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.     

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.     

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.     

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.     

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.     

Naloxone, not proglumide or MK-801, alters effects of morphine preexposure on morphine-induced taste aversions

Both cholecystokinin (CCK) antagonists and N-methyl-D-aspartate (NMDA) antagonists block or reduce the development of morphine tolerance in several analgesic assays. The present experiments were performed to assess the ability of the CCK antagonist proglumide and the NMDA antagonist MK-801 to affect tolerance to the aversive properties of morphine as indexed by conditioned taste aversion (CTA) learning. Specifically, male Sprague-Dawley rats were exposed to either vehicle or morphine (5 mg/kg) in combination with either proglumide (5 mg/kg; Experiment 1), MK-801 (0.1 mg/kg; Experiment 2) or naloxone (1, 3.2 mg/kg; Experiment 3). Saccharin was then presented and was followed by an injection of either vehicle or morphine (10 mg/kg). Animals preexposed to and conditioned with morphine acquired an attenuated morphine-induced aversion to saccharin. While neither proglumide nor MK-801 had an effect on this attenuation, naloxone blocked the effects of morphine preexposure, suggesting that neither CCK nor NMDA may be involved in the aversive effects of morphine (or their modulation by drug exposure). That the attenuating effects of morphine preexposure on a morphine-induced CTA can be blocked suggests that the weakening of the aversive effects of morphine with chronic use can be prevented, an effect that may have implications for overall drug acceptability.     

Involvement of dorsal hippocampal nicotinic receptors in the effect of morphine on memory retrieval in passive avoidance task

The present study evaluated the possible role of nicotinic acetylcholine receptors of the dorsal hippocampus on morphine-induced amnesia and morphine state-dependent memory in adult male Wistar rats. The animals were bilaterally implanted with chronic cannulas in the CA1 regions of the dorsal hippocampi, trained in a step-through type passive avoidance task, and tested 24 h after training to measure step-through latency. Results indicate that post-training subcutaneous (s.c.) administration of morphine (2.5-7.5 mg/kg) dose-dependently reduced the step-through latency, showing an amnestic response. Post-training intra-CA1 microinjection of nicotine (0.5-1 microg/rat) decreased significantly the amnesia induced by post-training morphine (7.5 mg/kg). Moreover, co-treatment of mecamylamine (0.5 and 1 microg/rat, intra-CA1) with an ineffective dose of morphine (2.5 mg/kg), immediately after training, caused inhibition of memory retrieval. On the other hand, amnesia produced by post-training morphine (7.5 mg/kg) was reversed by pre-test administration of the opioid that is due to a state-dependent effect. Interestingly, pre-test intra-CA1 microinjection of nicotine (0.25 and 0.5 microg/rat) improved post-training morphine (7.5 mg/kg)-induced retrieval impairment. Moreover, pre-test administration of the same doses of nicotine in combination with a lower dose of morphine (0.5 mg/kg), which had no effects alone, synergistically improved memory performance impaired by post-training morphine. Pre-test injection of mecamylamine (0.5-2 microg/rat) prevented the restoration of memory by pre-test morphine. It is important to note that post-training or pre-test intra-CA1 administration of the same doses of nicotine or mecamylamine, alone did not affect memory retrieval. These results suggest that nicotinic acetylcholine receptors of the hippocampal CA1 regions may play an important role in morphine-induced amnesia and morphine state-dependent memory.     

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.     

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.     

Morphine conditioned reward is inhibited by MPEP,the mGluR5 antagonist

In the present study we examined the effect of MPEP [2-methyl-6-(phenylethynyl)-pyridine] a potent, selective and systemically active metabotropic glutamate receptor (mGluR) type I (subtype mGluR5) antagonist on conditioned morphine reward in mice. In an unbiased version of conditioned place preference (CPP) paradigm, single conditioning with 10 mg/kg of morphine produced reliable place preference. MPEP at 30, but not 10 mg/kg significantly inhibited the acquisition as well as expression of morphine-induced CPP, but it neither produced place preference or aversion, nor affected locomotor activity of mice. Effects of MPEP on learning and memory were studied in the elevated plus maze model of spatial learning. In contrast to 0.1 mg/kg of MK-801, which inhibited the acquisition of this task, 30 mg/kg of MPEP affected neither learning nor memory retrieval. These data suggest that mGluR5 may be involved in conditioned morphine reward.     

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.     

Opposite effects of MK-801 on the expression of food and morphine-induced conditioned place preference in rats

Behavioural studies have provided strong evidence for common substrates in the rewards of natural and addictive substances, but it is still unclear whether there is a common glutamatergic NMDA receptor mechanism involved in the processing of reward for both. The present study was designed to investigate the effects of MK-801 (0.1mg/kg) on the expression of place preference conditioned with food and morphine (5.0mg/kg) in rats. The data indicates that MK-801 potentiates the expression of food-induced conditioned place preference (CPP) but retards that of morphine CPP. It also demonstrates that the opposite effects of MK-801 on food and morphine CPP expression were caused neither by hyperactivity nor by the impairment of memory retrieval. These results suggest that MK-801 enhances food craving and inhibits morphine craving in rats, and that the roles of glutamatergic NMDA receptor mechanisms in the reward processing of natural reinforcers and addictive drugs may be dissociable.     

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.     

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.     

Intra-hippocampal inhibition of protein kinase AII attenuates morphine-induced conditioned place preference

Morphine and other drugs of abuse modulate protein kinase A (PKA) signaling within the mesolimbic reward pathway. Using a balanced conditioned place preference (CPP) paradigm, we studied the possible involvement of protein kinase AII (PKA II) on the acquisition, expression and consolidation of morphine place conditioning in male Wistar rats. Subcutaneous administration of various doses of morphine sulfate (1-9 mg/kg) induced CPP in a dose-dependent manner. H-89, a selective PKA II inhibitor, was administered into CA1 region of the hippocampus at 1, 2.5 and 5 microM/rat. Using a 3-day schedule of conditioning, it was found that the H-89 did not produce a significant place preference or place aversion. H-89 (1, 2.5 and 5 microM/rat) significantly reduced the time spent by rats in the morphine compartment when given immediately after each conditioning session (consolidation), whereas it had no effect when administered before morphine during the conditioning phase (acquisition) or before testing for place preference in the absence of morphine (expression). It is concluded that the PKA II may play an active role in the consolidation of reward-related memory of morphine in CA1 region of the hippocampus.     

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.     

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.     

Effect of imipramine on the expression and acquisition of morphine-induced conditioned place preference in mice

The effect of imipramine and alpha-adrenoceptor agonists and antagonists on the acquisition or expression of morphine-induced conditioned place preference (CPP) was studied in mice. An unbiased CPP paradigm was used to study the effect of the agents. In the first set of experiments, the drugs were used during the development of CPP by morphine or they were used alone in order to see if they induce CPP or conditioned place aversion (CPA). Our data showed that intraperitoneal injection of morphine sulphate (2.5-10 mg/kg) induced CPP in mice. Imipramine (0.5-2.5 mg/kg), phenylephrine (0.5-2 mg/kg), yohimbine (0.5-2 mg/kg) or prazosin (0.1-1 mg/kg) did not influence CPP, but clonidine (0.002-0.05 mg/kg) induced CPA. Yohimbine increased, while clonidine and prazosin reversed, morphine-induced CPP. Phenylephrine did not influence the CPP induced by morphine. In the second set of experiments, when the drugs were used before testing on Day 6, in order to test their effects on the expression of morphine-induced CPP, imipramine (0.5-5 mg/kg) reversed morphine-induced CPP and this reversal was blocked by naloxone (2 mg/kg). Clonidine and prazosin reversed, while yohimbine decreased morphine-induced CPP. Phenylephrine did not alter the morphine response. Furthermore, yohimbine and prazosin reversed the imipramine effect. None of the drugs influenced locomotion. However, prazosin or yohimbine in combination with morphine altered locomotor activity during the acquisition of CPP. Yohimbine by itself increased locomotion. It is concluded that imipramine can induce CPA through an opioid receptor mechanism and alpha-adrenoceptor agents may influence morphine CPP.     

Inhibition of morphine-induced amnesia in morphine-sensitized mice: involvement of dorsal hippocampal GABAergic receptors

In the present study, the effects of bilateral injections of the GABAergic receptor agents into the dorsal hippocampal CA1 regions (intra-CA1) on morphine-induced amnesia were examined in morphine sensitized-mice. Pre-training subcutaneous (s.c.) administration of morphine (5 mg/kg) suppressed the learning of a one-trial passive avoidance task. Amnesia induced by pre-training morphine was significantly reversed in mice which had previously received once daily injections of morphine (20 and 30 mg/kg, s.c.) for 3 days, which may be due to behavioral sensitization. Intra-CA1 injections of GABAA receptor agonist, muscimol (0.125, 0.25, 0.5 and 1 microg/mouse) or the GABAB receptor agonist, baclofen (1, 1.5 and 2 microg/mouse) prior to injection of morphine (20 mg/kg per dayx3 days) decreased the reversion of morphine-induced amnesia in morphine sensitized-mice. Daily intra-CA1 injections of muscimol or baclofen plus saline for 3 days did not alter memory formation. Furthermore, during development of sensitization, the combination of GABAA receptor antagonist, bicuculline (0.25, 0.5, 1 and 2 microg/mouse) with an ineffective dose of morphine (5 mg/kg, s.c.) reversed the amnesia induced by pre-training morphine. However, the same treatment with GABAB receptor antagonist, CGP35348 (2.5-40 microg/mouse) had no effect on the morphine response. On the other hand, daily intra-CA1 injections of bicuculline or CGP35348 alone for 3 days did not alter the amnesia induced by pre-training injection of morphine. The results suggest that morphine sensitization reverses the impairment of memory induced by morphine and that GABAergic receptors of the dorsal hippocampus may play an important role in this effect.     

The rewarding properties of NMDA and MK-801 (dizocilpine) as indexed by the conditioned place preference paradigm.

N-Methyl-D-aspartate (NMDA) ([R]-2-[Methylamino]succinic acid) is a specific excitatory amino acid. Two experiments were conducted to determine the rewarding properties of this compound using the conditioned place preference paradigm. In the first experiment, 40 male Sprague-Dawley rats received place preference conditioning for a 4 day period. The conditioned place preference apparatus consisted of two chambers with distinct visual and tactile cues, separated by a removable door. On days 2 and 4, rats were systemically administered NMDA (1.0, 15.0, and 30.0 mg/kg) paired with one chamber. On days 3 and 5, rats were systemically administered saline paired with the other chamber. Day 6 was the test day, and the rat was allowed free run of the entire apparatus in a drug-free state. Time spent in each side of the apparatus was computer recorded. NMDA produced a significant increase in the amount of time spent on the side previously paired with drug for 15.0 and 30.0, but not 1.0 mg/kg NMDA. In the second experiment, systemic administration of NMDA (30.0 mg/kg) paired with the noncompetitive NMDA receptor antagonist, MK-801 (0.5 mg/kg), resulted in neither place preference nor place aversion.