Thomas M. Tzschentke

Interactions of MK-801 and GYKI 52466 with morphine and amphetamine in place preference conditioning and behavioural sensitization

In an earlier study we showed that co-administration of the NMDA-receptor antagonist MK-801 during conditioning sessions blocks morphine-induced conditioned place preference (CPP). From this result, the question arose of whether this blockade is due to state-dependency effects induced by MK-801. Therefore, in a first experiment, animals were tested in the drugged state under which they had been conditioned. These animals did not show a CPP, thus it can be concluded that MK-801 does not make state-dependent the morphine conditioning. In the same experiment those animals receiving only morphine during conditioning sessions showed a significant CPP when tested in an undrugged state but failed to show CPP when tested after injection of MK-801 (i.e., in the drugged state). These results indicate that MK-801 not only blocks the development of morphine-induced CPP but is also able to block the expression of a conditioned response that has been acquired before. In the same experiment repeated injection of neither morphine nor MK-801 produced sensitized locomotor activity. However, a strong sensitization was observed following repeated injection of morphine plus MK-801. There was also cross-sensitization between morphine plus MK-801 and MK-801 alone but not with morphine alone, and also between morphine and MK-801, but not vice versa. In a second experiment the effects of the AMPA-receptor antagonist GYKI 52466 were examined. It was found that GYKI 52466 did not produce CPP or behavioural sensitization. Finally, in a third experiment, CPP was induced by morphine and amphetamine (animals tested in the drug-free state), and behavioural sensitization was induced by amphetamine. When animals were tested after an injection of GYKI 52466, neither the morphine- nor the amphetamine-conditioned animals showed a CPP. Likewise, challenge of sensitized animals with amphetamine plus GYKI 52466 failed to produce a sensitized response. It can be concluded, that GYKI 52466, like MK-801, can block the expression of a conditioned response, and can also block the expression of sensitized behaviour.

N-Methyl-d-aspartic acid-receptor antagonists block morphine-induced conditioned place preference in rats

We addressed the question of whether (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (MK-801) and DL-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid (CGP37849), a non-competitive and a competitive N-methyl-D-aspartate (NMDA) receptor antagonist, respectively, are able to block morphine-induced conditioned place preference (CPP). MK-801 alone (0.1 mg/kg) produced neither a place preference nor a place aversion, but was able to completely block morphine-induced CPP. CGP37849 alone (10 mg/kg) produced a small but significant CPP, and was able to significantly attenuate morphine-induced CPP. These results cannot be due to simple additive effects of drug actions, but suggest that NMDA receptors play a complex role in the development of morphine CPP.

Functional heterogeneity of the rat medial prefrontal cortex: effects of discrete subarea-specific lesions on drug-induced conditioned place preference and behavioural sensitization.

While the principal components of the brain reward system, the nucleus accumbens septi and the ventral tegmental area have received much attention, their efferent and afferent structures have not been investigated to the same degree. One major input to this system originates from the medial prefrontal cortex (mPFC) which is not a homogenous structure but can be divided into different subareas that can be distinguished on anatomical and possibly functional grounds. We examined the effects of discrete bilateral quinolinic acid lesions (45 nmol/0.5 μL) of each of the mPFC subareas, the infralimbic (il), prelimbic (pl) and the anterior cingulate (cg) mPFC, on the conditioned place preference (CPP) and psychomotor activation induced by several drugs. Lesions of the il mPFC blocked CPP induced by morphine (10 mg/kg) and CGP37849 [dl‐(E)‐2‐amino‐4‐methyl‐5‐phosphono‐3‐pentic acid, a competitive N‐methyl‐d‐aspartate receptor antagonist; 10 mg/kg]. Lesions of the pl mPFC blocked CPP induced by cocaine (15 mg/kg) and CGP37849, and lesions of the cg mPFC only blocked CGP37849‐induced CPP. Lesions of the whole mPFC blocked morphine‐, cocaine‐ and CGP37849‐induced CPP. None of the lesions affected dl‐amphetamine (4 mg/kg)‐induced CPP. During the conditioning period, none of the lesions affected amphetamine‐induced psychomotor activation and sensitization, whereas both phenomena were attenuated by pl and whole mPFC lesions in the case of cocaine, and by il and whole mPFC lesions in the case of morphine. These results show that the different mPFC subregions have distinct functional roles in the generation of behavioural effects produced by different classes of drugs. This heterogeneity should be taken into account in future studies addressing the role of the mPFC in drug reward and sensitization.

Discrete quinolinic acid lesions of the rat prelimbic medial prefrontal cortex affect cocaine- and MK-801-, but not morphine- and amphetamine-induced reward and psychomotor activation as measured with the place preference conditioning paradigm

As a part of the mesocorticolimbic system, the medial prefrontal cortex (mPFC) is thought to participate in the regulation of locomotor activity, motivation and reward. The mPFC consists of at least three different subareas. In previous lesion studies examining this region usually large parts of the mPFC were destroyed, with little discrimination between the different subareas. Therefore, this study was designed to selectively lesion the prelimbic area of the mPFC using a relatively low dose of quinolinic acid. In a conditioned place preference (CPP) experiment, lesioned and control animals were treated with cocaine (15 mg/kg), amphetamine (4 mg/kg), morphine (10 mg/kg) or MK-801 (0.3 mg/kg) to induce CPP. The lesion blocked the development of CPP only in animals receiving cocaine, but not in animals receiving amphetamine or morphine. MK-801 failed to produce a CPP in both lesioned and unlesioned animals. During the conditioning experiment, the acute locomotor response to the different drugs was also measured. Only the response (in terms of locomotion and rearing) to cocaine and MK-801 was reduced to a significant extent by the lesion, while the response to amphetamine and morphine was not affected. Also, the lesions did not cause any changes in the spontaneous activity of the animals when tested without drug. These results show that even small lesions of the prelimbic subarea of the mPFC are sufficient to produce behavioral effects. However, these are apparent only when the animals are challenged with cocaine or MK-801, but not with amphetamine or morphine, or when drug-free. This suggests that the mPFC might have a special role in mediating cocaine and MK-801 effects.

Blockade of morphine- and amphetamine-induced conditioned place preference in the rat by riluzole

Previous studies have shown that antagonists at glutamatergic N-methyl-D-aspartate (NMDA) or alpha-amino-3-hydroxy-5-methyl-4-isoxazolpropionic acid (AMPA) receptors can disrupt the development or expression, respectively, of conditioned place preference (CPP) induced by drugs of abuse. The present study examined the effects of inhibition of presynaptic glutamate release by riluzole on the development of morphine- and amphetamine-induced CPP. Morphine (10 mg/kg), D,L-amphetamine (4 mg/kg) and riluzole (4 mg/kg) itself each produced a significant CPP; however, when riluzole was co-administered with morphine or amphetamine during the conditioning sessions, no CPP developed. It is concluded that non-specific disruption of glutamatergic neurotransmission prevents the development of morphine- and amphetamine-induced CPP.

State-dependent blockade of haloperidol-induced sensitization of catalepsy by MK-801.

NMDA receptor antagonists have been shown to block several forms of neural and behavioural plasticity. The prototypical and most widely‐used noncompetitive NMDA receptor antagonist is dizocilpine (MK‐801). Here we have examined the effect of MK‐801 on the context‐dependent augmentation (‘sensitization’) of catalepsy in rats which develops with repeated administration of haloperidol. It was found that over a 7‐day treatment period animals receiving haloperidol (0.25 or 0.5 mg/kg) plus MK‐801 (0.16 mg/kg) showed a context‐dependent day‐to‐day increase in catalepsy similar to animals that received haloperidol alone. However, when all animals were treated with haloperidol alone on day 8 of the experiment, animals that had received haloperidol plus MK‐801 before displayed a much smaller cataleptic response, similar to that observed in the haloperidol group on the first treatment day, i.e. the previously‐established enhancement of catalepsy was no longer expressed. These results may be explained in terms of state‐dependency effects induced by MK‐801. Implications of these findings for the clinical use of NMDA receptor antagonists in the treatment of Parkinsons disease are discussed.

Memantine does not substantially affect brain stimulation reward : comparison with MK-801

The non-competitive N-methyl-D-aspartate (NMDA)-receptor antagonist MK-801 (dizocilpine) has been shown to potentiate brain stimulation reward (BSR). Memantine (1-amino-3,5-dimethyladamantane) also binds to the PCP binding site of the NMDA receptor but with markedly different kinetics and affinity than MK-801. Here, we examined the effects of memantine on BSR and compared its effects to those of MK-801. MK-801 (0.05 mg/kg-0.4 mg/kg) produced clear, dose-dependent decreases in threshold frequency, manifest in clear leftward shifts of the function relating stimulation frequency to response rate. Memantine (1 mg/kg-17.5 mg/kg) had only small effects on threshold frequencies and only at high doses, manifest in only small shifts in the frequency-response function. The highest dose of each drug also produced a decrease in maximum response rate. This study shows that memantine failed to substantially influence BSR at low to intermediate doses, suggesting that this substance is likely to be largely devoid of rewarding effects in a therapeutic dose range.

Effects of amphetamine, morphine and dizocilpine (MK-801) on spontaneous alternation in the 8-arm radial maze.

The induction of psychomotor activation, behavioural sensitization and of perseverative behaviours, resulting in reduced behavioural variability, have been proposed to be common properties of drugs of abuse. The present investigation tested whether these drug effects could be measured using spontaneous alternation in an 8-arm radial maze. Behavioural effects of repeated treatment with amphetamine (2 and 4 mg/kg, i.p.), morphine (1.25 and 10 mg/kg, i.p.) and the non-competitive NMDA receptor antagonist, MK-801 (0.1 and 0.2 mg/kg, i.p.), on spontaneous alternation were evaluated in this paradigm. All drugs induced psychomotor activation. Sensitized as well as reduced locomotor activity could be observed after repeated treatment depending on drug and dose. Analysis of the sequences of arm entries revealed that all drugs induced perseverative locomotor patterns, but the pattern induced by amphetamine and morphine differed qualitatively from the pattern induced by MK-801.

Differential effects of quinolinic acid lesions of the medial prefrontal cortex on the expression of morphine- and dizocilpine- induced behavioural plasticity in the rat.

Development and expression of behavioural sensitization have been shown to be differentially affected by drugs and lesions. Here we assessed the effects of quinolinic acid lesions of the rat medial prefrontal cortex on the expression of enhanced locomotion and rearing that has been induced prior to the lesions by 14 daily injections of morphine (10 mg/kg), dizocilpine (MK-801) (0.3 mg/kg) or the combination of both drugs. Expression of tolerance to morphine-induced behavioural inhibition was blocked by the lesions while the expression of MK-801 -induced sensitization was not affected and the expression of the sensitization induced by the drug combination was only mildly attenuated. These results suggest that the expression of behavioural plasticity induced by different drugs is mediated at least in part by different neural substrates.