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Biomedical subjects

A Kuzmin

Publications and source records attributed to A Kuzmin.

At least 91 records · Page 5Linked to original sources
PubMed2000

Genetic evidence that cocaine and caffeine stimulate locomotion in mice via different mechanisms.

The effects of cocaine and caffeine on motor activity in two mouse strains 129/OlaHsd (129) and C57BL/6J (C57) were compared. The former mice exhibited lower basal motor activity than the latter. Cocaine (3, 10, 30 mg/kg) injected i.p. in habituated C57 mice produced a dose-dependent increase in rearing, motility and locomotion. In 129 mice, little or no stimulation was seen and only with the highest dose of cocaine. In both strains caffeine (3, 15, 30 mg/kg) produced a dose-dependent increase in rearing, motility and locomotion. The effect of caffeine on rearing was greater in C57 than in 129 mice, but motility and locomotion were stimulated approximately to the same degree in both strains. Thus, differences in the sensitivity to caffeine and cocaine between mouse strains provide genetic evidence that these two stimulants probably produce locomotor stimulation via somewhat different mechanisms.

Animals↗
PubMed2000

Reinforcing and neurochemical effects of cocaine: differences among C57, DBA, and 129 mice.

C57BL/6J, DBA/2J, and 129/OlaHsd mice were compared as to their propensity to self-administer cocaine, the ability of cocaine injection to prevent extinction of nose poking in the absence of cocaine infusion, and cocaine's effect on NGFI-A and secretogranin II mRNA. Baseline nose-poke activity tended to be highest in C57 and lowest in DBA mice. C57 and DBA mice self-administered cocaine, as indicated by more frequent nose pokes in mice allowed to infuse cocaine through nose pokes than in mice passively receiving the same amount of cocaine. DBA mice had the larger ratio between active and yoked-control animals, but the response rate in DBA mice was four times lower, and cocaine intake 10 times lower than in C57 mice. The 129 mice showed little response to cocaine. C57 and DBA mice that had been self-administering cocaine showed an extinction of responding when infusions were stopped, preventable by IP cocaine (5 mg kg(-)(1)). A single cocaine injection (2 mg kg(-)(1)) increased NGFI-A mRNA and decreased secretogranin II mRNA in the caudate putamen in C57 mice. These effects were more widespread in DBA and absent in the 129 mice. The marked differences among mouse strains described here will be important to consider when transgenic mice are to be used in cocaine-related studies.

Animals↗
PubMed2000

Differences in the effect of chronic and acute caffeine on self-administration of cocaine in mice.

We have compared the ability of an acute injection of caffeine (3 mg/kg, i.p.) and long-term peroral caffeine consumption for 10 days ( approximately 150 mg/kg/day in tap water) to affect cocaine self-administration in mice. The peak plasma and brain levels of caffeine and its metabolites were similar in the two experimental set-ups. Moreover, the levels reached are close to those obtained in humans upon coffee ingestion. Neither type of caffeine administration affected the reinforcing effect of cocaine, defined as a selective increase in nose-poke responses in mice self-administering cocaine compared to their yoked controls. However, caffeine injection increased the amount of cocaine self-administered whereas caffeine drinking reduced it. A low dose of cocaine, by itself essentially ineffective, produced an increase in c-fos and NGFI-A mRNA in the cerebral cortex in mice that had been drinking caffeine. An acute caffeine injection also enhanced the immediate early gene response to cocaine, but to a lesser degree. Cocaine and caffeine also synergistically increased NGFI-A expression in caudate-putamen. Thus, regular caffeine drinking decreased the cocaine intake without significantly affecting its reinforcing properties, perhaps because it enhanced the activation of the predominantly inhibitory frontal cortical areas produced by low doses of cocaine.

Animals↗
PubMed2000

Dose- and time-dependent bimodal effects of kappa-opioid agonists on locomotor activity in mice.

The kappa-opioid agonists U50488H, bremazocine, and BRL52537, and the mu-opioid agonist morphine were compared in their ability to modify spontaneous motor activity in male NMRI mice. Higher, analgesic doses of the kappa-agonists reduced rearing, motility, and locomotion in nonhabituated mice. These effects, as well as the analgesic action of U50488H, were blocked by the selective kappa-opioid antagonists nor-binaltorphimine and DIPPA. In contrast, lower, subanalgesic doses (1.25 and 2.5 mg/kg for U50488H; 0.15 and 0.075 mg/kg for bremazocine, and 0.1 mg/kg for BRL52537) time dependently increased motor activity. The stimulatory effects of U50488H and bremazocine were not observed in habituated animals and were reduced by dopamine depletion. Surprisingly, the stimulatory effects of U50488H and bremazocine were not blocked by nor-binaltorphimine and DIPPA but they were completely eliminated by naloxone (0.1 mg/kg). The effects of morphine were dose-dependent; an initial limited suppression was followed by increased motility and locomotion (but not rearing) with a peak effect at 20 mg/kg both in habituated and nonhabituated mice. The selective mu-opioid antagonist beta-funaltrexamine blocked morphine-induced motor stimulation and analgesia but failed to affect the analgesic and motor stimulatory effects of U50488H. The results indicate that kappa-opioid agonists interact with different functional subtypes of opioid receptors. A stimulatory, naloxone-sensitive but nor-binaltorphimine- and DIPPA-insensitive subtype of opioid receptor appears to operate only when the dopamine system is tonically active in nonhabituated animals. At higher doses, kappa-agonists produce analgesia and motor suppression, effects mediated by a "classic" (inhibitory) kappa-opioid receptor.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1999

Effects of calcium channel blockade on intravenous self-administration of ethanol in rats.

In the present study the involvement of voltage-operated calcium channels (VOCCs) in the acquisition and maintenance of operant i.v. ethanol (EtOH) self-administration was investigated in rats. Rats readily learned to self-administer EtOH (unit dose range: 0.5-4% v/v) within five daily 2-h sessions, when infusions were made contingent upon nose-poking in a hole containing infrared sensors. Response rate was related to the EtOH concentration in an inverted U-shaped manner, the maximal rate and intake being observed at a unit dose of 1% v/v (0.27 mg EtOH/infusion). Self-administration of EtOH appeared to be behaviorally specific, as responding in the reinforced hole did not coincide with increased responding in a nonreinforced hole. Daily treatment with the dihydropyridine VOCC blocker nimodipine (2.5-20 mg/kg, i.p., t-15 min) dose-dependently attenuated acquisition of EtOH self-administration; the 5 mg/kg dose resulting in a partial, and the 10 and 20 mg/kg doses in a complete prevention of i.v. self-administration behavior. The effects of nimodipine (2.5-5.0 mg/kg) were considered to be relatively specific, as an inhibition of the reinforced responding could be demonstrated in the absence of a significant effect on nonreinforced responding. When tested in rats showing stable self-administration behavior (unit dose: 1% v/v EtOH), nimodipine showed biphasic dose-response effects; with 2.5 and 5 mg/kg resulting in a mild increase, and 10 and 20 mg/kg resulting in a decrease of self-administration behavior, respectively. The present study suggests that blockade of VOCCs attenuates the reinforcing stimulus effects of EtOH; and, as such, the data may offer an explanation for the previously reported EtOH intake-reducing effects of dihydropyridine calcium channel ligands obtained in two-bottle choice paradigms. Dihydropyridine derivatives, such as nimodipine, may therefore offer an interesting approach to the pharmacotherapy of alcoholism.

Animals↗
PubMed1999

Expression of c-fos, NGFI-A and secretogranin II mRNA in brain regions during initiation of cocaine self-administration in mice.

Intravenous cocaine self-administration in mice was studied to find correlates of the acquisition of cocaine-oriented operant behaviour in the expression of nerve growth factor-induced clone A (NGFI-A), c-fos and secretogranin II mRNAs. Yoked control animals, receiving cocaine passively, served as controls for the neurochemical effect of non-contingent cocaine infusion. Animals controlling their cocaine infusions did more nose-pokes during a 30-min trial than yoked controls and animals receiving only saline, indicating a reinforcing effect of cocaine. Compared with saline, an increase in c-fos mRNA in lateral and basolateral amygdala was found in active cocaine-receiving animals, and a decrease in yoked controls receiving cocaine. There is previous evidence for an involvement of the amygdala, particularly its basolateral part, in cocaine's effects on motivation. In caudate putamen, both contingent and non-contingent cocaine increased c-fos mRNA. Non-contingent cocaine infusions increased NGFI-A mRNA expression in the core of nucleus accumbens, medial caudate putamen and frontal cortex, whereas self-administration eliminated these effects. In the core of the nucleus accumbens and piriform cortex there was increased, and in medial amygdala decreased secretogranin II mRNA in yoked controls compared with saline controls. In contrast, in basomedial and central nuclei of amygdala, increased secretogranin II mRNA was found in self-administering mice. Previous studies measuring gene expression after cocaine administration obviously did not give the complete picture of changes in gene expression in the drug-taking organism. As differences in c-fos and secretogranin II mRNA between active mice and yoked controls were robust, measuring these mRNAs may identify neurons selectively involved in acquisition of cocaine-taking behaviour.

Amygdala↗
PubMed1999

Caffeine, acting on adenosine A(1) receptors, prevents the extinction of cocaine-seeking behavior in mice.

Drug-naive DBA/2 mice were trained to self-administer cocaine (40 microgram/kg/infusion) i.v. by nose poking. The number of nose-poke responses was higher in mice receiving response-contingent injections of cocaine (active group) than in yoked controls or in animals receiving response-contingent saline injections. Twenty-four hours after the training session (cocaine or saline self-administration), mice were injected i.p. with saline, cocaine, caffeine, 1,3-dipropyl-8-cyclopentyl xanthine (DPCPX), 8-cyclopentyl theophylline (8-CPT), 5-amino-7-(2-phenylethyl)2-(2-furyl)-pyrazolo-[4,3-e]-1,2, 4-triazolo[1,5-c]pyrimidine (SCH 58261), or 9-chloro-2(2-furyl)[1,2, 4]triazolo[1,5-c]quinazolin-5-amine (CGS 15943) and placed again in exactly the same operant boxes as during the training session but without response-contingent i.v. infusions. Saline injection elicited similar responding in animals from the active group and from the yoked control group. A low dose of cocaine (5 mg/kg) or caffeine (3 mg/kg), but not higher doses, produced greater responding in the active group than in the yoked control group during a single extinction trial. The adenosine A(1)-receptor antagonists DPCPX and 8-CPT and the nonselective antagonist CGS 15943 partially reproduced the effect of a low dose of caffeine on the cocaine-associated behavior in a dose-dependent manner and did not alter the nose-poke activity of yoked control mice in the extinction experiment. In contrast, the adenosine A(2A) antagonist SCH 58261, in doses above 1 mg/kg, reduced nose-poke activity equally in active and yoked control animals. This confirms that a drug from a different pharmacological class (adenosine-receptor antagonist) can induce behavior changes similar to the effects of the original self-administered drug (indirect dopamine-receptor agonist). The data also suggest that the effects of caffeine on cocaine-seeking behavior might be related to interaction with adenosine A(1) receptors, but not A(2A) receptors.

Animals↗
PubMed1996

Modulation of cocaine intravenous self-administration in drug-naive animals by dihydropyridine Ca2+ channel modulators.

The dihydropyridine Ca2+ channel blocker nimodipine and the dihydropyridine Ca2+ channel activator BayK 8644 (1,4-dihydropyridine-2,6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)-py ridine- 5-carboxylate) were administered to drug-naive mice and rats that were tested for intravenous cocaine self-administration. A range of cocaine doses was tested to investigate the nature of the effect. The results indicate that nimodipine and BayK 8644 shifted the dose-response curve for cocaine's reinforcing action to the right and left, respectively. Thus, the Ca2+ channel blocker nimodipine decreases the sensitivity of mice and rats to the reinforcing effects of cocaine while the Ca2+ channel activator BayK 8644 makes the animals more sensitive to cocaine reward. The results suggest that a dihydropyridine-sensitive mechanism is implicated in the initiation of cocaine self-administration.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1996

Effect of isradipine, a dihydropyridine-calcium antagonist on i.v. self-administration of morphine in rats.

The effect of dihydropyridine calcium channel antagonist isradipine (PN 200-110) on morphine reinforcement has been investigated using i.v. self-administration test in rats. Rats were given the opportunity to self-administer a solution of morphine (1 mg/ml, i.v.) in a 1 hr limited access paradigm (FR = 1). Within 5-7 days rats had learned to self-administer approximately 1 mg of morphine in 1 hr as evidenced by a plateau of responding. The administration of isradipine (1.2, 2.5 and 5.0 mg/kg s.c.) 90 min before the morphine self-administration session, induced dose-dependent increase in the number of morphine self-infusions with respect to basal values. This response pattern was very similar to the one observed when morphine solution was substituted by saline in trained rats not treated with isradipine. The results indicate that isradipine inhibits partially the reinforcing properties of morphine in self-administration test.

Animals↗
PubMed1996

Enhancement of morphine self-administration in drug naive, inbred strains of mice by acute emotional stress.

The primary reinforcing effect of morphine was compared in two genetically inbred strains of mice (C57BL/6 and DBA/2) using the intravenous self-administration procedure in drug naive animals. The morphine self-administration differed between the mouse strains. DBA/2 but not C57BL/6 acquired self-administration of morphine with a bell-shaped unit dose-response curve. Acute physical stress induced by electrical footshocks did not significantly affect the self-administration in both strains. Acute emotional stress induced by forcing mice to witness another mouse being subjected to acute physical stress caused a shift of the bell-shaped unit dose-response curve of morphine self-administration to the left in the DBA/2 mice. The C57BL/6 mice, which initially failed to demonstrate stable self-administration, started to self-administer morphine after emotional but not physical stress. Emotional distress may increase the individual sensitivity to the rewarding effects of morphine and may render an individual more susceptible to development of drug dependence.

Animals↗
PubMed1995

Strain differences in the analgesic and reinforcing action of morphine in mice.

The analgesic and reinforcing effects of morphine were compared in four strains of mice (C57BL/6, BALB/c, DBA, CBA). The analgesic action of morphine was measured in tail immersion (49 degrees C), hot plate (60 degrees C), and tail clip (four-point scale of nociceptive response) tests. The reinforcing action of morphine was studied in i.v. self-administration and conditioned place preference techniques. The results demonstrate strain differences in the analgesic and reinforcing action of morphine in mice. The relative rank order of the strains varied for the several tests as well as for the morphine effects. The lack of correlation between analgesic and reinforcing action of morphine in inbred strains supports the conclusion that analgesia and reinforcement are separate processes with different genetic control.

Analgesics↗
PubMed1995

Isradipine inhibits nicotine intravenous self-administration in drug-naive mice.

The effect of isradipine, a dihydropyridine calcium antagonist, on intravenous self-administration of nicotine in naive mice has been investigated. When nicotine injections were made contingent upon nose-poke response by naive mice, they increased their rate of nose poking with respect to animals receiving contingent saline injections or yoked control animals receiving noncontingent nicotine injections. Pretreatment of mice with mecamylamine (2.4 mg/kg) inhibited self-administration of nicotine contingent upon a nose-poke response. The same effect was observed with isradipine (0.5-1.0 mg/kg) in a dose-related manner and stereospecifically. These data suggest that isradipine suppresses the reinforcing properties of nicotine and might be useful for treatment of nicotine abuse.

Animals↗
PubMed1994

Effects of the calcium antagonist isradipine on cocaine intravenous self-administration in rats.

The effect of isradipine, a dihydropyridine calcium antagonist, on cocaine intravenous self-administration in rats was investigated. Administration of (+/-)isradipine (1.25-5 mg/kg SC) 2 h before the cocaine self-administration session induced a significant and dose-dependent increase in the number of cocaine injections with respect to basal values. This effect was stereospecific, with the (+) form of isradipine being active, while the (-) stereoisomer was ineffective. These results suggest that isradipine antagonizes the rewarding properties of cocaine, possibly by inhibiting those dopaminergic systems related to reward mechanisms. These results further indicate a possible use of isradipine, or structurally similar compounds, in the treatment of cocaine related disorders.

Animals↗