Dopamine directly activates a ligand-gated channel in snail neurones

Synaptically released dopamine is known to evoke fast as well as slow synaptic potentials in neurones of gastropod molluscs. Here evidence is presented that the fast excitatory response to dopamine is mediated by the direct activation of a ligand-gated channel unitary currents were observed in outside-out patches of neurones exposed to dopamine, and the response persisted in the presence of intracellular guanosine 5-o-(2-thiobiphosphate), GDP[-S], a condition known to block G-protein-coupled responses to dopamine and other agents. In whole-cell recordings, the fast response desensitized very rapidly; it was less desensitized in outside-out patches, suggesting dependence of desensitization on an intracellular factor. The response to dopamine was blocked by D-tubocurarine and strychnine (both probably by channel blockade), by apomorphine, chlorpromazine and relatively high doses of (±)-sulpiride and spiperone. The channel conducts predominantly monovalent cations. Unexpectedly, the fast response to dopamine was also observed in an identified dopaminergic neurone when maintained in isolation in culture. The receptors on the dopaminergic neurone were unevenly distributed, being more abundant on the axon-hillock, axon and neurite terminals.     

Indirect effects of apomorphine on serotoninergic neurons in rats

We have studied the effects of apomorphine on central serotoninergic system by using fluorescence histochemistry and high performance liquid chromatography coupled with electrochemical detection. Apomorphine has been shown selectively to elevate intracellular serotonin fluorescence in dorsal raphe neurons and serotonin and/or 5-hydroxyindoleacetic acid concentrations in the major terminal area of the dorsal raphe, the striatum. Apomorphine has no effect on serotonin neurons in the median raphe or its corresponding projection site, the hippocampus. In the present study, intraventricular 6-hydroxydopamine, when administered together with desimipramine and pargyline, antagonized the apomorphine-induced elevations of serotonin fluorescence in the dorsal raphe and serotonin and 5-hydroxyindoleacetic acid levels in the striatum. This antagonism was found when 6-hydroxydopamine was given either 3 or 10 days before 3 mg/kg apomorphine. Apomorphine also elevated extraperikaryal serotonin fluorescence and catecholamine fluorescence in the dorsal raphe selectively and these effects were also blocked by 6-hydroxydopamine. Additionally, 6-hydroxydopamine accelerated striatal serotonin turnover when it was given 10 days prior to death. This phenomenon probably reflects some compensatory change of mesostriatal serotonin neurons in response to the prolonged depletion of brain dopamine. The above results suggest that the observed effects of apomorphine on the serotoninergic system are mediated indirectly through dopaminergic neurons and that postsynaptic dopamine receptors are probably not responsible for apomorphine's effects.     

Release of taurine, GABA and dopamine from rat striatal slices: mutual interactions and developmental aspects

The spontaneous and potassium-stimulated release of preloaded taurine and GABA from striatal slices of adult and 7-day-old rats were studied using a superfusion system. Particular attention was paid to mutual interactions of taurine and GABA with dopamine in the release processes. Potassium stimulation (50 mM) enhanced taurine release more in the immature than in the adult striatum, whereas the response was the opposite with GABA release. Spontaneous taurine efflux was increased by dopamine and apomorphine, whereas stimulated release was suppressed by these agents in both age groups. This dopamine effect was partially antagonized by haloperidol, suggesting that dopaminergic systems were able to modify taurine release, possibly via dopaminergic receptors. Dopamine and apomorphine had similar but more inconsistent effects on striatal GABA release, which were not, however, mediated through conventional dopamine receptors. Stimulation with 25 mM K+ caused an 11-fold increase in striatal dopamine release: this effect was potentiated by taurine, while the actions of GABA on dopamine release were variable.     

Anti-opioid effects of neuropeptide FF receptors in the ventral tegmental area

The present study investigates the modulatory effects of neuropeptide FF (NPFF) receptors on the mesolimbic dopaminergic pathway controlled by opioid receptors. A stable NPFF₂ receptor agonist, dNPA, was injected into the ventral tegmental area (VTA) and the release of dopamine and serotonin within the nucleus accumbens (NAc), induced by intraperitoneal injection of morphine, was monitored using the brain microdialysis, in non-constrained rat. dNPA decreased systemic morphine-induced elevation of dopamine and serotonin metabolites within the NAc. Furthermore, co-injected with morphine into the VTA, NPFF inhibited morphine-induced stereotypy 60–120 min after the injection. This neurochemical and behavioural anti-opioid effect mediated by NPFF₂ receptors at the level of VTA suggests the involvement of NPFF in the rewarding effects of opiates on the mesolimbic dopamine system.     

Priming of rotational behavior by a dopamine receptor agonist in hemiparkinsonian rats: Movement-dependent induction

Repetitive stimulation of dopamine receptors located in the basal ganglia may lead to the manifestation of sensitized, abnormal, motor responses in dopamine-denervated rats. In order to study the role of motor behavior execution on the expression of these altered motor responses, we evaluated how “priming”, a phenomenon displaying neurochemical and behavioral features peculiar to a sensitized abnormal motor response in dopamine-denervated rats, depends on actual movement performance. To this end, unilaterally 6-hydroxydopamine-lesioned rats received apomorphine (0.2 mg/kg s.c.), being either allowed to move or immobilized (1 h) before, concomitantly to, or after its administration, respectively. Three days after apomorphine, the dopamine D₁ receptor agonist 1-Phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol (SKF 38393, 3 mg/kg s.c.) was administered to all animals. Rats that had performed rotational behavior following apomorphine administration displayed robust contraversive rotational behavior in response to SKF 38393, whereas rats that had been immobilized concomitantly to, but neither before nor after apomorphine, did not. To clarify whether stress, which may be increased by immobilization, mediated the results observed, additional rats received apomorphine paired with immobilization plus the corticosterone-synthesis inhibitor metyrapone (100 mg/kg i.p.), or apomorphine paired with a tail stressor, being not immobilized. Metyrapone did not affect the capacity of immobilization to prevent priming and tail stressor imposition did not affect priming magnitude, suggesting that stress has minimal or no effect on the results observed. This study demonstrates how movement performance following initial dopaminergic stimulation governs the occurrence of a sensitized, abnormal, motor response to a subsequent dopaminergic challenge in dopamine-denervated rats.     

Characterization of the prostanoid receptors and of the contractile effects of prostaglandin F2a in human pial arteries

The contractile and relaxant effects of various prostanoids were studied on isolated human pial arteries. Contractions were elicited with the following order of potency: U46619?U44069>PGB₂>PGF_2a>PGE₂?PGD₂>PGF_1a≥TXB₂, indicating that prostanoid-induced contractions probably are mediated by a thromboxane-sensitive receptor. Relaxation of PGF_2a-contracted arteries was induced with the order of potency: PGE₂> PGE₁>PGD₂?PGD₁. Vessels contrated by K⁺ were relaxed only by PGE,. Since PGI₂ was previously found to be more potent than all the prostanoids tested in the present study, relaxant responses are probably mediated via a PGI₂-sensitive receptor. The roles of free extracellular and cellularly bound calcium for the contractile effects of PGF_2a and K⁺ were estimated by incubating the arteries for various times in calcium-free medium containing 10^-5 M EGTA. Incubation for 5–10 min abolished K⁺-induced contractions, whereas after 40 min of incubation PGF_2a still induced contractions that reached 70% of control. The PGF_2a-induced contraction was biphasic in 8 out of 10 preparations. The second phase could be eliminated by increasing the EGTA-concentration to 10^-4 M, as well as by nifedipine pretreatment. In calcium-free, high K⁺ medium calcium-induced contractions were elicited at lower concentrations in the presence of PGF_2a. The results suggest that PGF_2a-induced contractions in human pial arteries are relatively independent of free extracellular calcium. PGF_2a may promote trans-membrane influx of calcium, as well as release calcium from seemingly superficially located cellular stores.     

Further characterization of tolerance to the corticosterone-elevating effect of pergolide in rats

Four daily injections of pergolide, an ergoline dopamine agonist, made male rats tolerant to the corticosterone-elevating effects of an acute injection of pergolide on the fifth day. This tolerance occurred not only to acute treatment with pergolide, but also to other dopamine agonists differing in structure, potency and receptor subtype selectivity. Plasma corticosterone was elevated following administration of opioid or serotonin agonists in both vehicle- and pergolide-pretreated rats. The current findings strengthen the conclusion that tolerance to the acute elevation of corticosterone by pergolide is not due to impairment of pituitary-adrenocortical function but instead to changes in dopamine receptors that initiate the response.     

Prevention of immunosuppression in stressed mice by altering the activity of neurotransmitter systems

The spleens of CBA mice stressed by being immobilized for 3 h in the supine position and then immunized with sheep erythrocytes showed evidence of immunosuppression manifested in reduced numbers of plaque-forming cells on day 4 and of rosette-forming cells on day 5 after the stress and immunization. The depletion of serotonin stores in the brain caused by p-chlorophenylalanine administered 48 h before stressing the animals abolished immunosuppression under the action of immobilization stress, and a similar effect resulted from the activation of postsynaptic dopamine receptors D₁ and D₂ by apomorphine injected at 30 min before stress. The prevention of immunosuppression observed to occur when the balance between the serotoninergic and dopaminergic systems was shifted so that the latter system became predominant, suggests that the stress reduces immune reactivity by altering the brain's neurochemical pattern and interfering with the mechanisms of neuroimmunomodulation. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 122, No. 7, pp. 22–24, July, 1996     

Effects of intrasubthalamic injection of dopamine receptor agonists on subthalamic neurons in normal and 6-hydroxydopamine-lesioned rats: an electrophysiological and c-Fos study.

Subthalamic neuronal activity is controlled by a dopaminergic innervation, which may act via D1 and D2 dopamine receptors. This study investigates the effect of apomorphine and the selective D1 and D2 agonists, SKF 82958 and quinpirole respectively, in normal and 6-hydroxydopamine-lesioned rats. The effect of microinjection of these drugs into the subthalamic nucleus was assessed by recording unit activity and the expression of the c-Fos-immunoreactive protein in the subthalamic nucleus. Dopaminergic agonists reduced the discharge rate and did not induce c-Fos expression in the normal rat. Apomorphine and quinpirole increased the discharge rate and induced a strong expression of c-Fos-like immunoreactive proteins, whereas SKF 82958 induced a decrease of the discharge rate and a slight expression of c-Fos in 6-hydroxydopamine-lesioned rats. The striking contrast in the changes obtained with apomorphine and quinpirole in normal and 6-hydroxydopamine-lesioned rats is discussed in relation to a hyperexpression of D2 dopaminergic receptors on the GABAergic terminals into the subthalamic nucleus. These results show that, in normal rats, dopamine agonists exert an inhibitory control on subthalamic neurons via D1 and D2 receptors. However, in 6-hydroxydopamine-lesioned rats, the hyperactivity of subthalamic neurons is also reduced by D1 receptor agonist but not by D2 dopamine agonists. This last result points out one aspect of the complex mechanisms underlying the physiopathology of Parkinson's disease.     

Reversal of quinpirole inhibition of ventral tegmental area neurons is linked to the phosphatidylinositol system and is induced by agonists linked to G(q)

Putative dopaminergic (pDAergic) ventral tegmental area neurons play an important role in brain pathways related to addiction. Extended exposure of pDAergic neurons to moderate concentrations of dopamine (DA) results in a time-dependent decrease in sensitivity of pDAergic neurons to DA inhibition, a process called dopamine inhibition reversal (DIR). We have shown that DIR is mediated by phospholipase C and conventional protein kinase C through concurrent stimulation of D2 and D1-like receptors. In the present study, we further characterized this phenomenon by using extracellular recordings in brain slices to examine whether DIR is linked to phosphatidylinositol (PI) or adenylate cyclase (AC) second-messenger pathways. A D1-like dopaminergic agonist associated with PI turnover (SKF83959), but not one linked to AC (SKF83822), promoted reversal of inhibition produced by quinpirole, a dopamine D2-selective agonist. Other neurotransmitter receptors linked to PI turnover include serotonin 5-HT(2), α(1)-adrenergic, neurotensin, and group I metabotropic glutamate (mGlu) receptors. Both serotonin and neurotensin produced significant reversal of quinpirole inhibition, but agonists of α(1)-adrenergic and group I mGlu receptors failed to significantly reverse quinpirole inhibition. These results indicate that some agonists that stimulate PI turnover can facilitate desensitization of D2 receptors but that there may be other factors in addition to PI that control that interaction.     

Effects of amantadine on modification of dopamine dependent behaviours by molindone

Amantadine, a dopamine agonist is reported to act by releasing dopamine from the dopaminergic nerve terminals as an anti-Parkinsonian drug. In the present behavioural study in the rat, molindone-induced catalepsy and ptosis, which are dopamine dependent-behaviors are reversed by amantadine. Amantadine has also revered molindone-induced inhibition of traction response in mice. Our study indicates that amantadine, like other DA agonists, e.g. amphetamine and apomorphine can antagonize or even reverse the neuroleptic induced dopaminergic behaviors.     

Separation of drinking and pressor responses to central angiotensin by monoamines

This study investigated the neurotransmitters involved in the increase in blood pressure and drinking produced when angiotension II is injected intraventricularly (ivt). Using pharmacologic manipulations of the monoamines norepinephrine, dopamine, and serotonin it has been possible to separate the pressor response from dipsogenic responses to angiotension II. Alpha-adrenergic blockade with phentolamine restricted to the brain blocked the pressor response to angiotensin II in a dose-related manner, while drinking remained unaffected. Norepinephrine alone, injected into the ventricles elevated blood pressure, but did not produce drinking. The norepinephrine effect was also blocked by phentolamine by the same ventricular route. Other monoamines were not involved. Dopamine alone did not produce thirst. Cardiovascular effects with dopamine were observed only with large doses. The dopaminergic agonist apomorphine produced no change in blood pressure or drinking. Reduction of central serotonin stores by p-chlorophenylalanine intraperitoneally or 5,7-dihydroxytryptamine intraventricularly had no effect on the pressor or dipsogenic effects of angiotensin II. The serotonin agonist N,N-dimethyl-5-methoxytryptamine ivt did not produce a rise in blood pressure or drinking. It is concluded that the pressor effect of angiotensin II, but not the drinking effect is mediated by noradrenergic stimulation of alpha-receptors. The drinking response does not appear to be mediated by the monoamines.     

The serotonin (5-HT)1A agonist, LY 165,163, induces contralateral rotation in unilateral substantia nigra-lesioned rats via dopamine receptors

The serotonin (5-HT)_1A agonist, LY 165,163 (1-[2-(4-aminophenyl)ethyl]-4-(3-trifluoromethylphenyl)-piperazine), also known as PAPP, has been suggested to exert effects via an interaction with dopamine receptors. Thus, in this study, we examined its ability to induce rotation in rats sustaining unilateral 6-hydroxy-dopamine lesions of the substantia nigra, an in vivo model of dopaminergic activity. In analogy to the direct dopamine (mixed D₁/D₂) agonist, apomorphine, (0.01–0.63 mg/kg), LY 165,163 (0.16–10.0 mg/kg) dose-dependently elicited robust and substained contralateral rotation. Its maximal effect was comparable to that of apomorphine and its duration of action more extended. Rotation elicited by LY 165,163 (10.0 mg/kg) was resistant to the 5-HT_1A antagonist, (−)-alprenolol. It was also unaffected by the selective D₁ antagonist, SCH 23390 (R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5,tetraphydro-1H-3- benzazepine) (2.5 mg/kg) or the selective D₂ antagonist, raclopride (10.0 mg/kg) when each was administered alone. However, upon joint administration they clearly diminished the effect of LY 165,163. The dopamine antagonist, haloperidol (D₂ > D₁) also reduced the action of LY 165,163. This profile of partial antagonism by mixed D₁ and D₂ receptor blockade has been reported previously for apomorphine and contrasts to that seen with selective D₁ or D₂ agonists, the actions of which are completely blocked by D₁ or D₂ antagonists, respectively. In conclusion, the present data demonstrate that LY 165,163 exerts pronounced rotation in nigral-lesioned rats: this reflects a mixed D₁/D₂ action rather than an activation of 5-HT_1A sites. Thus, in addition to an agonist action at 5-HT_1A receptors, dopaminergic effects contribute to the pharmacological profile of LY 165,163.     

Two distinctive apomorphine-induced phenotypes in the Roman high- and low-avoidance rats

Strain differences in spontaneous locomotor activity and the behavioral patterns induced by dopaminergic agonists in rodents can disclose differential genetic susceptibilities to dopaminergic dysfunction (i.e. vulnerability to psychosis). Psychogenetic selection of hypoemotional Roman High-Avoidance (RHA) and hyperemotional Low-Avoidance (RLA) rats leads to divergence in dopaminergic function as well. The present study was designed to characterize their spontaneous activity and their responses to apomorphine (0.067-3 mg/kg, s.c.) as compared to those of the standard Sprague-Dawley (SD) strain. The Roman strains displayed higher spontaneous activity than SD rats and RHA exhibited the higher response to novelty which agrees with a higher sensitivity to apomorphine in this strain. The biphasic effect induced by apomorphine (locomotor inhibition and yawning at low doses but stimulation of locomotion and stereotyped behavior at higher ones) was reproduced in the standard SD strain. Low doses were less effective inducing locomotor inhibition in RHA whereas these animals were much more sensitive to high dose-induced stereotyped behavior. In contrast, RLA was characterized as a high-yawning strain and low doses of apomorphine also induced a striking motor inhibition suggesting functional enhancement of dopamine receptors mediating these behaviors. The detailed and distinctive behavioral profiles described in this work suggest between strain differences both at the presynaptic and postsynaptic dopaminergic function and may serve as paths to better specify functional mechanisms in future studies of risk of developing dopaminergic dysfunctions.     

Binding of [3H]sulpiride to purified rat striatal synaptic membranes

Previous results showing that sulpiride, unlike classical neuroleptics, does not block the effects of dopamine on the dopamine-sensitive adenylate cyclase have led to the concept of dopaminergic D₁ and D₂ receptors. It has been suggested that sulpiride is a specific antagonist of D₂ receptors and [³H]sulpiride has been used as a specific ligand for these. This report examines the binding of [³H]sulpiride to purified synaptic membranes from rat striata. There appears to be a single saturable binding component with an affinity constant of 7 nm and a maximum binding capacity of 240 fmol/mg protein. This binding site appears to be dopaminergic in origin since it is present in high concentration in the striatum and nucleus accumbens but in low concentration in nori-dopaminergic regions of the brain. Our results show that sulpiride binding is potently inhibited by classical neuroleptics and benzamides, whilst dopamine agonists have much weaker activity. The binding site shows stereochemical specificity for cis-flupenthixol, cis-clopenthixol, (+)-butaclamol and s-(?)sulpiride.The rank order of potency of the dopamine antagonists is not consistent with a specific benzamide binding site since the classical neuroleptics were very potent inhibitors of binding. In particular, the thioxanthines, reputedly good inhibitors of the dopamine-sensitive adenylate cyclase, were amongst the most potent inhibitors of [³H]sulpiride binding.Thus it is clear that these results are not in accord with the present concept and classification of dopaminergic D₁ and D₁ receptors.     

Neonatal dopamine depletion reveals a synergistic mechanism of mRNA regulation that is mediated by dopamine(D1) and serotonin(2) receptors and is targeted to tachykinin neurons of the dorsomedial striatum

It has been hypothesized that dopamine(D1) and serotonin(2) receptors become sensitized to agonist-mediated regulation of gene expression following loss of dopaminergic innervation to the striatum. We have previously demonstrated that the combined administration of dopamine(D1) and serotonin(2) receptor agonists to dopamine-depleted adult rats induced preprotachykinin mRNA expression within the periventricular rostral striatum to levels which were significantly different than what could be elicited by either agonist alone. In the present study, we have determined that this phenomenon is revealed only after dopamine depletion. In addition, it is targeted primarily to tachykinin producing neurons of the dorsomedial striatum and is dependent on both dopamine(D1) and serotonin(2) receptor activation. Preprotachykinin mRNA levels in the intact striatum were unaltered 4 h following an i.p. injection of either SKF-38393 (1 mg/kg, dopamine(D1) partial agonist) or (+/-)-1-(4-Iodo-2,5-dimethoxyphenyl)-2-aminopropane (DOI 1 mg/kg, serotonin(2) agonist). However, the combined application of both agonists increased (+44%) preprotachykinin message levels, but these changes were restricted to the dorsomedial striatum. In adult animals depleted of dopamine as neonates, striatal preprotachykinin mRNA expression was reduced by approximately 50%. From this lowered level of basal expression, DOI or SKF-38393 raised preprotachykinin mRNA levels within the dorsomedial, but not the dorsolateral striatum. Furthermore, co-stimulation of dopamine(D1) and serotonin(2) receptors produced a nearly four-fold induction of preprotachykinin message levels in the dorsomedial striatum that was significantly greater than either agonist alone. Application of both agonists also elevated preprotachykinin mRNA expression within the dorsolateral striatum, but to a lesser extent. All increases in preprotachykinin mRNA resulting from co-application of SKF-38393 and DOI were prevented by pretreatment with either SCH-23390 (1 mg/kg, dopamine(D1) antagonist) or ritanserin (1 mg/kg, serotonin(2) antagonist). Alternately, preproenkephalin mRNA expression was unaffected by dopamine(D1) receptor stimulation, but was slightly elevated by DOI or both agonists together (42-58%) in intact animals. However, neither agonist treatment in this experiment significantly altered preproenkephalin mRNA expression in the dopamine-depleted striatum which was elevated in response to dopamine lesion alone.Dopamine depletion appears to promote a synergistic interaction between dopamine(D1) and serotonin(2) receptors that leads to enhanced expression of striatal preprotachykinin mRNA levels. The localization of this phenomenon to tachykinin neurons of the direct striatonigral pathway specifically within the dorsomedial regions of the rostral striatum may be relevant to the problem of dyskinetic behaviors which arise during the pharmacological treatment of movement disorders.     

Characterization of a neuronal interleukin-1 receptor and the corresponding mRNA in the mouse anterior pituitary cell line AtT-20.

The serotonin (5-HT)_1A agonist, LY 165,163 (1-[2-(4-aminophenyl)ethyl]-4-(3-trifluoromethylphenyl)-piperazine), also known as PAPP, has been suggested to exert effects via an interaction with dopamine receptors. Thus, in this study, we examined its ability to induce rotation in rats sustaining unilateral 6-hydroxy-dopamine lesions of the substantia nigra, an in vivo model of dopaminergic activity. In analogy to the direct dopamine (mixed D₁/D₂) agonist, apomorphine, (0.01–0.63 mg/kg), LY 165,163 (0.16–10.0 mg/kg) dose-dependently elicited robust and substained contralateral rotation. Its maximal effect was comparable to that of apomorphine and its duration of action more extended. Rotation elicited by LY 165,163 (10.0 mg/kg) was resistant to the 5-HT_1A antagonist, (−)-alprenolol. It was also unaffected by the selective D₁ antagonist, SCH 23390 (R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5,tetraphydro-1H-3- benzazepine) (2.5 mg/kg) or the selective D₂ antagonist, raclopride (10.0 mg/kg) when each was administered alone. However, upon joint administration they clearly diminished the effect of LY 165,163. The dopamine antagonist, haloperidol (D₂ > D₁) also reduced the action of LY 165,163. This profile of partial antagonism by mixed D₁ and D₂ receptor blockade has been reported previously for apomorphine and contrasts to that seen with selective D₁ or D₂ agonists, the actions of which are completely blocked by D₁ or D₂ antagonists, respectively. In conclusion, the present data demonstrate that LY 165,163 exerts pronounced rotation in nigral-lesioned rats: this reflects a mixed D₁/D₂ action rather than an activation of 5-HT_1A sites. Thus, in addition to an agonist action at 5-HT_1A receptors, dopaminergic effects contribute to the pharmacological profile of LY 165,163.     

Action of dopamine and serotonin on the membrane potential of cultured astrocytes

Summary The actions of dopamine, apomorphine and serotonin on the membrane potential of cultured astrocytes from rat spinal cord and striatum were examined. All three compounds caused a hyperpolarization of the majority of astrocytes tested. A small number of cells was depolarized and on a relatively large number of cells the amines had no effect. The dopamine antagonists cis-flupenthixol and domperidone reversibly blocked the effects of dopamine whereas the action of serotonin was antagonized by ketanserin. It is therefore concluded that the effects of both amines are due to activation of specific dopamine and serotonin receptors, respectively. Our electrophysiological data together with autoradiographic binding studies provide evidence that astrocytes possess receptors for dopamine and serotonin in addition to adrenoceptors and histamine receptors.     

The effects of dopaminergic drugs in the ventral hippocampus of rats in the nicotine-induced anxiogenic-like response

Nicotine an active alkaloid of tobacco has dopaminergic properties. The drug alters anxiety-like behavior in rodents. Ventral hippocampus (VHC) may be a site for modulation of anxiety-like behaviors. The possible involvement of ventral hippocampal dopaminergic receptor mechanism in the nicotine influence on anxiogenic-like response has been investigated in the present study. The effects of apomorphine, sulpiride and SCH23390 on nicotine response in elevated plus maze in rats have been investigated. Intraperitoneal administration of nicotine (0.6 mg/kg) decreased percentage of open arm time (%OAT) but not percentage of open arm entries (%OAE) and locomotor activity, indicating an anxiogenic-like response. Intra-hippocampal injection (intra-VHC) of apomorphine, a D₁/D₂ dopamine receptor agonist (0.1 and 0.2 μg/rat) also caused anxiogenic-like effects, but the drug blocked that of nicotine. Intra-VHC administration of the D₂ receptor antagonist, sulpiride (1, 2.5 and 5 μg/rat) or the D₁ receptor antagonist, SCH23390 (0.01, 0.1 and 1 μg/rat) did not elicit any response. However, pretreatment with sulpiride (1 μg/rat) or SCH23390 (0.1 μg/rat) decreased nicotine's effect. The results may indicate a modulatory effect for the D₁ and D₂ dopamine receptors of VHC in the anxiogenic-like response induced by nicotine.     

The role of dopamine receptors in ventrolateral orbital cortex-evoked anti-nociception in a rat model of neuropathic pain

The present study examined the role of dopamine and D₁-and D₂-like dopamine receptors in ventrolateral orbital cortex (VLO)-evoked anti-hypersensitivity in a rat model of neuropathic pain, as well as the possible underlying mechanisms. Results showed that microinjection of apomorphine [(R(−)-apomorphine hydrochloride)], a non-selective dopamine receptor agonist, into the VLO attenuated spared nerve injury (SNI)-induced mechanical allodynia in a dose-dependent manner. This effect was completely blocked by the D₂-like dopamine receptor antagonist S(−)-raclopride(+)-tartrate salt (1.5 μg), but was enhanced by the D₁-like dopamine receptor antagonist SCH23390 (R(+)-SCH-23390 hydrochloride, 5.0 μg). The attenuating effect of apomorphine on mechanical allodynia was mimicked by application of the D₂-like dopamine receptor agonist quinpirole [((−)-quinpirole hydrochloride, 0.5, 1.0, and 2.0 μg)]. In addition, microinjection of larger doses (10 and 20 μg) of SCH23390 into the VLO significantly attenuated allodynia. Furthermore, microinjections of GABA_A receptor antagonists, bicuculline [(+)-bicuculline,(S), 9(R)] and picrotoxin (200 and 300 ng for both drugs), into the VLO attenuated mechanical allodynia. A small dose of bicuculline or picrotoxin (100 ng) resulted in increased quinpirole (0.5 μg)-induced anti-allodynia. In contrast, GABA_A receptor agonists, muscimol hydrochloride (250 ng) or THIP [(2,5,6,7-retrahydroisoxazolo(5,4-c)pyridine-3-ol hydrochloride, 1.0 μg)], blocked quinpirole (2.0 μg)-induced attenuation. These results suggest that the dopaminergic system is involved in mediating VLO-induced anti-hypersensitivity, activation of D₂-like dopamine receptors, and inhibition of D₁-like receptors resulting in anti-hypersensitivity. In addition, the mechanisms of GABAergic disinhibition might be involved in D₂-like receptor mediating effects in neuropathic pain.