Nitric oxide within the ventral tegmental area is involved in mediating morphine reward

In the present study, the effects of intra-ventral tegmental area 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-ventral tegmental area administration of a low dose of L-arginine (0.05 microg/rat) with an ineffective dose of morphine (0.5 mg/kg) elicited significant conditioned place preference; however, a higher dose of L-arginine (0.1 microg/rat) reduced the morphine response. Intra-ventral tegmental area administration of L-NAME (0.03 and 0.1 microg/rat) decreased the acquisition of morphine (7.5 mg/kg)-induced place preference. 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; however, intra-ventral tegmental area administration of L-arginine (0.01-0.1 microg/rat) and a higher dose of L-NAME (0.1 microg/rat) 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 (0.03 microg/rat). 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.     

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.     

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.     

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.     

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.     

Mesolimbic NMDA receptors are implicated in the expression of conditioned morphine reward

Systemic administration of a variety of N-methyl-d-aspartate (NMDA) receptor antagonists inhibits morphine’s rewarding properties in the conditioned place preference test. In this study, we investigated the anatomical loci implicated in the inhibition of expression of morphine’s reward by bilateral microinjections of a selective NMDA antagonist into the mesolimbic areas, including ventral tegmental area and nucleus accumbens. During conditioning, injections of 1 mg/kg morphine were associated with placing rats in one chamber of the place preference box; the exposures to the other chamber were associated with placebo administration. On the test day, drug-free control subjects demonstrated a marked preference for the morphine-associated chamber. Systemic administration of 5 mg/kg and 10 mg/kg of the competitive NMDA antagonist, NPC 17742 (2R,4R,5S-2-amino-4,5-(1,2-cyclohexyl)-7-phosphonoheptanoic acid), significantly reduced the expression of morphine-induced conditioned place preference; the dose of 10 mg/kg produced also an inhibition of locomotor activity. Similar attenuation of the expression of morphine-induced conditioned place preference was observed in rats receiving 15.6 and 62.5 ng/0.5 μl side of NPC 17742 injected bilaterally into the nucleus accumbens and ventral tegmental area. While the higher intra-accumbal dose of NPC 17742 produced behavioral stimulation, intra-tegmental injection did not affect locomotor activity. These findings suggest that activation of NMDA receptors in the nucleus accumbens and ventral tegmental area is necessary for the elicitation of approach by environments previously associated with morphine’s rewarding action. Received: 22 September 1998 / Accepted: 21 January 1999     

The effects of nitric oxide on the acquisition and expression of nicotine-induced conditioned place preference in mice

In the present study, the possible role of nitric oxide on the conditioned place preference (CPP) induced by nicotine in mice was investigated. Intraperitoneal (i.p.) injections of nicotine (1 mg/kg) and the nitric oxide (NO) precursor, L-arginine (200 and 500 mg/kg), produced significant place preference. However, injection of mecamylamine (0.05 and 0.1 mg/kg; i.p.) or the NO synthase (NOS) inhibitor, L-Nitro-amino-methyl-ester, L-NAME (5-20 mg/kg; i.p.), had no effect. Ineffective doses of nicotine in combination with ineffective doses of L-arginine produced significant place preference. Administration of L-arginine (50, 100 and 150 mg/kg; i.p.) on the test day reduced the expression of nicotine-induced place preference. Nicotine injection (0.25, 0.5 and 0.75 mg/kg) on the test day reduced the expression of place preference induced by L-arginine, while both mecamylamine (0.05 and 0.1 mg/kg) and L-NAME (5, 10 and 20 mg/kg) inhibited the acquisition of place preference induced by nicotine (1 mg/kg) and L-arginine (200 mg/kg). Moreover, neither of the antagonists reduced the expression of nicotine- or L-arginine-induced place preference. It is suggested that nitric oxide may play an important role in nicotine-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.     

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.     

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.     

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.     

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.     

Ascorbic acid antagonizes nicotine-induced place preference and behavioral sensitization in mice

In the present study, the influence of ascorbic acid on the nicotine-induced behavioral sensitization and conditioned place preference was investigated in mice. In the place preference paradigm, intraperitoneal (i.p.) nicotine (1 and 1.5 mg/kg, three drug sessions) but not ascorbic acid (1, 10, 100 and 1000 mg/kg) administration induced place preference. Ascorbic acid administration (10, 100 and 1000 mg/kg, i.p.) reduced both the acquisition and expression of nicotine-induced place conditioning. Locomotor sensitization in mice was produced by intraperitoneal injection of nicotine (0.25 mg/kg) for 7 consecutive days. On the 9th day of the experiments, activity of the mice was recorded after challenge with nicotine (0.1 mg/kg, i.p.). Ascorbic acid (10, 100 and 1000 mg/kg, i.p.) was injected 20 min before each injection of nicotine (acquisition of sensitization) or acutely 20 min before a challenge nicotine injection (expression of sensitization). It was shown that ascorbic acid attenuated the acquisition of nicotine sensitization in a dose-independent manner but the expression of nicotine-induced sensitization was not affected by ascorbic acid. In conclusion, it seems that ascorbic acid may interfere with nicotine-induced place preference and behavioral sensitization in mice.     

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.     

Conditioned place preference after single doses or "binge" cocaine in C57BL/6J and 129/J mice

The rewarding effect of cocaine as reflected by the development of conditioned place preference was examined in C57BL/6J and 129/J mice. Cocaine was administered in a single daily dose (2.5, 5, 10 and 20 mg/kg ip) or in a "binge" pattern (15 mg/kg ip x3, hourly). Mice remained in the conditioning compartment for 30 min immediately after each injection. Single injections of cocaine from 5 to 20 mg/kg induced conditioned place preference in each strain of mice. Only C57BL/6J mice developed conditioned place preference after "binge" cocaine administration. Both strains showed significantly greater locomotion in the conditioning compartment across the range of single doses of cocaine and after "binge" cocaine administration, but only 129/J mice showed sensitization. When mice that had received the single 10 mg/kg dose were retested 4 weeks later, the amount of time spent in the preferred side was significantly reduced compared to the initial test in the 129/J, but not in C57BL/6J mice. Thus, the persistence of conditioned place preference is strain dependent. The fact that 129/J mice did not develop conditioned place preference after "binge" cocaine administration, but did after single doses, suggests that the rewarding effects of cocaine are influenced by pattern of administration, a factor that may be relevant to the development of human cocaine addiction.     

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.     

Dose-dependent effects of the D3-preferring agonist 7-OH-DPAT on motor behaviors and place conditioning

Dose-dependent effects of 7-OH-DPAT on several behaviors, including place preference, were assessed. Three 2-day conditioning trials were conducted. On 1 day, animals received an injection of one of eight doses of 7-OH-DPAT (0–5 mg/kg) and were placed into a distinct compartment for 40 min. On the other day, animals received an injection of saline and were placed into a different compartment for 40 min. Locomotion, sniffing, and yawning were measured following the first and last injection of 7-OH-DPAT. Place conditioning was assessed on the day following the last trial. 7-OH-DPAT produced a U-shaped dose-dependent change in locomotion and sniffing, and an inverted U-shaped dose-dependent change in yawning. Additionally, repeated administration of 0.1 mg/kg sensitized yawning, whereas 5 mg/kg sensitized locomotion. None of the doses of 7-OH-DPAT produced conditioned place preference, however, there was a trend for conditioned place aversion at 0.03 mg/kg. By contrast, LiCl (127 mg/kg) produced conditioned place aversion and amphetamine (1 mg/kg) produced conditioned place preference using the same conditioning parameters. A subsequent experiment in which the number of animals and conditioning trials were increased demonstrated that the 0.03 mg/kg dose of 7-OH-DPAT produced conditioned place aversion. 7-OH-DPAT has a higher affinity for D₃ receptors relative to D₂ receptors. Therefore, it is suggested that intermediate doses (0.01–0.1 mg/kg) that increase yawning, and decrease locomotion and sniffing, may preferentially occupy D₃ receptors. Furthermore, the results suggest that these putative D₃-preferring doses have weak aversive effects.     

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.