Spontaneous and drug-stimulated locomotor activity after the administration of pertussis toxin into the ventral tegmental area.

Pertussis toxin (PTX) injected into the ventral tegmental area (VTA) produces an enhanced locomotor response to amphetamine. In the present study, we have evaluated the role of dopamine receptors on spontaneous locomotor activity and the enhanced locomotor response to dopaminergic agonists after the administration of PTX into the VTA. PTX injected into the VTA of rats produced a delayed increase in spontaneous locomotor activity with a latency of 4 d. This activity was markedly increased by day 6 and remained elevated for at least 28 d after PTX treatment. This increased spontaneous locomotor activity of PTX-treated animals was antagonized by the administration of the D1 receptor antagonist SCH23390 (0.03 and 0.1 mg/kg sc), but not by the D2 receptor antagonist eticlopride (0.1 and 0.3 mg/kg sc). After adaptation to the locomotor cages, the animals showed a markedly enhanced motor response to amphetamine (0.5 mg/kg ip) and apomorphine (5 mg/kg sc). The heightened locomotor responses to these dopaminergic agonists could be elicited for at least 2 mo after PTX administration. The enhanced response to amphetamine was antagonized by the administration of SCH23390 (0.03 and 0.1 mg/kg sc), but not by eticlopride (0.1 mg/kg). The increased response to apomorphine in PTX-treated animals was inhibited by SCH23390 (0.1 mg/kg sc) and partially inhibited by eticlopride (0.1 mg/kg sc). Both of these antagonists inhibited the spontaneous and the drug-induced locomotor responses in vehicle-treated control animals. These results suggest that the administration of PTX into the VTA leads to an increase in spontaneous and drug-induced locomotor activity in which D1 receptors seem to play an important role.     

Acceleration of desipramine-induced changes on the dopamine receptor-coupled adenylate cyclase system by pertussis toxin

Summary Mice treated with reserpine (5 mg/kg IP), 24h beforehand, were completely akinetic. Fluent locomotion was reinstated with the D₁-selective agonist SKF 38393 (3–30 mg/kg IP), the D₂-selective agonist RU 24213 (0.5–5 mg/kg SC) and the mixed D₁/D₂ agonist apomorphine (0.025–0.5 mg/kg SC). Clonidine (0.03125–1 mg/kg IP) caused a dose-dependent sedation in dopamine-intact mice, but had no effect by itself on the locomotor activity of monoamine-depleted mice. In drug interaction experiments, clonidine did not modify the motor stimulant action of SKF 38393, but greatly enhanced the motor responses to RU 24213 and apomorphine. These results support the hypothesis that -adrenoceptor agonists facilitate dopamine D₂ but not dopamine D₁ motor responding in the reserpinetreated mouse model of Parkinson's disease.     

Qualitative aspects on motility changes in mice induced by low doses of apomorphine and clonidine

Summary Single mice were treated with apomorphine (0.05, 0.2 or 0.8 mg/kg) or clonidine (0.025 or 0.05 mg/kg), and were placed in a new kind of motility meter, allowing classification of movements in terms of size, and also charting the motility with the help of an X/Y pen recorder. All treatments induced reduction of motility in this model. Apomorphine, 0.8 mg/kg, considerably changed the motility type, whereas the lower doses did not. This finding is consistent with earlier studies on gross locomotor activity and suggests that the higher dose alone evokes a significant direct net stimulation of postsynaptic dopamine receptors, whereas the lower doses merely reduce the physiological stimulation of these receptors by inhibiting dopamine neurotransmission. Clonidine, 0.025 mg/kg, depressed motility at least as much as did 0.05 mg/kg, in agreement with previous behavioural studies.     

Behavioural supersensitivity following neonatal 6-hydroxydopamine: Attenuation by MK-801

Male rat pups were administered 6-hydroxydopamine (6-OHDA, 75 microg, intracisternally, 30 min after desipramine, 25 mg/kg, s.c.) on Days 1 or 2 after birth, or were sham-operated (receiving vehicle). In four experiments, the acute effects of apomorphine, with or without pretreatment with MK-801 (0.03 mg/kg), upon motor activity in test chambers was measured. Acute treatment with apomorphine (0.1 mg/kg) increased locomotor, rearing and total activity markedly compared to both the acute saline administered 6-OHDA rats and the sham-operated rats administered saline. Acute MK-801 (0.03 mg/kg) co-administered shortly before (5 min) apomorphine (0.3 or 1.0 mg/kg) reduced markedly locomotion and total activity in 6-OHDA-treated and sham-operated rats. Rearing behaviour was increased in both the 6-OHDA groups of rats. Acute MK-801 increased activity in the 6-OHDA-treated rats, which was not observed in sham-operated rats. At the 0.3 and 1.0 mg/kg doses of apomorphine, neonatal 6-OHDA treatment increased all three parameters of motor activity. Acute treatment with apomorphine (0.1 mg/kg) induced different effects on the motor activity of 6-OHDA-treated and sham-operated mice. In sham-operated rats apomorphine reduced motor activity during the 1st 30-min period but increased locomotion and total activity, but not rearing, during the 2nd and 3rd periods, whereas in 6-OHDA-treated rats, apomorphine increased locomotor, rearing and total activity markedly. Dopamine loss and serotonin elevation in the striatum and olfactory tubercle were confirmed. The present findings confirm the influence of non-competitive glutamate antagonists in attenuating the behavioural supersensitivity to dopamine antagonists.     

Nicotine induced behavioral locomotor sensitization

1. Nicotine behavioral sensitization of locomotor activity was investigated in adult female Sprague Dawley rats. Five different experiments were performed with nicotine in various doses of 0.1, 0.32, or 1.0 mg/kg i.p. These included: 1) effects of daily nicotine for 6 days, 2) effects of once per week nicotine for 3 weeks, 3) effects of MK-801 on nicotine-induced locomotor activity, 4) effects of dexamethasone on nicotine-induced locomotor activity, 5) induction of tolerance to nicotine-induced locomotor sensitization and lack of cross tolerance to caffeine. 2. Locomotor activity was measured with a photoelectric computerized system. The first dose of nicotine (0.32 mg/kg) induced marked locomotor depression. Once daily injection of 0.32 mg/kg of nicotine for 6 days produced tolerance to its depressant effects and sensitized the rats to its stimulant effects. Three once weekly doses of 0.32 mg/kg of nicotine also produced tolerance to its depressant effects and some locomotor stimulation. 3. Daily pretreatment for 5 days with a dose of 0.18 mg/kg of MK-801 i.p. partially antagonized the locomotor depressant and stimulant actions of nicotine. 4. Dexamethasone (1 mg/kg i.p.) daily pretreatment barely reduced nicotine locomotor depression and only very slightly enhanced locomotor stimulation. 5. Accumulating doses of 0.32 and 1.0 mg/kg b.i.d. of nicotine produced tolerance to its locomotor stimulant effects in rats previously sensitized to 0.32 mg/kg. There was no cross-tolerance to 32 mg/kg of caffeine citrate in previously sensitized animals tolerant to the stimulant effects of nicotine.     

The effect of single and repeated electroconvulsive shock (ECS) on locomotor activity in rats

Locomotor activity following administration of apomorphine (0.1 mg/kg), and amphetamine (1 mg/kg) was studied in rats receiving single and multiple electroconvulsive shock (ECS). Three groups of rats were utilized, one half of each group received sham treatment and the other half received either 1,5, or 10 daily ECS. Significant enhancement of the locomotor response to amphetamine, but not apomorphine, was seen in rats given repeated ECS as compared to controls. This study suggests that the number of ECS, is an important variable in ECS enhancement of locomotor response to amphetamine.     

Spontaneous and drug-induced locomotor activity after partial dopamine denervation of the ventral striatum

Spontaneous and drug-induced locomotor behavior was investigated in rats subjected to lesions of the ventral striatum, using the neurotoxin 6-hydroxydopamine to produce selective depletions of dopamine. Locomotor activity changed with time after lesion. At 2 weeks postoperative less spontaneous rearings were observed compared to controls, a reduced response to 1.0 mg/kg amphetamine and an increased response to 0.1 mg/kg apomorphine. These changes were not observed 9 weeks postoperative; that is, spontaneous locomotor activity and the response to amphetamine were not different from those of controls, and the rearing response to apomorphine was now reduced. The neurochemical assays of the lesioned ventral striate showed equivalent dopamine depletions of about 48% in both lesion groups relative to controls.     

Behavioral sensitization to dopaminergic inhibitory and stimulatory effects induced by low vs. high dose apomorphine treatments: An unconventional dose and response reversal sensitization challenge test reveals sensitization mechanisms

Low dose apomorphine treatments preferentially activate dopamine autoreceptors and inhibit dopamine neurons as well as behavior. In contrast, high doses of apomorphine induce locomotor stimulation by activating dopamine postsynaptic receptors. We compared the effects of low (0.05 mg/kg) vs. high (2.0 mg/kg) repeated apomorphine treatments (5) using paired/unpaired protocols upon the development of Pavlovian conditioned drug responses and upon drug sensitization effects. In addition to the conventional challenge test for sensitization, we also conducted a treatment reversal sensitization test in which low dose groups received the high dose treatment and vice versa. The high dose treatment produced the expected Pavlovian conditioned locomotor stimulant response as well as a sensitization effect in the high dose challenge test; but in the low dose challenge test, the effect was desensitization. The low dose apomorphine regimen induced an inhibitory sensitization effect in the low dose challenge test. In the high dose reversal challenge test, there was a sensitization effect to the locomotor stimulant effect. The low dose apomorphine treatments, however, did not produce a Pavlovian conditioned locomotor inhibitory effect. Surprisingly, the dose reversal challenge test revealed context-independent as well as context-specific sensitization/desensitization effects. These findings demonstrate that Pavlovian drug conditioned effects and drug sensitization effects are independent phenomena and that sensitization effects are not response specific. Moreover, context-specific vs. context-independent sensitization effects were protocol dependent but not drug dose dependent.     

The demonstration of a change in responsiveness of mice to physostigmine and atropine after withdrawal from long-term haloperidol pretreatment

Summary Mice, administered haloperidol 3 mg/kg/day, in their drinking water for 21 days, were tested for their responsiveness to cholinergic and anticholinergic drugs 4 days after withdrawal from haloperidol (or vehicle). Haloperidol-treated animals administered methylhyoscine (1 mg/kg i.p.) and various doses of physostigmine (5 to 1215g/kg) displayed significantly less depression of locomotor activity than vehicle-treated animals. Atropine, 5 mg/kg, whilst ineffective in producing locomotor stimulation in vehicle-treated animals, produced marked stimulation in haloperidol-treated animals. Methylatropine (5 mg/kg) did not produce significant stimulation in either group. Dopamine receptor supersensitivity was present in these animals as haloperidol-treated mice, pretreated with-methyl-tyrosine and reserpine, displayed a significantly greater locomotor response to apomorphine than did vehicle-treated animals. The data support the hypothesis that long-term administration of haloperidol produces an apparent hyposensitivity of central muscarinic receptors.     

Paradoxical reinforcing properties of apomorphine: Effects of nucleus accumbens and area postrema lesions

Apomorphine (0.01–10.0 mg/kg, subcutaneously) paradoxically produced both dose-dependent aversive and positive reinforcing effects, as measured in conditioned taste aversion and place preference paradigms, respectively. The conditioned taste aversions produced by apomorphine were not modified in rats with bilateral 6-hydroxydopamine (6-OHDA) lesions of the nucleus accumbens (producing 92% depletion of dopamine in the nucleus accumbens) nor in rats with thermal lesions of the area postrema. Both types of lesions were behaviorally verified as effective in other paradigms; the 6-OHDA lesions potentiated the facilitatory effects of apomorphine on locomotor activity in photocell cages, and the area postrema lesions attenuated the conditioned taste aversions to a novel flavor paired with scopolamine methylnitrate (1.0 mg/kg, intraperitoneally). However, 6-OHDA lesions of the nucleus accumbens did clearly potentiate the conditioned place preferences induced by apomorphine. These results suggest that both the positive reinforcing and locomotor effects of apomorphine may partially result from activation of post-synaptic dopamine receptors in the nucleus accumbens. Moreover, the dissociation of apomorphine's aversive and positive reinforcing properties revealed by the 6-OHDA lesions may provide the first step in attempts to pinpoint the different brain sites of action where apomorphine produces its opposite motivational effects.     

Effects of low,autoreceptor selective doses of dopamine agonists on the discriminative cue and locomotor hyperactivity produced by d-amphetamine

Summary The ability of low doses of the dopamine (DA) agonists quinpirole and (+)-3-PPP to reduce the discriminative stimulus properties and locomotor hyperactivity produced by d-amphetamine (0.5 mg/kg) was assessed in two groups of rats. Quinpirole (0.0125–0.05mg/kg) and (+)-3-PPP (1.0–2.0 mg/kg) completely antagonized d-amphetamine-induced locomotor hyperactivity. In contrast, only single doses of quinpirole (0.025 mg/kg) and (+)-3-PPP (2.0 mg/ kg) were effective in the drug discrimination paradigm; the antagonisms were small (18–47%), but significant. The inhibitory effects of quinpirole and (+)-3-PPP in these behavioural models are probably due to their ability to selectively stimulate DA autoreceptors in the nucleus accumbens and reduce the increase in DA release produced by d-amphetamine. It is suggested that the much weaker effects of the drugs in the discrimination paradigm are due to changes produced by the long-term periodic administration of d-amphetamine to these animals, such as a down-regulation in the sensitivity of DA autoreceptors.     

Area postrema mediates gastric motor response induced by apomorphine in rats

The effects of apomorphine administration on the autonomic responses were investigated in rats. Distinctive gastric motor responses were observed after the intravenous administration of apomorphine (0.1 mg/kg body weight). Gastric motor responses in the distal stomach induced by apomorphine administration were classified into two types. One type involved inhibition of phasic contractions which appeared just after the administration of apomorphine. The other involved an increase in the frequency of small phasic contractions accompanied by increased gastric tone appearing with a relatively longer delay. No relaxation was observed in either the proximal or distal stomach. These gastric motor responses showed a dose–response effect to the amount of apomorphine administered (0.002–0.1 mg/kg body weight). In addition, submandibular salivary secretion was observed in response to the intravenous administration of apomorphine at a dose of 3 or 10 mg/kg body weight. Pretreatment with domperidone (1 or 2 mg/kg body weight) or the ablation of the area postrema (AP) abolished the gastric motor response and salivary secretion induced by the administration of apomorphine. In conclusion, rats showed definitive autonomic phenomena in response to the administration of apomorphine. Dopamine 2-like receptors situated in the AP mediate apomorphine-induced autonomic phenomena in rats.     

A behavioural study of the changes in the central nervous system of mice after subchronic treatment with the selective dopamine autoreceptor agonist 3-PPP (dl-3-[3-hydroxyphenyl]-N-n-propylpiperidine)

Summary In naive mice the selective dopamine (DA) autoreceptor agonist 3-PPP (dl-3-[3-hydroxyphenyl]-N-n-propylpiperidine) produced a dose-dependent depression of locomotor activity. The duration of action of the depression was short, with no significant depression being noted one or more hours after a dose of 23.47 mg/kg (expressed as the base). Mice, administered the drug twice daily (23.47 mg/kg, in the morning and the evening, i.p.) for 5 days, were, 15 to 25 hours after the last dose, marginally less sensitive to the locomotor depressant effects of a challenge with the same drug. There was no change in the sensitivity of postsynaptic DA and-adrenergic receptors, as assessed by the locomotor stimulant effects of apomorphine and apomorphine plus clonidine, respectively, in reserpine and-methyltyrosine pretreated animals. However, 3-PPP-pretreated mice were more sensitive to the activating effects ofd-amphetamine, and this increased sensitivity was blocked by pretreatment with reserpine. In naive mice, a low, DA autoreceptor selective dose of haloperidol (25g/kg) potentiated the locomotor stimulant effects ofd-amphetamine. One explanation for the data obtained is that subchronic pretreatment with 3-PPP produced DA autoreceptor subsensitivity with no concomitant change in postsynaptic DA or-adrenergic receptor sensitivity. The increased sensitivity tod-amphetamine in the 3-PPP pretreated mice may be due to a reduction in the feedback control exerted by the DA released by thed-amphetamine due to the DA autoreceptors having become subsensitive.     

CCK2 receptor-deficient mice have increased sensitivity of dopamine D2 receptors

The present study supports a role of CCK(2) receptors in the regulation of dopamine neurones. In pharmacological studies conducted on male CCK(2) receptor-deficient mice the changes in the activity of dopamine system were established. A low dose of dopamine agonist apomorphine (0.1 mg/kg), stimulating the pre-synaptic dopamine receptors, induced significantly stronger suppression of locomotor activity in mutant mice (-/-) compared to their wild-type littermates (+/+). The administration of amphetamine (3-6 mg/kg), a drug increasing dopamine release, caused a dose-dependent stimulation of locomotor activity in wild-type mice. In mice lacking CCK(2) receptors, a lower dose of amphetamine (3 mg/kg) tended to suppress the motor activity, whereas the higher dose (6 mg/kg) induced the significantly stronger motor stimulation in mutant mice. Moreover, in the CCK(2) receptor-deficient mice the affinity of dopamine D(2) receptors, but not 5-HT(2) receptors, was increased. Altogether, the targeted genetic suppression of CCK(2) receptors increased the sensitivity of pre- and post-synaptic dopamine D(2) receptors.     

Diazepam and nicotine increase social interaction in gerbils: a test for anxiolytic action

The effects of two drugs with anxiolytic actions, diazepam (0.1, 0.3 and 1 mg/kg) and nicotine (0.1 and 0.5 mg/kg) were examined on the time spent in social interaction by pairs of male gerbils. In a test arena lit by high light, diazepam (0.1 mg/kg) increased social interaction, without changing locomotor activity. Diazepam (0.3 and 1 mg/kg) produced a dose-related increase in locomotor activity, which reached significance at the higher dose. Nicotine produced a dose-related increase in social interaction, which reached significance at 0.5 mg/kg, but was without effect on locomotor activity. The specific increases in social interaction observed with diazepam and nicotine are similar to those seen in the well-validated social interaction test of anxiety in rats and suggest that social interaction in gerbils may also be used to screen for anxiolytic action of novel compounds.     

MK-801 increases locomotor activity without elevating extracellular dopamine levels in the nucleus accumbens

In vivo microdialysis was used in freely moving rats to determine whether the locomotor stimulant effects of dizocilpine maleate (MK-801) were related to increased dopamine (DA) release within the nucleus accumbens (N. Acc.). Each experiment began with a baseline period of at least 2 h (starting 15–20 h after insertion of concentric, removable dialysis probes), during which activity records and dialysate samples were collected every 20 min. Rats in the first experiment then were injected with MK-801 (0.125, 0.25, or 0.50 mg/kg, i.p.) or saline, and activity and extracellular levels of DA, dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) were measured for a further 160 min post-injection. In a second experiment, rats were given 1.5 mg/kg d-amphetamine sulphate 40 min after receiving the same doses of MK-801, and testing was continued for 120 min. Rats in a third experiment were given low, autoreceptor-preferring doses of apomorphine hydrochloride (25 or 50 μg/kg, s.c.) or its vehicle 40 min after injection of 0.25 mg/kg MK-801 and then monitored for 120 min. MK-801 produced strong and consistent increases in locomotor activity that were augmented by amphetamine and greatly reduced by the low doses of apomorphine. MK-801 did not increase extracellular DA levels within the N. Acc. when given alone, and it failed to influence the changes in extracellular DA produced by d-amphetamine and apomorphine. MK-801 did produce consistent, dose-related increases in DOPAC and HVA that were probably not related to transmitter release. These results indicate that the increases in locomotor activity seen following MK-801 do not arise from a drug-induced increase in DA levels within the N. Acc. © 1996 Wiley-Liss, Inc.     

Possible involvement of serotonergic neurons in the reduction of locomotor hyperactivity caused by amphetamine in neonatal rats depleted of brain dopamine

This experiment attempted to determine the mechanism by which amphetamine reduces locomotor hyperactivity in neonatal rats given brain dopamine (DA)-depleting 6-hydroxydopamine (6-OHDA) injections. Brain DA neurons were destroyed selectively in neonatal rats by intraventricular (i.v.t.) injections of 6-OHDA following desmethylimipramine (DMI) pretreatment. Control rats received DMI and i.v.t. injections of the 6-OHDA vehicle solution. Rats given the 6-OHDA treatment displayed 7-fold increases in locomotor activity compared to controls during days 16–55 of life. Throughout this period, amphetamine (1 mg/kg) reduced locomotor hyperactivity in 6-OHDA-treated rats but increased locomotor activity in control rats. The reduction of hyperactivity caused by amphetamine (0.5–4 mg/kg) was dose-related and was not accompanied by stereotyped behavior. Like amphetamine, methylphenidate (4 mg/kg) reduced locomotor hyperactivity in rats given 6-OHDA. The DA antagonist, spiroperidol (50–200 μg/kg) failed to attenuate the hyperactivity-reducing effect of amphetamine in 6-OHDA-treated rats at doses which abolished the stimulant effect of amphetamine in control rats. However, the serotonin antagonist methysergide (0.5–4 mg/kg) produced dose-dependent antagonism of the effect of amphetamine in 6-OHDA-treated rats. Pretreatment with propranolol (5 mg/kg), phentolamine (5 mg/kg), atropine (0.5 mg/kg) or naloxone (10 mg/kg) failed to alter the reduction in locomotor hyperactivity caused by amphetamine. The serotonin releasing agent, fenfluramine (3 mg/kg), and the serotonin agonist, quipazine (0.5–4 mg/kg), both reduced locomotor hyperactivity in 6-OHDA-treated rats while not altering locomotion in control rats. These results confirm previous observations that amphetamine reduces locomotor hyperactivity caused by neonatal 6-OHDA administration and suggest that this effect is mediated by increased serotonergic neurotransmission.     

The effect of age on concentrations of monoamines, amino acids, and their related substances in the cerebrospinal fluid

Summary In 24 h reserpine-treated mice, the locomotion induced by the D₁ dopamine agonist SKF 38393 (30 mg/kg IP) was facilitated by the NMDA antagonists MK 801 (0.4 mg/kg IP), CPP (1 mg/kg IP), CGP 40116 (1 mg/kg IP) and HA 966 (2 mg/kg IP), and by the AMPA antagonist NBQX (0.2 mg/kg IP). By contrast, CPP, CGP 40116 and NBQX had no effect on, while MK 801 and HA 966 suppressed, the locomotion elicited by the selective D₂ agonist RU 24213 (5 mg/kg SC). When these same doses of glutamate antagonists were tested against the locomotion induced by a threshold (0.025 mg/kg SC), intermediate (0.1 mg/kg SC) or large dose (0.5 mg/kg SC) of the mixed D₁/D₂ agonist apomorphine, CPP, CGP 40116 and HA 966 were found to have no significant effect, whilst MK 801 was strongly inhibitory and NBQX potentiated the response to 0.1 mg/kg apomorphine only. It is evident from these data that the behavioural interaction profiles between glutamate antagonists and dopamine agonists are complex and depend on the receptor selectivities of the drugs concerned. The manner of the interaction between these glutamate antagonists and selective D₁ or D₂ agonists, is not predictive of the way that blockade of glutamate transmission interferes with the actions of drugs which have combined D₁ and D₂ motor stimulant properties.     

Comparison of the effects of the cholecystokinin-B receptor antagonist,PD 134308, and the cholecystokinin-A receptor antagonist,L-364,718, on dopamine neuronal activity in the substantia nigra and ventral tegmental area

Extracellular single-unit recording techniques were used to study the effects of the cholecystokinin-A (CCK-A) antagonist, L-364, 718, and the CCK-B antagonist, PD 134308, on DA neuronal activity in chloral hydrate anesthetized rats. Neither L-364, 718 (0.1-1.6 mg/kg i.v.) nor PD 134308 (0.1-6.4 mg/kg) altered the basal firing rate of substantia nigra or ventral tegmental area DA neurons. The ability of PD 134308 and L-364, 718 to alter the apomorphine-induced inhibition of substantia nigra DA neurons was assessed. Pretreatment with L-364, 718 (0.6 or 4.16 mg/kg i.v.) did not shift the apomorphine dose-response curve (0.5-32 μg/kg i.v.). In contrast, PD 134308 (0.6 or 6.4 mg/kg i.v.) produced dose-related, significant shifts to the right of the apomorphine dose-response curve. However, these effects were small in comparison to the haloperidol (0.1 mg/kg i.p.)-induced shift of the apomorphine curve. These data suggest that in the substantia nigra there may be a tonic level of CCK release that, through actions on CCK-B receptors, may modulate DA agonist-induced inhibition of DA neuronal activity. © 1993 Wiley-Liss, Inc.     

Ascorbic acid administration produces an antidepressant-like effect: Evidence for the involvement of monoaminergic neurotransmission

Ascorbic acid is highly concentrated in the brain, being considered as a neuromodulator. This study investigated the effect of ascorbic acid in the tail suspension test (TST) and in the forced swimming test (FST) in mice and the contribution of the monoaminergic system to its antidepressant-like effect. Moreover, the effects of fluoxetine, imipramine and bupropion in combination with ascorbic acid in the TST were investigated. Ascorbic acid (0.1–10 mg/kg, i.p., 1–10 mg/kg p.o. or 0.1 nmol/mice i.c.v.) produced an antidepressant-like effect in the TST, but not in the FST, without altering the locomotor activity. The effect of ascorbic acid (0.1 mg/kg, i.p.) in the TST was prevented by i.p. pre-treatment with NAN-190 (0.5 mg/kg), ketanserin (5 mg/kg), MDL72222 (0.1 mg/kg), prazosin (62.5 µg/kg), yohimbine (1 mg/kg), propranolol (2 mg/kg), haloperidol (0.2 mg/kg), sulpiride (50 mg/kg), but not with SCH23390 (0.05 mg/kg, s.c.). Additionally, ascorbic acid (1 mg/kg, p.o.) potentiated the effect of subeffective doses (p.o. route) of fluoxetine (1 mg/kg), imipramine (0.1 mg/kg), or bupropion (1 mg/kg) in the TST. The combined treatment of ascorbic acid with antidepressants produced no alteration in the locomotion in the open-field test. In conclusion, our results show that administration of ascorbic acid produces an antidepressant-like effect in TST, which is dependent on its interaction with the monoaminergic system. Moreover, ascorbic acid caused a synergistic antidepressant-like effect with conventional antidepressants. Therefore, the present findings warrant further studies to evaluate the therapeutical relevance of ascorbic acid for the treatment of depression and as a co-adjuvant treatment with antidepressants.