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The analeptic effect of methamphetamine in pentobarbital-narcotized rats is mediated via a dopaminergic-cholinergic
1Department of Pharmacology, University of Washington School of Medicine, Seattle.
Abstract:
Methamphetamine (MAP) administered in doses of 0.5 to 5 mg/kg i.p. to rats anesthetized with pentobarbital produced a shortening of the duration of loss of righting reflex. This analeptic effect of MAP was blocked by atropine but not by atropine methylbromide, indicating the central cholinergic nature of the response. This effect was also blocked by the D1 and D2 dopamine antagonists SCH 23390 (0.2 mg/kg) and raclopride (2 mg/kg), respectively. Pentobarbital decreased sodium-dependent high-affinity choline uptake (HACU) in frontal cortex and hippocampus as measured in synaptosomes from treated rats. MAP given to pentobarbital-narcotized rats restored HACU activity to nonanesthetized levels, but this restorative effect of MAP was blocked by SCH 23390 or raclopride. These data suggest that in addition to a cholinergic mechanism, the analeptic effect of MAP involves the dopamine system. alpha-Methyl-p-tyrosine, but not reserpine, pretreatment completely blocked the MAP analeptic response. In reserpinzed rats, MAP produced a markedly enhanced analeptic response. Studies of the effects of repeated administration of MAP on its analeptic activity were also undertaken in view of the well known sensitization to the locomotor and stereotypic effects of the amphetamines that occur with repeated intermittent administration. Rats pretreated daily with MAP (5 mg/kg) for 5 or 12 days showed neither tolerance nor sensitization to the analeptic effect of subsequent MAP administrations. 3H-quinuclidinyl benzilate-binding studies also showed no changes in muscarinic binding characteristics of membranes prepared from cortex or hippocampus of rats pretreated chronically with MAP. These and our earlier studies suggest that the analeptic effect of MAP is mediated via a dopaminergic-cholinergic mechanism.
Insights
Methamphetamine (MAP) reverses pentobarbital-induced anesthesia by acting on central cholinergic and dopamine systems. This analeptic effect involves restoring choline uptake and is not altered by chronic MAP administration.
Area of Science:
- Neuroscience
- Pharmacology
- Neurochemistry
Background:
- Pentobarbital anesthesia impairs central nervous system function, including neurotransmitter uptake.
- Methamphetamine (MAP) is known to have stimulant properties and can counteract depressant effects.
Purpose of the Study:
- To investigate the neurochemical mechanisms underlying the analeptic (resuscitation-inducing) effect of methamphetamine.
- To determine the involvement of cholinergic and dopaminergic systems in MAP's ability to reverse pentobarbital-induced anesthesia.
Main Methods:
- Administered MAP to pentobarbital-anesthetized rats and assessed the duration of anesthesia.
- Utilized specific antagonists (atropine, SCH 23390, raclopride) to block MAP's effects.
- Measured sodium-dependent high-affinity choline uptake (HACU) in rat brain synaptosomes.
- Investigated effects of tyrosine hydroxylase inhibition and reserpine pretreatment.
- Examined analeptic activity and muscarinic receptor binding after chronic MAP administration.
Main Results:
- MAP shortened the duration of pentobarbital-induced loss of righting reflex, an effect blocked by atropine and dopamine antagonists (SCH 23390, raclopride).
- MAP restored pentobarbital-decreased HACU in the frontal cortex and hippocampus, an effect also blocked by dopamine antagonists.
- alpha-Methyl-p-tyrosine blocked MAP's analeptic effect, while reserpine enhanced it.
- Chronic MAP administration did not lead to tolerance or sensitization of the analeptic effect, nor did it alter muscarinic receptor binding.
Conclusions:
- The analeptic effect of MAP is mediated by a complex interaction involving both central cholinergic and dopaminergic systems.
- MAP's ability to reverse pentobarbital-induced anesthesia is linked to its restoration of high-affinity choline uptake.
- The dopamine system, particularly D1 and D2 receptors, plays a crucial role in mediating MAP's analeptic action.
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