Synapse depression

Selected for clinical trials as a compound to calm agitated patients, imipramine was relatively ineffective. However, it was observed to be effective in the treatment of certain depressed patients (38). Early studies on the mechanism of action showed that imipramine potentiates the effects of the catecholamines, primarily norepinephrine. This finding, along with other evidence, led to the hypothesis that the compound exerts its antidepressant effects by elevating norepinephrine levels at central adrenergic synapses. Subsequent studies have shown that the compound is a potent inhibitor of norepinephrine reuptake and, to a lesser extent, the uptake of serotonin, thus fitting the hypothesis that had been developed to explain the antidepressant actions ofMAOIs. 

Figure 1.8 Some basic neuronal systems. The three different brain areas shown (I, II and III) are hypothetical but could correspond to cortex, brainstem and cord while the neurons and pathways are intended to represent broad generalisations rather than recognisable tracts. A represents large neurons which have long axons that pass directly from one brain region to another, as in the cortico spinal or cortico striatal tracts. Such axons have a restricted influence often only synapsing on one or a few distal neurons. B are smaller inter or intrinsic neurons that have their cell bodies, axons and terminals in the same brain area. They can occur in any region and control (depress or sensitise) adjacent neurons. C are neurons that cluster in specific nuclei and although their axons can form distinct pathways their influence is a modulating one, often on numerous neurons rather than directly controlling activity, as with A . Each type of neuron and system uses neurotransmitters with properties that facilitate their role...

The monoamine hypothesis predicts that drugs which increase the concentration of noradrenaline and/or 5-HT in the synapse should relieve depression. This could be achieved in two ways, as illustrated in Figure 20.1 ... 

The tricyclic antidepressants (TCAs), such as imipramine, can alleviate symptoms of ADHD. Like bupropion, TCAs likely will improve symptoms associated with comorbid anxiety and depression. The mechanism of action of TCAs is in blocking norepinephrine transporters, thus increasing norepinephrine concentrations in the synapse the increase in norepinephrine is believed to alleviate the symptoms of ADHD. TCAs have been demonstrated to be an effective non-stimulant option for ADHD but less effective than stimulants. However, their use in ADHD has declined owing to case reports of sudden death and anticholinergic side effects6,13 (Table 39-3). Further, TCAs may lower seizure threshold and increase the risk of car-diotoxicity, (e.g., arrythmias). Patients starting on TCAs should have a baseline and routine electrocardiograms. 

Long-term potentiation and depression of glutamatergic synapses are involved in many models for brain function and development. A key factor in the plasticity is a change in the AMPA and kainate... 

After neurotransmitter molecules have influenced the firing of a receiving neuron (more technically called a postsynaptic neuron), some of them are destroyed by enzymes in the synaptic cleft (the synapse), some are reabsorbed by the sending presynaptic neuron in a process that is called reuptake , and the rest remain in the space between the two neurons. The chemical-imbalance hypothesis is that there is not enough serotonin, norepinephrine and/or dopamine in the synapses of the brain. This is more specifically termed the monoamine theory of depression, because both serotonin and norepinephrine belong to the class of neurotransmitters called monoamines. 

Here then is the logic behind the first version of the chemical-imbalance theory. Iproniazid is a monamine oxidase inhibitor - it inhibits the oxidation of norepinephrine and serotonin in the synapses, thereby leaving more of these neurotransmitters available in the brain. When depressed people take iproniazid, they get better. Therefore insufficient norepinephrine and/or serotonin causes depression.12... 

There was a problem with this first version of the biochemical theory of depression. Iproniazid was not the only drug that had been reported to be effective as an antidepressant. Imipramine, the drug that had been tested by the Swiss psychiatrist Roland Kuhn, seemed to have similar effects. But imipramine is not an MAOI it does not inhibit the destruction of neurotransmitters in the synapse. So if antidepressants worked by inhibiting monoamine oxidase, why was imipramine effective How could its apparent effectiveness be reconciled with the chemical-imbalance theory ... 

Neurochemical theories for the affective disorders propose that there is a link between dysfunctional monoaminergic synapses within the central nervous system (CNS) and mood problems. The original focus was the neurotransmitter noradrenaline, or NA (note noradrenaline is called norepinephrine, or NE, in American texts). Schildkraut (1965) suggested that depression was associated with an absolute or relative deficiency of NA, while mania was associated with a functional excess of NA. Subsequently, another monoamine neurotransmitter 5-hydroxytryptamine (5-HT), or serotonin, was put forward in a rival indoleamine theory (Chapter 2). However, it was soon recognised that both proposals could be reconciled with the available clinical biochemical and pharmacological evidence (Luchins, 1976 Green and Costain, 1979). 

Weisskopf M, Zalutsky R, Nicoll RA. The opioid peptide dynorphin mediates heterosynaptic depression of hippocampal mossy fibre synapses and modulates long-term potentiation. Nature 1993 365 188-190. 

LONG-TERM POTENTIATION OR DEPRESSION OF GLUTAMATERGIC SYNAPSES MAY UNDERLIE LEARNING 271... 

The monoamine oxidase inhibitors (MAOIs) phenelzine and tranylcypromine increase the concentrations of NE, 5-HT, and DA within the neuronal synapse through inhibition of the monoamine oxidase (MAO) enzyme system. Both drugs are nonselective inhibitors of MAO-A and MAO-B. Selegiline is available as a transdermal patch for treatment of major depression. It inhibits MAO-A and MAO-B in the brain, but has reduced effects on MAO-A in the gut. 

Frerking, M., Schmitz, D., Zhou, Q., Johansen, J., and Nicoll, R. A. (2001) Kainate receptors depress excitatory synaptic transmission at CA3-CA1 synapses in the hippocampus via a direct presynaptic action. J. Neurosci. 21, 2958-2966. 

Adams DJ, Takeda K, Umbach JA. 1985. Inhibitors of calcium buffering depress evoked transmitter release at the squid giant synapse. J Physiol 369 145-159. 

This conclusion is supported by the mechaiusm of action of imipramine. Once a neurotransmitter has been released into the synapse, there are two ways to terminate its action. The first is to degrade it to inactive products, by MAO for example. The second is to remove the neurotransmitter through reuptake into the presynaptic neuron. This mechaiusm is the predominant one for clearing the synapse of serotonin, norepinephrine, and dopamine. Specific proteins embedded in the neuronal plasma membrane mediate the reuptake of these monoamine neurotransmitters. Imipramine is a nonspecific monoamine reuptake inhibitor that is, it slows the reuptake of aU three of these monoamines, which enhances the activity of these neurotransmitters. This also suggests that a deficit in the activity of one or more of the monoamines underlies the problem of depression. 

A breakthrough in the treatment of major depression was the discovery of fluoxetine, marketed as Prozac. Fluoxetine has a mechanism of action similar to that of imipramine with an important exception. It is a selective serotonin reuptake inhibitor, an SSRI. This strongly suggests that, in some sense, the symptoms of major depression result from a deficit in serotonin specifically. By inhibiting its reuptake from the synapse, the activity of serotonin is enhanced. Two other important drugs for major depression, sertraline (Zoloft) and paroxetine (Paxil), among several others,... 

When we talk about what a psychiatric medication does, we are invariably discussing its effect on neurotransmission between nerve cells across the synapse. Psychiatric medications act by modulating chemical neurotransmission in the synapse. However, as you probably know, it often takes several days or weeks for depression or psychosis to respond to treatment. Clearly, psychiatric medications work. Why, however, is there often a delay before they begin to do so ... 

Since GABA-ergic synapses are confined to neural tissues, specific inhibition of central nervous functions can be achieved for instance, there is little change in blood pressure, heart rate, and body temperature. The therapeutic index of benzodiazepines, calculated with reference to the toxic dose producing respiratory depression, is greater than 100 and thus exceeds that of barbiturates and other sedative-hypnotics by more than tenfold. Benzodiazepine intoxication can be treated with a specific antidote (see below). 

The clinical picture of carbaryl intoxication results from inactivation of cholinesterase, resulting in the accumulation of acetylcholine at synapses in the nervous system, skeletal and smooth muscle, and secretory glands. Signs and symptoms of overexposure may include (1) muscarinic manifestations such as miosis, blurred vision, lacrimation, excessive nasal discharge or salivation, sweating, abdominal cramps, nausea, vomiting, and diarrhea (2) nicotinic manifestations including fasiculation of fine muscles and tachycardia and (3) central nervous system manifestations characterized by headache, dizziness, mental confusion, convulsions, coma, and depression of the respiratory center. 

Oral gavage of rat pups with 14mg/kg/day ftom posmatal day 5 through 20 caused reductions in serum thyroxine levels that correlated with depressed behavioral parameters. Further studies using the same protocol reported decreased cell proliferation in the cerebellum and forebrain on postnatal days 11 and 21, respectively. In yet another study, 14mg/day of chlorine dioxide on posmatal days 1-20 was associated with some neurotoxicity (decreased forebrain weight and reduced synapse formation on day 35), but the neurotoxicity was not correlated with any antithyroid activity of this chemical. ... 

Exposure to disulfoton can result in inhibition of cholinesterase activity in blood and at nerve synapses of muscles, secretory organs, and nervous tissue in the brain and spinal cord. Central nervous system signs and symptoms include anxiety, restlessness, depression of respiratory and circulatory centers, ataxia, convulsions, and coma. 

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