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From Motivation to Action: A Review of Dopaminergic Regulation of Limbic → Nucleus Accumbens → Ventral Pallidum → Pedunculopontine Nucleus Circuitries Involved in Limbic-Motor Integration
Published in Peter W. Kalivas, Charles D. Barnes, Limbic Motor Circuits and Neuropsychiatry, 2019
Gordon J. Mogenson, Stefan M. Brudzynski, Michael Wu, Charles R. Yang, Conrad C.Y. Yim
Injection of the D2 receptor agonist into the accumbens can attenuate the increase in locomotor activity elicited by NMDA stimulation of the hippocampal output to the accumbens. NMDA can activate glutamatergic hippocampal-accumbens neurons to release DA in the accumbens. In turn, D2 agonists activate D2 type autoreceptors on the dopaminergic terminals to reduce DA release. In our recent behavioral studies, injecting the D2 agonist, quinpirole, into the accumbens was shown to reduce amphetamine-induced, as well as hippocampus-mediated exploratory locomotion (Figure 4). Increased locomotor activity associated with exploration in a partitioned open-field might result from an activation of the glutamatergic hippocampal-accumbens pathway, which subsequently released DA in the accumbens and triggered locomotion. Quinpirole might act presynaptically on dopaminergic terminal autoreceptors to inhibit the release of DA,67,68 in addition to its presynaptic inhibitory effects on the hippocampal-accumbens glutamatergic terminals, as mentioned above.
Prejunctional Dopamine Receptor Stimulants
Published in M.D. Francesco Amenta, Peripheral Dopamine Pathophysiology, 2019
Numerous findings support the thesis that quinpirole is not only a very potent, but also a very selective DA2 receptor agonist. Low concentrations inhibit electrically evoked release of [3H]dopamine from rabbit retinae,16 and [3H]noradrenaline release from cat atrial slices, the compound acting in the latter as a full agonist.193 It depresses prolactin secretion from the isolated anterior pituitary gland194 and a-MSH release from the intermediate lobe.195 The IC50 values calculated in each of these models lie between 10 and 40 μM. By contrast, concentrations of 50 to 100 μM are devoid of stimulant activity on adenylate cyclase in carp retinae and rat striatal tissue.187,195 Experiments in vivo corroborate this selectivity. Neuronally mediated pressor and vasoconstrictor responses to electrical stimulation are depressed,186,190,196 as are contractile responses of the nictitating membrane197 and the tachycardia evoked by ganglionic or postganglionic stimulation of the cardiac sympathetic nerve,22,197,198 in the absence of detectable blockade of a- or β-adrenoceptors. Confirmation that the effect of quinpirole in each study results from selective stimulation of prejunctional DA2 receptors (vs. α2-adrenoceptors) was obtained using appropriate antagonists. Selectively for the DA2 (vs. DA1) receptor is exemplified by a study in the isolated perfused rat kidney, in which concentration-dependent reductions in evoked [3H]-noradrenaline release elicited during periarterial nerve stimulation occurred from a concentration of 10−8M, whereas renal perfusion pressure (elevated with vasopressor agents) was not significantly reduced up to a concentration of 5 x 10−7M.199 Likewise, in pithed rats in which blood pressure is restored to normotensive levels with a noradrenaline or vasopressin infusion, blood pressure does not fall in response to quinpirole at doses up to 150 times the threshold for inducing hypotension in the same species.186,190,191
Non-adrenergic Non-cholinergic Autonomic Transmission
Published in Kenneth J. Broadley, Autonomic Pharmacology, 2017
Subsequently, additional subtypes of dopamine receptor have been identified in the brain, and molecular biological approaches have resulted in the cloning of several D1 receptor subtypes (D1A, D1B and D5) which are known as D1-like and all coupled to the stimulation of adenylyl cyclase. The D2 receptor has two isoforms synthesized by alternative splicing. A shorter form composed of 415 amino acids is termed the D2 short receptor. The long form (D2 long receptor) is composed of 444 amino acids with a 29-amino acid insert in the third intracellular loop of the seven membrane spanning helical arrangement of the receptor (Chapter 13). Both receptors are coupled to the inhibition of adenylyl cyclase and display identical pharmacological profiles, but are expressed differently among brain areas. The extra 29 amino acids are not in ligand binding regions of the receptor. The D5 receptor may be distinguished from the D1 receptor by the 10-fold higher binding affinity of dopamine itself for this cloned receptor. D3 and D4 receptors have also been identified which are closely related to the D2 receptor and the three receptors are referred to as D2-like. D3 and D4 receptors, however, can be distinguished since they do not appear to be consistently linked to adenylyl cyclase. Furthermore, clozapine (ClozarilR) (Figure 12.5), the recently introduced antipsychotic drug for schizophrenia patients resistant to other conventional drugs, is a selective antagonist for D4 receptors, although it also has a-adrenoceptor, 5-HT and histamine receptor blocking properties. Quinpirole is a selective D3/D4 agonist. Of the cloned receptors, the mRNA of the D3 receptor has been reported to occur in the kidney. D1 and D2 receptors have been identified in the kidney by radioligand binding to tissue homogenates and by autoradiography. The D1 receptors are located in the proximal tubules of the nephron and in the renal vasculature (Jose et al. 1992, Sokoloff & Schwartz 1995).
Real world considerations for newly approved CGRP receptor antagonists in migraine care
Published in Expert Review of Neurotherapeutics, 2022
Damiana Scuteri, Paolo Tonin, Pierluigi Nicotera, Giacinto Bagetta, Maria Tiziana Corasaniti
Therefore, as it occurs in chronic pain, brainstem nuclei alteration can both facilitate trigeminovascular pain transmission and derange descending spinal and medullary dorsal horn migraine pain inhibition [25]. In susceptible populations the altered brainstem excitability may respond to an innocuos input, e.g. exposure to ambient light [23], with exacerbated migraine pain as rostroventromedial medulla activation can facilitate non nociceptive stimuli [25]. Incidentally, descending A11 dopaminergic projections with D2 receptors involvement can influence the transmission of nociceptive inputs from the trigeminal afferents, as demonstrated by the facilitation of trigeminal neuronal firing evoked by nociceptive stimuli occurring after lesion of the A11 nucleus inhibited by the selective D2-like receptor agonist quinpirole [26]. In particular, quinpirole and naratriptan in combination can lower the firing under the baseline registered before the lesion, demonstrating the need for both correct serotonergic and dopaminergic trigeminal neurotransmissions for the treatment of sensitization [26].(Figure 3).
Reduced phasic dopamine release and slowed dopamine uptake occur in the nucleus accumbens after a diet high in saturated but not unsaturated fat
Published in Nutritional Neuroscience, 2022
Cherie N. Barnes, Conner W. Wallace, Brielle S. Jacobowitz, Steve C. Fordahl
Next, we evoked phasic dopamine release with 5-pulse stimulation trains from 5 to 100 Hz, and 2-way ANOVA revealed main effects of diet (F(1,70) = 6.556; p = 0.0126) and stimulation frequency (F(4,70) = 23.23; p < 0.0001) between the Control and SF groups (Figure 5A). Phasic dopamine release across frequencies was not different between the Control, Flax, or Blend diets (Figure 5A). The average AUC of compiled line traces corresponding with dopamine release after 5-pulses at 20 Hz (the physiological burst firing rate of dopamine neurons) was significantly greater than one-pulse for each diet group (p < 0.001) (Figure 5B), and the 5-pulse 20 Hz AUC was only significantly different between the Control and SF groups (p < 0.05). Notably, the difference between 5-pulse to one-pulse AUC shows the SF group had the smallest dynamic range of tonic (1-pulse) to phasic (5-pulse) dopamine release. We then examined D2 auto-receptor function to determine if reduced phasic release in the SF group was associated with increased D2 auto-receptor inhibition of dopamine release. There was a main effect of quinpirole dose on dopamine release (F(2.719,35.34) = 177.8; p < 0.0001), as expected with a D2 agonist, but no differences in quinpirole’s ability to reduce dopamine release was detected between groups (Figure 5C), suggesting reduced dynamic range of 1:5 pulse release in the SF group is not driven by heightened sensitivity of D2 auto-receptors.
Involvement of D2 receptor in the NAc in chronic unpredictable stress-induced depression-like behaviors
Published in Stress, 2020
Hui Qiao, Sha Yang, Chang Xu, Xin-Ming Ma, Shu-Cheng An
Considering that, to date there have been no reports on the interaction of D2R and kalirin7, we designed experiment II to further confirm the relationship among D2R, kalirin-7 and spine plasticity in the NAc. We pretreated mice with quinpirole or eticlopride (via an intraperitoneal injection) and evaluate the expression of kalirin-7 and spine density in the NAc. Quinpirole decreased both the expression of kalirin-7 and spine density, while by contrast, eticlopride treatment increased their levels (Figure 3). There was a significant difference between quinpirole and eticlopride treatment. A previous study found that PPHT (a D2R agonist, i.p.) reduce the spine density in mPFC (Castillo-Gomez, Varea, Blasco-Ibanez, Crespo, & Nacher, 2016).We confirmed that D2R regulates the expression of kalirin-7 and is involved in the modulation of spine plasticity. The D2R-kalirin-7 pathway may play a role in the effect of D2R on depression-like behaviors induced by CUS. However, (1) we did not repeat the stress procedure of experiment I on mice, so we are cautious with this conclusion considering the species and age-specific differences (Burstein & Doron, 2018; Geng et al., 2019). (2) we do not know if there is an interaction between D1 receptor and kalirin-7, so the mechanism could be much complicated than expected.