Opioid potentiated chromatophorotropin regulation of pigment migration in the land crab Gecarcinus lateralis

In Gecarcinus lateralis dopamine treatment results in dispersion of black and concentration of red pigments within chromatophores. These effects of dopamine on the migration of pigments can be blocked by the dopamine antagonist haloperidol. These results strongly indicate the presence of a dopamine receptor mediated system in this organism. Serotonin injections also result in the dispersion of black pigment; however, this effect cannot be blocked by haloperidol. Norepinephrine was found to be without effect on this pigment regulatory system. Injections of crude eyestalk extract results in pigment migration within the chromatophores in both stalked and destalked animals. Injection of the stable methionine enkephalin analog FK 33 824 into the organisms causes no observable effects on the pigment system. However, coinjection with eyestalk extract strongly potentiates the effect of the extract. This potentiation can be completely blocked by the opiate antagonist naloxone, thus indicating that an endogenous opioid system may be part of the overall regulation of pigmentation movement.     

Central dopaminergic and serotoninergic systems in the regulation of adrenal tyrosine hydroxylase.

Administration of the dopamine receptor agonists apomorphine, piribedil and bromocryptine caused an increase in adrenal tyrosine hydroxylase (TH; tyrosine-3-monooxygenase, EC 1.14.16.2) which could be partially abolished by prior injection of the dopamine blocker haloperidol. Injection of L-dihydroxyphenylalanine, along with the decarboxylase inhibitor carbidopa, also led to a highly significant increase in adrenal TH activity. Intraventricular injection of 5,7-dihydroxytryptamine (DHT), which destroys serotonin neurons, doubled adrenal TH activity in both normal and hypophysectomized rats. Splanchnicotomy abolished this effect of DHT. The increase in enzyme activity mediated by DHT could be partially prevented by peripheral administration of L-5-hydroxytryptophan together with carbidopa. Blockade of serotoninergic functions with the antagonist methiothepin also increased adrenal TH activity. The interrelationship between the dopamine and the presumed serotonin system was investigated. Intraventricular injection of 6-hydroxydopamine partially prevented the DHT-induced increase in adrenal TH activity. Administration of haloperidol to DHT-treated rats had the same effect. This suggests that an intact dopaminergic system is required. When DHT and either apomorphine or piribedil were adminstered simultancously the dopamine agonist-induced increase was potentiated. An intact serotoninergic system is therefore not required for dopamine function. Thus, the increase in adrenal TH activity is associated with either stimulation of central dopamine receptors or destruction of serotonin neurons. It is suggested that dopaminergic and serotoninergic systems are involved in the regulation of adrenal TH and that these systems have net excitatory and inhibitory roles, respectively. Furthermore, the present evidence favors the view that the interaction between the two systems is sequential, with the serotonin system preceding the dopamine one.     

Effects of dopaminergic system activation on feeding behavior and growth performance of the sea bass (Dicentrarchus labrax): A self-feeding approach

Dopamine is synthesized from l-dopa and subsequently processed into norepinephrine and epinephrine. Any excess neurotransmitter can be taken up again by the neurons to be broken down enzymatically into DOPAC. The effect of dopamine on mammalian food intake is controversial. Mice unable to synthesize central dopamine die of starvation. However, studies have also shown that central injection of dopamine inhibits food intake. The effect of dopaminergic system in the fish feeding behavior has been scarcely explored. We report that the inclusion of l-dopa in the diets results in the activation of sea bass central dopaminergic system but also in the significant increase of the hypothalamic serotonin levels. Dietary l-dopa induces a decrease of food intake and feed conversion efficiency that drives a decline of all growth parameters tested. No behavioral effects were observed after l-dopa treatment. l-dopa treatment stimulated central expression of NPY and CRF. It suggests that CRF might mediate l-dopa effects on food intake but also that CRF neurons lie downstream of NPY neurons in the hierarchical forebrain system, thus controlling energy balance. Unexpectedly, dietary administration of haloperidol, a D₂-receptor antagonist, cannot block dopamine effects but also induces a decline of the food intake. This decrease seems to be a side effect of haloperidol treatment since fish exhibited a decreased locomotor activity. We conclude that oral l-dopa inhibits sea bass food intake and growth. Mechanism could also involve an increase of hypothalamic serotoninergic tone.     

The effect of chronic levodopa on haloperidol induced behavioral supersensitivity in the guinea pig

The effect of chronic levodopa-carbidopa administration (200 mg/kg for 21 days) on guinea pigs rendered behaviorally supersensitive by the prior administration of haloperidol (.5 mg/kg for 21 days) was examined. Animals who showed an increased behavioral response to apomorphine after chronic haloperidol administration were treated with levodopa-carbidopa and then apomorphine - induced stereotypy was reexamined. Although the chronic levodopa control groups and the chronic haloperidol control remained supersensitive to the behavioral effect of apomorphine, the haloperidol-levodopa group's behavioral response to apomorphine returned to normal. Both chronic dopaminergic antagonist and agonist administration have been demonstrated to induce heightened apomorphine-induced stereotypy and this has been interpreted as a reflection of altered striatal dopamine receptor site sensitivity. The finding that the serial administration of a chronic dopaminergic antagonist followed by a chronic dopaminergic agonist results in a return to normal of a striatal dopamine receptor-dependent behavior suggests that these chronic treatments affect dopamine receptor sites by different mechanisms of action. Since neuroleptic induced dopaminergic supersensitivity in animals is an accepted model of tardive dyskinesia, levodopa may also reverse dopaminergic supersensitivity in patients and might be a potential therapeutic agent in tardive dyskinesia.     

Dopaminergic mediation of the diuretic and natriuretic action of centrally administered rat atrial natriuretic factor (99-126)

Intracerebroventricular administration of either rat atrial natriuretic factor (99-126) or dopamine to conscious male hydrated rats resulted in an increase in urinaryvolume and sodium excretion. This activity was prevented, in both cases, by nonselective dopamine antagonist haloperidol (2.5 or 1.25 mg/kg sc, 18 and 2 hr before intracerebroventricular administration of atrial natriuretic factor). Our findings suggest that atrial natriuretic factor exerts its centrally mediated effects on sodium and water metabolism, at least in part, via a dopaminergic mechanism.     

Repeated treatment with the kappa opioid receptor agonist U69593 reverses enhanced K+ induced dopamine release in the nucleus accumbens, but not the expression of locomotor sensitization in amphetamine-sensitized rats

The effects after the acute activation of the kappa opioid receptor (KOR) can be distinguished from the effect after repeated administration of KOR agonist. Here, we report the effect of repeated administration of U69593 during abstinence after amphetamine-induced locomotor sensitization. Rats were injected once daily with amphetamine for five consecutive days. From day 6 to 9, rats that developed locomotor sensitization, received once daily injection of U69593 or vehicle. On day 10, all rats were injected with a challenging dose of amphetamine and locomotor activity was measured to assess the expression of sensitization. Microdialysis studies were carried out to assess dopamine extracellular levels in NAc. Rats that develop and express horizontal locomotor sensitization to amphetamine show increased dopamine release in the NAc induced by high K(+). The repeated treatment with U69593 reverses the sensitized depolarization-stimulated dopamine release in the NAc, but not the expression of locomotor sensitization induced by amphetamine. Thus, repeated activation of KORs during early amphetamine withdrawal dissociates the behavioral responses and the neurochemical responses that accompany the expression of sensitization to amphetamine.     

Identification of a new functional target of haloperidol metabolite: implications for a receptor-independent role of 3-(4-fluorobenzoyl) propionic acid

Haloperidol, a dopamine D2 receptor blocker, is a classical neuroleptic drug that elicits extrapyramidal symptoms. Its metabolites include 3-(4-fluorobenzoyl) propionic acid (FBPA) and 4-(4-chlorophenyl)-4-piperidinol (CPHP). Until now, the biological significance of these metabolites has remained largely unknown. Here, we report that the administration of FBPA to mice effected a suppression of locomotor activity and induced catalepsy in a manner similar to that observed with haloperidol, whereas CPHP had no significant effects. Neither of these two metabolites, however, exhibited any ability to bind to the dopamine D2 receptor. FBPA blocked dopamine-induced extracellular signal-regulated kinase 1/2 phosphorylation, and it specifically affected mitogen-activated protein kinase kinase (MEK)1/2 activity in hippocampal HN33 cells. Moreover, FBPA was capable of direct interaction with MEK1/2, and inhibited its activity in vitro. We demonstrated the generation of haloperidol metabolites within haloperidol-treated cells by mass spectrometric analyses. Collectively, our results confirm the biological activity of FBPA, and provide initial clues as to the receptor-independent role of haloperidol.     

Prevention of cocaine-induced hyperactivity by a naloxone isomer with no opiate antagonist activity

Dextro-naloxone [(+)-naloxone], an isomer with almost no opiate antagonist activity and no effect on spontaneous locomotor activity, can reduce cocaine-induced hyperactivity in mice. The classical opiate antagonist,levo-naloxone [(−)-naloxone], is known to counteract the excitatory motor effects of amphetamine and cocaine, but it has been tacitly assumed that this action oflevo-naloxone is dependent on its ability to antagonize endogenous opioids. Our finding that a naloxone isomer with little or no opioid antagonist activity is also able to inhibit the cocaine effect on spontaneous motility, calls for a reconsideration of this assumption.     

An analysis of the behavioral effects of stimulation of the dopamine D2 receptors at the level of the ventral tegmental area in the rat brain]

It was shown that intracerebral injections of D2 dopamine receptor agonist quinpirol after systemic administration of D2 antagonist sulpiride inhibited both locomotor and food-procuring activity in rats. It was concluded that this effect is connected with involvement of the negative feedback mechanisms of dopaminergic neurons. The involvement of this mechanism into the regulation of the motivated behavior seems to require the definite level of dopaminergic structures.     

Prenatal haloperidol alters the expression of DNA polymerases in brain regions of neonate rats

1. Previous studies have reported a marked reduction in the [3H]thymidine incorporation in forebrain after administration of a dopamine antagonist such as haloperidol. 2. We have investigated the possibility that the expression levels of genes related to DNA metabolism could be altered by haloperidol treatment. 3. By Northern blot analysis, we have studied the steady-state mRNA levels for genes involved in DNA metabolism, in neonate rat mesencephalon and forebrain, after chronic prenatal blockade of dopamine receptors with haloperidol. 4. We found that the expression levels for DNA polymerases alpha and beta were clearly reduced in forebrain by haloperidol treatment. On the contrary, the expression of DNA polymerase beta was increased in mesencephalon. 5. Our results suggest that dopamine receptors occupancy may be a critical factor in controlling cell proliferation during brain development, through a mechanism(s) involving changes in the expression of DNA polymerases.     

Orexin A in the VTA is critical for the induction of synaptic plasticity and behavioral sensitization to cocaine

Dopamine neurons in the ventral tegmental area (VTA) represent a critical site of synaptic plasticity induced by addictive drugs. Orexin/hypocretin-containing neurons in the lateral hypothalamus project to the VTA, and behavioral studies have suggested that orexin neurons play an important role in motivation, feeding, and adaptive behaviors. However, the role of orexin signaling in neural plasticity is poorly understood. The present study shows that in vitro application of orexin A induces potentiation of N-methyl-D-aspartate receptor (NMDAR)-mediated neurotransmission via a PLC/PKC-dependent insertion of NMDARs in VTA dopamine neuron synapses. Furthermore, in vivo administration of an orexin 1 receptor antagonist blocks locomotor sensitization to cocaine and occludes cocaine-induced potentiation of excitatory currents in VTA dopamine neurons. These results provide in vitro and in vivo evidence for a critical role of orexin signaling in the VTA in neural plasticity relevant to addiction.     

Involvement of neurotransmitters in the action of apelin-13 on passive avoidance learning in mice

The widespread distribution of apelin-13 and apelin receptors in the brain suggests an important function of this neuropeptide in the brain that has not been explored extensively so far. In the present work, apelin-13 was found to facilitate the consolidation of passive avoidance learning in mice. In order to assess the possible involvement of transmitters in this action, the animals were pretreated with the following receptor blockers in doses which themselves did not influence the behavioral paradigm: phenoxybenzamine (a nonselective α-adrenergic receptor antagonist), propranolol (a β-adrenergic receptor antagonist), cyproheptadine (a nonselective 5-HT2 serotonergic receptor antagonist), atropine (a nonselective muscarinic acetylcholine receptor antagonist), haloperidol (a D2, D3 and D4 dopamine receptor antagonist), bicuculline (a γ-aminobutyric acid subunit A (GABA-A) receptor antagonist), naloxone (a nonselective opioid receptor antagonist), and nitro-l-arginine (a nitric oxide synthase inhibitor). Phenoxybenzamine, cyproheptadine, atropine, haloperidol, bicuculline and nitro-l-arginine prevented the action of apelin-13. Propranolol and naloxone were ineffective. The data suggest that apelin-13 elicits its action on the consolidation of passive avoidance learning via α-adrenergic, 5-HT2 serotonergic, cholinergic, dopaminergic, GABA-A-ergic and nitric oxide mediations.     

Gastric mucosal lesions induced by complete dopamine system failure in rats. The effects of dopamine agents, ranitidine, atropine, omeprazole and pentadecapeptide BPC 157.

Up to now, for gastric lesions potentiation or induction, as well as determination of endogenous dopamine significance, dopamine antagonist or dopamine vesicle depletor were given separately. Therefore, without combination studies, the evidence for dopamine significance remains split on either blockade of dopamine post-synaptic receptor or inhibition of dopamine storage, essentially contrasting with endogenous circumstances, where both functions could be simultaneously disturbed. For this purpose, a co-administration of reserpine and haloperidol, a dopamine granule depletor combined with a dopamine antagonist with pronounced ulcerogenic effect, was tested, and the rats were sacrificed 24 h after injurious agent(s) administration. Haloperidol (5 mg x kg(-1) b.w. i.p.), given alone, produced the lesions in all rats. Reserpine (5 mg x kg(-1) b.w. i.p.), given separately, also produced lesions. When these agents were given together, the lesions were apparently larger than in the groups injured with separate administration of either haloperidol or reserpine alone. Along with our previous results, when beneficial agents were co-administered, all dopaminomimetics (bromocriptine 10 mg, apomophine 1 mg, amphetamine 20 mg x kg(-1) i.p.) apparently attenuated the otherwise consistent haloperidol-gastric lesions. Likewise, an apparent inhibition of the reserpine-lesions was noted as well. However, if they were given in rats injured with combination of haloperidol and reserpine, their otherwise prominent beneficial effects were absent. Ranitidine (10 mg), omeprazole (10 mg), atropine (10 mg), pentadecapeptide BPC 157 (Gly-Glu-Pro-Pro-Pro-Gly-Lys-Pro-Ala-Asp-Asp-Ala-Gly-Leu-Val) (10 microg or 10 ng x kg(-1) i.p.) evidently prevented both haloperidol-gastric lesions and reserpine-gastric lesions. Confronted with potentiated lesions following a combination of haloperidol and reserpine, these agents maintained their beneficial effects, noted in the rats treated with either haloperidol or reserpine alone. The failure of dopaminomimetics could be most likely due to more extensive inhibition of endogenous dopamine system activity, and need for remained endogenous dopamine for their salutary effect, whereas the beneficial activities of ranitidine, omeprazole, atropine, pentadecapeptide BPC 157 following dopamine system inhibition by haloperidol+reserpine suggest their corresponding systems parallel those of dopamine system, and they may function despite extensive inhibition of endogenous dopamine system activity.     

Effect of nicotine on extracellular levels of neurotransmitters assessed by microdialysis in various brain regions: Role of glutamic acid

We studied the effect of local administration of nicotine on the release of monoamines in striatum, substantia nigra, cerebellum, hippocampus, cortex (frontal, cingulate), and pontine nucleus and on the release of glutamic acid in striatum of rats in vivo, using microdialysis for nicotine administration and for measuring extracellular amine and glutamic acid levels. Following nicotine administration the extracellular concentration of dopamine, increased in all regions except cerebellum; serotonin increased in cingulate and frontal cortex; and norepinephrine increased in substantia nigra, cingulate cortex, and pontine nucleus. Cotinine, the major nicotine metabolite, had no effect at similar concentrations. The cholinergic antagonists mecamylamine and atropine, the dopaminergic antagonists haloperidol and sulpiride, and the excitatory amino acid antagonist kynurenic acid all inhibited the nicotine-induced increase of extracellular dopamine in the striatum. The fact that kynurenic acid almost completely prevented the effects of nicotine, and nicotine at this concentration produced a 6-fold increase of glutamic acid release, suggests that the effect of nicotine is mainly mediated via glutamic acid release.     

A comparison of domperidone and haloperidol effects on different dopaminergic neurons in the rat brain

Domperidone, a dopamine (DA) receptor antagonist with reportedly preferential actions outside of the blood-brain barrier, and haloperidol, a centrally active DA antagonist, were compared with respect to their abilities to increase the activity of dopaminergic neurons in the rat brain. The activity of nigrostriatal, mesolimbic, tuberohypophyseal and tuberoinfundibular dopamine nerves was estimated by measuring the $\text{in vivo}$ rate of DA synthesis (dihydroxyphenylalanine accumulation following administration of an inhibitor of aromatic L-amino acid decarboxylase) in the striatum, olfactory tubercle, posterior pituitary and median eminence, respectively. In an initial study, the rates of DA synthesis in striatum, olfactory tubercle, and posterior pituitary were determined at 2, 8, and 16 h after subcutaneous administration of 0.25, 2.5, or 25 mg/kg domperidone. At the lowest dose of domperidone, DA synthesis was increased only in the posterior pituitary at 8 and 16 h; at the intermediate dose, DA synthesis increased in the posterior pituitary at 8 and 16 h and in the olfactory tubercle at 8 h. Only at 8 h after the highest dose of domperidone was DA synthesis increased in the striatum. When 2.5 mg/kg of doperidone or haloperidol were administered, DA synthesis in posterior pituitary and median eminence was increased in a similar fashion (in the latter region only at 16 h). In contrast, domperidone promoted only modest and delayed increases in DA synthesis in the olfactory tubercle and had no effect in the striatum. These results indicate that systemically administered domperidone preferentially increases DA synthesis in neurons terminating outside the blood-brain barrier, but after a pronounced delay, high doses of the drug can also activate DA neurons which project to the forebrain.     

Morphine- and opioid peptide-induced inhibition of the release of dopamine from tuberoinfundibular neurons

Dopamine concentrations in pituitary stalk plasma ovariectomized rats and ovariectomized, estrogen-treated rats were measured following the subcutaneous administration of morphine or the intraventricular administration of ß-endorphin or [D-Ala²]-methionine-enkephalinamide, a synthetic enkephalin analog. The administration of morphine or the opioid peptides led to an 85–89% reduction in the concentration of dopamine in pituitary stalk plasma when compared to the mean concentration of dopamine in stalk plasma of vehicle-treated animals. Pretreatment of rats with naloxene, an opiate antagonist, prevented the opioid peptide-induced reduction in the stalk plasma concentration of dopamine. These results are supportive of the hypothesis that endogenous opioid peptides modulate the release of dopamine by tuberoinfundibular neurons into hypophysial portal blood.     

Haloperidol and Cerebral Metabolism in the Conscious Rat: Relation to Pharmacokinetics

The time course and distribution of alterations in cerebral metabolic activity after haloperidol administration were evaluated in relation to the pharmacokinetics of haloperidol and the topography of the dopaminergic system in the brain. Local cerebral glucose utilization was measured, using the 2-deoxyglucose technique, in awake rats after i.p. administration of the dopamine antagonist haloperidol (0.5 or 1 mg/kg). Haloperidol significantly reduced glucose utilization in 60% of 59 brain regions examined, but produced a large increase in the lateral habenula. The regional distribution of changes in glucose utilization was not closely related to the known anatomy of the brain dopaminergic system. The time course of the effect of haloperidol on cerebral metabolism was different for the two doses studied (0.5 and 1 mg/kg), and was not simply related to estimated brain concentrations of haloperidol. However, a linear relation between the metabolic effect and the time-integrated brain concentration was demonstrated. These results show that haloperidol has an effect on CNS metabolic activity that is more widespread than would be predicted from the topography of the dopaminergic system; this may be due to indirect propagation of the primary effects of haloperidol. The metabolic response to haloperidol depends on brain concentration and duration of exposure to the drug.     

The effects of apomorphine and haldol on PCP induced behavioral and motor abnormalities in the rat

Behavioral abnormalities and motor dysfunctions induced by the administration of PCP to rats is antagonized by both the dopamine agonist apomorphite and the dopamine antagonist haloperidol. In the test situation used, however, the antagonistic effects of apomorphine were much more rapid than those of haloperidol. These results suggest that PCP may be acting on specific presynaptic dopamine receptors and that this reaction is effectively antagonized by low doses of apomorphine in a manner similar to its effects in reducing schizophrenic symptoms and choreiform movement disorders.     

Microdialysis and mass spectrometric monitoring of dopamine and enkephalins in the globus pallidus reveal reciprocal interactions that regulate movement

Pallidal dopamine, GABA and the endogenous opioid peptides enkephalins have independently been shown to be important controllers of sensorimotor processes. Using in vivo microdialysis coupled to liquid chromatography-mass spectrometry and a behavioral assay, we explored the interaction between these three neurotransmitters in the rat globus pallidus. Amphetamine (3 mg/kg i.p.) evoked an increase in dopamine, GABA and methionine/leucine enkephalin. Local perfusion of the dopamine D(1) receptor antagonist SCH 23390 (100 μM) fully prevented amphetamine stimulated enkephalin and GABA release in the globus pallidus and greatly suppressed hyperlocomotion. In contrast, the dopamine D(2) receptor antagonist raclopride (100 μM) had only minimal effects suggesting a greater role for pallidal D(1) over D(2) receptors in the regulation of movement. Under basal conditions, opioid receptor blockade by naloxone perfusion (10 μM) in the globus pallidus stimulated GABA and inhibited dopamine release. Amphetamine-stimulated dopamine release and locomotor activation were attenuated by naloxone perfusion with no effect on GABA. These findings demonstrate a functional relationship between pallidal dopamine, GABA and enkephalin systems in the control of locomotor behavior under basal and stimulated conditions. Moreover, these findings demonstrate the usefulness of liquid chromatography-mass spectrometry as an analytical tool when coupled to in vivo microdialysis.     

Increased amphetamine potency following chronic naltrexone administration in rats

Chronic administration of the long acting opiate antagonist naltrexone potentiated the amphetamine and apomorphine- -induced stimulation of locomotor activity in rats. Similar treatment also resulted in increased locomotor activity in saline injected rats. The results suggest that chronic opiate receptor blockade may lead to the development of supersensitivity in dopamine systems that mediate motor control. The results provide further support for the notion that endogenous opioids modulate the function of dopamine systems in the brain.