Fenamate-induced enhancement of heterologously expressed HERG currents in Xenopus oocytes

In the present study, the effects of intra-nucleus accumbens injection of L-arginine, a nitric oxide (NO) precursor, and N(G)-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase (NOS) inhibitor, on morphine-induced conditioned place preference in male Wistar rats were investigated. Our data showed that subcutaneous (s.c.) injection of morphine sulphate (0.5-10 mg/kg) significantly increased the time spent in the drug-paired compartment in a dose-dependent manner. Intra-accumbens administration of L-arginine (0.03 and 0.05 microg/rat) with an ineffective dose of morphine (0.5 mg/kg) elicited significant conditioned place preference, while intra-accumbens administration of L-NAME (0.3, 0.1 and 1 microg/rat) decreased the acquisition of conditioned place preference induced by morphine (7.5 mg/kg). The response to different doses of L-arginine was decreased by L-NAME (0.03 microg/rat). L-Arginine and L-NAME by themselves did not elicit any effect on place conditioning. Intra-accumbens administration of L-arginine but not L-NAME significantly decreased the expression of morphine (7.5 mg/kg)-induced place preference. The attenuation of already established morphine-induced place preference on the test day by L-arginine was inhibited by L-NAME. The results indicate that NO may be involved in the acquisition and expression of morphine-induced place preference.     

Morphine-induced place preference: involvement of cholinergic receptors of the ventral tegmental area

In the present study, the effects of intra-ventral tegmental area injections of cholinergic agents on morphine-induced conditioned place preference were investigated by using an unbiased 3-day schedule of place conditioning design in rats. The conditioning treatments with subcutaneous injections of morphine (0.5-7.5 mg/kg) induced a significant dose-dependent conditioned place preference for the drug-associated place. Intra-ventral tegmental area injection of an anticholinesterase, physostigmine (2.5 and 5 microg/rat) or nicotinic acetylcholine receptor agonist, nicotine (0.5 and 1 microg/rat) with an ineffective dose of morphine (0.5 mg/kg) elicited a significant conditioned place preference. Furthermore, intra-ventral tegmental area administration of muscarinic acetylcholine receptor antagonist, atropine (1-4 microg/rat) or nicotinic acetylcholine receptor antagonist, mecamylamine (5 and 7.5 microg/rat) dose-dependently inhibited the morphine (5 mg/kg)-induced place preference. Atropine or mecamylamine reversed the effect of physostigmine or nicotine on morphine response respectively. The injection of physostigmine, but not atropine, nicotine or mecamylamine, into the ventral tegmental area alone produced a significant place aversion. Moreover, intra-ventral tegmental area administration of the higher doses of physostigmine or atropine, but not nicotine or mecamylamine decreased the locomotor activity. We conclude that muscarinic and nicotinic acetylcholine receptors in the ventral tegmental area may critically mediate the rewarding effects of morphine.     

Role of nitric oxide in the rat hippocampal CA1 area on morphine-induced conditioned place preference

Effects of intrahippocampal CA1 injections of L-arginine, a nitric oxide (NO) precursor, and N(G)-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor, on morphine-induced conditioned place preference in male Wistar rats were investigated. Animals received subcutaneous (s.c.) injections of saline (1.0 ml/kg) or morphine (0.5-7.5 mg/kg) once daily for 3 days to induce conditioned place preference. The administration of L-arginine (0.3, 1.0, and 3.0 microg/rat), but not L-NAME (0.3, 1.0, and 3.0, microg/rat), prior to administration of morphine (5.0 mg/kg) during acquisition of morphine-induced conditioned place preference increased morphine-induced conditioned place preference, but the interaction between the response to morphine and/or L-arginine was not statistically significant. The response to L-arginine was blocked by L-NAME pre-administration. L-Arginine or L-NAME by itself did not induce conditioned place preference. The administration of L-arginine but not L-NAME, 1 min before conditioned place preference testing, increased the expression of morphine-induced conditioned place preference. Pre-administration of L-NAME blocked the L-arginine response. It is concluded that NO in the rat hippocampal CA1 area may be involved in morphine-induced conditioned place preference.     

Different effects of GABAergic receptors located in the ventral tegmental area on the expression of morphine-induced conditioned place preference in rat

In the present study, an unbiased conditioned place preference paradigm was used to study the effects of intra-ventral tegmental area injections of Gama-amino-butyric acid (GABA)-A and B (GABA(A) and GABA(B)) receptor agonists and antagonists on the expression of morphine-induced conditioned place preference (CPP) in rats. Subcutaneous (s.c.) injections of morphine sulfate (5 mg/kg) induced CPP. Intra-ventral tegmental area administration of the GABA(A) receptor agonist, muscimol (6 microg/rat) reduced the expression of morphine-induced CPP. Muscimol (25 microg/rat) increased the expression of CPP induced by morphine. A reduction of the expression of morphine-induced CPP was observed on intra-ventral tegmental area injection of GABA(A) receptor antagonist bicuculline (25 microg/rat). Bicuculline (10 microg/rat) increased the expression of CPP induced by morphine. Baclofen (12 microg/rat) increased where as (19 and 25 microg/rat) reduced the expression of morphine-induced CPP. Injection of CGP38345 (10, 19, 25 and 50 microg/rat) into the ventral tegmental area significantly reduced the expression of CPP induced by morphine. It is concluded that GABA(A) and GABA(B) receptor subtypes within the ventral tegmental area may have different effects on the expression of morphine-induced CPP.     

Influence of nitric oxide on morphine-induced conditioned place preference in the rat central amygdala

Effects of intra-central amygdala injections of L-arginine, a nitric oxide (NO) precursor, and N(G)-nitro-L-arginine methyl ester (L-NAME), a NO synthase (NOS) inhibitor, on morphine-induced conditioned place preference in rats were investigated by using an unbiased 3-day schedule of place conditioning design. Animals receiving once daily injections of morphine (0.5-7.5 mg/kg, subcutaneously, s.c.) or saline (1.0 ml/kg, s.c.) showed a significant place preference in a dose-dependent manner. The maximum response was observed with 5.0 mg/kg of the opioid. Co-administration of morphine (5.0 mg/kg) with L-arginine (0.3, 1.0 and 3.0 microg/rat), but not with L-NAME (0.3, 1.0 and 3.0 microg/rat), during the acquisition of morphine-induced conditioned place preference increased morphine-induced conditioned place preference. The response to L-arginine was blocked by L-NAME preadministration. L-arginine and L-NAME by themselves did not induce conditioned place preference. When L-arginine or L-NAME at 0.3-3.0 microg/rat was administered 1 min before conditioned place preference testing, L-arginine but not L-NAME caused an increase in the expression of morphine-induced conditioned place preference, the effect that was blocked by L-NAME preadministration. A dose of L-arginine (0.3 microg/rat), but not L-NAME, during expression of morphine-induced conditioned place preference produced an increase in locomotion compared with that in the control group. It may be concluded that an increase in the NO levels in the central amygdala may have an effect on the acquisition and expression of morphine-induced conditioned place preference.     

Involvement of nucleus accumbens in L-arginine-induced conditioned place preference in rats

In the present study, the effects of intraperitoneal, intra-accumbal and intra-ventral tegmental area administration of L-arginine and N(G)-nitro-L-arginine methyl-ester (L-NAME) on conditioned place preference behavior were studied. Intraperitoneal (i.p.; 0.5, 1 and 5 mg/kg) and intra-accumbal (intra-NAc; 0.3, 1 and 3 microg/rat), but not intra-ventral tegmental area (intra-VTA; 0.3, 1 and 3 microg/rat) administrations of L-arginine produced a significant place conditioning. Similar injections of L-NAME did not produce any response. However, intraperitoneal pretreatment of the animals with L-NAME (5, 10 and 20 mg/kg), 30 min before L-arginine administration, significantly abolished the acquisition of place conditioning induced by either intraperitoneal or intra-accumbal injection of L-arginine. Moreover, injection of L-NAME (5, 10 and 20 mg/kg) on the test day did not alter the L-arginine response. The results may indicate that L-arginine induces conditioned place preference via an increase in nitric oxide (NO) in the nucleus accumbens.     

The role of nitric oxide within the nucleus accumbens on the acquisition and expression of morphine-induced place preference in morphine sensitized rats

In the present study, the effects of intra-accumbal administration of L-arginine, a nitric oxide precursor, and N(G)-nitro-L-arginine methyl-ester (L-NAME), a nitric oxide synthase inhibitor, on the acquisition and expression of morphine-induced place conditioning in morphine-sensitized rats were studied. Subcutaneous (s.c.) administration of morphine (2.5, 5 and 7.5 mg/kg) induced conditioned place preference. Repeated pretreatment of morphine (5 mg/kg, i.p.) followed by 5 days without drug treatment, increased conditioning response induced by morphine (0.25, 0.5 and 0.75 mg/kg). Intra-accumbal (intra-nucleus accumbens; 1 microg/rat) administration of L-arginine (0.3, 1 and 3 microg/rat) significantly increased or reduced the acquisition of morphine place conditioning in non-sensitized and sensitized rats respectively. However, the drug reduced expression of place conditioning by morphine in sensitized animals. Intra-nucleus accumbens injections of L-NAME (0.3, 1 and 3 microg/rat) reduced the acquisition and expression of morphine place conditioning in the sensitized animals. The results indicate that nitric oxide (NO) within the nucleus accumbens is involved in the acquisition and expression of morphine place conditioning in morphine-sensitized rats.     

Role of the cholinergic system in the rat basolateral amygdala on morphine-induced conditioned place preference

The effects of intra-basolateral amygdala (intra-BLA) injections of physostigmine, atropine, nicotine and/or mecamylamine on morphine-induced conditioned place preference (CPP) in rats was investigated by using an unbiased 3-day schedule of place conditioning design. Animals that received 3 daily injections of morphine (0.5-10 mg/kg) subcutaneously (s.c.) or saline (1.0 ml/kg, s.c.) showed a significant preference for compartment paired with morphine. The maximum response was observed with 7.5 mg/kg of the opioid. Administration of the anticholinesterase drug, physostigmine (1, 3 and 5 microg/rat) with an ineffective dose of morphine (0.5 mg/kg) elicited a significant CPP. Injections of antimuscarinic receptor agent, atropine (1, 4 and 7 microg/rat) dose-dependently inhibited the morphine (7.5 mg/kg)-induced place preference. The injections of nicotine (0.75, 1 and 2 microg/rat) potentiated the morphine (0.5 mg/kg)-induced place preference, while the nicotinic receptor antagonist, mecamylamine (1, 3 and 6 microg/rat) dose-dependently inhibited the morphine (7.5 mg/kg)-induced place preference. Furthermore, administration of atropine (7 microg/rat) but not mecamylamine (6 microg/rat) reduced the response induced by different doses of physostigmine plus morphine. Moreover, mecamylamine (6 microg/rat) but not atropine (7 microg/rat) reduced the response induced by different doses of nicotine plus morphine. It is concluded that the muscarinic and nicotinic receptor mechanisms in the BLA may be involved in the acquisition of morphine-induced place preference.     

NMDA receptors of dorsal hippocampus are involved in the acquisition, but not in the expression of morphine-induced place preference

In the present study, involvement of the N-methyl-d-aspartate (NMDA) receptors of the CA1 region of dorsal hippocampus (intra-CA1) in the acquisition or expression of morphine-induced conditioned place preference in rats was studied. Male Wistar rats were used in these experiments. NMDA-receptor agonist (NMDA) and antagonist (MK-801) were injected into the CA1 region of the dorsal hippocampus (intra-CA1) and morphine was injected subcutaneously. An unbiased conditioned place preference paradigm was used to study the effect of these agents. In the first set of experiments, the drugs were used during the development of conditioned place preference by morphine or they were used alone in order to see if they induce conditioned place preference or conditioned place aversion. Our data showed that subcutaneous (s.c.) injection of morphine sulphate (2.5-10 mg/kg) induced conditioned place preference in rat. NMDA (0.1-1 microg/rat) or MK-801 (1-4 microg/rat) did not induce conditioned place preference or conditioned place aversion. Intra-CA1 administration of different doses of NMDA (0.1-1 microg/rat) increased, while MK-801 (1-4 microg/rat) decreased morphine-induced place preference. MK-801 reversed the effect of NMDA on morphine response. In the second set of experiments, when the drugs were used before testing on Day 5, in order to test their effects on the expression of morphine (7.5 mg/kg)-induced place preference, intra-CA1 administration of NMDA or MK-801 did not alter the morphine response. None of the drugs influenced locomotion. It is concluded that NMDA receptor of the CA1 region of hippocampus are involved in the acquisition but not expression of morphine-induced place preference.     

Involvement of dopamine D2 receptors of the central amygdala on the acquisition and expression of morphine-induced place preference in rat

In the present study, the effects of intra-central amygdala (CeA) injections of dopamine (DA) D2-like receptor agonist and antagonist on the acquisition and expression of morphine-induced place preference in male Wistar rats have been investigated. Subcutaneous administration of different doses of morphine sulphate (0.5-10 mg/kg) produced a dose-dependent conditioned place preference (CPP). Using a 3-day schedule of conditioning, it was found that the DA D2/D3 receptor agonist, quinpirole (0.3-3 microg/rat), or the DA D2 receptor antagonist, sulpiride (0.04-5 microg/rat), did not produce a significant place preference or place aversion. Intra-CeA administration of quinpirole (0.3 and 1 microg/rat) with an ineffective dose of morphine (0.5 mg/kg) elicited a significant CPP. On the other hand, quinpirole (0.3 microg/rat) injection into the CeA induced CPP in combination with the lower doses of morphine (0.5 and 2.5 mg/kg), but decreased the response of higher dose (7.5 mg/kg) of morphine. This response of quinpirole was attenuated by sulpiride (0.2 microg/rat). Sulpiride by itself (0.04-5 microg/rat) reduced the acquisition of morphine (7.5 mg/kg)-induced place preference. The administration of the higher dose of sulpiride (1 and 5 microg/rat) or the higher dose of quinpirole (3 microg/rat) during acquisition decreased the locomotor activity of the animals on the testing days. The injection of the low dose of quinpirole (0.3 microg/rat) on the test day reduced the expression of morphine-induced CPP, but the high dose of quinpirole (3 microg/rat) potentiated this expression. The administration of sulpiride (5 microg/rat) attenuated the quinpirole response. The injection of sulpiride (1 and 5 microg/rat) abolished the expression of morphine-induced CPP. It is concluded that the CeA DA D2-like receptors may play an active role in morphine reward.     

Effect of cyclosporin A on morphine-induced place conditioning in mice: involvement of nitric oxide

Cyclosporin A is shown to attenuate antinociceptive effects of morphine, development and expression of morphine-induced tolerance and dependency via nitric oxide (NO) pathway. In the present study, the effect of systemic cyclosporin A on morphine-induced conditioned place preference (CPP) and the probable involvement of nitric oxide were assessed in mice. Our data showed that administration of morphine (1, 2.5, 5, 7.5, 10 mg/kg) significantly increased the time spent in the drug-paired compartment in a dose-dependent manner. The maximum response was obtained with 5 mg/kg of morphine. Cyclosporin A (5, 10 mg/kg) and N(G)-nitro-L-arginine methyl ester (L-NAME; 2.5, 5, 10 mg/kg), a nonselective nitric oxide synthase (NOS) inhibitor, did not induce either conditioned place preference or conditioned place aversion (CPA), while cyclosporin A (20 mg/kg) induced CPA. Both cyclosporin A (10, 20 mg/kg) and L-NAME (5, 10 mg/kg), in combination with morphine (5 mg/kg) during conditioning, significantly suppressed acquisition of morphine-induced place preference. Lower and per se noneffective doses of Cyclosporin A (1, 2.5, 5 mg/kg) and L-NAME (2.5 mg/kg), when coadministered, exerted a significant potentiating effect on the attenuation of morphine-induced place preference. Aminoguanidine (50, 100 mg/kg), the specific inducible nitric oxide synthase (iNOS) inhibitor, whether alone or in combination with cyclosporin A failed to show this inhibitory effect on morphine-induced place preference. In conclusion, decreasing nitric oxide production through inhibiting constitutive nitric oxide synthase may be a mechanism through which cyclosporin A attenuates morphine-induced place preference.     

GABA(A) receptors of hippocampal CA1 regions are involved in the acquisition and expression of morphine-induced place preference.

In the present study, the effects of bilateral intra-hippocampal CA1 (intra-CA1) injections of GABA(A) receptor agonist and/or antagonist on the acquisition and expression of morphine-induced place preference in male Wistar rats have been investigated. The conditioning treatments with subcutaneous (s.c.) injections of different doses of morphine (0.5-7.5 mg/kg) induced a conditioned place preference (CPP) for the drug-associated place in a dose-dependent manner. Intra-CA1 administration of the GABA(A) receptor agonist, muscimol (0.25, 0.5 and 1 microg/rat) significantly inhibited the morphine (5 mg/kg, s.c.)-induced CPP. Intra-CA1 injections of different doses of the GABA(A) receptor antagonist, bicuculline (0.25, 0.5 and 1 microg/rat), in combination with an ineffective dose of morphine (0.5 mg/kg, s.c.) elicited a significant CPP. However, muscimol or bicuculline by themselves did not elicit any effect on place conditioning. Furthermore, the muscimol-induced inhibition of morphine response was reversed by bicuculline (1 microg/rat, intra-CA1) administration. On the other hand, the bilateral intra-CA1 injections of muscimol (0.25, 0.5 and 1 microg/rat) or bicuculline (0.5, 1 and 2 microg/rat) significantly decreased the expression of morphine-induced CPP. Intra-CA1 administration of different doses of muscimol or bicuculline had no effect on locomotor activity in the testing phase. Our data indicated that the GABA(A) receptors of the hippocampal CA1 regions may play an important role in the acquisition and expression of morphine-induced place preference.     

GABAB receptors within the ventral tegmental area are involved in the expression and acquisition of morphine-induced place preference in morphine-sensitized rats

The influence of intra-ventral tegmental area administration of gamma-amino-butyric-acid-B (GABA_B) receptor agonist and antagonist on the expression and acquisition of morphine-induced conditioned place preference (CPP) in morphine-sensitized female rats was examined. Our pilot experiment showed that subcutaneous administration of morphine-(2.5, 5 and 7.5 mg/kg) induced CPP. Administration of one dose daily morphine (5 mg/kg) for 3 days followed by 5 days rest, enhanced the conditioning induced by ineffective doses of morphine (0.25, 0.5 and 1 mg/kg). Injections of GABA_B receptor agonist, baclofen, (1.5 and 12 µg/rat) reduced the expression of morphine CPP whereas the dose of 6 µg/rat of the drug increased it. Baclofen also significantly reduced the acquisition of morphine CPP in morphine-sensitized animals. Administration of GABA_B receptor antagonist, CGP 35348, significantly reduced the expression (12 µg/rat) and acquisition (1.5, 6 and 12 µg/rat) of morphine CPP in morphine-sensitized animals.In conclusion, results confirmed the importance of GABA_B receptors within the ventral tegmental area of morphine CPP in morphine-sensitized female rats.     

Effects of ultra-low doses of nicotine on the expression of morphine-induced conditioned place preference in mice

In the present study, the effects of acute administration of nicotine, as well as nicotinic and muscarinic acetylcholine receptor antagonists, on the expression of morphine-induced conditioned place preference, have been investigated in male Swiss-Webster mice. Animals received different doses of morphine 5 days after surgical cannulation in the lateral ventricle. Subcutaneous injections of morphine (2-5 mg/kg) in mouse produced place preference in a dose-dependent manner. Furthermore, both intraperitoneal (0.0006-0.1 mg/kg) and intracerebroventricular (0.007-25 ng) nicotine administration significantly reduced the expression of morphine-induced place preference, in a dose-dependent manner. Nicotine, however, was effective over narrow ultra-low dose ranges (0.0012, 0.0025, 0.005 and 0.01 mg/kg; intraperitoneal) and (0.03, 0.1, 0.3 and 0.6 ng/mouse; intracerebroventricular). In addition, locomotor activity was reduced when higher doses of nicotine [both intraperitoneal (0.02, 0.03 and 0.1 mg/kg) and intracerebroventricular (10 and 24 ng/mouse)] were used. Nicotine alone, however, did not cause motivational effects. Intracerebroventricular injection of hexamethonium (0.03, 0.1 and 0.3 mug/mouse; 10 min before nicotine) diminished the effects of nicotine on morphine-induced conditioned place preference. This effect could neither be obtained by intraperitoneal administration of hexamethonium (1, 5 and 10 mg/kg; 30 min before nicotine), nor be reproduced after either intracerebroventricular or intraperitoneal injection of atropine (a muscarinic receptor antagonist). The antagonists, themselves, did not show any motivational effects when used alone and were unable to affect the expression of morphine-induced conditioned place preference. It appears that ultra-low doses of nicotine can reduce the expression of morphine-induced place preference, and that central nicotinic acetylcholine receptors play a role in this regard.     

Involvement of dopamine receptors of the dorsal hippocampus on the acquisition and expression of morphine-induced place preference in rats

In the present study, the effects of bilateral intrahippocampal CA1 injections of dopamine receptor agonists and antagonists on the acquisition and expression of morphine-induced place preference were examined in male Wistar rats. Subcutaneous administration of different doses of morphine sulphate (0.5-10 mg/kg) produced a conditioned place preference (CPP) dose-dependently. Using a 3-day schedule of conditioning, it was found that dopamine D1 receptor agonist, SKF 38393 (0.01-1 microg/rat), dopamine D1 receptor antagonist, SCH 23390 (0.25-1 microg/rat), dopamine D(2/3) receptor agonist, quinpirole (0.3-3 microg/rat) or dopamine D2 receptor antagonist, sulpiride (0.04-5 microg/rat) did not produce significant place preference. The administration of SKF 38393 (1 microg/rat) significantly potentiated the acquisition of morphine (0.5 and 2.5 mg/kg)-induced place preference. This potentiation was reversed by SCH 23390 (1 microg/rat) pretreatment. Quinpirole injection (0.3 microg/rat) induced CPP in combination with the lower doses of morphine but decreased the response of the higher doses of morphine. These responses of quinpirole were reversed by sulpiride (5 microg/rat) pretreatment. SCH 23390 or sulpiride reduced the acquisition of morphine (7.5 mg/kg)-induced place preference. The administration of sulpiride, but not other drugs, during acquisition showed an increase in the locomotor activity on the testing days. SKF 38393, SCH 23390 or sulpiride, but not quinpirole when used before testing, reduced the expression of morphine-induced place preference. Sulpiride, but not other drugs, increased locomotion when used before testing. It is concluded that dorsal hippocampal dopamine receptors may play an active role in morphine reward.     

Agmatine potentiates morphine-induced conditioned place preference in mice: modulation by alpha2-adrenoceptors.

The effects of agmatine, an endogenous polyamine metabolite formed by decarboxylation of L-arginine, and its combination with morphine on conditioned place preference (CPP) has been investigated in male mice. Our data show that subcutaneous administration of morphine (1-7.5 mg/kg) significantly increases the time spent in the drug-paired compartment in a dose-dependent manner. Intraperitoneal administration of agmatine (1-40 mg/kg) alone does not induce either CPP or conditioned place aversion, while combination of agmatine and subeffective doses of morphine leads to potent rewarding effects. Lower doses of morphine (0.1, 0.05, and 0.01 mg/kg) are able to induce CPP in mice pretreated with agmatine 1, 5, and 10 mg/kg, respectively. Concomitant intraperitoneal administration of UK 14 304 (0.5 mg/kg), a highly selective alpha2-agonist, with per se noneffective dose of morphine (0.5 mg/kg) and also its combination with noneffective doses of agmatine (1 mg/kg) plus morphine (0.05 mg/kg) produces significant CPP. UK 14 304 (0.05, 0.5 mg/kg) alone, or in combination with agmatine (1, 5 mg/kg) have had no effect. We have further investigated the possible involvement of the alpha2-adrenoceptors in the potentiating effect of agmatine on morphine-induced place preference. Selective alpha2-antagonists, yohimbine (0.005 mg/kg) and RX821002 (0.1, 0.5 mg/kg), block the CPP induced by concomitant administration of agmatine (5 mg/kg) and morphine (0.05 mg/kg). Yohimbine (0.001-0.05 mg/kg) or RX821002 (0.05-0.5 mg/kg) alone or in combination with morphine (0.05 mg/kg) or agmatine (5 mg/kg) fail to show any significant place preference or aversion. Our results indicate that pretreatment of animals with agmatine enhances the rewarding properties of morphine via a mechanism which may involve alpha2-adrenergic receptors.     

Theophylline inhibits tolerance and sensitization induced by morphine: a conditioned place preference paradigm study in female mice

The effect of theophylline on reward properties of morphine was examined in the present study. A biased conditioned place preference paradigm was used to study the effects of theophylline on the development of conditioned place preference by morphine in sensitized and tolerant female mice. Subcutaneous injection of morphine (0.5-10 mg/kg) induced conditioned place preference in mice, while intraperitoneal administration of theophylline (2.5-100 mg/kg) did not induce conditioned place preference or conditioned place aversion. Theophylline (2.5-100 mg/kg) in combination with morphine (5 mg/kg), during conditioning sessions, decreased the acquisition of morphine conditioned place preference dose independently. Administration of theophylline (2.5-100 mg/kg) before testing also caused a significant reduction of the expression of morphine-induced conditioned place preference in a dose-independent manner. Administration of morphine (12.5, 25 or 50 mg/kg) daily, for 3 days, produced tolerance to conditioned place preference induced by the drug (5 mg/kg). Administration of theophylline (2.5 and 10 mg/kg) 1 h before morphine (12.5, 25 mg/kg), during development of tolerance, abolished morphine tolerance. A higher dose of theophylline (100 mg/kg), however, did not alter morphine tolerance. In addition, theophylline (2.5, 10 and 100 mg/kg) failed to reduce tolerance to a higher dose of morphine (50 mg/kg). Daily administration of morphine (5 mg/kg) for 3 days followed by a 5-day interval caused sensitization to morphine place conditioning. When theophylline was administered (2.5, 10 and 100 mg/kg) 1 h before morphine (5 mg/kg), during development of sensitization, inhibition of morphine-induced sensitization was demonstrated. The effect of theophylline was dose independent. It is concluded that while theophylline has no effect by itself, it reduced both the acquisition and expression of morphine conditioned place preference. In addition, theophylline reduced the acquisition of morphine conditioned place preference in morphine-sensitized and morphine-tolerant mice.     

The NMDA receptor antagonist dizocilpine (MK-801) stereoselectively inhibits morphine-induced place preference conditioning in mice

The effect of the non-competitive NMDA receptor antagonist dizocilpine (MK-801) on conditioned place preference induced by morphine was studied in mice. As expected, morphine (1–8 mg/kg, IP) elicited a significant preference for the drug-paired compartment. Pretreatment of mice with (+)-dizocilpine (0.1 and 0.2 mg/kg, IP), the more active dizocilpine enantiomer, dose-dependently reversed the conditioned place preference produced by morphine (4 mg/kg, IP), whereas (–)-dizocilpine (0.2 mg/kg, IP) did not modify morphine-induced effects. In contrast, both enantiomers of dizocilpine (at a dose of 0.2 mg/kg, IP) elicited a conditioned place preference. These data suggest that (1) NMDA receptors play a role in morphine-induced place preference, and (2) dizocilpine-reinforcing properties in the place preference paradigm do not seem to be dependent on NMDA receptor blockade.     

Involvement of glucose and ATP-sensitive potassium (K+) channels on morphine-induced conditioned place preference

In the present study, the effects of glucose and ATP-sensitive K+ channel compounds on the acquisition of morphine-induced place preference in male mice were investigated. Subcutaneous administration of different doses of morphine (2.5-7.5 mg/kg) produced a dose-dependent conditioned place preference. With a 3-day conditioning schedule, it was found that glucose (100, 200, 500 and 1000 mg/kg), diazoxide (15, 30 and 60 mg/kg) or glibenclamide (3, 6 and 12 mg/kg) did not produce significant place preference or place aversion. Intraperitoneal administration of the glucose (1000 mg/kg) or glibenclamide (6 and 12 mg/kg) with a lower dose of morphine (0.5 mg/kg) elicited the significant conditioned place preference. The response of glibenclamide (6 mg/kg) was reversed by diazoxide (15, 30 and 60 mg/kg). Drug injections had no effects on locomotor activity during the test sessions. It is concluded that glucose and the ATP-sensitive K+ channel may play an active role in morphine reward.     

Repeated administration of dopaminergic agents in the dorsal hippocampus and morphine-induced place preference

The aim of the present experiments was to investigate whether repeated intra-hippocampal CA1 (intra-CA1) administration of dopaminergic agents can affect morphine-induced conditioned place preference (CPP). Effects of repeated intra-CA1 injections of dopamine (DA) receptor agonists and antagonists on morphine-induced CPP in rats were investigated using an unbiased 3-day schedule of place conditioning. Animals receiving once-daily subcutaneous (s.c.) injections of morphine (1-9 mg/kg) or saline (1.0 ml/kg, s.c.) showed a significant place preference in a dose-dependent manner: the maximum response was observed with 3 mg/kg morphine. Three days' intra-CA1 injections of apomorphine (0.25-1 microg/rat) followed by 5 days free of the drug, significantly decreased morphine CPP (1 and 3 mg/kg, s.c.). Moreover, pre-treatment with the highest dose of apomorphine (1 microg/rat) altered the effect of morphine to an aversive response. The morphine (1 and 3 mg/kg) CPP was also significantly decreased in animals that previously received three intra-CA1 injections of SKF 38393 (2-9 microg/rat), quinpirole (1-3 microg/rat) or sulpiride (1-3 microg/rat), and significantly increased in animals that had previously received three intra-CA1 injections of SCH 23390 (0.02 microg/rat). The 3-day pre-treatment with apomorphine, SKF 38393 or quinpirole reduced locomotor activity in the test session, while SCH 23390 and sulpiride did not have any influence on locomotor activity. It is concluded that repeated injections of DA receptor agents in the dorsal hippocampus, followed by 5 days free of the drugs, can affect morphine reward.