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Biomedical subjects

P G Simson

Publications and source records attributed to P G Simson.

6 recordsLinked to original sources
PubMed1986

Depression in an animal model: focus on the locus ceruleus.

When rats are exposed to highly stressful events over which they have no control, they subsequently show many of the symptoms seen in depression in humans. In the attempt to discover neurochemical factors underlying depression, the neurochemical basis of stress-induced behavioural depression in rats has been studied extensively. Initial research (1968-1976) indicated that behavioural depression in this model was produced by alteration of noradrenaline (NA) concentrations in the brain. More recent research has indicated that the critical change may be a large depletion of NA in the locus ceruleus (LC). Behavioural depression may result when such NA depletion is sufficient to reduce NA release in the LC region, leading to a 'functional blockade' of inhibitory alpha 2-receptors in that brain region. Studies have now shown that behavioural depression after uncontrollable shock can be mimicked by pharmacological blockade of alpha 2-receptors in the LC region. Conversely, behavioural depression can be eliminated by either infusion of clonidine into the LC to replace at the alpha 2-receptors the NA depleted after uncontrollable shock, or infusion of pargyline into the LC to prevent the depletion of NA that otherwise follows uncontrollable shock. If alpha 2-receptors are functionally blocked in depression, then release of NA in regions innervated by the LC should be increased and stimulation of postsynaptic adrenoceptors outside the LC should be higher than normal. Thus, higher-than-normal stimulation of postsynaptic NA receptors should also produce behavioural depression; this has been demonstrated.

Action Potentials↗
PubMed1986

Infusion of a monoamine oxidase inhibitor into the locus coeruleus can prevent stress-induced behavioral depression.

Behavioral depression produced by exposing animals to a stressor that they cannot control (uncontrollable shock) was reversed by infusion of the monoamine oxidase (MAO) inhibitor pargyline into the locus coeruleus (LC) region of the brain stem. Following exposure to uncontrollable shock, rats were infused through bilateral cannulas implanted in the LC region with either pargyline or vehicle. At 110 min after infusion, animals were tested for behavioral activity in a swim tank. Immediately following the behavioral test, animals were sacrificed for determination of the monoamines [norepinephrine (NE), dopamine (DA), serotonin (5-HT)], as well as 5-hydroxy-indoleacetic acid (5-HIAA) in various brain regions. The results showed that animals exposed to uncontrollable shock and then infused with vehicle exhibited significantly less activity in the swim test than animals not exposed to shock and similarly infused with vehicle; thus, the usual behavioral depression following exposure to uncontrollable shock was observed. On the other hand, shocked animals infused with pargyline did not show reduced activity in the swim test. Unshocked animals infused with pargyline showed no more activity than did shocked animals infused with pargyline or unshocked animals infused with vehicle, which demonstrated that the infusion of pargyline into shocked animals did not eliminate the shock-induced depression of activity simply by generally stimulating motor activity. Measurement of the concentration of NE, DA, 5-HT, and 5-HIAA present in seven brain regions at the conclusion of the swim test showed that pargyline infusion into the LC eliminated the large depletion of NE in the LC that is normally observed after exposure to uncontrollable shock while having no effect on NE levels in the other brain regions examined. The level of 5-HT in the LC was also raised by infusion of pargyline into the LC, but again, there was no effect of pargyline infusion on 5-HT levels in any of the other brain regions. In conclusion, infusion of pargyline into the LC region of the brain eliminated both the large depletion of NE in the LC region and the behavioral depression that otherwise results from exposure of animals to uncontrollable shock.

Animals↗
PubMed1986

Infusion of adrenergic receptor agonists and antagonists into the locus coeruleus and ventricular system of the brain. Effects on swim-motivated and spontaneous motor activity.

These studies examined how pharmacological stimulation and blockade of alpha receptors would affect active motor behavior in rats. In experiment I, alpha-2 receptor antagonists (piperoxane, yohimbine) and agonists [clonidine, norepinephrine (NE)] were infused into various locations in the ventricular system of the brain, including the locus coeruleus region, and motor activity was measured. Activity was measured principally in a swim test but spontaneous (ambulatory) activity was also recorded while drugs were being infused. When infused into the locus coeruleus region, small doses of the antagonists piperoxane and yohimbine depressed activity in the swim test while infusion of the agonists clonidine and NE had the opposite effect of stimulating activity. These effects were highly specific to the region of the locus coeruleus, since infusions of these drugs into other nearby locations in the ventricular system or use of larger doses had different, often opposite effects. This was especially true of clonidine and NE which profoundly depressed activity when infused posterior to the locus coeruleus, particularly over the dorsal vagal complex. Infusion of small doses of these drugs into the lateral ventricle had effects similar to infusion into the locus coeruleus region, though less pronounced. Changes in spontaneous motor activity were also observed, but this measure differentiated the groups less well than did the swim test. In experiment II, the predominantly postsynaptic receptor agonists isoproterenol (beta agonist) and phenylephrine (alpha-1 agonist) were infused into the ventricular system. Since infusions of piperoxane and yohimbine into the locus coeruleus that decreased activity in experiment I increase the release of NE by blocking alpha-2 inhibitory receptors on cell bodies and dendrites of the locus coeruleus, experiment II tested whether ventricular infusion of predominantly postsynaptic receptor agonists would also decrease activity in the swim test. Both isoproterenol and phenylephrine produced this effect, but did so selectively with respect to dose and location of infusion in the ventricular system. These findings are consistent with recent results relating to the mechanism that underlies stress-induced depression of active behavior.

Adrenergic alpha-Agonists↗
PubMed1986

Reversal of behavioral depression by infusion of an alpha-2 adrenergic agonist into the locus coeruleus.

This experiment demonstrated that behavioral depression produced by exposure of rats to strong uncontrollable shocks could be reversed by infusion of the alpha-2 adrenergic agonist clonidine into the region of the locus coeruleus (LC). A 20-min infusion, through bilateral cannulae, into the locus coeruleus of clonidine, piperoxane (alpha-2 antagonist) or inactive vehicle (0.85% saline), was given beginning 70 min after the animals were removed from the stress situation. The dose and volume of drug given in the infusion (0.16 microgram/microliter, 0.1 microliter/min) had been previously shown to produce effects specific to the locus coeruleus (Weiss, Simson, Hoffman, Ambrose, Cooper and Webster, 1986; Neuropharmacology 25: 367-384). At the conclusion of the infusion, active behavior of animals was measured in a 15-min swim test. Results showed that stressed animals infused with vehicle exhibited significantly less active behavior in the swim test than did non-stressed animals infused with vehicle, thereby showing the usual behavioral depression seen after exposure to an uncontrollable stress. Stressed animals infused with clonidine showed no difference in active behavior in comparison to non-stressed animals infused with vehicle and showed significantly more activity than did the stressed animals infused with vehicle. Stressed animals infused with piperoxane showed no significant difference in activity in comparison to the stressed animals infused with vehicle and were significantly less active than either the non-stressed animals infused with vehicle or the stressed animals infused with clonidine. Thus, infusion into the locus coeruleus of the alpha-2 agonist clonidine, but not the alpha-2 antagonist piperoxane, eliminated behavioral depression.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗