Caroverine inhibits the conditioned place aversion induced by naloxone-precipitated morphine withdrawal in rats.

Comparable to the anti-craving compound acamprosate, caroverine reduces alcohol withdrawal symptoms by an antagonism at ionotropic glutamate receptors and a blockade of calcium channels. The present study examines the effect of caroverine in a craving model, in which acamprosate has proved effective before. A place aversion was induced by a conditioned morphine withdrawal by administration of the opioid antagonist naloxone (0.1 mg/kg, s.c.) 5-6 days after the subcutaneous implantation of a morphine pellet in rats. Testing in the drug-free state, the acquisition of a conditioned aversion against the naloxone-associated cues was inhibited by pretreatment with caroverine (5 mg/kg, i.p.). This result corroborates the involvement of excitatory glutamate and calcium in the development of conditioned withdrawal and craving. It offers further evidence for the hypothesis that these neuronal systems are altered during withdrawal in a similar way by ethanol and opiates.

The effect of acamprosate on the development of morphine-induced behavioral sensitization in rats.

Recently we have shown that the alcohol anti-craving drug acamprosate (calcium acetylhomotaurinate), a functional N-methyl-D-aspartate (NMDA) receptor antagonist which is used therapeutically to prevent relapse in weaned alcoholics, was also effective in suppressing (1) conditioned place aversion induced by morphine withdrawal, and (2) expression of morphine-induced behavioral sensitization. Here, we addressed the question of whether the development of behavioral sensitization, induced by daily injections of morphine (10 mg/kg) over a period of 10 days, could also be suppressed by repeated pretreatment with acamprosate (200 mg/kg). Repeated intermittent injections of morphine produced sensitization of locomotor activity and sniffing behavior. Acamprosate did not block the development of morphine-induced behavioral sensitization. This lack of effect on the development of this phenomenon is inconsistent with the view that NMDA receptor antagonists block the development of sensitization. We suggest that this may derive from the relatively low NMDA receptor-specific antagonism of acamprosate as compared to other NMDA receptor antagonists used in this model. In conclusion, the effect of acamprosate on morphine-induced behavioral sensitization seems to be restricted to the expression of this phenomenon.

The anti-craving drug acamprosate inhibits the conditioned place aversion induced by naloxone-precipitated morphine withdrawal in rats.

The anti-craving drug acamprosate (Ca N-acetylhomotaurinate) is therapeutically used to prevent a relapse in weaned alcoholics. In the present place conditioning study, the effect of this compound on the motivational impact of morphine withdrawal was examined. Withdrawal was precipitated in rats by administration of the opioid antagonist naloxone (0.1 mg/kg, s.c.) 5-6 days after the subcutaneous implantation of a 75 mg morphine pellet. Aversion against the naloxone-paired cues was observed after conditioning in the drug-free state. The acquisition of conditioned place aversion was completely inhibited by the pretreatment with acamprosate (200 mg/kg, i.p.) 12 h and 30 min prior to conditioning. These results clarify that acamprosate inhibits the motivational component of morphine withdrawal and suggest that ethanol and opiates share similar properties in the neuronal mechanisms of conditioned withdrawal and craving.

Riluzole, a glutamate release inhibitor, and motor behavior.

Riluzole (2-amino-6-trigluoromethoxy benzothiazole) has neuroprotective, anticonvulsant, anxiolytic and anesthetic qualities. These effects are mediated by blockade of glutamate transmission, stabilizing of sodium channels and blockade of gamma-aminobutyric acid (GABA) reuptake. The action profile of riluzole is dominated by its effects on glutamate transmission which are predominately mediated by N-methyl-D-aspartate (NMDA) receptor-linked processes in vitro. In vivo studies show that blockade and stimulation of the different NMDA receptor complex binding sites or AMPA receptors modulate motor behavior in a characteristic manner. It was therefore interesting to examine if blockade of glutamatergic transmission by riluzole induced similar behavioral effects as direct NMDA/AMPA receptor antagonists and if these effects are mediated by a specific receptor. The effects of riluzole alone and in combination with several other neuroactive compounds on the central nervous system was assessed by behavioral paradigms to evaluate sniffing behavior, locomotion, ataxia and rigidity. Accompanying compounds included the NMDA receptor agonist NMDA, the partial glycine site agonist D-cycloserine (DCS), and the alpha-amino-3-hydroxy-5-phenyl-4-isoxazolepropionic acid (AMPA) receptor antagonist GYKI 52466 [1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzo-diazepine HCl]. Riluzole influenced neither stereotyped sniffing behavior nor locomotion but impaired motor coordination and attenuated rigidity induced by blockade of dopamine D1 and D2 receptor antagonists when given alone. At higher doses spontaneous behavioral activity decreased and motor coordination was more impaired. Augmentation of the riluzole effects were observed when NMDA, but not GYKI 52466, was coadministered. The glycine site agonist DCS increased the anticataleptic properties of riluzole. The results indicate that when given alone, riluzole has a behavioral profile resembling that of competitive NMDA receptor antagonists. However, coadministration of riluzole with NMDA/AMPA receptor ligands suggests that this assumption is incorrect, and that riluzole affects glutamatergic transmission by a more indirect mechanism. Nevertheless, the profile of riluzole together with its pre- and postsynaptic blockade of glutamatergic transmission implies beneficial properties in diseases where an overactive glutamate system induces chronic neurotoxicity and/or acute behavioral effects.

ACEA 1021, a glycine site antagonist with minor psychotomimetic and amnestic effects in rats.

Antagonists of the allosteric glycine site of the NMDA receptor complex have been suggested to be beneficial in the treatment of neurodegenerative disorders. However, unwanted side effects like psychomotor stimulation and amnesia must be expected. ACEA 1021 (5-nitro-6,7-dichloro-1,4-dihydroquioxaline-2,3dione) is one of the first high-selective glycine site antagonists which passes the blood-brain barrier and which has promising anticonvulsive and neuroprotective properties. In the present study the effects of ACEA 1021 (5, 7.5, 8, 10, 15 and 20 mg/kg i.p.) on sniffing stereotypy, locomotor activity, prepulse inhibition of the acoustic startle response, the anti-cataleptic properties and spatial learning were tested. Only 7.5 mg/kg ACEA 1021 induced a sniffing stereotypy which was antagonized by the partial glycine site agonist D-cycloserine (D-4-amino-3-isoxazolidinone). ACEA 1021 had neither an effect on motor behavior measured in the open field nor on the acoustic startle response in the prepulse inhibition paradigm nor on the acquisition of spatial learning in the 8-arm-radial maze. Anti-cataleptic properties of ACEA 1021 in dopamine D2 (haloperidol (4'fluoro-4-(1-(4-hydroxy-4-p-chlorophenyl-piperidino)-butyrophe non)) or D1 (SCH 23390 (7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzaze pin e hydrochloride)) receptor antagonist-pretreated rats were only minor. Thus, ACEA 1021 is a glycine site antagonist with minimal psychotomimetic side effects and with no amnesia properties. However, it has only minor anti-parkinsonian effects.