Quantification and pharmacological characterization of dialysate levels of noradrenaline in the striatum of freely-moving rats: release from adrenergic terminals and modulation by alpha2-autoreceptors

Information concerning striatal levels of noradrenaline (NA) remains inconsistent. Here we have addressed this issue using a sensitive method of HPLC coupled to amperometric detection. The NA reuptake-inhibitor, reboxetine, selectively elevated levels of NA versus dopamine (DA), and NA levels were also selectively elevated by the alpha2-adrenoceptor (AR) antagonist, atipamezole. The actions of atipamezole were mimicked by the preferential alpha2A-AR antagonist, BRL44408, while JO-1 and prazosin, preferential antagonists at alpha2C-ARs, caused less marked elevations in NA levels. In contrast to antagonists, the alpha2-AR agonist, S18616, decreased NA levels and likewise suppressed those of DA. Unilateral lesions of the substantia nigra with 6-hydroxydopamine depleted DA levels without affecting those of NA. Further, the D3/D2 receptor agonist, quinelorane, decreased levels of DA without modifying those of NA. However, the D3/D2 receptor antagonists, haloperidol and raclopride, and the DA reuptake-inhibitor, GBR12935, elevated levels of both DA and NA. Levels of 5-HT (but not of NA or DA) were increased only by the 5-HT reuptake-inhibitor, citalopram. They were decreased by S18616 and prazosin, reflecting the inhibitory and excitatory influence of alpha2- and alpha1-ARs, respectively, upon serotonergic pathways. In conclusion, NA in the striatum is derived from adrenergic terminals. Its release is subject to tonic, inhibitory control by alpha2-ARs, possibly involving both alpha2A- and alpha2C-AR subtypes, though their respective contribution requires clarification. A role of dopaminergic terminals in the reuptake of NA likely explains the elevation in its levels elicited by DA reuptake-inhibitors and D3/D2 receptor antagonists.     

Energy metabolism and memory processing: role of glucose transport and glycogen in responses to adrenoceptor activation in the chicken

From experiments using a discriminated bead task in young chicks, we have defined when and where adrenoceptors (ARs) are involved in memory modulation. All three ARs subtypes (α₁-, α₂- and β-ARs) are found in the chick brain and in regions associated with memory. Glucose and glycogen are important in the role of memory consolidation in the chick since increasing glucose levels improves memory consolidation while inhibiting glucose transporters (GLUTs) or glycogen breakdown inhibits memory consolidation. The selective β₃-AR agonist CL316243 enhances memory consolidation by a glucose-dependent mechanism and the administration of the non-metabolized glucose analogue 2-deoxyglucose reduces the ability of CL316243 to enhance memory. Agents that reduce glucose uptake by GLUTs and its incorporation into the glycolytic pathway also reduce the effectiveness of CL316243, but do not alter the dose–response relationship to the β₂-AR agonist zinterol. However, β₂-ARs do have a role in memory related to glycogen breakdown and inhibition of glycogenolysis reduces the ability of zinterol to enhance memory. Both β₂- and β₃-ARs are found on astrocytes from chick forebrain, and the actions of β₃-ARs on glucose uptake, and β₂-ARs on the breakdown of glycogen is consistent with an effect on astrocytic metabolism at the time of memory consolidation 30 min after training. We have shown that both β₂- and β₃-ARs can increase glucose uptake in chick astrocytes but do so by different mechanisms. This review will focus on the role of ARs on memory consolidation and specifically the role of energy metabolism on AR modulation of memory.     

Effects of chronic lesions of the anteroventral region of the third ventricle on cardiac β-adrenoceptor function in conscious rats

This study examined whether cardiac β-adrenoceptor (β-AR) function was altered in conscious rats with lesions surrounding the anteroventral third ventricle (AV3V). The findings were: (1) β_1,2-AR-mediated tachycardia was similar in sham and AV3V-lesion rats, (2) β₃- and/or atypical β-AR-mediated tachycardia elicited by isoproterenol (10 μg/kg, i.v.; ISO) was diminished in AV3V-lesion rats treated with β_1,2-AR antagonists, but was not in similarly-treated sham-lesion rats, and (3) the tachycardia elicited by the membrane permeable cAMP-analogue, 8-(4-chlorophenylthiol)-cAMP (10 μmol/kg, i.v.), was similar in AV3V- and sham-lesion rats. The possibility that increased plasma sodium/osmolality in AV3V-lesion rats down-regulated cardiac β₃- and/or atypical β-ARs, but not β_1,2-ARs or intracellular cAMP signaling is discussed.     

Adrenoreceptor-coupled signal-transduction mechanisms mediating lymphocyte apoptosis Induced by endogenous catecholamines

Our previous work has shown that lymphocytes synthesize catecholamines (CAs) and the endogenous CAs accelerate apoptosis of concanavalin A (Con A)-activated lymphocyte. Here, we explored the involvement of adrenoreceptors (ARs) and signal molecules coupled to the ARs in the endogenous CA-mediated modulation of lymphocyte apoptosis. Pargyline, an inhibitor of CA degradation, up-regulated the expression of cleaved caspase-3 protein and increased the number of apoptotic cells. Antagonists of α₁-ARs and β₂-ARs, not antagonists of α₂-ARs or β₁-ARs, blocked these effects of pargyline. The facilitating effects of pargyline on lymphocyte apoptosis were mimicked by activators of adenylate cyclase and PKC, but reversed by inhibitors of PKA, PLC and PKC. Pargyline-stimulated CREB activation and Smac/DIABLO expression were prevented by the inhibitors of PKA, PLC and PKC. These results imply that endogenous CA-induced lymphocyte apoptosis is mediated by cAMP-PKA- and PLC-PKC-linked CREB-Smac/DIABLO pathways coupled with α₁-ARs and β₂-ARs.     

β2-adrenoceptors are essential for desipramine, venlafaxine or reboxetine action in neuropathic pain

Neuropathic pain is a disease caused by a lesion or dysfunction of the nervous system. Antidepressants or anticonvulsants are presently the best available treatments. The mechanism by which antidepressants relieve neuropathic pain remains poorly understood. Using pharmacological and transgenic approaches in mice, we evaluated adrenergic receptor (AR) implication in the action of the tricyclic antidepressant desipramine, the noradrenaline and serotonin reuptake inhibitor venlafaxine, and the noradrenaline reuptake inhibitor reboxetine. Neuropathy was induced by cuff insertion around the sciatic nerve. We showed that chronic antidepressant treatment suppressed cuff-induced allodynia in wild-type mice but not in β₂-AR deficient mice, and/or that this antiallodynic action was blocked by intraperitoneal or intrathecal injection of the β₂-AR antagonist ICI 118,551 but not by the α₂-AR antagonist yohimbine. We also showed that the anticonvulsant gabapentin was still effective in β₂-AR deficient mice. Our results demonstrate that β₂-ARs are essential for the antiallodynic action of antidepressant drugs.     

The effects of intranigral GABA and dynorphin A injections on striatal dopamine and GABA release: Evidence that dopamine provides inhibitory regulation of striatal GABA neurons via D2 receptors

The effects of injections of γ-aminobutyric acid (GABA) and dynorphin A into the substantia nigra, pars reticulata on the levels of extracellular dopamine (DA) and GABA in the ipsilateral striatum of halothane-anaesthetized rats were studied using microdialysis. The effects of intranigral injections of substance P and neurokinin A were also studied. Intranigral GABA (300 nmol) or dynorphin A (0.5 nmol) injections produced a simultaneous decrease in DA and increase in GABA levels, while intranigral substance P (0.07 nmol) or neurokinin A (0.09 nmol) injections produced an increase in DA but had no effect on GABA levels. DA agnonists, apomorphine (D₁/D₂), SKF 38393 (D₁) and pergolide (D₂) were applied locally by perfusing them through the microdialysis probe, each at a concentration of 10⁻⁵ M. All 3 agonists decreased the levels of DA in the striatum. However, while apomorphine and SKF 38393 increased, pergolide decreased the levels of GABA in the striatum. The increase in striatal GABA produced by intranigral injections of GABA (300 nmol) was reversed by local perfusion with pergolide (10⁻⁵ M), but was not reversed by local perfusion with SKF 38393 (10⁻⁵ M). These findings suggest that D₁ and D₂ receptors differentially regulate striatal GABA release, and are stimulatory and inhibitory, respectively. Furthermore, it is suggested that nigrostriatal DA functions as an inhibitory modulator of striatal GABA neurons, acting via D₂ receptors.     

Catecholaminergic mediation of morphine-induced activation of pituitary-adrenocortical axis in the rat: implication of α- and β-adrenoceptors

The present study investigates the role of hypothalamic catecholamines in the effects of morphine on hypothalamo-pituitary-adrenocortical (HPA) axis. Acutely administered morphine (30 mg/kg i.p) increased plasma corticosterone and reduced the hypothalamic noradrenaline (NA) content but it did not change either the dopamine (DA) concentration or the ratio DOPAC/DA. After reserpine administration the hypothalamic contents of NA and DA were drastically reduced without changing plasma corticosterone concentrations. The increase in plasma corticosterone induced by morphine was significantly reduced by the pretreatment with reserpine. Theα₁-andα₂-antagonists prazosin and yohimbine, respectively, significantly antagonized the effect of morphine on plasma corticosterone. The β-antagonist propranolol also significantly attenuated the increase of corticosterone secretion induced by morphine. The results suggest that the action of the opiate on HPA axis activity may be dependent on stimulatory catecholaminergic systems which utilizeα₁-, α₂-andβ-adrenoceptors.     

Dopamine has inhibitory and accelerating effects on ischemia-induced neuronal cell damage in the rat striatum

Dopaminergic (DAergic) influence on ischemie neuronal cell damage in the dorsolateral striatum was studied. Intact and 6-hydroxydopamine (6-OHDA) lesioned rats, with and without pretreatment by D₁ and D₂ DA antagonists, were subjected to 20 min forebrain ischemia. Extracellular DA and glutamate (Glu) were measured using microdialysis technique. Histological examination was performed on the dorsolateral striatum and the hippocampal CA1 area 24 h after ischemia. DA increased 400–500 times the control level during ischemia among the groups except the 6-OHDA lesioned group. No significant changes were observed in the concentration of 3,4-dihydroxyphenylacetic acid (DOPAC), but a transient decrease was seen in homovanillic acid (HVA). Due to ischemia, Glu increased up to about 5 times the control level among the groups. Neuronal damage in the dorsolateral striatum was slightly attenuated by 6-OHDA lesion. Treatment by spiperone (D₂ antagonist, 7 μg/kg IP) alone attenuated the damage strongly. Treatment by SCH23390 (D₁ antagonist, 2.5 mg/kg IP) alone or both D₁ and D₂ antagonists had no effects. Data suggest that excessive Glu and DA are involved in neuronal cell damage. DA might enhance the damage via D₂ but inhibit via D₁ receptor.     

Noradrenaline and mixed α2-adrenoceptor/imidazoline-receptor ligands: effects on sodium intake

The effect of noradrenaline, and mixed ligands to α₂-adrenoceptors (α₂-AR) and imidazoline receptors (IR), injected intracerebroventricularly (i.c.v.), on sodium intake of sodium depleted rats, was tested against idazoxan, a mixed antagonist ligand to α₂-AR and IR. The inhibition of sodium intake induced by noradrenaline (80 nmol) was completely reversed by idazoxan (160 and 320 nmol) injected i.c.v. The inhibition of sodium intake induced by mixed ligands to α₂-AR and IR, UK14,304, guanabenz and moxonidine, was antagonized from 50 to 60% by idazoxan i.c.v. The results demonstrate that noradrenaline, a non-ligand for IR, acts on α₂-AR inhibiting sodium intake. The possibility that either α₂-AR or IR mediate the effect of mixed agonists on sodium intake remains an open question.     

Effect of repeated novel stressors on depressive behavior and brain norepinephrine receptor system in Sprague-Dawley and Wistar Kyoto (WKY) rats

This study compared the effects of repeated novel stressors on ‘depressive behaviors’, defined by the forced-swim and open-field tests, in Sprague-Dawley (S-D) and Wistar Kyoto (WKY) rats. Since stress appears to alter brain norepinephrine (NE) activity, this study also investigated the effects of the stressors on β-adrenoceptors (β-ARs),α₂-adrenoceptors (α₂-ARs) and NE transporter (NET) sites in S-D and WKY rats. Stress did not alter¹²⁵I-iodopindolol (¹²⁵I-PIN) binding to β-ARs, nor [³H]idazoxan ([³H]IDAZ) binding toα₂-ARs in S-D rats, compared to non-stressed controls. However, WKY-stressed rats showed a significant reduction in¹²⁵I-IPIN binding to β-ARs in the cortex, hippocampus, amygdala and hypothalamus, and a reduction in [³H]IDAZ binding toα₂-ARs in the amygdala. [³H]nisoxetine ([³H]NIS) binding to NET sites in WKY-stressed rats was also reduced in the cortex, hippocampus and amygdala. When both strains were compared, the most surprising finding was a significantly higher density of NET sites in the hippocampus and amygdala in WKY rats compared to S-D rats. The results of this study indicate that stress, not only exacerbates depressive behavior in WKY rats, but also selectively alters β-ARs,α₂-ARs and NET sites in limbic brain regions. Thus, the WKY strain may serve as a useful animal model for depressive behavior and for the investigation of novel antidepressant drugs.     

Regulation of Dopamine D1 and D2 Receptors on Striatal Acetylcholine Release in Rats

The effects of dopamine (DA) D₁ and D₂ receptors on striatal acetylcholine (ACh) releases were investigated by in vivo microdialysis. All drugs were applied via dialysis membrane directly to the striatum. The levels of ACh release were increased by 10⁻⁴ M SKF38393, a D₁ receptor agonist. Although 10⁻⁴ M SCH23390, a D₁ receptor antagonist, exhibited an increase in the levels of ACh release, the agonist (10⁻⁴ M) induced-increase in the levels of ACh release was suppressed by coperfusion of the antagonist (10⁻⁴ M). In contrast, the levels of ACh release were decreased by the D₂ receptor agonist, N-434, in a dose-dependent manner (10⁻⁵ M to 10⁻⁷ M) and increased by the D₂ receptor antagonist, sulpiride, in a dose-dependent manner (10⁻⁵ M to 10⁻⁷ M). The agonist (10⁻⁵ M) induced-decrease in the levels of ACh release was suppressed by coperfusion of the antagonist (10⁻⁶ M). Coperfusion of D₁ (10⁻⁴ M) and D₂ (10⁻⁵ M) agonists blocked both effects of respective drug alone. In order to clarify the effect of endogenous DA, two drugs with different mechanisms for enhancing DA concentration in the synaptic cleft, the DA release-inducer methamphetamine, and the DA uptake inhibitor nomifensine were perfused separately. Both (10⁻⁴ M to 10⁻⁶ M) produced a dose- and a time-dependent decrease in the levels of ACh release. Significant higher levels of ACh release were observed in the striatum of the 6-hydroxydopamine (8

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)-treated rats with significant depletion of striatal DA content. These results suggest that in striatal DA-ACh interaction ACh release, as cholinergic interneuron's activity, is tonically inhibited via the D₂ receptor, mainly by dopaminergic input, and the D₁ receptor probably modifies the effect of the D₂ receptor indirectly.     

Dopaminergic regulation of serotonin release in the substantia nigra of the freely moving rat using microdialysis

The functional regulation by dopamine (DA) receptors of serotonin (5-HT) release from the rat substantia nigra (SN) was investigated using in vivo microdialysis. A D₁- and D₂-receptor-mediated inhibition of nigral 5-HT release was demonstrated in this study. Continuous administration of the D₁-receptor agonist CY 208243 (10 μM) through the probe did not alter extracellular DA nor 5-HT from the SN, whereas intranigral administration of the D₁-receptor antagonist SCH-23390 HCl (10 μM) significantly increased both DA (to 214%) and 5-HT release (to 168%) from the SN. Co-perfusion of the D₁-receptor agonist and antagonist did not change nigral DA nor 5-HT release compared to perfusion of the antagonist alone. The continuous intranigral perfusion of the D₂-receptor agonist, (−)-quinpirole HCl (1 μM) significantly decreased both DA and 5-HT release to 71% and 78%, respectively. These decreases were abolished when the D₂-receptor antagonist S(−)-sulpiride (10 μM) and the D₂-receptor agonist (−)-quinpirole HCl (1 μM) were co-perfused. In contrast, the intranigral perfusion of the DA precursor, -DOPA (5 μM; 1 h), significantly increased nigral and striatal 5-HT release to 202% and 155%, respectively. This enhanced nigral 5-HT release might not be receptor-mediated. The results of the present study suggest a D₁ and D₂ regulation of nigral 5-HT release, either directly mediated by DA receptors on nigral 5-HT terminals or indirectly by nigral GABA, Glu or Asp. Alternatively, the observed DA–5HT-interaction in the SN might not reflect a local interaction but might involve an interaction at the level of the serotonin cell body region, the dorsal raphe nuclei (DRN).     

The role of dopamine in the maintenance and breakdown of D1/D2 synergism

The neurochemical factors involved in the maintenance and breakdown of dopamine D₁/D₂ receptor synergism were investigated by giving rats various pharmacological treatments that diminish the ability of dopamine to interact with its D₁ and/or D₂ receptors. Following these treatments, rats were observed for the expression of stereotyped motor behavior in response to independent stimulation of D₁ or D₂ receptors. Independent D₂-mediated responses were observed: (a) 2 h after the last of three daily reserpine (1 mg/kg) injections, (b) 48 h after bilateral 6-hydroxydopamine (6-OHDA) lesions of the mesostriatal pathways, (c) 24 h after a concentrated 48-h regimen (one injection/6 h) of eticlopride (0.5 mg/kg) or eticlopride + SCH 23390 (0.5 mg each), and (d) 2 h after a concentrated 48-h regimen (one injection/6 h) of α-methyl-p-tyrosine (αMPT; 100 mg/kg), but not after control treatments or a concentrated regimen of SCH 23390 alone. By contrast, independent D₁-mediated responses were observed only after three daily reserpine injections or 48 h after bilateral 6-OHDA lesions. Independent D₁-mediated stereotypy was not observed under control conditions or following a concentrated 48-h regimen of (a) SCH 23390 or eticlopride (0.5 mg/kg each) alone or in combination, (b) a high dose of SCH 23390 (1.0 mg/kg), (c) αMPT (100 mg/kg), or (d) αMPT (100 mg/kg)+SCH 23390 (1.0 mg/kg). Reserpine, bilateral 6-OHDA, and αMPT treatments produced striatal dopamine depletions of 96%, 92%, and 71%, respectively. These data indicate that the breakdown in D₁/D₂ synergism consists of two components: (a) D₁ independence from the controlling influence of D₂ receptors, and (b) D₂ independence from the controlling influence of D₁ receptors. The interaction of synaptic DA with its D₂ receptors plays a major role in determining whether these receptors can function independently of D₁ receptors, whereas reduced DA-D₁ activity alone appears insufficient to elicit D₁ independence.     

Chronic treatment with agonists of β2-adrenergic receptors in neuropathic pain

Expression of β₂-adrenoceptors (β₂-ARs) within the nociceptive system suggested their potential implication in nociception and pain. Recently, we demonstrated that these receptors are essential for neuropathic pain treatment by antidepressant drugs. The aim of the present study was to investigate whether the stimulation of β₂-ARs could in fact be adequate to alleviate neuropathic allodynia. Neuropathy was induced in mice by sciatic nerve cuffing. We demonstrate that chronic but not acute stimulation of β₂-ARs with agonists such as clenbuterol, formoterol, metaproterenol and procaterol suppressed neuropathic allodynia. By using a pharmacological approach with the β₂-AR antagonist ICI 118,551 or a transgenic approach with mice deficient for β₂-ARs, we confirmed that the antiallodynic effect of these agonists was specifically related to their action on β₂-ARs. We also showed that chronic treatment with the β₁-AR agonist xamoterol or with the β₃-AR agonist BRL 37344 had no effect on neuropathic allodynia. Chronic stimulation of β₂-ARs, but not β₁- or β₃-ARs, by specific agonists is thus able to alleviate neuropathic allodynia. This action of β₂-AR agonists might implicate the endogenous opioid system; indeed chronic clenbuterol effect can be acutely blocked by the delta-opioid receptor antagonist naltrindole. Present results show that β₂-ARs are not only essential for the antiallodynic action of antidepressant drugs on sustained neuropathic pain, but also that the stimulation of these receptors is sufficient to relieve neuropathic allodynia in a murine model. Our data suggest that β₂-AR agonists may potentially offer an alternative therapy to antidepressant drugs for the chronic treatment of neuropathic pain.     

Postnatal lead exposure induces supersensitivity to the stimulus properties of a D2-D3 agonist

To examine the impact of lead (Pb) exposure during the ontogeny of dopaminergic (DA) systems on resultant DA function, rats were exposed postnatally (0–21 days of age) via the lactating dam to 0, 100 or 350 ppm Pb acetate in drinking water. At 2 months of age, the postnatally Pb-exposed rats were trained to discriminate the stimulus properties of either the D₁ receptor agonist SKF38393 (6.0 mg/kg) or the D₂-D₃ receptor family subtype agonist quinpirole (0.05 mg/kg) from saline using a standard two-lever operant food-reinforced drug discrimination paradigm. In each training group, dose-effect curves describing drug lever responding to lower doses of the training drug and to preadministration of selective DA antagonists were obtained to examine Pb-induced changes in DA sensitivity. Doses of other DA agonists were substituted for the training drug to determine the generality of any changes in DA sensitivity, and doses of non-DA compounds were substituted to determine the specificity of any changes in DA sensitivity. In the D₁/saline training condition, Pb exposure was not associated with any specific or consistent changes in DA sensitivity. In contrast, exposure to Pb was associated with D₂-D₃ receptor subtype supersensitivity as was indicated by significantly elevated levels of drug lever responding in the presence of quinpirole and haloperidol and to at least one dose of apomorphine. No differences in the dose-effect curves for either (+)-amphetamine or NMDA were observed in the D₂-D₃-trained control and Pb-exposed groups, but an increase in drug lever responding in the presence of pentobarbital was noted in the Pb-exposed group relative to control. Taken together, these findings are consistent with a Pb-induced functional D₂-D₃ supersensitivity possibly mediated via autoreceptors. Moreover, this functional D₂-D₃ supersensitivity necessarily represents a permanent effect of postnatal Pb exposure since both blood and brain Pb levels were negligible at the time drug discrimination training began.     

Heightened Hippocampal β-Adrenergic Receptor Function Drives Synaptic Potentiation and Supports Learning and Memory in the TgF344-AD Rat Model during Prodromal Alzheimer's Disease

The central noradrenergic (NA) system is critical for the maintenance of attention, behavioral flexibility, spatial navigation, and learning and memory, those cognitive functions lost first in early Alzheimer''s disease (AD). In fact, the locus coeruleus (LC), the sole source of norepinephrine (NE) for >90% of the brain, is the first site of pathologic tau accumulation in human AD with axon loss throughout forebrain, including hippocampus. The dentate gyrus is heavily innervated by LC–NA axons, where released NE acts on β-adrenergic receptors (ARs) at excitatory synapses from entorhinal cortex to facilitate long-term synaptic plasticity and memory formation. These synapses experience dysfunction in early AD before cognitive impairment. In the TgF344-AD rat model of AD, degeneration of LC–NA axons in hippocampus recapitulates human AD, providing a preclinical model to investigate synaptic and behavioral consequences. Using immunohistochemistry, Western blot analysis, and brain slice electrophysiology in 6- to 9-month-old wild-type and TgF344-AD rats, we discovered that the loss of LC–NA axons coincides with the heightened β-AR function at medial perforant path–dentate granule cell synapses that is responsible for the increase in LTP magnitude at these synapses. Furthermore, novel object recognition is facilitated in TgF344-AD rats that requires β-ARs, and pharmacological blockade of β-ARs unmasks a deficit in extinction learning only in TgF344-AD rats, indicating a greater reliance on β-ARs in both behaviors. Thus, a compensatory increase in β-AR function during prodromal AD in TgF344-AD rats heightens synaptic plasticity and preserves some forms of learning and memory.SIGNIFICANCE STATEMENT The locus coeruleus (LC), a brain region located in the brainstem which is responsible for attention and arousal, is damaged first by Alzheimer''s disease (AD) pathology. The LC sends axons to hippocampus where released norepinephrine (NE) modulates synaptic function required for learning and memory. How degeneration of LC axons and loss of NE in hippocampus in early AD impacts synaptic function and learning and memory is not well understood despite the importance of LC in cognitive function. We used a transgenic AD rat model with LC axon degeneration mimicking human AD and found that heightened function of β-adrenergic receptors in the dentate gyrus increased synaptic plasticity and preserved learning and memory in early stages of the disease.     

Noradrenaline action on cat retinal ganglion cells is mediated by dopamine (D2) receptors

Effects of iontopheretically applied noradrenaline, dopamine and their receptor antagonists on the retinal ganglion cells, were studied in optically intact eyes of barbiturate-anaesthetized cats. Noradrenaline inhibited visually evoked and spontaneous firing of all classes of retinal ganglion cells: the effect being greater on ON-than on OFF-cells and slightly more potent than dopamine on a given cell. All α- and β-adrenoceptor blockers tested tended to change spikes but were generally ineffective in blocking the noradrenaline-induced inhibition, when not affecting spikes. The noradrenaline-induced inhibition was, however, effectively blocked by dopamine D₂-receptor antagonists. The α- and β-adrenoreceptor antagonists applied alone had no effect, suggesting the absence of endogenous noradrenergic antagonism, although α-type adrenergic antagonism was suggestive on a very small number of cells. These results suggest that: (1) noradrenaline action on cat retinal ganglion cells is mediated via dopamine D₂-receptors; (2) noradrenaline is not generally released on them, except there may be physiologically active α-receptors on a few cells; and (3) many of the adrenoreceptor blockers affect membrane properties of the retinal ganglion cells, in a similar manner to local anaesthetics.     

Infusion of quinpirole and muscimol into the ventral tegmental area inhibits fear-potentiated startle: implications for the role of dopamine in fear expression

Dopamine (DA) D₂ and γ-aminobutyric acid (GABA)_A somatodendritic receptors tonically inhibit mesolimbic projection neurons in the A10 DA cell grouping of the ventral tegmentum. In the present study we determined the contribution of the ventral tegmental area (VTA) to the expression of a classically conditioned fear-induced increase in the acoustic startle reflex. Saline applied to VTA neurons did not modify the capacity of a light previously associated with footshock to potentiate acoustic startle amplitudes; conversely, bilateral administration of the DA D_2/3 agonist quinpirole or the GABA_A receptor agonist muscimol into the ventral tegmentum blocked fear-potentiated startle without altering baseline acoustic startle responding. It was suggested that DA VTA neurons regulate the excitatory aspects of fear expression by gating levels of aversive emotional arousal within the amygdala-based fear system.     

Implication of dopamine D3 receptor activation in the reversion of Parkinson's disease-related motivational deficits

In addition to the classical motor symptoms, motivational and affective deficits are core impairments of Parkinson''s disease (PD). We recently demonstrated, by lesional approaches in rats, that degeneration of the substantia nigra pars compacta (SNc) dopaminergic (DA) neurons is likely to have a crucial role in the development of these neuropsychiatry symptoms. We have also shown that, as in clinical investigations, chronic treatment with levodopa or the DA D2/D3 receptor (D₂/D₃R) agonist ropinirole specifically reverses these PD-related motivational deficits. The roles of specific DA receptor subtypes in such reversal effects remain, however, unknown. We therefore investigated here the precise involvement of D₁, D₂ and D₃R in the reversal of the motivational and affective deficits related to SNc DA neuronal loss. Three weeks after bilateral and partial 6-hydroxydopamine (6-OHDA) SNc lesions, rats received 14 daily intraperitoneal administrations of the selective D1R agonist SKF-38393 (2.5 or 3.5 mg kg⁻¹), the selective D2R agonist sumanirole (0.1 or 0.15 mg kg⁻¹), or the preferring D3R gonist PD-128907 (0.1 or 0.15 mg kg⁻¹). Anxiety-, depressive-like and motivated behaviors were assessed in an elevated-plus maze, a forced-swim test, and an operant sucrose self-administration procedure, respectively. All DA agonists attenuated anxiety- and depressive-like behaviors. However, only PD-128907 reversed the motivational deficits induced by 6-OHDA SNc lesions. This effect was blocked by a selective D₃R (SB-277011A, 10 mg kg⁻¹), but not D₂R (L-741,626, 1.5 mg kg⁻¹), antagonist. These data provide strong evidence for the role of D3R in motivational processes and identify this receptor as a potentially valuable target for the treatment of PD-related neuropsychiatric symptoms.     

Rat brain hypothalamic and hippocampal monoamine and hippocampal β-adrenergic receptor changes during pregnancy

The concentration of noradrenaline (NA), dopamine (DA), serotonin (5-HT), and their metabolites was measured in hypothalamic and hippocampal brain tissue obtained from non-pregnant, 15- or 20-day pregnant and 4-day postpartum rats. At 20 days of pregnancy, hypothalamic NA and DA concentrations were significantly decreased and their turnover increased relative to postpartum and estrous values, respectively. Hippocampal 3-methoxy-4-hydroxy-phenylglycol (MHPG) levels were significantly decreased at 15 days of pregnancy and 4 days postpartum compared to estrous and 20-day pregnant levels and the MHPG/NA ratio was significantly reduced at 4 days postpartum relative to the estrous value. Hippocampal 5-HT and 5-hydroxyindole-3-acetic acid (5-HIAA) levels were significantly decreased at 15 days of pregnancy while 5-HIAA levels and the 5-HIAA/5-HT ratio were significantly decreased at 20 days of pregnancy. Hippocampal β-adrenergic receptor density was significantly lower at 4 days postpartum than at 15 days of pregnancy. A positive correlation was observed between plasma progesterone and hippocampal β-adrenoceptorK_d values, suggesting a possible causal relationship between these two variables. The monoamine and β-adrenoceptor changes which occur during pregnancy may be an important contributing factor in determining the mood changes which occur during pregnancy and postpartum.