Audrey Hashim

Effect of nicotine on extracellular levels of neurotransmitters assessed by microdialysis in various brain regions : role of glutamic acid

We studied the effect of local administration of nicotine on the release of monoamines in striatum, substantia nigra, cerebellum, hippocampus, cortex (frontal, cingulate), and pontine nucleus and on the release of glutamic acid in striatum of rats in vivo, using microdialysis for nicotine administration and for measuring extracellular amine and glutamic acid levels. Following nicotine administration the extracellular concentration of dopamine, increased in all regions except cerebellum; serotonin increased in cingulate and frontal cortex; and norepinephrine increased in substantia nigra, cingulate cortex, and pontine nucleus. Cotinine, the major nicotine metabolite, had no effect at similar concentrations. The cholinergic antagonists mecamylamine and atropine, the dopaminergic antagonists haloperidol and sulpiride, and the excitatory amino acid antagonist kynurenic acid all inhibited the nicotine-induced increase of extracellular dopamine in the striatum. The fact that kynurenic acid almost completely prevented the effects of nicotine, and nicotine at this concentration produced a 6-fold increase of glutamic acid release, suggests that the effect of nicotine is mainly mediated via glutamic acid release.

Ibogaine reduces preference for cocaine consumption in C57BL/6By mice

After a period of forced exposure to 300 mg/l cocaine HCl in drinking water for a period of one week, followed by forced exposure to 200 mg/l cocaine for an additional week, male C57BL/6By mice developed a preference for cocaine when given a choice of drinking either water or a solution containing cocaine (200 mg/l). The mean daily intake of cocaine during the choice period was 26 +/- 1 mg/kg or, when expressed as the ratio of cocaine over total fluid intake, represented a cocaine preference of 71 +/- 2%. Administration of ibogaine HCl (40 mg/kg, two injections 6 h apart) two weeks after the beginning of the choice period reduced the cocaine preference for at least five days; the mean daily intake of cocaine was reduced by 38% (to 16 +/- 1 mg/kg per day; p < 0.05) and cocaine preference was reduced to 41 +/- 2% (cocaine fluid consumption/total fluid intake). An acute challenge injection of cocaine (25 mg/kg SC) produced a significant increase in cocaine-induced locomotor activity and stereotypy in mice previously exposed to cocaine in their drinking water (cocaine choice group). Five days after ibogaine administration, locomotor and stereotypy activity were significantly lower after a challenge injection of cocaine (25 mg/kg SC). Brain levels of cocaine 35 min after the challenge injection of cocaine were approximately 25% higher in ibogaine-treated mice (7.2 +/- 0.5 and 9.3 +/- 0.8 micrograms/g wet wt for water vs. mice treated with water plus ibogaine and 9.3 +/- 0.2 and 11.8 +/- 0.7 micrograms/g wet wt for cocaine drinking vs. cocaine drinking plus ibogaine treatment).(ABSTRACT TRUNCATED AT 250 WORDS)

Nicotine-induced changes in neurotransmitter levels in brain areas associated with cognitive function.

Nicotine, one of the most widespread drugs of abuse, has long been shown to impact areas of the brain involved in addiction and reward. Recent research, however, has begun to explore the positive effects that nicotine may have on learning and memory. The mechanisms by which nicotine interacts with areas of cognitive function are relatively unknown. Therefore, this paper is part of an ongoing study to evaluate regional effects of nicotine enhancement of cognitive function. Nicotine-induced changes in the levels of three neurotransmitters, dopamine (DA), serotonin (5-HT), norepinepherine (NE), their metabolites, homovanillic acid (HVA), dihydroxyphenylacetic acid (DOPAC), 5-hydroxyindoleacetic acid (5-HIAA), and their precursor, l-DOPA, were evaluated in the ventral and dorsal hippocampus (VH and DH), prefrontal and medial temporal cortex (PFC and MTC), and the ventral tegmental area (VTA) using in vivo microdialysis in awake, freely moving, male Sprague-Dawley rats. The animals were treated with acute nicotine (0.5 mg/kg, s.c.) halfway through the 300-min experimental period. The reuptake blockers, desipramine (100 μM) and fluoxetine (30 μM), were given to increase the levels of NE and 5-HT so that they could be detected. Overall, a nicotine-induced DA increase was found in some areas, and this increase was potentiated by desipramine and fluoxetine. The two DA metabolites, HVA and DOPAC, increased in all the areas throughout the experiments, both with and without the inhibitors, indicating a rapid metabolism of the released DA. The increase in these metabolites was greater than the increase in DA. 5-HT was increased in the DH, MTC, and VTA in the presence of fluoxetine; its metabolite, 5-HIAA, was increased in the presence and absence of fluoxetine. Except in the VTA, NE levels increased to a similar extent with desipramine and fluoxetine. Overall, nicotine appeared to increase the release and turnover of these three neurotransmitters, which was indicated by significant increases in their metabolites. Furthermore, DA, and especially HVA and DOPAC, increased for the 150 min following nicotine administration; 5-HT and NE changes were shorter in duration. As gas chromatography experiments showed that nicotine levels in the brain decreased by 75% after 150 min, this may indicate that DA is more susceptible to lower levels of nicotine than 5-HT or NE. In conclusion, acute nicotine administration caused alterations in the levels of DA, 5-HT, and NE, and in the metabolism of DA and 5-HT, in brain areas that are involved in cognitive processes.

Reversal of Phencyclidine-Induced Hyperactivity by Glycine and the Glycine Uptake Inhibitor Glycyldodecylamide

Phencyclidine (PCP) induces a psychotic state that closely resembles schizophrenia. In preclinical studies, PCP has been shown to induce its unique behavioral effects by blocking excitatory neurotransmission mediated at the N-methyl-D-asparate (NMDA) receptors, suggesting that agents which potentiate NMDA receptor-mediated neurotransmission might have clinically beneficial effects. The present study demonstrates that the NMDA co-agonist glycine inhibits rodent hyperactivity induced by PCP, but not amphetamine. Glycyldodecylamide, a compound that blocks neuronal glycine uptake and which may therefore increase intrasynaptic glycine levels, inhibits PCP-induced hyperactivity more potently than glycine. These results complement recent clinical studies with glycine and suggest that glycine-uptake inhibitors, as well as glycine, may be beneficial in the treatment of PCP-induced psychosis and schizophrenia.

Receptors in the ventral tegmental area mediating nicotine-induced dopamine release in the nucleus accumbens

Nicotine or cocaine, when administered intravenously, induces an increase of extracellular dopamine in the nucleus accumbens. The nicotine-mediated increase was shown to occur at least in part through increase of the activity of dopamine neurons in the ventral tegmental area. As part of our continuing studies of the mechanisms of nicotine effects in the brain, in particular, effects on reward and cognitive mechanisms, in the present study we examined the role of various receptors in the ventral tegmental area in nicotine and cocaine reward. We assayed inhibition of the increase of dopamine in the nucleus accumbens induced by intravenous nicotine or cocaine administration by antagonists administered into the ventral tegmental area. Nicotine-induced increase of accumbal dopamine release was inhibited by intrategmental nicotinic (mecamylamine), muscarinic (atropine), dopaminergic (D1: SCH 23390, D2: eticlopride), and NMDA glutamatergic (MK 801) and GABAB (saclofen) antagonists, but not by AMPA-kainate (CNQX, GYKI-52466) antagonists under our experimental circumstances. The intravenous cocaine-induced increase of dopamine in the nucleus accumbens was inhibited by muscarinic (atropine), dopamine 2 (eticlopride), and GABAB (saclofen) antagonists but not by antagonists to nicotinic (mecamylamine), dopamine D1 (SCH 23390), glutamate (MK 801), or AMPA-kainate (CNQX, GYKI-52466) receptors. Antagonists administered in the ventral tegmental area in the present study had somewhat different effects when they were previously administered intravenously. When administered intravenously atropine did not inhibit cocaine effects. The inhibition by atropine may be indirect, since this compound, when administered intrategmentally, decreased basal dopamine levels in the accumbens. The findings indicate that a number of receptors in the ventral tegmental area mediate nicotine-induced dopamine changes in the nucleus accumbens, a major component of the nicotine reward mechanism. Some, but not all, of these receptors in the ventral tegmental area also seem to participate in the reward mechanism of cocaine. The importance of local receptors in the ventral tegmental area was further indicated by the increase in accumbal dopamine levels after intrategmental administration of nicotine or also cocaine.

Ibogaine antagonizes cocaine-induced locomotor stimulation in mice

Ibogaine (40 mg/kg i.p.), when given 2 hours before an acute injection of cocaine (25 mg/kg s.c.) to C57BL/6 mice, reduced the cocaine-induced locomotor stimulation. Such stimulation was also reduced in the ibogaine-treated mice when a second injection of cocaine was given 24 hr later. Thus, the reduction in locomotor activity was not just the short-term depression of locomotor activity seen after ibogaine administration. When mice were given a daily injection of cocaine for 3 days and ibogaine was given after the cocaine injection on day 3, and again on day 4, cocaine-induced locomotor activity was reduced three hours later on day 4. On days 5 and 9 of the cocaine administration, with no further ibogaine treatment ambulatory counts were still lower in the ibogaine-pretreated mice. Locomotor stimulation induced by amphetamine (10 mg/kg) was not affected by ibogaine. An acute injection of ibogaine resulted in a transient increase in turnover of dopamine, as indicated by the increase in the ratio of metabolites of the dopamine to dopamine, followed by a decrease in the metabolites in striatum and frontal cortex 24 hr later. In vivo treatment with ibogaine did not affect the binding of [3H]WIN 35,248 to the cocaine binding site in striatal tissue measured in vitro. In addition, ibogaine added in vitro had a weak affinity to the WIN 35,248 binding site (IC50 for cocaine = 120 nM and for ibogaine = 1,500 nM). The results suggest that ibogaine may have induced a selective change in the dopaminergic system that results in a decrease in responsiveness to cocaine that persisted for at least 1 week.

Chronic L-deprenyl-induced up-regulation of the dopamine uptake carrier

L-Deprenyl is an inhibitor of monoamine oxidase B and dopamine uptake. Chronic L-deprenyl (10 mg/kg i.p., twice weekly for 4 weeks) was shown to inhibit monoamine oxidase B activity by 89%, and also to induce an up-regulation of the [3H]mazindol binding site associated with the striatal dopamine uptake carrier. Scatchard analysis indicated a 56% increase in the maximal number of [3H]mazindol binding sites in chronic L-deprenyl animals, but no effect on the affinity of these binding sites. The ability of L-deprenyl to up-regulate the [3H]mazindol-associated dopamine uptake carrier appears to be a result of its role as a dopamine uptake inhibitor.

Receptor systems participating in nicotine-specific effects

It is generally accepted that self-administration of drugs is prompted primarily by a reward system driven by an increase in extracellular dopamine in the nucleus accumbens. Recent findings that dopamine increase in the accumbens can be caused by many other factors, among them stress, suggest a more complex mechanism, and possibly differences in the reward system for different compounds. In the present paper we compare the effects of receptor-specific antagonists on the increase of dopamine induced by nicotine with that induced by cocaine in the nucleus accumbens in conscious rats. The compounds alone or together were injected intravenously, and dopamine level changes were measured via microdialysis. When administered together the effect of nicotine and cocaine on the level of dopamine in the accumbens was additive. Apparently there is some interaction between the two compounds, since nicotine had no effect after combined nicotine and cocaine administration. Perhaps the available dopamine pool was exhausted by the prior administration. The nicotinic antagonist mecamylamine, the muscarinic antagonist atropine, and the NMDA glutamate receptor antagonist MK-801 each blocked nicotine-induced dopamine release in the accumbens, indicating the participation of more than a single receptor system in the nicotine-induced effect. These three antagonists did not inhibit cocaine-induced dopamine increase in the accumbens, indicating the lack of a role of these receptors in the cocaine effect under our experimental conditions. SCH-23390, a dopamine D1 receptor antagonist, blocked both nicotine- and cocaine-induced effects, indicating the possible role of this receptor in these reward effects. The results indicate that there are differences in some of the receptors mediating the central effects of the two compounds examined, nicotine and cocaine, although each influences dopamine levels, and that the two compounds interact.

Reduction of dopamine uptake and cocaine binding in mouse striatum by N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

Administration of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (NMPTP) (daily injections of 8 mg/kg for 5 days via tail vein) reduced [3H]dopamine uptake in striatal synaptosomes by 63% and reduced [3H]cocaine binding to striatal membranes by 61%. [3H]Cocaine binding was not affected in olfactory tubercle, suggesting a selective effect of NMPTP on the nigro-striatal but not on the mesolimbic dopaminergic system. The destruction of dopamine terminals in the striatum did not alter (up-regulate) [3H]spiroperidol binding. The results suggest that NMPTP causes a degenerative destruction of the striatal dopamine pathway and that NMPTP may be useful in developing a rodent model of Parkinsons disease.

Behavioral and biochemical effects of nicotine in an MPTP-induced mouse model of Parkinson's disease

This study examined the effects of nicotine on locomotor activity and on the level of dopamine (DA) and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the striatum and olfactory tubercle of mice that had been treated with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). MPTP significantly lowered the spontaneous locomotor activity 1-2 weeks and 2 months after 2 injections of MPTP (30 mg/kg SC, 24 hr apart) in young adult (3 months) and old mice (22-24 months old). The effect of nicotine on locomotion was biphasic; an initial stimulation of locomotor (0-5 min after nicotine) followed by a depressant period lasting from 5 to 20 min after injection. Tolerance to the depressant effect of nicotine developed after the 5th day of daily injections of nicotine (0.4 mg/kg SC, twice daily). Tolerance did not occur by day 8 to the initial stimulatory effect of nicotine. A similar effect of nicotine on locomotor activity was seen in mice treated with MPTP. The levels of DOPAC and HVA in the striatum were reduced by about 20% in the chronic nicotine-treated animals. The levels of DOPAC, DA, and HVA were reduced in the MPTP-treated mice; however, acute and chronic nicotine did not cause an additional change in the amine levels. The results suggest that nicotine has an influence on locomotor activity in MPTP-treated mice and that this effect is not due to changes in DA receptor activity in the striatum caused by chronic nicotine.