Central amygdala nicotinic and 5-HT1A receptors mediate the reversal effect of nicotine and MDMA on morphine-induced amnesia.

The present study was designed to investigate possible involvement of the central amygdala (CeA) nicotinic acetylcholine (nACh) and 5-hydroxytryptamine 1A (5-HT1A) receptors in the reversal effect of nicotine and 3,4-methylenedioxy-N-methylamphetamine (MDMA or ecstasy) on morphine-induced amnesia. Two guide cannulas were stereotaxically implanted in the CeA regions and a step-through passive avoidance task was used for the assessment of memory retrieval in adult male Wistar rats. Our results indicated that post-training s.c. administration of morphine (3-7-mg/kg) impaired memory retrieval. Pre-test administration of nicotine (0.3- and 0.5-mg/kg, s.c.) reversed morphine-induced amnesia. In addition, pre-test intra-CeA injection of MDMA (1-2-µg/rat) with an ineffective dose of nicotine (0.1-mg/kg, s.c.) improved memory retrieval, suggesting the interactive effect of the drugs on memory formation. It should be noted that that pre-test intra-CeA injection of 2-µg/rat of MDMA by itself produced amnesia. Interestingly, pre-test intra-CeA injection of mecamylamine, a nACh receptor antagonist (1-2-µg/rat) or (S)-WAY 100135 (0.25-1-µg/rat), a selective 5-HT1A receptor antagonist inhibited the improvement of morphine-induced amnesia which was produced by pre-test co-injection of nicotine and MDMA. Pre-test intra-CeA injection of the same doses of MDMA, mecamylamine or (S)-WAY 100135 by itself had no effect on morphine-induced amnesia. Moreover, pre-test injection of the same doses of mecamylamine or (S)-WAY 100135 into the CeA alone could not change memory retrieval. Taken together, it can be concluded that there is a functional interaction between morphine, nicotine and MDMA via the CeA nicotinic and serotonergic receptor mechanisms in passive avoidance memory retrieval. Moreover, cross state-dependent memory retrieval may have been induced between the drugs and this probably depends on the rewarding effects of the drugs.

Protective effects of a magnesium magnetic isotope (Mg25)-exchanging nanoparticle (25MgPMC16 ) on mitochondrial functional disorders in esmolol-induced cardiac arrest in rats.

In cardiac surgery, agents are needed to produce temporary cardiac arrest (cardioplegia). One of these agents is esmolol (ESM) which is a short-acting selective beta-1 adrenergic receptor antagonist and its overdose causes diastolic ventricular arrest. The (25) MgPMC(16) (porphyrin adducts of cyclohexil fullerene-C60) is known as a nanoparticle which has a cardioprotective effect when the heart is subjected to stressful conditions. In this study, we aimed to confirm the deleterious effects of ESM overdose on cardiac mitochondria and identify any protective effects of (25) MgPMC(16) in male Wistar rats. Esmolol 100 mg kg(-1) (LD50 = 71 mg kg(-1) ) was injected intravenously (i.v.) into tail vein to induce cardiac arrest. This dose was obtained from an ESM dose-response curve which induces at least 80% arrest in rats. (25) MgPMC(16) at three different doses (45, 90 and 224 mg kg(-1) ) was injected i.v. as pretreatment, eight hours before ESM injection. (25) MgCl(2) or (24) MgPMC(16) were used as controls. Following cardiac arrest, the heart was removed and the mitochondria extracted. Mitochondrial viability and the adenosine 5'-diphosphate sodium salt hydrate/Adenosine 5'-triphosphate disodium salt hydrate (ADP/ATP) ratio were measured as biomarkers of mitochondrial function. Results indicate that (25) MgPMC(16) caused a significant increase in mitochondrial viability and decrease in ADP/ATP ratio. No significant changes were seen with (24) MgPMC(16) or (25) MgCl(2) . It is concluded that cardiac arrest induced by ESM overdose leads to a significant decrease in mitochondrial viability and their ATP levels, whereas pretreatment by (25) MgPMC(16) can protect mitochondria by increasing ATP level through liberation of Mg into cells and the improvement of hypoxia.

Nitric oxide in the ventral tegmental area is involved in retrieval of inhibitory avoidance memory by nicotine.

In the present study, the possible involvement of nitric oxide systems in the ventral tegmental area (VTA) in nicotine's effect on morphine-induced amnesia and morphine state-dependent memory in adult male Wistar rats was investigated. Step-through type inhibitory avoidance task was used to test memory retrieval. Post-training administration of morphine (5 and 7.5 mg/kg) induced amnesia. The response induced by post-training morphine was significantly reversed by pre-test administration of the drug. Pre-test injection of nicotine (0.4 and 0.8 mg/kg s.c.) alone and nicotine (0.1, 0.4 and 0.8 mg/kg s.c.) plus an ineffective dose of morphine also significantly reversed the amnesia induced by morphine. Morphine amnesia was also prevented by pre-test administration of l-arginine (1 and 3 µg/rat, intra-VTA), a nitric oxide (NO) precursor. Interestingly, an ineffective dose of nicotine (0.1 mg/kg s.c.) in combination with low dose of l-arginine (0.3 µg/rat, intra-VTA) synergistically improved memory performance impaired by morphine given after training. In contrast, pre-test administration of NG nitro-l-arginine methyl ester hydrochloride (l-NAME), a nitric oxide synthase (NOS) inhibitor (2 µg/rat, intra-VTA) prevented the nicotine reversal of morphine effect on memory. The results suggest a possible role for nitric oxide of ventral tegmental area in the improving effect of nicotine on the morphine-induced amnesia.

Nicotinic acetylcholine receptors of the dorsal hippocampus and the basolateral amygdala are involved in ethanol-induced conditioned place preference.

The purpose of this study was to evaluate whether nicotinic acetylcholine receptors of the dorsal hippocampus and the basolateral amygdala (BLA) can potentiate ethanol response in the conditioned place preference (CPP) paradigm. I.p. administration of different doses of ethanol (0.25-1 g/kg) did not induce CPP. However, the higher dose of the drug (1.5 g/kg i.p.) induced place aversion. Furthermore, microinjection of nicotine (0.5-1 microg/rat) into both CA1 regions (intra-CA1) and the BLA (intra-BLA) did not produce a significant CPP. Interestingly, intra-CA1 or -BLA administration of nicotine plus ethanol (0.5 g/kg) during conditioning phase significantly induced a strong CPP. Microinjection of mecamylamine, the nicotinic acetylcholine receptor antagonist, into the CA1 regions or into the BLA did not alter CPP. However, intra-CA1 or -BLA microinjection of mecamylamine (1-4 microg/rat) reversed the response induced by the microinjection of nicotine (1 microg/rat, intra-CA1 or -BLA) plus ethanol (0.5 g/kg i.p.) in the CPP paradigm. On the other hand, the microinjection of nicotine (0.5-1.5 microg/rat) into the BLA, but not into the CA1 regions before the testing phase potentiated the response of ethanol on the expression of conditioned place preference. Moreover, intra-CA1 administration of nicotine plus ethanol increased the locomotor activity on the test day which was reversed by pretreatment with mecamylamine, while other treatments had no effect on locomotor activity. It can be concluded that the activation of nicotinic acetylcholine receptors of the dorsal hippocampus and the basolateral amygdala can potentiate the ethanol response in the CPP paradigm.

Influence of potassium channel modulators on morphine state-dependent memory of passive avoidance.

In a step-down passive avoidance task, the pre-training injection of 1.25-10 mg/kg of morphine impaired memory. This was restored when injection of the same dose of morphine (pre-test treatment) was repeated 24 h later (morphine state-dependent learning: morphine St-D). ATP-dependent potassium (K(ATP)) channels have been reported to be involved in several actions of morphine following mu-receptor stimulation. We have studied the effect of K(ATP) modulators and naloxone in the restoration of memory by morphine in mice. To investigate the part played by cholinergic systems in the effects of a K(ATP) antagonist (glibenclamide) on morphine St-D, we administered low doses of atropine before glibenclamide administration. Locomotor activity was also studied. Naloxone (0.06-1 mg/kg) reversed the effect of pre-test morphine administration. The effects of the K(ATP) channel blocker glibenclamide (2-18 mg/kg) were similar to those of the pre-test administration of morphine. Pre-test co-administration of glibenclamide and morphine showed no potentiation of the morphine effect. Glibenclamide alone or in combination with morphine did not affect locomotor activity. Pre-test administration of different doses of diazoxide (15-60 mg/kg), a K(ATP)-channel opener, had no effect on restoration of memory when used alone or in combination with morphine. In both cases, the locomotor activity was significantly reduced. Diazoxide blocked the effect of glibenclamide on memory recall. Low-dose atropine also prevented glibenclamide enhancement of memory recall, suggesting that this action of glibenclamide is through the cholinergic system.

Effects of adenosine receptor agonists and antagonists on pentylenetetrazole-induced amnesia.

The effect of adenosine agents on amnesia induced by pentylenetetrazole was examined in mice. Post-training administration of pentylenetetrazole (50 and 60 mg/kg) disrupted 24-h retention of a single-trial passive avoidance task. The adenosine receptor antagonists, theophylline (2.5-25 mg/kg) and 8-phenyltheophylline (0.5-2 mg/kg), administered 30 min before and just after training at doses which did not affect retention, reduced the amnestic effect of pentylenetetrazole in a dose-dependent manner. Post-training administration of the adenosine A(1) receptor agonists, N(6)-cyclohexyladenosine (CHA, 0.1 and 0.5 mg/kg) and N(6)-phenylisopropyladenosine (R-PIA, 0.03 and 0.1 mg/kg), but not the adenosine A(2) receptor agonist, 5'-N-ethylcarboxamidoadenosine (NECA, 0.01 and 0.001 mg/kg), impaired retention. Nonamnestic doses of CHA and R-PIA potentiated the disruption induced by a lower dose of pentylenetetrazole (40 mg/kg). NECA did not induce any response in this respect. It is suggested that an adenosine A(1) receptor mechanism is involved in amnesia induced by pentylenetetrazole.

The possible cross-tolerance between morphine- and nicotine-induced hypothermia in mice.

In the present study, cross-tolerance between hypothermia induced by morphine and nicotine in mice has been investigated. Different doses of morphine or nicotine induced dose-dependent hypothermia. The sub-maximal doses of both drugs were used for interaction studies. Administration of mecamylamine either intracerebroventricularly (2-6 microg/animal icv) or intraperitoneally (0.5 and 1 mg/kg ip) decreased both morphine- or nicotine-induced hypothermia. Naloxone either intracerebroventricularly (2-6 microg/animal) or intraperitoneally (1 and 2 mg/kg) reduced the response to morphine, but not nicotine's response. Hexamethonium (5 and 10 mg/kg ip) caused a slight decrease in morphine's hypothermia, but not that of nicotine. Nicotine's response was decreased in the animals which were made tolerant to hypothermic effect of morphine. Pre-treatment of the animals with low doses of morphine (12.5 or 25 mg/kg), once daily for 3 days, did not cause significant tolerance to the hypothermic response to morphine or nicotine. However, the administration of low doses of morphine (12.5 or 25 mg/kg) plus nicotine (2 mg/kg), once daily for 3 days, increased levels of tolerance to hypothermia induced by either drug. It is concluded that nicotinic receptor mechanism may play a role in morphine-induced hypothermia and there is cross-tolerance between the two drugs.

Involvement of adrenergic and cholinergic systems in nicotine-induced anxiogenesis in mice.

In the present study, the effect of alpha-adrenoceptor agents on response to nicotine in an anxiety model (elevated plus-maze) in mice was investigated. Administered nicotine reduced indices of anti-anxiety behaviour (percent open-arm time (%open-arm time) and percent open-arm entries (%open-arm entry)) and increased indices of anxiety behaviour (protected stretched attention posture and percent of protected head dipping (%protected dipping)), indicating that nicotine elicits an anxiogenic response. This response to the drug was obtained 7 min but not 30 min after drug injection and with doses of 0.25 and 0.5 mg/kg. Nicotinic receptor antagonists mecamylamine (0.5 and 1 mg/kg) and hexamethonium (5 and 10 mg/kg) reduced the response induced by nicotine (0.25 mg/kg). Mecamylamine (1 mg/kg; decreased %open-arm entry and increased protected stretched attention posture) and hexamethonium (10 mg/kg; decreased %open-arm time) showed an anxiogenic-like profile. A muscarinic receptor antagonist, atropine (2.5 and 5 mg/kg), did not alter the nicotine response but elicited an anxiogenic effect by itself. The alpha(1)-adrenoceptor antagonist prazosin (0.25 and 0.5 mg/kg), but not the alpha(1)-adrenoceptor agonist, phenylephrine (4 and 6 mg/kg), reversed the nicotine effect. Single administration of phenylephrine (6 mg/kg) increased %open-arm time, while prazosin did not alter the anxiety behaviour. The alpha(2)-adrenoceptor agonist clonidine (0.001 and 0.01 mg/kg), induced complete immobility when administered in combination with nicotine. However, an alpha(2)-adrenoceptor antagonist, yohimbine (0.5 and 1 mg/kg), appeared to reverse the nicotine response, but did not show interaction with nicotine's effect. Clonidine did not elicit any effect, but yohimbine (1 mg/kg) increased %open-arm entry and %open-arm time by itself. It can be concluded that certain doses of nicotine (0.25 and 0.5 mg/kg) 7 min after their injection induce an anxiogenic effect through nicotinic mechanism(s), and that involvement of alpha(1)- but not alpha(2)-adrenoceptors in the response to nicotine seems likely.

Effect of nicotine on sniffing induced by dopaminergic receptor stimulation.

Effects of nicotine on sniffing induced by amphetamine and apomorphine have been tested in rats. Intraperitoneal (i.p.) administration of nicotine (0.5 and 1 mg/kg), amphetamine (1-6 mg/kg) or apomorphine (0.1-1 mg/kg) induced sniffing. Nicotine (0. 25-1 mg/kg) potentiates sniffing induced by amphetamine (1 mg/kg). Nicotine (1 mg/kg) also potentiates the response induced by different doses (0.1-1 mg/kg) of apomorphine. Atropine induced sniffing and increased the response of both amphetamine and nicotine. Higher doses of hexamethonium decreased the sniffing response induced by amphetamine and the response induced by combination of amphetamine and nicotine. Sulpiride reduced the response induced by nicotine or amphetamine plus nicotine, while SCH23390 reduced normal sniffing behaviour of the animals and sniffing induced by either amphetamine or amphetamine plus nicotine. The data may indicate that nicotinic receptor mechanism(s) may be involved in the sniffing induced by dopaminergic receptor stimulation.

Baclofen-induced antinociception and nicotinic receptor mechanism(s).

In this study, the influences of nicotinic receptor agents on baclofen-induced antinociception in the tail-flick test have been studied. Intraperitoneal administration of baclofen (2.5, 5 and 10 mg/kg) to mice induced a dose-dependent antinociception in the tail-flick test. Subcutaneous injection of nicotine (0.5-2.5 mg/kg) also caused a dose-dependent antinociceptive response. Intracerebral (10 and 20 microg/mouse) but not intraperitoneal administration of hexamethonium (5 and 10 mg/kg) to mice decreased the response of both nicotine and baclofen. However, administration of the GABA(B) antagonist CGP 35348 (100 and 200 mg/kg) decreased the response induced by baclofen but not by nicotine. It is concluded that at least part of the baclofen-induced antinociception may be mediated through a nicotinic mechanism.

Adenosine A(2) receptors inhibit morphine self-administration in rats.

In the present study, the effect of adenosine receptor agonists and antagonists on morphine self-administration was investigated. Intravenous administration of morphine (0.3-3 mg/kg/injection) induced dose-dependent self-administration. The adenosine receptor antagonists, theophylline (2.5, 5, 10 mg/kg) and 3, 7-Dimethyl-1-propargylxanthine (DMPX; 0.25, 0.5, 1 mg/kg), when injected 1 h before the start of the test, reduced the number of self-administered morphine infusions. The adenosine receptor antagonists when administered in the training period (11 days) greatly increased the number of morphine infusions, however, they did not induce any response by themselves. 5'-N-ethylcarboxamido-adenosine (NECA; 0.5, 1 mg/kg) and 4-[2-[[6-Amino-9-(N-ethyl-beta-D-ribofuranuronamidosyl)-9H-purin-2 -yl ]amino] ethyl]benzenepropanoic acid (CGS21680; 0.001, 0.01, 0.025, 0. 05 mg/kg), given 1 h before the start of the test, increased morphine self-administration. Although the adenosine agonists, when injected during training period (11 days), reduced morphine self-administration. Furthermore, NECA, but not CGS21680, induced significant self-administration. The adenosine A(1) receptor agonist, N(6)-cyclohexyladenosine (CHA; 0.01, 0.1, 0.25, 0.5 and 1 mg/kg), and the adenosine A(1) receptor antagonist, 8-phenyletheophylline (2, 4, 6, 8 mg/kg), themselves neither altered morphine infusion nor induced any response. These results indicate a role for adenosine A(2) receptors in the expression and/or development of morphine self-administration.

Effects of adenosine receptor agents on the expression of morphine withdrawal in mice.

Effects of different doses of adenosine receptor agonists and antagonists on naloxone-induced jumping and diarrhea in morphine-dependent mice were studied. The adenosine A1 receptor agonists, N6-cyclohexyladenosine (CHA: 0.1, 0.25 and 0.5 mg kg(-1)) and R-isomer of N6-phenylisopropyladenosine (R-PIA: 0.1, 0.3 and 1 mg kg(-1)), decreased jumping and diarrhea induced by naloxone in morphine-dependent mice. The adenosine A1 receptor antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX: 0.3-9 mg kg(-1)), increased jumping but decreased diarrhea. The adenosine A2 receptor agonist, 5'-(N-cyclopropyl)-carboxamidoadenosine (CPCA), decreased jumping and diarrhea. However, the adenosine A2 receptor antagonist, 3,7-dimethyl-1-propargylxanthine (DMPX: 0.5 and 1 mg kg(-1)), did not elicit any response in this respect. DPCPX (0.3 and 3 mg kg(-1)), decreased the inhibition of jumping and diarrhea induced by CHA (0.5 mg kg(-1)), while DMPX (0.5 and 1 mg kg(-1)), decreased the inhibition of diarrhea induced by CPCA (0.1 mg kg(-1)). It is concluded that jumping induced by naloxone in morphine-dependent mice may be modified by the adenosine A receptor mechanism(s) and diarrhea induced by the opioid receptor antagonist could be mediated by the adenosine A1 and A2 receptors.

The development of cross-tolerance between morphine and nicotine in mice.

In the present study, cross-tolerance between nicotine and morphine in mice has been investigated. Mice were treated subcutaneously with three doses of morphine (12.5, 25 and 50 mg/kg) once daily, for 3 days in order to produce tolerance to morphine and nicotine antinociception. Tolerance only developed in the high dose group. On the 4th day, the antinociceptive effect of three test doses of morphine (3, 6 and 9 mg/kg) or nicotine (0.01, 0.05 and 0.1 mg/kg) were assessed. Tolerance to the responses of both drugs were observed. Intraperitoneal administration of nicotine (2 mg/kg) three times a day for a period of 12 days, also induced tolerance to the antinociceptive effects of both morphine and nicotine. When animals were tested on the 13th day, the antinociceptive responses of morphine or nicotine were reduced. Another group of animals was treated with low doses of morphine daily (12.5 or 25 mg/kg) plus nicotine (2 mg/kg) three times daily for 3 days. In this group of animals, the antinociception to either morphine or nicotine was tested. Combination of both drugs caused an increase in tolerance to either drug. It is concluded that there is cross-tolerance between the two drugs.

Effect of nicotine on apomorphine-induced licking behaviour in rats.

In the present study, the dopaminergic receptor agonist apomorphine (0.1, 0.25 and 0.5 mg/kg) induced a dose-dependent licking in rats. Nicotine administration (0.025-250 microg/kg) altered the apomorphine-induced licking. The lower doses of nicotine (0.05 and 0.5 microg/kg) increased while the higher dose of the drug (250 microg/kg) reduced the apomorphine response. The antimuscarinic drug atropine (2.5 and 5 mg/kg) reduced the effects of apomorphine or nicotine plus apomorphine. The central nicotinic receptor antagonist mecamylamine (0.05, 0.25 and 0.5 mg/kg) also reduced the response induced by apomorphine or nicotine plus apomorphine. However, the peripheral nicotinic receptor antagonist hexamethonium (2.5, 5 and 10 mg/kg) reduced the response induced by nicotine plus apomorphine but not that elicited by apomorphine alone. The results indicate that the nicotinic receptor mechanism(s) may interact with apomorphine-induced licking in rats. Although central nicotinic and cholinergic mechanisms may be involved in the licking induced by apomorphine, peripheral nicotinic mechanism may be involved in the nicotine-induced increased apomorphine effect.

Nicotine-induced grooming: a possible dopaminergic and/or cholinergic mechanism.

The ability of nicotine, to induce grooming in rats was studied. Grooming was induced by i.p. injection of different doses (0.0675-0.5 mg/kg) of nicotine to rats. The effect was dose-dependent. However, the response was decreased with increasing doses of the drug from 0.25-0.5 mg/kg. Administration of the dopamine (DA) D1/D2 receptor agonist apomorphine (0.025-5 mg/kg, i.p.) also caused grooming in a dose-dependent manner. High doses of apomorphine (0.1-0.5 mg/kg, i.p.) also induced a lower degree of response. Combination of a low dose of nicotine (0.0675 mg/kg) with different doses of apomorphine did not show any interaction. However, there was an interaction between a high dose of nicotine and apomorphine. Thus, combination of a higher dose of nicotine (0.125 mg/kg) with apomorphine, reduced apomorphine-induced grooming. The muscarinic receptor antagonist atropine (5 and 10 mg/kg), peripheral nicotinic receptor antagonist hexamethonium (5 and 10 mg/kg), central nicotinic receptor antagonist mecamylamine (1 and 3 mg/kg) and D1 DA receptor antagonist SCH23390 (0.05 and 0.1 mg/kg) all decreased the response to nicotine. Atropine, mecamylamine and SCH23390 by themselves reduced spontaneous grooming. It is concluded that nicotine elicits grooming indirectly through a possible D1 dopaminergic mechanism. However, muscarinic and nicotinic cholinergic mechanism(s) may be involved.

Nicotine potentiates sulpiride-induced catalepsy in mice.

The effects of nicotine on sulpiride-induced catalepsy in mice were investigated. Sulpiride (12.5-100 mg/kg) induced a low degree of catalepsy in mice which was dose dependent. Nicotine (0.0001-1 mg/kg) caused an even lower degree of catalepsy. When the drugs were co-administered a much higher cataleptogenic response was obtained. The potentiation of the effect of sulpiride by nicotine was elicited by 0.5 mg/kg or higher doses of the drug. The central nicotinic receptor antagonist mecamylamine (1-3 mg/kg) and the peripheral antagonist hexamethonium (5 and 10 mg/kg) decreased the response induced by the combination of nicotine and sulpiride. Higher doses of the cholinoceptor antagonist atropine (10 mg/kg) also reduced the catalepsy induced by the drug combination. It is concluded that nicotine potentiates sulpiride-induced catalepsy through activation of cholinergic mechanism(s) and that the central nicotinic mechanism mediates nicotine's action.

Involvement of cholinergic and opioid receptor mechanisms in nicotine-induced antinociception.

In this work we have studied the influences of nicotinic agents on the antinociception of morphine in formalin test. Nicotine (0.001-0.1 mg/kg) induced antinociception in mice in a dose-dependent manner in the early phase of formalin test, and also potentiated the morphine effect. The nicotinic receptor antagonist, mecamylamine (0.5 mg/kg), but not hexamethonium decreased the antinociception induced by nicotine (0.1 mg/kg) in both phases. The muscarinic receptor antagonist atropine (5 and 10 mg/kg) also decreased the response of nicotine. Mecamylamine, hexamethonium or atropine did not alter morphine antinociceptive response, while naloxone decreased responses induced by nicotine or morphine. The antagonists by themselves did not elicit any response in formalin test, however, high does of mecamylamine tend to increase pain response. It is concluded that central cholinergic and opioid receptor mechanisms may be involved in nicotine-induced antinociception.

Adenosine receptor agents and conditioned place preference.

1. The effects of different doses of the adenosine agonists N5-ethylcarboxamido-adenosine (NECA), R-isomer of N6-phenylisopropyladenosine (R-PIA), and N6-cyclohexyladenosine (CHA) or of the antagonists theophylline and 8-phenyltheophylline (8-PT) on conditioned place preference (CPP) have been studied. 2. The results show that R-PIA and CHA induced conditioned place aversion (CPA) whereas NECA induced conditioned place preference (CPP). 3. Low doses of theophylline elicit CPP, but high doses of the drug induced CPA. 8-PT also produced the CPP. 4. The responses of R-PIA and CHA but not NECA was decreased by theophylline and 8-PT administration. 5. It is concluded that the induction of CPP an CPA by adenosine antagonsists may be mediated by different adenosine receptors.

Adenosine A3 receptor activation produces nociceptive behaviour and edema by release of histamine and 5-hydroxytryptamine.

This study evaluated the pain enhancing properties of the adenosine A3 receptor agonist N6-benzyl-5'-N-ethylcarboxamidoadenosine (N6-benzyl-NECA) by assessing behavioural effects following s.c. administration alone to the dorsal hindpaw of the rat, or in combination with a low concentration of formalin (0.5%). Edema formation was monitored by determining paw volume with plethysmometry. N6-benzyl-NECA (0.005-10 nmol) produced a dose-related increase in intrinsic flinching behaviours, as well as an increase in phase 2A flinch responses in the presence of formalin. Intrinsic effects were blocked by the histamine H1 receptor antagonist mepyramine and the 5-hydroxytryptamine2 (5-HT2) receptor antagonist ketanserin, but not by other 5-HT receptor antagonists or adenosine A1 or A2 receptor antagonists. N6-benzyl-NECA also produced an increase in paw volume, both alone and in the presence of formalin, with higher doses being required to produce this effect than for the flinch response. The increase in paw volume was also blocked by mepyramine and ketanserin but not by other antagonists. These results indicate both a nociceptive response and a proinflammatory response resulting in edema formation following activation of adenosine A3 receptors which is mediated by both 5-HT and histamine released most likely from mast cells.

Effects of monoamine receptor antagonists on nicotine-induced hypophagia in the rat.

(--)-Nicotine, in doses of 0.2-0.6 mg/kg intraperitoneally (i.p.), induced a dose-dependent anorexia 1 h, 2 h and 4 h after food presentation in 20-h food-restricted male rats. The anorectic response of nicotine (0.4 mg/kg, 30 min before the test) was prevented by pretreatment with the central nicotine receptor antagonist mecamylamine (0.5 and 1 mg/kg). The peripheral nicotine receptor antagonist hexamethonium (5 and 10 mg/kg), the muscarinic receptor antagonist atropine (5 and 10 mg/kg), the dopamine D2 receptor antagonist pimozide (0.5 and 1 mg/kg), the dopamine D1 receptor antagonist SCH23390 (R-(+)-8-chloro-2, 3, 4, 5-tetrahydro-3-methyl-5-phenyl-1 H-3-benzazepine-7ol maleate; 0.05 and 0.1 mg/kg), the alpha-adrenoceptor antagonist phenoxybenzamine (5 and 10 mg/kg), and the beta-adrenoceptor antagonist propranolol (5 and 10 mg/kg) amplified the nicotine response while promoting anorexia by themselves. The dopamine D2 receptor antagonist sulpiride (25, 50 and 100 mg/kg) increased food intake and amplified the anorectic effect of nicotine. The 5-HT receptor antagonists metergoline (0.5 and 1 mg/kg) and mianserin (1 and 2 mg/kg) increased the nicotine effect. When the antagonists were used alone, metergoline did not change food intake, while mianserin increased food intake. It can be concluded that part of nicotine-induced anorexia is mediated through central nicotinic receptors.