Posted by SLS on May 13, 2000, at 9:03:43
In reply to Re: Amphetamine Treatment of Mania, posted by PeterJ on May 13, 2000, at 4:20:26
> My own personal observations is that amphetamine initially sedates me, with delayed stimulation after a few hours. Other dopaminergic drugs are almost invariably sedating and de-activating to me. These include ritalin, pemoline, bromocriptine, diethylpropion, bupropion, l-dopa, and isocarboxazid. For example, if I take ritalin, I have to lie down, and am virtual immobile for several hours. All the other drugs in the list produce similar effects.
This appears to be similar to a low-dose apomorphine effect. Under a microscope, your presynaptic autoreceptors probably resemble tiny membrane-bound Arnold Schwarzeneggers.
My reactions to amphetamine and bromocryptine are the reverse. I experience an improvement in energy and mood from amphetamine within an hour. This effect disappears after a few more hours, whereafter I lose the improvement and get sleepy and irritable. When last I tried bromocryptine, it was in combination with Parnate and desipramine. I experienced an improvement within the first day. Unfortunately, as seems to be always the case, I lost it after three days. It's as if my gas-tank is near empty, and is quickly drained after the engine starts up and runs for a little while.
I don't see Provigil in your list.
One study I came across indicated that modafinil produces an increase in the release of dopamine in the nucleus accumbens. (I also found a glucose-utilization study representing regional brain activity that contradicted this). I would interpret this to be an indicator of a downstream net effect representing the increased activation and the elevations in mood and motivation produced by this drug. It is proposed that this is accomplished through an inhibition of GABAergic neurotransmission, most likely controlled via noradrenergic pathways that are influenced by the NE alpha-1 agonist actions of modafinil. Other structures important for wakefulness and activation are also stimulated, but not by direct action at the dopamine synapse. As a matter of fact, neuroleptics apparently are unable to reverse modafinil-induced increases in behavioral activity in lab animals. (I am suspicious that the technicians are sometimes placed in this category). Modafinil is much more selective as to which pathways are stimulated when compared to the shotgun blast of amphetamine.
Perhaps Provigil would accomplish your mission by not depending on dysregulated dopaminergic synapses, and by not stimulating those pathways that may produce counterproductive effects that are idiosyncratic to your condition.
I just wanted to fill up a page. I'm sure you've already tried it.
- Scott
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Neuroscience 1998 Dec;87(4):905-11 Related Articles, Books
Brain regional substrates for the actions of the novel wake-promoting agent modafinil in the rat: comparison with amphetamine.Engber TM, Dennis SA, Jones BE, Miller MS, Contreras PC
Department of Pharmacology, Cephalon, Inc., West Chester, PA 19380, USA.
Modafinil is a novel wake-promoting compound for which the mechanism and sites of action are unknown. We examined the neural substrates in the brain for the actions of modafinil using 2-deoxyglucose autoradiography and compared the findings to those obtained with amphetamine. Modafinil showed a relatively restricted pattern of changes in brain regional metabolic activity, while amphetamine altered glucose utilization in a wide variety of brain regions. Both modafinil and amphetamine increased glucose utilization in all subregions of the hippocampus (subiculum, CA1-CA3 and dentate gyrus) and in the centrolateral nucleus of the thalamus. Modafinil also increased glucose utilization in the central nucleus of the amygdala, but amphetamine had no effect in this region. Brain structures in which amphetamine increased metabolic rate but modafinil had no effect included regions of the basal ganglia, other nuclei of the thalamus, the frontal cortex, the nucleus accumbens, the ventral tegmental area and the pontine reticular fields. These findings suggest that, while both modafinil and amphetamine promote wakefulness, they act via distinctly different mechanisms. Modafinil appears to act on a specific subset of brain pathways which regulate sleep and wakefulness, whereas amphetamine affects a greater number of cerebral structures involved in the regulation of these behavioral states. Modafinil also lacks the pronounced effects on the extrapyramidal motor system which are characteristic of amphetamine and other psychomotor stimulants, implying that the effects of modafinil are not mediated by the dopamine system and that modafinil may selectively increase wakefulness with fewer side effects.
PMID: 9759978, UI: 98430778
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6 : Eur J Pharmacol 1996 Jun 13;306(1-3):33-9 Related Articles, Books
The vigilance promoting drug modafinil increases dopamine release in the rat nucleus accumbens via the involvement of a local GABAergic mechanism.Ferraro L, Tanganelli S, O'Connor WT, Antonelli T, Rambert F, Fuxe K
Institute of Pharmacology, University of Ferrara, Italy.
The present in vivo microdialysis study demonstrated that the subcutaneous injection of modafinil (diphenyl-methyl-sulfinyl-2-acetamide) in doses of 30-300 mg/kg dose dependently increased dopamine release from the intermediate level of the nucleus accumbens along the rostro-caudal axis of the halothane anaesthetized rat. The effect of modafinil in a dose of 100 mg/kg was counteracted by the local perfusion in the nucleus accumbens with the GABAB receptor antagonist phaclofen (beta-p-chlorophenyl-gamma-aminopropyl-phosphonic acid) (50 microM), the GABAA agonist muscimol (3-hydroxy-5-aminomethyl-isoxazolol) (10 microM) and the neuronal GABA reuptake inhibitor SKF89976A (4,4-diphenyl-3-butenyl-nipecotic acid) (0.1 microM), whereas it was increased by the GABAB receptor agonist (-)-baclofen [beta-(p-chlorophenyl-gamma-aminobutyric acid)] (10 microM). In addition, the modafinil-induced increase of dopamine release was associated with a significant reduction of accumbens GABA release. These results suggest that the dopamine releasing action of modafinil in the rat nucleus accumbens is secondary to its ability to reduce local GABAergic transmission, which leads to a reduction of GABAA receptor signaling on the dopamine terminals.
PMID: 8813612, UI: 96408605
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poster:SLS
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