Opioid blockade attenuates acquisition and expression of cocaine-induced place preference conditioning in rats.

Endogenous opioid systems have been implicated in experimental cocaine addiction. One aspect of this involvement may be the modulation of the motivational properties of cocaine by endogenous opioids. The present study assessed the effect of opioid blockade with naloxone (NLX) on cocaine's motivational properties using the conditioned place preference procedure. Treatment with doses of NLX that did not induce place aversion (0.01-1.0 mg/kg-1, SC), dose-dependently attenuated place preference induced by cocaine (10 or 20 mg/kg-1, IP). This effect of NLX was present when administered during acquisition of cocaine-induced place preference and when administered before expression of cocaine's motivational effects. These data support the notion that the (conditioned) motivational properties of cocaine are modulated through activation of opioid systems by endogenous opioid peptides. Furthermore, it is suggested that an interaction between endogenous opioid systems and dopaminergic systems in the brain might be of importance in the motivational facilitation of experimental cocaine addiction.

Isradipine is able to separate morphine-induced analgesia and place conditioning.

The effect of isradipine, a dihydropyridine calcium antagonist, on morphine-induced place preference and analgesia in rats and mice was studied. Isradipine (0.6-5.0 mg/kg s.c.) inhibited an acquisition of morphine-induced place preference in rats and mice in a dose-related manner. Isradipine did not affect or strengthen morphine-induced analgesia as measured by tail-clip and hot-plate tests in mice and tail-clip and tail-flick tests in rats. The results suggest that analgesic and reinforcing effects of morphine might be pharmacologically separated by isradipine.

Analgesic and reinforcing effects of morphine in mice. Influence of Bay K-8644 and nimodipine.

The aim of the present work was to clarify the role of calcium influx through L-type calcium channels in the rewarding and analgesic effects of morphine. Therefore the effects of Bay K-8644 and nimodipine, dihydropyridine calcium agonist and antagonist, respectively, on the analgesic and rewarding effects of morphine in mice were studied. Morphine-induced analgesia was measured with the aid of writhing test, hot plate test and tail clip test. The rewarding properties of morphine were studied using i.v. self-administration in drug-naive mice. Bay K-8644 potentiated morphine-induced analgesia in all the tests. The influence of nimodipine on morphine analgesia was more complicated and depended on the dose of morphine and test used. In self-administration experiments morphine exhibited the bell-shaped concentration-response curve. Bay K-8644 produced a shift of the curve to the left, while nimodipine had the opposite action indicating, respectively, facilitating and inhibitory influence on morphine rewarding effect. It is concluded that nimodipine exhibits partial antagonistic properties towards the rewarding action of morphine and slightly potentiates morphine-induced analgesia while Bay K-8644 increases either the rewarding or the analgesic effects of morphine.

Experimental estimation of addictive potential of a mixture of organic solvents.

In the present study we investigated in rats the reinforcing properties of glue vapours which are a mixture of four organic solvents (toluene 25%, benzine fraction 37%, ethyl acetate 31% and methylene chloride 7%). This mixture is used as a glue thinner and is a very popular among glue-sniffing children. Immediately after inhalation at a concentration of 7200 ppm, the glue vapours increased locomotor activity in the open field and response rate of self-stimulation in the lateral hypothalamus. Contrary to classical drug abuse, glue vapours enhanced the threshold current of self-stimulation. While the response rate of self-stimulation decreased to the control level 30 min after inhalation, the threshold current was still enhanced. Increasing the concentration of the vapours produced a decrease in response rate of self-stimulation and locomotor activity. When glue vapours were inhaled at a concentration of 14,400 ppm and higher, the response rate of self-stimulation was completely suppressed. The discriminative stimulus effects of the glue vapours appeared to be similar to those of general anaesthetics such as ether and pentobarbital. At vapour concentrations of 7200 and 14,400 ppm, conditioned place preference was established. The ability of solvents to reinforce conditioning in the place preference paradigm and to activate the brain reward system in intracranial self-stimulation experiments may be useful for predicting the addictive potential of inhalants.

Caffeine place conditioning in rats: comparison with cocaine and ethanol.

The present study employed the place conditioning technique to compare rewarding potential of caffeine with that of cocaine and ethanol. In Experiment 1 caffeine, cocaine and ethanol place conditioning were estimated independently, whereas in Experiments 2 and 3 the preference of the external cues associated with caffeine vs. cocaine and caffeine vs. ethanol was assessed in a single test. Caffeine (1.5 mg/kg, i.p.) cocaine (5 mg/kg, i.p.) and ethanol (1.2 g/kg, i.g.) did produce secondary reinforcing effects comparable in magnitude (Experiment 1). In Experiments 2 and 3 animals had the opportunity 'to compare' rewarding effects of two drugs. Data showed that the preference of cocaine-paired cues was absolutely (100%) higher than those of caffeine, whereas reinforcing actions of caffeine and ethanol seemed to be equal. The proposed modification of conditioned place preference procedure may be useful for the comparison of rewarding values of different drugs with presumed addictive potential.

Involvement of endogenous digitalis-like factors in voluntary selection of alcohol by rats.

This study tested the hypothesis that endogenous digitalis-like factor (DLF) is involved in the development of alcohol dependence in rats. In 33 male Wistar rats in conditioned place preference (CPP) experiment, ethanol evoked increase in time spent in the ethanol-associated compartment (702+/-82 in ethanol-treated vs. 426+/-86 sec in the controls). Digoxin pretreatment (125 microg/kg, i/p) did not affect the time spent in the water-associated compartment (476+/-80 sec), but prevented the acquisition of ethanol CPP (385+/-112 sec in ethanol-paired side, P<0.05). In a two bottle choice test, where rats (n=6 per group) chose between drinking water and 9% ethanol, immunization against two putative DLFs, marinobufagenin and ouabain (MBG and OLC) resulted in a 60% increase of ethanol consumption. Acute intragastric administration of 9% ethanol to the rats was associated with increased OLC in cerebrospinal fluid, and stimulated urinary excretion of MBG and OLC. Thus, in rats, digoxin, which mimics the effects of DLFs, suppresses the free choice of alcohol, while immunization against DLFs is associated with alcohol seeking behavior.

Effect of serotoninergic drugs on positive and negative reinforcing systems in cats.

Administration of tryptophan and 5-hydroxytryptophan produced inhibition of self-stimulation through hypothalamic electrodes which was accompanied by drowsiness and decrease of motor activity. In cats pretreated with Ro 4-4602, an inhibitor of peripheral decarboxylase, both drugs did not produce drowsiness and markedly activated self-stimulation. Both drugs prolonged the latency of the escape reaction and inhibited the punishment reaction. The data suggest an activating effect of serotonin on the system of reward and an inhibitory effect on the system of punishment.

Effects of catecholaminergic drugs on systems of reward and punishment in experiments on cats.

Injection of amantadine or DOPA produced inhibition of both self-stimulation and negative-reinforcing effects of stimulation of the hypothalamus. After injections of l-DOPA in cats pretreated with RO 4-4602, an inhibitor of peripheral decarboxylase, or disulfiram, a dopamine-beta-hydroxylase inhibitor, the inhibitory action on the reinforcing system was enhanced. Amphetamine activated both reward and punishment systems. This data supports an inhibitory function of dopamine in systems of reinforcement and of an activating function of noradrenaline in these systems.

[Alteration of the hypothalamic electrical stimulation disconnection reaction in rats during chronic morphine administration]. / Izmenenie reaktsii vykliucheniia élektricheskoi stimuliatsii gipotalamusa u krys pri khronicheskom vvedenii morfina.

Rats with electrodes implanted in the hypothalamus were trained to switch off the central stimulation. Animals were administered 12--30 injections of morphine in increasing doses (from 20 up to 120--180 mg/kg/injection). The drug exerted a dose-proportional suppressive effect on the escape response. During repeated injections an absolute or relative tolerance to the suppressive action developed in the responses both to central and to peripheral painful stimulation. The suppressive action seems to be specific and does not correlate with the catatonic reaction and changes in general motor activity. The activation of gnawing response was noted after the morphine injections in doses of 60 mg/kg and higher. In one of the animals the transformation of the negative effect into ambivalent one as well as self-stimulation were observed. "Antiaversive" effect is considered to be one of the determinants of morphine abuse and addiction liability.

[The receptor organization of the reinforcing and analgetic opiate systems in the rat]. / Retseptornaia organizatsiia podkrepliaiushchei i anal'geticheskoi opiatnykh sistem u krys.

Comparative study of topographic and receptor selectivity of emotionally positive (place preference test) and analgetic (electrical and pressure nociceptive stimulation of the tail) effects of opioids was performed in rats. Morphine and selective agonists of mu-, kappa-, delta- and sigma-opiate receptors were administered through cannulae implanted into the periaqueductal grey and ventral tegmental area (VTA). Reinforcing effects of opioids in VTA was shown to be mediated mainly by mu-, delta- and sigma-receptors, while analgetic effect was realised with the aid of mu- and delta-opioid receptors.

[Characteristics of baroreceptor reflexes as affected by negative and positive emotions]. / Kharakter baroretseptornykh refleksov pri negativnykh i pozitivnykh émotsiogennykh vozdeistviiakh.

Changes of blood pressure (BP), intersystolic intervals (II), baroreflex sensitivity (BS) were studied during negative and positive emotions in unrestrained rats. Negative emotions induced raise of BP and reduced II and BS. The hemodynamic component of positive self-stimulation was due to its rewarding properties and not to direct effect of cerebral stimulation. It was characterized by BP elevation and II decrease, BS remaining unchanged. Hemodynamic manifestations of positive and negative emotions are discussed.

[Effect of psychotropic agents on the manifestation of the morphine abstinence syndrome in mice]. / Vliianie nekotorykh psikhotropnykh sredstv na proiavleniia morfinnogo abstinentnogo sindroma u myshei.

Abstinence syndrome pattern produced by withdrawal of morphine injections in doses of 240 mg/kg daily was studied in experiments on mice. Pirroksan, butyroxan and carbidine (10 mg/kg intraperitoneally) inhibited manifestations of morphine withdrawal in an "open field" situation and depressed jumping activity. Phenazepam (20 mg/kg) depressed emotional hyperactivity in abstinent animals.

[Rat behavior in an "open field" when chronically administered morphine]. / Povedenie krys v "otkrytom pole" pri khronicheskom vvedenii morfina.

15-day long administration of morphine in doses of 20 to 120 mg/kg, injected twice daily produced initially a depression followed by an increased locomotor activity, more pronounced grooming behavior and less so--rearing. Abnormal forms of behavior like combined arrests and rapid movements, circling, stereatyped gnawing were also observed. Abstinence provoked by withdrawal of morphine or nalophine was characterized predominantly by the stimulation of locomotion and grooming with depressed rearing.

[Study of the monoaminergic mechanisms of the effect of haloperidol in experiments using cats]. / Izuchenie monoaminergicheskikh mekhanizmov deistviia galoperidola, v opytakh na koshkakh.

Monoaminergic mechanisms of the haloperidol action on the systems "rewards" and "punishments" were studied in 22 cats with nichrome electrodes implanted into the hypothalamus. Haloperidol was introduced against the background of the dopaminomimetic amantadine, precursors of biogenic amines L-DOPA, tryptophan and 5-OTP. The inhibitory influence of haloperidol on the system "rewards" was found to be materialized largely at the expense of its serotonin-negative effect, while in the activating action of haloperidol on the system "punishment" its serotonin- and dopamino-negative effects partook.

[Comparative characteristics of the discriminative and analgesic effects of morphine]. / Sravnitel'naia l kharakteristika stimul'nogo i anal'geticheskogo éffektov morfina.

Experiments on mice were made to study and compare the discriminative and analgesic effects of morphine. The time-course of tolerance to the drug effects was found to be different. The Schild method permitted one to determine significantly different characteristics of naloxone antagonism (pA2) as regards the analgesic and discriminative effects of morphine. The data obtained attest to the different mechanisms of the analgesic and discriminative effects of morphine.

[Reinforcing, but no analgesic, effect of opioid stimulation of the ventral tegmental area]. / Podkrepliaiushchee, no ne anal'geticheskoe deistvie opioidnoi stimuliatsii ventral'noi tegmental'noi oblasti.

Analgesic and secondary reinforcing effects of morphine, bremazocine and phencyclidine microinjections into ventral tegmental area were studied in rats. The drugs under study failed to affect nociceptive reactions produced by thermal, mechanic and electrical stimuli. Morphine and phencyclidine have shown reinforcing properties in place preference paradigm. Ventral tegmental area seems to be a triggering zone of the reinforcing, and not analgesic effect of opioid agonists, with an important role of mu- and sigma-receptors revealed.