Matilde E. Otero Losada

Changes in central GABAergic function following acute and repeated stress.

1 The function of γ‐aminobutyric acid (GABA)ergic systems in response to acute and repeated stressful manipulations was evaluated in both the corpus striatum and frontal cerebral cortex of the rat. 2 In the corpus striatum the activity of the synthetic enzyme for GABA (glutamic acid decarboxylase, GAD) and the levels of GABA were reduced by acute immobilization stress (1 h). GABA turnover was reduced only by acute cold stress (3 h, 4°C). 3 In the frontal cerebral cortex no changes were observed after acute stressful manipulations, but repeated stress (0.5 h immobilization per day for 14 days) enhanced both GAD activity and GABA turnover, and reduced GABA levels. 4 In conclusion, it would appear that the GABAergic system in the corpus striatum of the rat is most sensitive to acute stress and that the system in the frontal cerebral cortex area is preferentially responsive to chronic stress. It is speculated that the cortical GABAergic system is responsible for adaptive responses to the adverse conditions prevailing during chronic stress.

Area-dependent changes in GABAergic function after acute and chronic cold stress.

(1) The function of the gamma-aminobutyric acid (GABA)ergic system in certain areas of the rat brain was investigated after acute and chronic cold stress. (2) GABA concentration, [3H]GABA uptake and the activity of the synthesis enzyme glutamate decarboxylase (GAD) were measured. (3) Acute stress: (a) reduced GABA concentration in the corpus striatum (29%); (b) decreased GAD activity (under non-saturating substrate concentration) in the olfactory bulbs (24%); (c) diminished neuronal uptake of [3H]GABA in the frontal cerebral cortex (65%), hypothalamus (86%) and olfactory bulbs (82%). (4) Chronic stress: (a) reduced the endogenous levels of GABA in the frontal cerebral cortex (51%), hypothalamus (26%) and olfactory bulbs (15%); (b) decreased GAD activity in the corpus striatum (32%) and olfactory bulbs (34%); (c) decreased neuronal uptake of [3H]GABA in the hypothalamus (83%). (5) These findings suggest that compensatory changes may develop in the GABAergic system after chronic stress.

Acute effects of S-adenosyl-L-methionine on catecholaminergic central function

Catecholaminergic function was studied in rat brain areas after acute administration of S-adenosyl-L-methionine (SAM: 10 mg/kg i.p.). The noradrenaline (NA) concentration increased in the hippocampus and frontal cortex and decreased in the olfactory bulbs between 1 and 2 h after the SAM injection. NA biosynthesis was stimulated in vivo and the concentration of normetanephrine was increased only in the hippocampus. SAM may indirectly affect NA biosynthesis and metabolism. This effect on noradrenergic function might participate in its putative antidepressive action.

Striatal dopamine and motor activity changes observed shortly after lithium administration

SummaryLithium chloride was given to rats i.p. at single doses of 2 and 10 meq/kg, respectively. It produced a suppression of motor activity and an increase in the dopamine content of the striatum. The magnitude of these effects were dose- and time-dependent as well as transient in nature. After 60 min of injection, the higher dose (10 meq/kg) reduced motor activity by 67% and increased striatal dopamine content by 56% while the lower dose (2 meq/kg) reduced motor activity by 42% and elevated striatal dopamine by 36%. These effects vanished 24 h after administration regardless the dose employed.None of the two doses of LiCl altered either dopamine biosynthesis in vivo (measured as the accumulation of a precursor of synthesis after decarboxylase inhibition), or the activity of tyrosine hydroxylase ex vivo under subsaturating conditons (i.e. enzyme activity in the tissues obtained from the animals post mortem).An increased deamination of tyramine by mono-amineoxidase (MAO) was found in striatal homogenates after 60 min of the injection of 2 or 10 meq/kg of LiCl. This was due to a lowerKm for the substrate as revealed by kinetic studies. LiCl treatment did not change the proportion of MAO A∶B.As neither dopamine synthesis was increased nor the activity of the catabolic enzyme MAO was reduced (but it was oppositely enhanced), the increment in striatal dopamine content might have likely resulted from a reduced release and/or an increased amine reuptake by the neurons. We postulate that the reduced motor activity observed shortly after injection of LiCl would be related to an interference with striatal dopaminergic neurotransmission.

Acute stress and GABAergic function in the rat brain

1 The function of the γ‐aminobutyric acid (GABA)‐ergic system in certain areas of the rat brain was investigated after acute (5 min) exposure to immobilization stress. 2 The activities of glutamate decarboxylase and GABA‐transaminase, GABA concentrations, GABA turnover in vivo and uptake of [3H]‐GABA were measured. 3 After 5 min of immobilization stress, GABA concentrations and [3H]‐GABA uptake were reduced, and GABA turnover stimulated in the olfactory bulbs. In contrast the uptake of [3H]‐GABA was increased in the corpus striatum after 5 min of immobilization stress. 4 None of the parameters measured was significantly altered by acute immobilization stress in the frontal cortex, hippocampus or medio‐basal hypothalamus. 5 These findings show that the olfactory bulbs and the corpus striatum are sensitive to the effects of acute stress. Since GABA in the olfactory bulbs is involved in the development of aggression and increased emotional state, it follows that neurochemical changes induced by acute stress might underlie some behavioural manifestations observed after stress.

Acute and chronic effects of lithium chloride on GABA-ergic function in the rat corpus striatum and frontal cerebral cortex

SummaryThe acute (1 h, i. p.) and chronic (14 days, p. o.) effects of LiCl treatment upon GABA-ergic neurons were studied in the rat corpus striatum and frontal cerebral cortex.One hour after a single injection of LiCl the activity of glutamic acid decarboxylase (GAD) was reduced by 29% in the striatum (2 meq/kg LiCl) and by 38% in the cerebral cortex (10 meq/kg LiCl). In contrast, striatal GAD was activated by 34% 1 h after the injection of 10 meq/kg of LiCl; this dose also reduced the endogenous striatal GABA level by 24%.After 14 days of oral LiCl administration (2 meq/kg/day): a) cortical GAD activity was enhanced by 50% and GABA concentration was decreased by 28%; b) no changes were observed in the striatum.These findings suggest that: LiCl administration stimulates GABA-ergic function in specific areas (depending on the dose and length of treatment) increasing both GAD activity and probably GABA release. This occurs in the striatum after acute treatment only with a high dose, and in the frontal cerebral cortex after chronic treatment with a low dose.

Changes in the central GABAergic system after acute treatment with corticosterone

The acute effects of corticosterone (0.5 and 1 mg/ kg, i. p.) upon the GABAergic system have been investigated. While no changes were detected after treatment with corticosterone 0.5 mg/kg, the administration of 1 mg/kg lowered the levels of gamma-aminobutyric acid (GABA) (29%) in the mediobasal hypothalamus either 30 or 60 min after injection in both young (3–4 weeks old) and adult (7–8 weeks old) rats. No changes were found in the frontal cerebral cortex. Only in young rats did the administration of corticosterone (1 mg/kg, 30 min) reduced GABA levels in the corpus striatum (34%). In young rats this dose of corticosterone: 1. did not affect the activity of the enzymes of the metabolism of GABA (GAD and GABA-T); 2. reduced neuronal 3H-GABA uptake in the corpus striatum (30%) and in the mediobasal hypothalamus (46%), and increased it in the frontal cortex (2-fold); 3. enhanced the turnover of GABA (2-fold) in the corpus striatum. These values were unaffected by 0.5 mg/kg. Corticosterone 0.5 and 1 mg/kg did not alter non-neuronal 3H-GABA uptake. These findings show an area-related and age- and dose-dependent response of the GABAergic pathways to acute corticosterone treatment. This is discussed in relation to the age-related sensitivity to the environmental stimuli which cause this release of corticosteroids. The stimulation of GABAergic function which occurs mainly in the corpus striatum as estimated from the increase in its turnover may be related to the postulated anticonvulsant role of corticosteroids.

Effects of baclofen on amino acid release

This study showed the effects of baclofen on endogenous excitatory (Glu and Asp) and non-excitatory (Tau, Gly and Ala) amino acid release. (A) Release was stimulated by K+ 30 mM in rat frontal cortex slices in vitro (evoked release in ng/g tissue per 5 min): 3739 +/- 215 (Asp), 3429 +/- 357 (Glu), 763 +/- 181 (Tau), 945 +/- 71 (Ala), 468 +/- 44 (Gly). (B) Release was largely Ca(2+)-dependent for all amino acids but Ca(2+)-independent release was observed for Asp and Glu (29 and 32%, of total evoked release respectively)

Effects of i.c.v. lithium chloride administration on monoamine concentration in rat mediobasal hypothalamus

We investigated the acute effects of a single i.c.v. injection of lithium chloride (LiCl) the neuroamine content of the rat mediobasal hypothalamus (MBH). The effects of lithium on amine synthesis and degradation enzymes were also studied in vitro. Noradrenaline (NA), dopamine (DA), serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) concentrations were reduced 10 min after i.c.v. injection of 24 nmol of LiCl and returned to control values 30 min after the injection. Two nmol of LiCl reduced the concentration of DA (10 and 30 min after injection) and 5-HIAA (30 min after injection). LiCl (0.5-10 mM) inhibited tyrosine hydroxylase activity (catecholamine synthesis) in vitro in a concentration dependent manner. The i.c.v. administration of a high dose of LiCl reduced the content of neuroamines in the MBH. This might result from and inhibition of synthesis. A possible link between the observed changes and some reported side effects of lithium therapy is discussed.

Baclofen and noradrenergic function in the rat frontal cerebral cortex

Possible changes in noradrenergic function were investigated in rat frontal cerebral cortex after acute treatment (1, 2 h) with the GABAB agonist, baclofen. A single i.p. injection of d,l-baclofen 10 mg/kg both reduced noradrenaline (NA) biosynthesis in vivo (31%) and the endogenous concentration of normetanephrine (NMN) (32%) and increased NA levels (28%). Increased [3H]NA uptake (15%) and [3H]dihydroxyphenyl-ethyleneglycol ([3H]DOPEG formation (39%) were observed in cortex slices ex vivo from baclofen-treated animals. The activity of monoamineoxidase (MAO) was unchanged after baclofen treatment. We suggest that baclofen might interfere in vivo with noradrenergic neurotransmission, reducing NA biosynthesis and release in the rat cerebral cortex.