant belonging to the family Scrophulariaceae. Hippocampus is the major region of the brain belonging to the limbic system and plays an important role in epileptogenesis, memory and learning. Scatchard analysis of [3H]GABA and [3H]bicuculline in the hippocampus of the epileptic rat showed significant decrease in Bmax (P < 0.001) compared to control. Real Time PCR amplification of GABAA receptor sub-units such as GABAAά1, GABAAά5, GABAAδ, and GAD were down regulated (P < 0.001) in the hippocampus of the epileptic rats compared to control. GABAAγ subunit was up regulated. Epileptic rats have deficit in the radial arm and Y maze performance. Bacopa monnieri and Bacoside-A treatment reverses all these changes near to control. Our results suggest that decreased GABA receptors in the hippocampus have an important role in epilepsy associated behavioral deficit, Bacopa monnieri and Bacoside-A have clinical significance in the management of epilepsy.
The amygdala is a temporal lobe structure that is the center of emotion processing in the mammalian brain. Recent interest in the amygdala arises from its role in processing fear and the relationship of fear to human anxiety. The... more
The amygdala is a temporal lobe structure that is the center of emotion processing in the mammalian brain. Recent interest in the amygdala arises from its role in processing fear and the relationship of fear to human anxiety. The amygdaloid complex is divided into a number of subnuclei that have extensive intra and extra nuclear connections. In this review we
Novel racemic 4-amino-1-, 2-, and 3-hydroxybutylphosphinic acids and the corresponding 4-amino-1-, 2-, and 3-hydroxybutyl methylphosphinic acids have been synthesized. The phosphinic acid groups are bioisosteres of the carboxylic acid... more
Novel racemic 4-amino-1-, 2-, and 3-hydroxybutylphosphinic acids and the corresponding 4-amino-1-, 2-, and 3-hydroxybutyl methylphosphinic acids have been synthesized. The phosphinic acid groups are bioisosteres of the carboxylic acid group, and some of these hydroxy amino acids are GABAB antagonists. The novel phosphinic acids were evaluated for their GABAA and GABAB receptor binding properties using rat brain synaptosomes and were also tested for GABAergic activity in a guinea pig ileum model. None of the phosphinic acids tested were found to be active.Graphic
Gamma-amino butyrate (GABA) is the most prevalent inhibitory neurotransmitter in the adult brain. In this review, we summarize the pharmacology and regulation of GABAergic transmission components (biosynthetic enzymes, receptors and... more
Gamma-amino butyrate (GABA) is the most prevalent inhibitory neurotransmitter in the adult brain. In this review, we summarize the pharmacology and regulation of GABAergic transmission components (biosynthetic enzymes, receptors and transporters) in adult non-neurogenic brain regions. The effects of targeted mutations in genes relevant for GABAergic functions and how they influence specific neuronal circuits and pathological states are presented. We then review GABA actions on neuronal differentiation. During brain development, GABA has depolarizing activity in cerebrocortical neural precursors, controlling cell division and contributing to neuronal migration and maturation. In the adult forebrain there are two neurogenic regions exposed to synaptic and non-synaptic GABA release. Neural stem cells and neuronal progenitors express GABA receptors in subventricular and subgranular zones. GABA effects in these cells are very similar to those found in embryonic cortical precursor cells, and therefore it is possible that this amino acid has important roles during adult brain plasticity.
Toluene is a volatile organic compound (VOC) and a ubiquitous air pollutant of interest to EPA regulatory programs. Whereas its acute functional effects are well described, several modes of action in the CNS have been proposed. Therefore,... more
Toluene is a volatile organic compound (VOC) and a ubiquitous air pollutant of interest to EPA regulatory programs. Whereas its acute functional effects are well described, several modes of action in the CNS have been proposed. Therefore, we sought to identify potential pathways mediating direct or indirect effects of VOCs by investigating the genomic response of the rat CNS to