The involvement of adenosine receptors in the effect of dizocilpine on mice in the elevated plus-maze

It has been claimed that blockade of receptors for N-methyl-D-aspartate (NMDA) can enhance adenosine receptor function on single neurones. Previous work has also indicated that the NMDA channel blocker dizocilpine, and the A₁ selective agonist N6-cyclopentyladenosine (CPA) both had anxiolytic profiles in the elevated plus-maze. The anxiolytic effect of dizocilpine was accompanied by an increase in locomotor activity. In the present study, the elevated plus-maze has been used to determine whether dizocilpine's effects on behaviour are mediated through activation of adenosine receptors. When co-administered with dizocilpine (0.05 mg/kg), CPA (0.05 mg/kg) reduced the anxiolytic and locomotor effects of dizocilpine. The A₁ selective antagonist 1,3-dipropyl-8-cyclopentylxanthine (CPX, 0.05 mg/kg) had no effect when administered alone. When co-administered with dizocilpine, CPX reversed the anxiolytic and increased locomotor effects induced by dizocilpine. The A₂ receptor selective agonist N6-[2-(3,5-dimethoxyphenyl)-2(2-methylphenyl)-ethyladenosine (DPMA) (1 mg/kg) reversed both the anxiolytic effect and the increased locomotion induced by dizocilpine, while the A₂ selective antagonist 3,7-dimethyl-1-propargylxanthine (DMPX) (1 mg/kg) did not. It is concluded that at least part of the anxiolytic and locomotor stimulant properties of dizocilpine may be explained by the release of endogenous adenosine acting at A1, but not A2 receptors.     

Biphasic effects of clonidine on conflict behavior: involvement of different alpha-adrenoceptors

The effect of the alpha-2-adrenoceptor agonist clonidine on anxiety-related behavior was investigated using two different rat anxiety models: a modified Vogel's drinking conflict model and Montgomery's elevated plus-maze. In both models biphasic dose-response curves were obtained; in a narrow low-dose range (6.25-10.0 micrograms/kg) the drug produced anxiolytic-like effects, while anxiogenic-like properties were found after higher doses (12.5-80.0 micrograms/kg). Attempts to block the effects obtained were made in Montgomery's elevated plus-maze. The specific alpha-2-adrenoceptor antagonist idazoxan blocked the anxiolytic-like effect but did not influence the anxiogenic-like activity. Conversely, the specific alpha-1-adrenoceptor antagonist prazosin blocked the anxiogenic-like effect but did not alter the anxiolytic-like activity. These findings may suggest that alpha-1- and alpha-2-adrenergic receptor mechanisms are reciprocally involved in anxiety-related behavior.     

Role of the cannabinoid system in the effects induced by nicotine on anxiety-like behaviour in mice

Rationale Acute behavioural effects and motivational responses induced by nicotine can be modulated by the endocannabinoid system supporting the existence of a physiological interaction between these two systems. Objectives The present study was designed to examine the possible involvement of the cannabinoid system in the anxiolytic- and anxiogenic-like responses induced by nicotine in mice. Methods Animals were only exposed once to nicotine. The acute administration of low (0.05) or high (0.8 mg/kg, s.c.) doses of nicotine produced opposite effects in the elevated plus-maze, i.e. anxiolytic- and anxiogenic-like responses, respectively. The effects of the pretreatment with the CB1 cannabinoid receptor antagonist, rimonabant (0.25, 0.5 and 1 mg/kg, i.p.), and the cannabinoid agonist, Δ9-tetrahydrocannabinol (Δ9-THC, 0.1 mg/kg, ip), were evaluated on the anxiolytic- and anxiogenic-like responses induced by nicotine. Results Rimonabant completely abolished nicotine-induced anxiolytic-like effects and increased the anxiogenic-like responses of nicotine, suggesting an involvement of CB1 receptors in these behavioural responses. On the other hand, Δ9-THC failed to modify nicotine anxiolytic-like responses but attenuated its anxiogenic-like effects. In addition, the association of non-effective doses of Δ9-THC and nicotine produced clear anxiolytic-like responses. Conclusions These results demonstrate that the endogenous cannabinoid system is involved in the regulation of nicotine anxiety-like behaviour in mice and provide new findings to support the use of cannabinoid antagonists in the treatment of tobacco addiction.     

Involvement of 5-HT1A receptors in behavioural effects of the cannabinoid receptor agonist CP 55,940 in male rats

We have studied the possible interaction between the cannabinoid receptor agonist CP 55,940 (1 and 50 microg/kg) and the 5-HT1A receptor antagonist WAY 100635 (1 mg/kg) in the modulation of plus-maze and holeboard activity in Wistar adult male rats. In the plus-maze, the higher dose of CP 55,940 induced an anxiogenic-like effect, whereas the lower dose induced anxiolytic-like responses. The 5-HT1A antagonist, which was silent in this test, attenuated the anxiogenic, but not the anxiolytic, effect of CP 55,940. In the holeboard, the higher dose of CP 55,940 significantly decreased head-dipping duration, and WAY 100635, which did not affect exploratory head-dipping when administered alone, antagonized this effect. The administration of WAY 100635 significantly increased grooming behaviour, and this effect was inhibited by the two doses of CP 55,940, which did not exert any effect, per se, on this parameter. We provide the first evidence implicating 5-HT1A receptors in anxiety-related behavioural responses to a cannabinoid agonist.     

Adenosine A1 receptors modulate the anxiolytic-like effect of ethanol in the elevated plus-maze in mice

The anxiolytic property of ethanol is generally accepted to be an important motivational factor for its consumption and the development of alcohol dependence. Recent studies suggest that adenosine receptors mediate important actions of ethanol, such as motor incoordination and hypnotic effects. In addition, several lines of evidence support the involvement of adenosine in anxiety. The aim of the present study was to evaluate the role of adenosine receptors in the anxiolytic-like effect of ethanol in mice. The effects of acute administration of the adenosine receptor antagonists caffeine (nonselective), 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, adenosine A1 receptor antagonist) and 4-(2-[7-amino-2-[2-furyl][1,2,4]triazolo-[2,3-a][1,3,5]triazin-5-yl-amino]ethyl)phenol (ZM241385, adenosine A(2A) receptor antagonist), together with the adenosine A1 receptor agonist 2-chloro-N6-cyclopentyladenosine (CCPA), and their interaction with ethanol in the elevated plus-maze test in mice were studied. The highest doses of caffeine (30.0 mg/kg, i.p.) and DPCPX (6.0 mg/kg, i.p.) produced an anxiogenic-like effect, while CCPA administration (0.25 mg/kg, i.p.) showed an anxiolytic-like activity. The prior administration of "non-anxiogenic" doses of caffeine (10.0 mg/kg, i.p.) and DPCPX (3.0 mg/kg, i.p.), but not ZM241385 (1.0 mg/kg, i.p.), significantly reduced the anxiolytic-like effect of ethanol (1.2 g/kg, i.p.). Moreover, anxiolytic-like response was observed by the co-administration of "non-anxiolytic" doses of CCPA (0.125 mg/kg) and ethanol (0.6 g/kg). These results reinforce the involvement of adenosine in anxiety and suggest that the activation of adenosine A1 receptors, but not adenosine A(2A) receptors, mediate the anxiolytic-like effect induced by ethanol in mice.     

Purine modulation of dizocilpine effects on spontaneous alternation

 The Y-maze was used to assess spontaneous alternation behaviour in mice to examine possible interactions between the N-methyl-D-aspartate receptor channel blocker dizocilpine and purine receptor agonists and antagonists. Scopolamine reduced spontaneous alternation. Dizocilpine also produced a dose-dependent reduction in alternation scores, which was accompanied by an increase in locomotion. The selective A₁ adenosine receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (CPX) had no effect when administered alone, or in combination with scopolamine. However, when co-administered with dizocilpine, CPX reversed both the deficit in alternation behaviour and also the increase in locomotion induced by dizocilpine. The A₁ selective agonist N ⁶-cyclopentyladenosine (CPA) had no effect on either locomotion or alternation scores when administered alone, but in combination with scopolamine, CPA attenuated the scopolamine-induced deficit. CPA had no significant effect on the dizocilpine-induced deficit. The A₂ selective agonist N ⁶-[2-(3, 5-dimethoxyphenyl)-2(2-methylphenyl)-ethyl]adenosine (DPMA), had no effect on spontaneous alternation when administered alone, but did cause a depression of locomotion. DPMA had no significant effect when co-administered with scopolamine, but reversed the deficit in spontaneous alternation, and the increase in locomotion induced by dizocilpine. The A₂ selective antagonist 3,7-dimethyl-1-propargylxanthine (DMPX) had no effect when given alone or in combination with scopolamine, but when co-administered with dizocilpine, DMPX reversed the reduction in spontaneous alternation caused by dizocilpine. It is concluded that dizocilpine has a detrimental effect on spontaneous alternation which is mediated partly by A₁ and A₂ adenosine receptors. Received: 21 March 1996 / Final version: 6 November 1996     

8-OH-DPAT, but not deramciclane, antagonizes the anxiogenic-like action of paroxetine in an elevated plus-maze

OBJECTIVE: To investigate whether a 5-hydroxytryptamine (5-HT) reuptake inhibitor (paroxetine) has an anxiogenic-like effect and what possible pharmacological mechanism underlies that action. METHODS: We used the rat elevated plus-maze paradigm followed by measurement of locomotor activity. Some of the rats were subjected to handling and adaptation to the experimental situation, while the rest were naive to the test situation. Paroxetine was administered as a single treatment and in combination with the 5-HT1A receptor agonist (8-OH-DPAT) or 5-HT2A/2C receptor antagonist (deramciclane). RESULTS: The administration of paroxetine induced an anxiogenic-like action in rats adapted to handling, but not in handling naive animals. Treatment with paroxetine (0.1-2 mg/kg) reduced the number of open arm visits and time spent in open arms, and the ratio between open and total arm entries in the elevated plus-maze. Paroxetine also decreased the number of line crossings and head-dips. Paroxetine caused the strongest anti-exploratory action at a dose of 0.5 mg/kg. Paroxetine did not suppress the locomotor activity of rats, showing that the described anti-exploratory effect was behaviourally specific to the plus-maze. Pretreatment with 8-OH-DPAT (0.05 mg/kg) completely reversed the anxiogenic-like action of paroxetine, whereas treatment with deramciclane (2 mg/kg) affected only the number of closed arm visits. Deramciclane (0.5-2 mg/kg) and 8-OH-DPAT (0.01-0.1 mg/kg) changed neither exploratory behaviour nor locomotor activity if given as single treatments to the habituated rats. CONCLUSION: The 5-HT reuptake inhibitor, paroxetine, at a low dose (0.5 mg/kg) induces an anxiogenic-like action in handling adapted rats. The effectiveness of 8-OH-DPAT against paroxetine probably supports a role of both pre- and postsynaptic 5HT-ergic mechanisms in the anxiogenic-like action of paroxetine.     

Effects of purine analogues on spontaneous alternation in mice

The Y-maze was used to examine the effects of purines acting at A₁ and A₂ adenosine receptors upon spontaneous alternation, a model of working memory, in mice. In support of previous work, scopolamine produced a loss of spontaneous alternation behaviour to the 0.5 chance level. The A₁ receptor selective agonist N6-cyclopentyladenosine (CPA) did not change spontaneous alternation behaviour alone, but it prevented the decrease of spontaneous alternation scores produced by scopolamine. The A₁ receptor selective antagonist 1,3-dipropyl-8-cyclopentylxanthine (CPX) blocked the effect of CPA in combination with scopolamine but had no effect alone. The A₂ receptor selective agonist (N6-[2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)ethyl]adenosine (DPMA), and the A₂ receptor selective antagonist 3,7-dimethyl-1-propargylxanthine (DMPX) had no effect of alternation behaviour alone and did not modify the effect of scopolamine. The results indicate the ability of A₁ but not A₂ receptor activation to modify working memory deficits induced by scopolamine, but suggest that endogenous adenosine does not normally participate in working memory processes.     

Interaction of angiotensin II and adenosine A1 and A2A receptor ligands on the writhing test in mice

The effects of adenosine A1 and A2A receptor agonists and antagonists administered intraperitoneally (i.p.) and their interaction with angiotensin II (Ang II) administered intracerebroventricularly (i.c.v.) were studied in mice using the acetic acid-induced abdominal constriction test. Ang II (0.1 microg/mouse) induced antinociception in this model. The adenosine A1 receptor agonist N6-cyclopentyladenosine (CPA; 0.05, 0.25 and 0.5 mg/kg) also showed a well-developed antinociceptive effect. Ang II (0.1 microg/mouse) administered 5 min before CPA (0.25 mg/kg) decreased the number of writhes, i.e., it enhanced the antinociceptive effect of CPA. Losartan, an AT1 receptor antagonist (25 microg/mouse i.c.v.), enhanced the antinociceptive effect of CPA, while the AT2 receptor antagonist 1-[-4-(dimethylamino)-3-methylphenylmethyl]-5-diphenylacetyl)-4,5,6,7-tetrahydro 1H-4-imidazol [4,5c]pyridine-6 carboxylic acid, ditrifluoroacetate, dihydrate (PD 123319; 10 microg/mouse) had less effect. 8-Cyclopentyl-1,3-dipropylxanthine (DPCPX; 0.1 mg/kg), an adenosine A1 receptor antagonist, exhibited a pronociceptive effect and did not change the antinociceptive effect of Ang II. The adenosine A2A receptor agonist PD-125944 (DPMA; 0.1, 0.5 and 1 mg/kg) showed pronounced antinociceptive effect. Ang II (0.1 microg/mouse) did not significantly influence the antinociceptive effect of DPMA (0.1 mg/kg). The A2A receptor antagonist 3,7-dimethyl-1-propargilxanthine (DMPX; 0.1 mg/kg) had no effect on the number of writhes and did not influence the effect of Ang II. These data indicate that the antinociceptive effect of Ang II interacts with that produced by adenosine A1 receptor agonist.     

The differential role of A1 and A2 adenosine receptor subtypes in locomotor activity and place conditioning in rats

Previous studies have demonstrated that the non-specific adenosine antagonist caffeine possesses both motor activating and rewarding properties in a place-conditioning paradigm. The present experiments were designed to determine the relative contribution of A1 and A2 adenosine receptor subtypes to these effects. The A2 adenosine antagonist CGS 15943A (0.1-10.0mg/kg) dose-dependently produced both a place preference and enhanced locomotor activity. In contrast, the A1 antagonist CPX (0.01-40.0mg/kg) failed significantly to alter either behavioral measure. Both the A1 receptor agonist CPA (0.01-10.0mg/kg) and the A2 receptor agonist CGS 21680 (0.01-1.0mg/kg) reliably decreased activity but failed to produce significant place conditioning. The increased activity produced by the A2 antagonist CGS 15943A (1.0mg/kg) was attenuated by behaviourally active doses of either CPA or CGS 21680. The place preference produced by CGS 15943A (1.0mg/kg) was attenuated by CPA and CGS 21680, at agonist doses that failed to produce place conditioning when administered alone. In general, the results suggested that although it is the A2 receptor subtype that participates in the establishment of place conditioning and enhanced activity, both receptors participate in the diffuse depressant effects associated with adenosine.     

Interactions between ifenprodil and dizocilpine on mouse behaviour in models of anxiety and working memory

The N-methyl- -aspartate (NMDA) receptor polyamine site antagonist, ifenprodil, had no effect on spontaneous alternation or locomotor activity in the Y-maze when given alone. The NMDA receptor/ion channel blocker, dizocilpine, induced a deficit in spontaneous alternation, but when ifenprodil was co-administered with dizocilpine, it showed a strong tendency to attenuate the dizocilpine-induced deficit. In the plus-maze, ifenprodil had an anxiolytic profile which was accompanied by an increase in locomotion. Dizocilpine had an anxiolytic profile in this model and increased locomotor activity. When co-administered with dizocilpine, ifenprodil reduced both the anxiolytic and locomotor effects of dizocilpine. When co-administered with ifenprodil, cyclopentyladenosine (CPA) and 1,3-dipropyl-8-cyclopentylxanthine (CPX) reduced the anxiolytic effect of ifenprodil. CPA and CPX in combination did not reverse the anxiolytic effect of ifenprodil. It is concluded that NMDA antagonists with different sites of action can show distinct behavioural profiles, with dizocilpine but not ifenprodil inducing a deficit in working memory, while both are anxolytic. Blockade of NMDA receptors by ifenprodil, however, can preclude any response to dizocilpine. The anxiolytic activity of ifenprodil may involve the release of purines acting at adenosine receptors.     

GABA(B) receptors involvement in the effects induced by nicotine on anxiety-related behaviour in mice

The aim of the present study was to evaluate the possible involvement of GABA(B) receptors in the anxiolytic- and anxiogenic-like responses induced by nicotine in mice. Animals were exposed to nicotine only once. The acute administration of low (0.05mg/kg, sc) or high (0.8mg/kg, sc) doses of nicotine produced opposite effects in the elevated plus maze test; respectively, anxiolytic- and anxiogenic-like responses. The effect of pretreatment with either the GABA(B) receptor antagonist 2-OH-saclofen (0.25, 0.5 and 1mg/kg; ip) or the GABA(B) receptor agonist baclofen (0.5, 1 and 2mg/kg; ip), was evaluated on the anxiolytic- and anxiogenic-like responses induced by nicotine. 2-OH-saclofen completely abolished both nicotine-induced effects (p<0.001) at the highest dose tested, suggesting an involvement of GABA(B) receptors in these behavioural responses. On the other hand, baclofen failed to modify the anxiety-related effects of nicotine. These results suggest that the GABA(B) receptors are involved in the regulation of nicotine-induced anxiety-related behavioural responses in mice, and provide new findings to support a potential pharmaco therapeutic use of GABAergic drugs in the treatment of tobacco addiction.     

Involvement of the dopaminergic receptors of the rat basolateral amygdala in anxiolytic-like effects of the cholinergic system

Cholinergic system stimulation in some parts of the brain may affect anxiety-related behaviors. This system has many interactions with dopaminergic neurotransmission in the brain. We have studied the effect of cholinergic system activation in the basolateral amygdala on anxiety-related behaviors in adult male wistar rats using the acetylcholinesterase inhibitor physostigmine. Furthermore, the possible involvement of dopamine D(1) and D(2) receptors of basolateral amygdala in physostigmine induced effects has been evaluated. The elevated plus-maze task was used to assess anxiety parameters and all drugs were delivered into basolateral amygdala via bilaterally implanted chronic cannulas. Physostigmine (20 μg/rat) increased the percentage of open arm time (%OAT) and open arm entries (%OAE), revealing an anxiolytic-like effect. However, muscarinic receptor antagonist scopolamine (8 μg/rat) decreased %OAT indicating anxiogenic-like effect. A sub-effective dose of scopolamine (2 μg/rat) plus physostigmine decreased %OAT and %OAE in comparison to saline plus physostigmine (20 μg/rat). Muscarinic receptor agonist pilocarpine (5 μg/rat), dopamine D(1) receptor antagonist SCH23390 (1 μg/rat) and dopamine D(2) receptor antagonist sulpiride (5 μg/rat) significantly increased %OAT which may show anxiolytic-like effects of drugs. Sulpiride (5 μg/rat) also increased %OAE parameter. Pre-treatment with SCH23390 (0.5 and 1 μg/rat) or sulpiride (5 μg/rat) blocked anxiolytic-like effect of physostigmine (20 μg/rat). All drugs were devoid of any significant effect on locomotor activity. It is concluded that intra-basolateral amygdala administration of physostigmine has anxiolytic-like effects which may be via muscarinic mechanisms. Furthermore, dopaminergic system activation probably via dopamine D(1) and D(2) receptors is necessary for mediating anxiolytic-like effects of physostigmine.     

Nicotine-induced anxiogenic-like behaviours of rats in the elevated plus-maze: possible role of NMDA receptors of the central amygdala

The objective of the present study was to investigate the possible role of the N-methyl-D-aspartate (NMDA) receptor system of the central amygdala (CeA) in the anxiogenic-like effect of nicotine. Male Wistar rats with cannulas aimed to the CeA were submitted to the elevated plus-maze (EPM). Intraperitoneal (i.p.) injections of nicotine (0.6 and 0.8 mg/kg) decreased percentage open arm time spent (%OAT) and percentage open arm entries (%OAE), but not locomotor activity, indicating an anxiogenic-like response. Bilateral intra-CeA microinjection of NMDA (0.005-0.1 μ g/rat) decreased %OAT, but not %OAE and locomotor activity. Moreover, intra-CeA microinjection of NMDA (0.05 μ g) with an ineffective dose of nicotine (0.4 mg/kg, i.p.) reduced %OAT and %OAE without effect on locomotor activity. On the other hand, intra-CeA microinjection of the NMDA receptor antagonist D-AP5 (0.05-0.5 μ g/rat) increased both %OAT and %OAE, showing an anxiolytic-like effect of the drug. Co-administration of the same doses of D-AP5 with nicotine (0.6 mg/kg, i.p.) increased %OAT and %OAE, but not locomotor activity. Intra-CeA microinjection of D-AP5 reversed the response induced by NMDA (0.1 μ g/rat) in the EPM. The results may support the possible involvement of glutamate transmission, through NMDA receptors of central amygdala in the anxiogenic-like effect of nicotine in the EPM task.     

Neuropeptide Y Y(5) receptor antagonist CGP71683A: the effects on food intake and anxiety-related behavior in the rat

The effects of neuropeptide Y Y(5) receptor antagonist (trans-naphtalene-1-sulphonic acid [4-[(4-amino-quinazolin-2-ylamino)-methyl]-cyclohexylmethyl]-amide hydrochloride; CGP71683A), on food intake, anxiety and locomotor activity were studied. CGP71683A (1-10 mg/kg, i.p.) dose-dependently decreased nocturnal and fasting-induced food intake. CGP71683A did not have an anxiogenic-like effect in the rat social interaction test. In the elevated plus-maze test, where novel neuropeptide Y Y(1) receptor antagonist (2R)-5-([amino(imino)methyl)amino)-2-[(2.2-diphenylacetyl)-amino]-N-[(1R)-1-(4-hydroxyphenyl)ethyl-pentanamide (H 409/22) had anxiogenic-like effect, CGP71683A was inactive. In the open-field test, carried out immediately after the elevated plus-maze test, CGP71683A inhibited horizontal and vertical activity. CGP71683A did modify the habituation of locomotor response in novel environment. These data show that the inhibition of food intake induced by CGP71683A could not be explained by increased fearfulness, a state that is induced by neuropeptide Y Y(1) receptor antagonists. Thus, our data, obtained with first neuropeptide Y Y(5) receptor antagonist CGP71683A, suggest that in contrast to the neuropeptide Y Y(1) receptor, Y(5) receptor is not involved in tonic neuropeptide Y-induced anxiolysis.     

Activation of adenosine A1 receptors reduces anxiety-like behavior during acute ethanol withdrawal (hangover) in mice.

Elevated signs of anxiety are observed in both humans and rodents during withdrawal from chronic as well as acute ethanol exposure, and it represents an important motivational factor for ethanol relapse. Several reports have suggested the involvement of brain adenosine receptors in different actions produced by ethanol such as motor incoordination and hypnotic effects. In addition, we have recently demonstrated that adenosine A1 receptors modulate the anxiolytic-like effect induced by ethanol in mice. In the present study, we evaluated the potential of adenosine A1 and A2A receptor agonists in reducing the anxiety-like behavior during acute ethanol withdrawal (hangover) in mice. Animals received a single intraperitoneal administration of saline or ethanol (4 g/kg) and were tested in the elevated plus maze after an interval of 0.5-24 h. The results indicated that hangover-induced anxiety was most pronounced between 12 and 18 h after ethanol administration, as indicated by a significant reduction in the exploration of the open arms of the maze. At this time interval, ethanol was completely cleared. The acute administration of 'nonanxiolytic' doses of adenosine and the selective adenosine A1 receptor agonist 2-chloro-N6-cyclopentyladenosine (CCPA), but not the adenosine A2A receptor agonist N6-[2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)ethyl]adenosine (DPMA), at the onset of peak withdrawal (18 h), reduced this anxiogenic-like response. In addition, the effect of CCPA on the anxiety-like behavior of ethanol hangover was reversed by pretreatment with the selective adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX). These results reinforce the notion of the involvement of adenosine receptors in the anxiety-like responses and indicate the potential of adenosine A1 receptor agonists to reduce the anxiogenic effects during ethanol withdrawal.     

Anxiolytic- and antidepressant-like effects of 7-OH-DPAT, preferential dopamine D3 receptor agonist, in rats

The aim of the present study was to examine a potential anxiolytic- and antidepressant-like action of (+)-7-hydroxy-2-(di-n-propylamino)tetralin hydrobromide (7-OH-DPAT), a preferential dopamine D(3) receptor agonist, and N-{4-[4-(2-methoxyphenyl)-1-piperazinyl]butyl}-2-naphthylcarboxamide (BP 897), a partial dopamine D(3) receptor agonist, in male Wistar rats. Diazepam or imipramine were used as reference compounds. The anxiolytic-like effect of those drugs was tested in the elevated plus-maze test. The antidepressant-like effect was estimated using the forced swimming test. The obtained results showed that 7-OH-DPAT at low doses and BP 897 (like diazepam) induced anxiolytic-like effects in the elevated plus-maze test. 7-OH-DPAT, BP 897 and diazepam, tested at the doses effective in the model of anxiolytic-like actions, did not affect motor coordination. Moreover, 7-OH-DPAT at higher doses, like imipramine, showed antidepressant-like effect, significantly reducing immobility time in the forced swimming test. Combined treatment with 7-OH-DPAT and imipramine induced a stronger effect in Porsolt's test than administration of either drug alone, but did not increase the locomotor activity. In contrast, BP 897 was inactive in the forced swimming test when given alone but it potentiated the antidepressant-like effect of imipramine. These data suggest that preferential D(3) receptor agonists may play a role in the therapy of anxiety and/or depression, however, further studies are necessary to elucidate the mechanism of these actions.     

Involvement of the opioid system in the effects induced by nicotine on anxiety-like behaviour in mice

Rationale Recent studies have revealed the participation of the endogenous opioid system in several behavioural responses induced by nicotine including antinociception, rewarding properties, and physical drug dependence. Objectives The present study was designed to examine the possible involvement of the various opioid receptors in the anxiolytic- and anxiogenic-like responses induced by nicotine in mice. Methods The acute administration of low (0.05) or high (0.8 mg/kg) doses of nicotine subcutaneously produced opposite effects in the elevated plus maze, i.e. anxiolytic- and anxiogenic-like responses, respectively. Animals were only exposed once to nicotine. The effects of the pretreatment with the μ-opioid receptor antagonist, β-funaltrexamine (5 mg/kg), the δ-opioid antagonist, naltrindole (2.5 mg/kg) and the κ-opioid antagonist, nor-binaltorphimine (2.5 mg/kg) intraperitoneally were evaluated on the anxiolytic- and anxiogenic-like responses induced by nicotine. Results β-funaltrexamine, but not nor-binaltorphimine or naltrindole, abolished nicotine-induced anxiolytic-like effects, suggesting an involvement of μ-opioid receptors in this behavioural response. On the other hand, naltrindole, but not nor-binaltorphimine or β-funaltrexamine, increased the anxiogenic-like responses of nicotine, suggesting an involvement of δ-receptors in this behavioural effect. Conclusions These results demonstrate that the endogenous opioid system is involved in the effects induced by nicotine on anxiety-like behaviour and provide new findings to further clarify the interaction between these two neurochemical systems.     

Effects of the brain-penetrant and selective 5-HT6 receptor antagonist SB-399885 in animal models of anxiety and depression

The effects of a selective 5-HT(6) receptor antagonist, SB-399885 (N-[3,5-dichloro-2-(methoxy)phenyl]-4-(methoxy)-3-(1-piperazinyl)benzenesulfonamide), were evaluated in behavioural tests sensitive to clinically effective anxiolytic- and antidepressant-compounds using diazepam and imipramine as reference drugs. In the Vogel conflict drinking test in rats, SB-399885 (1-3mg/kg i.p.) caused an anxiolytic-like activity comparable to that of diazepam (2.5-5mg/kg i.p.). An anxiolytic-like effect was also seen in the elevated plus-maze test in rats, where SB-399885 (0.3-3mg/kg i.p.) was slightly weaker than diazepam (2.5-5mg/kg i.p.). In the four-plate test in mice, SB-399885 (3-20mg/kg i.p.) showed an anxiolytic-like effect which was weaker than that produced by diazepam (2.5-5mg/kg i.p.). In the forced swim test in rats, SB-399885 (10mg/kg i.p.) significantly shortened the immobility time and the effect was stronger than that of imipramine (30mg/kg i.p.). In the forced swim test in mice, SB-399885 (20-30mg/kg i.p.) had an anti-immobility action, comparable to imipramine (30mg/kg i.p.) and also in the tail suspension test in mice, SB-399885 (10-30mg/kg i.p.) had an antidepressant-like effect, though was weaker than imipramine (10-20mg/kg i.p.). The tested 5-HT(6) antagonist (3-20mg/kg i.p.) shortened the walking time of rats in the open field test and, at a dose of 30mg/kg i.p. reduced the locomotor activity of mice. SB-399885 (in doses up to 30mg/kg i.p.) did not affect motor coordination in mice and rats tested in the rota-rod test. Such data indicate that the selective 5-HT(6) receptor antagonist SB-399885had specific effects, indicative of this compound's anxiolytic and antidepressant potential.     

The anxiogenic-like and anxiolytic-like effects of MDMA on mice in the elevated plus-maze: a comparison with amphetamine

Many abused substances have been found to possess anxiogenic-like or/and anxiolytic-like properties. Discrepancies about the effects of MDMA, one of the most popular recreational drugs in recent years, on anxiety have been seen in the literature, and almost all of the data in this respect were derived from retrospective studies. The present study was thus designed to examine the drug's actions by using an animal model of anxiety, the elevated plus-maze test in male mice. Intraperitoneal MDMA at 1 mg/kg was ineffective, at 4 mg/kg decreased the percent of open arm entries (p < 0.01), and increased enclosed entries (p < 0.05), at 12 mg/kg had no significant effect, and at 20 mg/kg induced an increase of percent of open time (p < 0.01). As control drugs, amphetamine (0.5-4 mg/kg, i.p.) produced a dose-dependent, anxiogenic-like effect and diazepam (1 mg/kg, i.p.) induced an anxiolytic-like effect in the test. The results indicate that MDMA has anxiogenic-like properties at lower doses and anxiolytic-like at higher doses. The effects of MDMA and amphetamine on the mouse's responses to the plus-maze are compared. These findings provide a possible explanation for the controversies over MDMA's effects on anxiety in the literature.