Presynaptic autoreceptor regulation

At low doses, both psychostimulants could theoretically stimulate tonic, extracellular levels of monoamines, and the small increase in steady state levels would produce feedback inhibition of further release by stimulating presynaptic autoreceptors. While this mechanism is clearly an important one for the normal regulation of monoamine neurotransmission, there is no direct evidence to support the notion that the doses used clinically to treat ADHD are low enough to have primarily presynaptic effects. However, alterations in phasic dopamine release could produce net reductions in dopamine release under putatively altered tonic dopaminergic conditions that might occur in ADHD and that might explain the beneficial effects of methylphenidate in ADHD. 

FIGURE 6-35. Mechanism of action of serotonin selective reuptake inhibitors (SSRIs)—part 1. Depicted here is a serotonin neuron in a depressed patient. In depression, the serotonin neuron is conceptualized as having a relative deficiency of the neurotransmitter serotonin. Also, the number of serotonin receptors is up-regulated, or increased, including presynaptic autoreceptors as well as postsynaptic receptors. 

On the other hand, it has been suggested that the primary problem in depression is an increased sensitivity to receptors that are located on the presynaptic terminals of amine synapses.54 These presynaptic autoreceptors normally regulate and limit the release of amine transmitters, such as norepinephrine or serotonin, from the presynaptic terminal. Increasing their sensitivity could result in a relative lack of adequate neurotransmitter release at these synapses. By causing overstimulation of these presynaptic receptors, antidepressant drugs could eventually normalize their sensitivity and help reestablish proper control and regulation of these amine synapses.54... 

Dopamine induces biochemical and physiological effects in the mammalian neostriatum. The occurrence of a D-l dopamine receptor (in the classification scheme of Kebabian and Caine) accounts for the ability of dopamine to enhance cyclic AMP formation. The occurrence of a D-2 dopamine receptor accounts for the ability of dopamine to inhibit cyclic AMP formation brought about by stimulation of a D-l dopamine receptor. Dopamine receptors mediate the regulation of (1) the release or turnover of acetylcholine (postsynaptic dopamine receptor) and (2) the release or turnover of dopar mine (presynaptic autoreceptor). Both receptors can be classified as D-2 dopamine receptors. Indications for the occurrence of dopamine receptors affecting the release or turnover of GABA, glutamate, serotonin and several neuropeptides are evaluated. 

Evidence exists that DATs are regulated by multple cell surface receptors. D2 receptor (D2R) antagonists decrease DA transport in vivo and in vitro, but not in all cell types (67-69). Recently, Mayfield Zahniser showed that D2R activation increases DAT expression on the cell surface in Xenopus oocytes, indicating that the presynaptic autoreceptor can play a significant role in DAT regulation. Muscarinic agonists also cause an increase in extracellular DA, which could be due to a reduction in DAT activity (70), and a 2-receptors may regulate DAT activity via a PKC dependent pathway (71). 

Histamine immunoreactive neurons have been identified in the tuberal region of the posterior hypothalamus (tuberomammilary nucleus), projecting to nearly all parts of the brain. Three histamine receptors are known histamine-related functions in the central nervous system (CNS) are regulated at postsynaptic sites by the H and H2 receptors, while the H3 receptor exhibits the features of a presynaptic autoreceptor, mediating the synthesis and release of histamine. The Hi receptor is widely distributed in the CNS. It is present in all areas and layers of the cerebral cortex, limbic system, caudate putamen, nucleus accumbens, thalamus, hypothalamus, mesencephalon, and lower brainstem and spinal cord. The H2 and H3 receptors are also distributed extensively and in a heterogeneous fashion in the CNS. Regarding the role of histamine in the CNS, there is substantial evidence that it plays a role in control of the sleep/wake cycle. Whether the... 

Evidence suggests that co-transmitters in a terminal have their own autoreceptors and, in some cases, activation of their own presynaptic receptor can influence the release of the co-stored, classical transmitter. For instance, activation of P2Y-autoreceptors by ATP is thought to affect the release of noradrenaline from sympathetic neurons. However, in other cases, feedback modulation of release of classical and their associated co-transmitters seems to have separate control mechanisms. This would suggest that either the two types of transmitter are concentrated in different nerve terminals or that mechanisms for regulating release target different vesicles located in different zones of the terminal (Burnstock 1990). 

Starke, K (1987) Presynaptic a-autoreceptors. Rev. Physiol. Biochem. Pharmacol. 107 73-146. Zhong, H and Minneman, KP (1999) i-Adrenoceptor subtypes Eur. J. Pharmacol. 375 261-276. Zigmond, RE, Schwarzschild, MA and Rittenhouse, AR (1989) Acute regulation of tyrosine hydroxylase by nerve activity and by neurotransmitters via phosphorylation. Ann. Rev. Neurosci. 12 451-461. 

ACh regulates the cortical arousal characteristic of both REM sleep and wakefulness (Semba, 1991, 2000 Sarter Bruno, 1997, 2000). Medial regions of the pontine reticular formation (Figs. 5.2 and 5.7) contribute to regulating both the state of REM sleep and the trait of EEG activation. Within the medial pontine reticular formation, presynaptic cholinergic terminals (Fig. 5.1) that release ACh also are endowed with muscarinic cholinergic receptors (Roth et al, 1996). Autoreceptors are defined as presynaptic receptors that bind the neurotransmitter that is released from the presynaptic terminal (Kalsner, 1990). Autoreceptors provide feedback modulation of transmitter release. Autoreceptor activation... 

Presynaptic receptor A receptor, either an autoreceptor or heteroreceptor, located on the presynaptic neuronal membrane which regulates the release of the neurotransmitter. 

Presynaptic dopaminergic receptors are typically of the D2 type and found on most portions of the dopaminergic neuron (as autoreceptors). They regulate DA... 

Some authors (Flament et ah, 1987) found that response to treatment with clomipramine was correlated with a marked decrease in platelet serotonin concentration and monoamine oxidase (MAO) activity. Changes in cerebrospinal fluid (CSF) neuropeptides and monoamine metabolites have also been described with chronic clomipramine administration (Swedo et ah, 1992 Altemus et ah, 1994). Despite these observations, the exact mechanism of action of serotonergic drugs (and the serotonin hypothesis ) remains unproven, although it is thought they mediate their effects via down-regulation of the presynaptic 5-HTlD autoreceptor (Rauch et ah, 1994). 

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