Marise B. Parent

Application of capillary electrophoresis with laser-induced fluorescence detection to the determination of biogenic amines and amino acids in brain microdialysate and homogenate samples

A procedure is described to derivatize 16 primary-amine-containing biogenic amines and amino acids in brain mixtures with the fluorogenic reagent 5-furoylquinoline-3-carboxaldehyde (FQ). These FQ-tagged compounds in the brain sample were resolved in less than 16 min based on micellar electrokinetic chromatography and laser-induced fluorescence. There was a linear relationship between the concentration of analyte and the fluorescence intensity, with correlation coefficients in the range of 0.96-1.00. The utility of this method for the quantification of the important inhibitory neurotransmitter gamma-aminobutyric acid in microdialysates and brain homogenates from rats is illustrated.

Infusions of physostigmine into the hippocampus or the entorhinal cortex attenuate avoidance retention deficits produced by intra-septal infusions of the GABA agonist muscimol

Septal gamma-aminobutyric acid (GABA) receptor activation is known to disrupt memory formation, although the mechanisms underlying this impairment remain unclear. The present study explored the possibility that high levels of septal GABA receptor activity might impair memory by down-regulating acetylcholine (ACh) function in archicortex and entorhinal cortex. To test this possibility, rats were trained on an avoidance task 15 min after receiving intra-septal infusions of vehicle or muscimol (5 nmol/0.5 microl) combined with unilateral intra-hippocampal (10 microl/1 microl) or intra-entorhinal cortex (1.875 microg/0.25 microl) infusions of vehicle or the acetylcholinesterase inhibitor physostigmine. We demonstrate that these infusions do not alter acquisition performance on a continuous multiple trial inhibitory avoidance task. However, intra-septal infusions of muscimol dramatically impair retention performance 48 h later. More importantly, infusions of physostigmine into the hippocampus or the entorhinal cortex, at doses that do not influence acquisition or retention performance when infused alone, attenuate the impairing effects of the muscimol infusions on retention. We suggest that high levels of septal GABA receptor activity might impair memory by down-regulating ACh levels in the hippocampal region, and that such memory impairments can be ameliorated by increasing ACh levels in the hippocampus or entorhinal cortex.

Time-dependent changes in brain monoamine oxidase activity and in brain levels of monoamines and amino acids following acute administration of the antidepressant/antipanic drug phenelzine.

Phenelzine (PLZ) is a non-selective monoamine oxidase (MAO) inhibitor commonly used to treat depression and panic disorder. Acute administration of PLZ produces several neurochemical changes, including an increase in brain levels of the catecholamines norepinephrine (NE) and dopamine (DA), of 5-hydroxytryptamine (5-HT), and of the amino acids alanine and gamma-aminobutyric acid (GABA). The goal of the present series of experiments was to characterize the time course of these PLZ-induced changes. Male Sprague-Dawley rats were sacrificed 6, 24, 48, 96, 168, or 336 hr after acute PLZ administration (15 or 30 mg/kg, i.p., based on free base weight). Whole brain levels of monoamines and amino acids were determined using HPLC, and MAO A and B activities were determined using a radiochemical procedure. The results indicated that PLZ changed amino acid levels 6 and 24 hr after injection, but not 48 hr later. In contrast, the effects of PLZ on MAO activity and monoamines were longer-lasting. For example, PLZ-induced increases in dopamine and 5-HT were observed 1 week after injection, and PLZ-induced inhibition of MAO activity persisted for 2 weeks. Thus, in addition to demonstrating that the effects of PLZ on MAO activity and monoamines were long-lasting, these results indicate that the effects of PLZ on MAO activity and on brain levels of monoamines and amino acids are temporally dissociated. These findings regarding the long-term effects of PLZ on neurochemistry will have considerable critical implications for the design and interpretation of behavioral studies of the acute effects of PLZ.

Effects of the antidepressant/antipanic drug phenelzine and its putative metabolite phenylethylidenehydrazine on extracellular γ-aminobutyric acid levels in the striatum

Phenelzine (PLZ) is a non-selective monoamine oxidase inhibitor (MAOI) commonly used to treat depression and panic disorder. As expected, PLZ increases brain levels of dopamine, norepinephrine, and serotonin. Interestingly, PLZ also elevates brain levels of gamma-aminobutyric acid (GABA), and previous studies have suggested that these increases may also contribute to the anxiolytic effects of PLZ. Using in vivo microdialysis in conscious, freely moving rats, combined with high performance liquid chromatography, the present experiments determined that PLZ (15 or 30 mg/kg, free base weight) increases extracellular levels of GABA in the caudate-putamen and nucleus accumbens. The results also indicated that phenylethylidenehydrazine (PEH; 29.6 mg/kg, free base weight), a putative intermediate metabolite of PLZ that is not an MAOI, also significantly increases extracellular GABA levels in the caudate-putamen. These findings provide further evidence that GABA may play an important role in the actions of PLZ and suggest that PEH should be pursued further as a GABAergic drug in its own right.

A memory-enhancing emotionally arousing narrative increases blood glucose levels in human subjects

To examine the contribution of glucose to the memory-enhancing effects of emotional arousal, we determined whether a memory-enhancing emotional narrative would increase blood glucose levels. Blood glucose was measured before and after participants viewed slides accompanied by a neutral or an emotionally arousing narrative. Prior to the slide show, the participants drank a beverage containing either glucose or saccharin. Participants who heard the emotionally arousing narrative had better memory of the narrative and slide show 2 weeks later than did participants who heard the neutral narrative. Blood glucose levels increased after the emotionally arousing narrative, but not after the neutral narrative. Glucose administration produced a larger increase in blood glucose levels than did the emotionally arousing narrative and prevented the memory-enhancing effect of emotional arousal. These findings indicate that small increases in blood glucose levels may contribute to the memory-enhancing effects of emotional arousal, whereas larger glucose increases may prevent its effects.

Amygdala lesions do not impair shock-probe avoidance retention performance

The present experiment used the shock-probe paradigm, a procedure usually used to assess anxiolytic processes, to assess memory in amygdala-lesioned rats. Rats were placed in a chamber that contained a probe protruding from 1 of 4 walls and were kept there for 15 min after they contacted the probe. For half the rats, the probe was electrified (2 mA). Four days later, sham or neurotoxic amygdala lesions were induced. Retention performance was assessed 8 days later by measuring the latency to contact the probe and the number of contact-induced shocks. The results indicated that, although shock-naive amygdala-lesioned rats were impaired on the 2nd shock-probe test, shock-experienced amygdala-lesioned rats were not. These data indicate that the memory of a shock experience, as indexed with a shock-probe avoidance response, is spared in rats with large amygdala lesions.

Task-dependent effects of the antidepressant/antipanic drug phenelzine on memory

Abstract Phenelzine (PLZ) is a non-selective monoamine oxidase (MAO) inhibitor commonly used to treat depression and panic disorder. In addition to increasing levels of biogenic amines in the brain, PLZ elevates brain levels of the amino acid gamma-aminobutyric acid (GABA; Baker et al. 1991; present study). Given the extensive evidence implicating biogenic amines and GABA in mnemonic processes, PLZ may affect learning and memory. To investigate this possibility, male Sprague-Dawley rats were given PLZ sulfate (15 or 30 mg/kg, based on free base weight) 2 h prior to training in a continuous multiple trial inhibitory avoidance (CMIA) and spatial water maze task. Retention was assessed 48 h later. The results indicated that PLZ enhanced CMIA and impaired water maze retention performance. Compared to control rats, rats given PLZ took significantly longer to re-enter the shock compartment and swam longer distances before reaching the escape platform on the retention tests. These effects of PLZ did not appear to be the result of PLZ-induced changes in acquisition or retrieval processes, activity levels, or footshock sensitivity. Combined, these findings indicate that PLZ influences memory in a task-dependent manner. These differential effects of PLZ may be the result of contrasting influences of GABA and biogenic amines on memory.