Dopamine antidepressant effects

Cocaine and desipramine inhibit the reuptake of monoamine neurotransmitters whereas amphetamine, which is a phenylalkylamine - similar in structure to the catecholamines, see Fig. 4 - competes for uptake and more importantly, evokes efflux of the monoamine neurotransmitters. All of them exert antidepressant effects. Cocaine and amphetamine are addictive whereas tricyclic antidepressants and their modern successors are not. The corollaty of the addictive properties is interference with DAT activity. Blockade of DAT by cocaine or efflux elicited by amphetamine produces a psychostimulant effect despite the different mechanisms even the experienced individual can hardly discern their actions. Because of the risk associated with inhibiting DAT mediated dopamine clearance the antidepressant effects of psychostimulants has not been exploited. 

The atypical tricyclic antidepressant amineptine (Survector) is an indirect dopamine agonist, which selectively inhibits dopamine uptake and induces its release, with additional stimulation of the adrenergic system. Its antidepressant effects are similar to those of other tricyclic antidepressant drugs. However, it acts more rapidly, is better... 

Another action of hypericum constituents that is particularly relevant to antidepressant effects is the ability to inhibit neuronal reuptake of monoamines. The half-maximal inhibition for monoamine uptake is 100 times lower than for the inhibition of MAOA or MAOB (Chatterjee et al. 1998a). Hyperforin is the major contributor to this action, blocking reuptake of 5-HT, norepinephrine, and dopamine (Muller et al. 1998). Half-maximal inhibition occurs at nanomolar concentrations (80 to... 

Antidepressant effects Hypericum has been shown to have antidepressant effects in several animal models. An extract fraction high in naphthodianthrones showed antidepressant effects in the forced-swim test, and was attenuated by a dopamine antagonist (sulpiride) (Butterweck et... 

These mediators probably play significant roles in CNS functions consistent with the stimulant effects of MAO inhibitors on mood and psychomotor drive and their use as antidepressants in the treatment of depression (A). Tranylcypromine is used to treat particular forms of depressive illness as a covalently bound suicide substrate, it causes long-lasting inhibition of both MAO isozymes, (MAOa, MAOb). Moclobemide reversibly inhibits MAOa and is also used as an antidepressant. The MAOb inhibitor selegiline (deprenyl) retards the cat-obolism of dopamine, an effect used in the treatment of parkinsonism (p. 188). 

Mechanism of Action A tricyclic antidepressant that blocks the reuptake of neu-rotransmitfers, such as norepinephrine and serotonin, at CNS presynaptic membranes, increasing their availability at postsynaptic receptor sites. The metabolite, 7-OH-amoxapine has significant dopamine receptor blocking activity similarto halo-peridol. Therapeutic Effect Produces antidepressant effects. 

MecfianismofAction An antidepressant that inhibits the MAO enzyme system at central nervous system (CNS) storage sites. The reduced MAO activity causes an increased concentration in epinephrine, norepinephrine, serotonin, and dopamine at neuron receptor sites. Therapeutic Effect Produces antidepressant effect. 

Serra G, Forgioni A, D Aquila PS, et al Possible mechanism of antidepressant effect of L-sulpiride. Chn Neuropharmacol 13 (suppl l 576-583, 1990a Serra G, CoUn M, D Aquila PS, et al Possible role of dopamine D1 receptor in the behavioral supersensitivity to dopamine agonists induced by chronic treatment with antidepressants. Brain Res 527 234-243, 1990b Sershen H, Hashim, A, Lajtha A Behavioral and biochemical effects of nicotine in an MPTP-induced mouse model of Parkinson s disease. Pharmacol Biochem Behav 28 299-303, 1987... 

Monoamine oxidase A (MAO A) acts selectively on the substrates norepinephrine and serotonin, whereas monoamine oxidase B (MAO B) preferentially affects phenylethylamine. Both MAO A and MAO B oxidize dopamine and tyramine. MAO A inhibition appears to be most relevant to the antidepressant effects of these drugs. Drugs that inhibit both MAO A and MAO B are called non-selective. The MAOI antidepressants currently available in the United States are nonselective inhibitors. Because tyramine can be metabolized by either MAO A or MAO B, drugs that selectively inhibit one of these enzymes but not the other do not require dietary... 

Tricyclic antidepressants are the most commonly used drugs. They produce antidepressant effect by blocking the neuronal uptake of noradrenaline and exert anti-cholinergic activity. They also inhibit neuronal uptake of 5HT and dopamine. The exact mechanism of action is not known. The antidepressant effect is noticed after three to four weeks of drug administration. 

The antidepressant effect of agents that enhance dopamine transmission... 

It has been proposed that COMT inhibitors -administered with L-dopa could have beneficial effects in the treatment of depressive illness [40]. This can be caused by either the better availability of dopamine or by the elevated noradrenaline levels in the brain. Another hypothesis suggests that the increasing level of AdoMet caused by COMT inhibition may cause an antidepressive effect [33]. 

FIGURE 6—49- In this diagram, the norepinephrine reuptake inhibitor (NRI) and the dopamine reuptake inhibitor (DRI) portions of the NDRI molecule are shown inserted in the norepinephrine and the dopamine reuptake pumps, respectively, blocking them and causing an antidepressant effect. 

As i.n. administration delivers the drug to the brain directly via the olfactory nerve and olfactory epithelium, this method may be favored for administration of drugs that are rapidly metabolized when given systemically or have difficulty crossing the blood-brain barrier (27). For example, in rats, i.n. dopamine has been shown to decrease grooming activity and increase locomotor activity in the open field at one tenth of the dose needed to observe these effects when the drug is administered i.p. (27) also see data on its antidepressant effects (28). 

Delini-Stula, A. Vassout, A. 1979, Modulation of dopamine-mediated behavioural responses by antidepressants effects of single and repeated treatment, Eur.J.Pharmacol., vol. 58, no. 4, pp. 443-451. 

The antidepressant effect of thymoleptics manifests after a prolonged latency usually 1-3 weeks pass before subjective or objective improvement becomes noticeable (A). In contrast, somatic effects are immediately evident specifically, the interference with neuronal transmitter/modulator systems (norepinephrine, serotonin, acetylcholine, histamine, dopamine). Reuptake of released serotonin, norepinephrine, or both is impaired (—< elevated concentration in synaptic cleft) and/or receptors are blocked (example in A). These effects are demonstrable in animal studies and are the cause of acute adverse effects. 

Monoamine oxidase inhibitors (MAOIs), which were amongst the first antidepressant drugs to be used clinically. They affect one or both of the brain monoamine oxidase enzymes that play a role in the metabolism of serotonin, noradrenaline, dopamine and adrenaline. MAOIs inhibit breakdown of the neurotransmitters important in determining mood, which results in the antidepressant effect. 

Monoamine oxidase, which exists in two distinct forms, referred to as MAO A and MAO B, is one of the enzymes responsible for the degradation of biologically important amines. Compounds that block the catalytic action of MAO A, which is selective for the degradation of norepinephrine and serotinin, have antidepressant effects whereas compounds that inhibit MAO B, which degrades dopamine in the brain, are useful for treating Parkinson s disease [190, 191]. Both MAO A and MAO B contain flavin co-enzyme attached at the 8-a-position to an enzyme-active cysteine residue (54). A one-electron transfer mechanism (Scheme 15) for the oxidations catalyzed by MAO was first proposed by Silverman [192] and Krantz [193,194]. 

Dopamine D2 receptor Dopamine antagonists Anxiolytic/antidepressive effects of neuroleptics 140... 

Suzuki A, Kondo T, Mihara K, et al. The -141C Ins/Del polymorphism in the dopamine D2 receptor gene promoter region is associated with anxiolytic and antidepressive effects during treatment with dopamine antagonists in schizophrenic patients. Pharmacogenetics 2001 ll(6) 545 50. 

Saint-John s-wort is one example of a natural herbal remedy for depression that has recently gained in popularity and prevalence across the United States. In Europe, it is reportedly outselling the prescription medication Prozac. Saint-John s-wort (Hypericum perforatum) is a lush green herb with bright yellow flowers that has traditionally been used to heal wounds and as a tea to soothe nerves and relieve melancholy. The natural antidepressant effect that results enhances the neurochemical serotonin, norepinephrine, and dopamine with few side effects (Lemonick, 1997). 

It was initially believed that the antidepressant effectiveness of MAOIs was the direct result of MAO inhibition. This acute effect decreases degradation of monoamines (e.g., norepinephrine, serotonin, or dopamine) stored in presynaptic neurons, thereby resulting in an increased amount of these neurotransmitters available at the synapse. More recent research indicates that this model does not fully explain the mechanism of MAOIs efficacy. For example, the positive (h-) stereoisomer of tranylcypromine is a poor antidepressant despite inhibiting MAO. The main pharmacologic difference between the negative (-) and + isomers of tranylcypromine is that the former has much weaker effects as a norepinephrine reuptake inhibitor in relation to its potency as an MAOI. The other MAOIs may also block the reuptake of selected neurotransmitters. However, like the non-MAOI uptake inhibitors, these acute effects often precede clinical antidepressant effects by weeks. More consistent with the 2- to 4-week lag in therapeutic effect, chronic treatment with a diverse number of MAOIs has been shown to reduce the number of a2- and P-adrenergic and serotonin (5-HT2) postsynaptic binding sites in the brain. 

OLANZAPINE/FLUOXETINE HYDROCHLORIDE (Symbyax capsules olanzapine 6 mg/fluoxetine hydrochloride 25 mg, capsules olanzapine 6 mg/ fluoxetine hydrochloride 50 mg, capsules olanzapine 12 mg/fluoxetine hydrochloride 25 mg, capsules olanzapine 12 mg/fluoxetine hydrochloride 50 mg) Olanzapine/flnoxetine hydrochloride is an antidepressant. It is thonght that activation of 3 monoaminergic neural systems (dopamine, norepinephrine, and serotonin) is responsible for an enhancement of the antidepressant effect. 

Adverse effects are similar to those seen with tricyclic antidepressants. Additionally, dopamine-related effects, such as akathisia, galactorrhea/amenorrhea. and Parkinson-like symptoms are seen. 

Another strategy is to directly enhance dopamine function as well as the activities of B-cell lymphoma protein 2 (Bcl-2), which is another important component that may play a role, eventually, in the resolution of depression. Examples of various non-selective enhancers of dopamine that also stimulate Bcl-2 are pergolide, ropinirole, and selegiline, while pramipexole may directly enhance Bcl-2. The antidepressant effect exhibited by enhanced dopaminergic transmission is thought to be at least partially related to increased dopaminergic transmission in limbic structures (e.g. the nucleus accumbens). - ... 

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