Dopamine release/inhibiting reuptake

Methylphenidate like cocaine largely acts by blocking reuptake of monoamines into the presynaptic terminal. Methylphenidate administration produces an increase in the steady-state (tonic) levels of monoamines within the synaptic cleft. Thus, DAT inhibitors, such as methylphenidate, increase extracellular levels of monoamines. In contrast, they decrease the concentrations of the monoamine metabolites that depend upon monoamine oxidase (MAO), that is, HVA, but not catecholamine-o-methyltransferase (COMT), because reuptake by the transporter is required for the formation of these metabolites. By stimulating presynaptic autoreceptors, methylphenidate induced increase in dopamine transmission can also reduce monoamine synthesis, inhibit monoamine neuron firing and reduce subsequent phasic dopamine release. 

After more than a decade of use, bupropion (24) is considered a safe and effective antidepressant, suitable for use as first-line treatment. In addition, it is approved for smoking cessation and seasonal affective disorder. It is also prescribed off-label to treat the sexual dysfunction induced by SSRIs. Bupropion is often referred to as an atypical antidepressant and has much lower affinity for the monoamine transporters compared with other monoamine reuptake inhibitors. The mechanism of action of bupropion is still uncertain but may be related to inhibition of dopamine and norepinephrine reuptake transporters as a result of active metabolites [71,72]. In a recently reported clinical trial, bupropion extended release (XL) had a sexual tolerability profile significantly better than that of escitalopram with similar re-... 

Triple reuptake inhibitors (TRIs), which inhibit reuptake at all three transporters, have attracted considerable interest in recent years [77]. The involvement of dopamine reuptake in the etiology of depression and other CNS disorders has been recognized [29,30]. As a result, TRIs have been proposed to offer a faster onset of action and improved efficacy for depression over currently prescribed single or dual action monoamine reuptake inhibitors. Historically, the mesocorticolimbic dopamine pathway is thought to mediate the anhedonia and lack of motivation observed in depressed patients [78,79]. In addition, methylphenidate, both immediate release and extended release formula, has been found to be effective as an augmenting agent in treatment-resistant depression [4]. Furthermore, clinical studies using the combination of bupropion and an SSRI or SNRI have showed improved efficacy for the treatment of MDD in patients refractory to the treatment with SSRIs, SNRIs, or bupropion alone [5,80,81]. 

Amantadine, an antiviral agent, was by chance found to have antiparkinsonism properties. Its mode of action in parkinsonism is unclear, but it may potentiate dopaminergic function by influencing the synthesis, release, or reuptake of dopamine. It has been reported to antagonize the effects of adenosine at adenosine 2 receptors, which are receptors that may inhibit D2 receptor function. Release of catecholamines from peripheral stores has also been documented. 

This is an antiviral agent which was accidentally discovered to be of some value in the initial treatment of Parkinson s disease. While the precise mechanism of action of this drug is uncertain, there is experimental evidence to show that it increases the release and synthesis of dopamine and inhibits its reuptake, thereby facilitating the action of the neurotransmitter in those dopaminergic terminals that are still able to function. It has been found that patients soon develop a tolerance to the beneficial effects of the drug, which has largely precluded its long-term use. 

Amphetamines are available in various forms. It is metabolized primarily by CYP2D6 There is a salt form - methylamphetamine ( speed ) - and a free base form ( base ), which looks like a damp or oily paste Crystalloid form ( ice or crystal meth ) is taken orally or intranasally ( snorting ), or injected intravenously Primary mode of action is t release of dopamine. Also inhibits dopamine metabolism and its reuptake, and t release of norepinephrine and serotonin Toxic effects include restlessness, tremor, anxiety, irritability, insomnia, psychosis, aggression, sweating, palpitations, chest pain, t blood pressure, shortness of breath and headache ... 

The effects of amphetamines are due to the increase of neurotransmitters norepinephrine, serotonin, and dopamine in central synapses. This increase is from increased release and reuptake blockade of catecholamines. Amphetamines may also inhibit monoamine oxidase. These mechanisms combine to produce the sympathomimetic and central nervous system (CNS) effects seen with amphetamine abuse. 

Amphetamine. Amphetamine facilitates dopamine release and inhibits norepinephrine reuptake, which results in increased postsynaptic norepinephrine levels. Amphetamine increases wakefulness and reduces REM sleep. These effects may be prevented by the preadministration of pimozide, a specific D, receptor antagonist, which inhibits presynaptic dopamine release. Propranolol, a p-adrenergic blocker, does not prevent the effect of amphet-... 

EDS [excessive daytime sleepiness], the most disabling symptom, is treated with amphetamine - like stimulants or modafinil. These compounds act by stimulating dopamine release. .. and/or inhibiting dopamine reuptake (modafinil).66... 

Mechanism of action Amantadine enhances dopaminergic neurotransmission by unknown mechanisms that may involve increasing synthesis or release of dopamine or inhibition of reuptake of dopamine. The drug also has muscarinic blocking actions. Pharmacologic effects Amantadine may improve bradykinesia, rigidity, and tremor but is usually effective for only a few weeks. Amantadine also has antiviral effects. 

Cocaine and amphetamine inhibit reuptake of dopamine. Amphetamine also causes release of presynaptic dopamine. Both drugs affect the nucleus accumbens. Opiates and tetrahydrocannabinol, the active principle in cannabis, bind to p opioid and cannabin (CB) 1 receptors. The CBl receptor is found chiefly in the brain but also in other regions. The CB2 receptor is found only outside the brain. 

The pharmacology of amphetamine is considerably more complex. It does not only block monoamine reuptake, but also directly inhibits the vesicular monoamine transporter, causing an increase in cytosolic but not vesicular dopamine concentration. This may lead to reverse transport of the amines via the membrane-bound transporters. Further mechanisms of amphetamine action are direct MAO inhibition and indirect release of both dopamine and serotonin in the striatum. 

In neurochemical terms, amphetamine and cocaine boost monoamine activity. Amphetamine has a threefold mode of action first, it causes dopamine and noradrenaline to leak into the synaptic cleft second, it boosts the amount of transmitter released during an action potential and third, it inhibits the reuptake of neurotransmitter back into presynaptic vesicles. These three modes all result in more neurotransmitter being available at the synapse, thus generating an increase in postsynaptic stimulation. Cocaine exerts a similar overall effect, but mainly by reuptake inhibition. The main neurotransmitters affected are dopamine and noradrenaline, although serotonin is boosted to a lesser extent. These modes of action are outlined in Chapter 3, and the neurochemical rationale for drug tolerance is covered more fully in Chapter 10. The main differences between amphetamine and cocaine are their administration routes (summarised above) and the more rapid onset and shorter duration of action for cocaine. 

Caffeine increases extracellular serotonin levels in the hippocampus (Okada et al. 1999). Enhanced release of dopamine and norepinephrine occurs at higher doses (Morgan and Vestal 1989). An inhibition of monoamine reuptake occurs, but only in the millimolar range, which would not matter at normal oral doses (Reith et al. 1987). 

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