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L Ahtee

Publications and source records attributed to L Ahtee.

At least 19 recordsLinked to original sources
PubMed2006

Effects of repeated morphine on locomotion, place preference and dopamine in heterozygous glial cell line-derived neurotrophic factor knockout mice.

Glial cell line-derived neurotrophic factor (GDNF) has been shown to be involved in the maintenance of striatal dopaminergic neurons. Neurotrophic factors are crucial for the plasticity of central nervous system and may be involved in long-term responses to drug exposure. To study the effects of reduced GDNF on dopaminergic behaviour related to addiction, we compared the effects of morphine on locomotor activity, conditioned place preference (CPP) and extracellular accumbal dopamine in heterozygous GDNF knockout mice (GDNF+/-) with those in their wild-type (Wt) littermates. When morphine 30 mg/kg was administered daily for 4 days, tolerance developed towards its locomotor stimulatory action only in the GDNF+/- mice. A morphine 5 mg/kg challenge dose stimulated locomotor activity only in the GDNF+/- mice withdrawn for 96 h from repeated morphine treatment, whereas clear and similar sensitization of the locomotor response was seen after a 10 mg/kg challenge dose in mice of both genotypes. Morphine-induced CPP developed initially similarly in Wt and GDNF+/- mice, but it lasted longer in the Wt mice. The small challenge dose of morphine increased accumbal dopamine output slightly more in the GDNF+/- mice than in the Wt mice, but doubling the challenge dose caused a dose-dependent response only in the Wt mice. In addition, repeated morphine treatment counteracted the increase in the accumbal extracellular dopamine concentration we previously found in drug-naive GDNF+/- mice. Thus, reduced endogenous GDNF level alters the dopaminergic behavioural effects to repeatedly administered morphine, emphasizing the involvement of GDNF in the neuroplastic changes related to long-term effects of drugs of abuse.

Animals↗
PubMed2003

The effects of systemically administered taurine and N-pivaloyltaurine on striatal extracellular dopamine and taurine in freely moving rats.

The second most abundant cerebral amino acid, taurine, is widely consumed in the so-called "energy drinks". Therefore, its possible actions on the brain are of great interest. In the present experiments taurine was given intraperitoneally to rats in order to study if it can be administered systemically in large enough amounts to alter cerebral dopaminergic transmission or to induce hypothermia. In addition, the effects of subcutaneously administered lipophilic taurine analogue, N-pivaloyltaurine, were studied. The extracellular striatal taurine and dopamine concentrations were estimated using in vivo microdialysis in awake and freely moving rats, and the rectal temperatures were measured. Taurine at the total dose of 45 mmol/kg i.p. led to a maximally 8-fold increased striatal extracellular taurine concentration, induced a long-lasting hypothermia, and significantly reduced the striatal extracellular dopamine concentration. The latter effect was strengthened by co-treatment with reuptake inhibitor nomifensine. N-pivaloyltaurine (15 mmol/kg in total, s.c.) only slightly elevated the striatal extracellular taurine concentration, failed to alter the rectal temperature, and in contrast to taurine somewhat elevated the striatal extracellular dopamine concentration suggesting a different mechanism or locus of action from that of taurine. Finally, our experiments using brain microdialysis confirmed the earlier findings that taurine is slowly eliminated from the brain. The results clearly indicate that systemically given taurine enters the brain in concentrations that induce pharmacological effects.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2001

Effects of repeated cocaine treatment on striatal dopamine release in alcohol-preferring AA and alcohol-avoiding ANA rats.

Modulation of striatal dopamine (DA) release by acute or repeated cocaine treatment was studied in the nucleus accumbens and caudate-putamen of alcohol-preferring (AA, Alko Alcohol) and alcohol-avoiding (ANA, Alko Non-Alcohol) rats. Cocaine (5-10 mg/kg i.p.) was administered daily for 4 days and the concentrations of extracellular DA measured by in vivo microdialysis on days 1 and 4 in the freely moving rats. The first administration of cocaine increased DA concentration similarly in rats of both lines in both the nucleus accumbens and caudate-putamen. On the 4th day, the effect of cocaine was significantly larger in the nucleus accumbens of AA than in that of ANA rats, whereas no such enhanced effect of cocaine was found in the caudate-putamen of either line. The results suggest that mesolimbic DA release in response to cocaine is sensitized more readily in AA than in ANA rats, which would not only render the former more susceptible to alcohol, but to other drugs of abuse, and might explain our previous findings that AA rats are more susceptible to psychomotor sensitization than ANA rats.

Alcohol Drinking↗
PubMed2001

Induction of Fos-immunostaining by nicotine and nicotinic receptor antagonists in rat brain.

Using Fos protein immunohistochemistry, we have studied the effects of acute nicotine (0.5 mg/kg s.c.) and nicotinic acetylcholine receptor (nAChR) antagonists in eleven rat brain areas. Acute nicotine elevated Fos-like immunostaining (Fos IS) significantly in all studied areas except the medial prefrontal cortex. Nicotine increased the Fos IS in cortical, limbic and hypothalamic areas by 2-10-fold, and in the interpeduncular nucleus as well as in the visual areas the increases were 15-150-fold. When given alone, the nAChR antagonists mecamylamine (1.0 or 5.0 mg/kg i.p.) and dihydro-beta-erythroidine (DHE; 1.4 or 2.8 mg/kg i.p.) increased Fos IS in most brain areas maximally by 2-10-fold, but methyllycaconitine (MLA; 4.0 mg/kg i.p.) only in three areas and maximally by 4-fold. The efficacy of nAChR antagonists in blocking nicotine's effects on Fos IS varied noticeably with respect to region and antagonist, and the combined effect of nicotine+antagonist did not exceed that of either treatment alone. Mecamylamine and DHE significantly reduced nicotine-induced Fos IS in most of the studied areas, and MLA only in two areas. Thus, nAChRs seem to mediate the effects of nicotine on Fos IS, and the differences in the effects of the antagonists studied suggest that more than one subtype of nAChRs are involved. The present experiments also provide evidence that nAChR blockade itself may result in increased Fos protein expression in the brain. This could be due to blockade of presynaptic nAChRs modulating transmitter release or interruption of complex polysynaptic feedback pathways.

Animals↗
PubMed2001

Enhanced motor activity and brain dopamine turnover in mice during long-term nicotine administration in the drinking water.

Nicotine was administered chronically to NMRI mice in their drinking water in gradually increasing concentrations to measure gross motor activity and brain nicotine concentrations over 24 h on the 50th day of nicotine administration. Also, the striatal postmortem tissue concentrations and accumbal extracellular concentrations of dopamine (DA) and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were measured to study the role of dopaminergic systems in nicotine-induced hyperactivity in mice. The cerebral nicotine concentration was at its highest at the end of the dark period. The activity of nicotine-treated mice and their striatal DA metabolism were parallelly increased at 2 to 3 h after midnight and in the forenoon. Microdialysis experiments carried out in the forenoon showed that the extracellular levels of DA and DOPAC were elevated in the nucleus accumbens of these mice. Nicotine did not alter the circadian rhythmicity of activity in the mice. Rather, our findings suggest that the mice consume more nicotine when active and this might lead to enhanced release and metabolism of DA and further, to enhanced motor behavior. These findings support the suggestions that nicotine's effects on limbic and striatal DA are critical for its stimulating effects.

Animals↗
PubMed2000

The effects of nicotine on locomotor activity and dopamine overflow in the alcohol-preferring AA and alcohol-avoiding ANA rats.

The aim of the study was to investigate the importance of the interaction between central dopaminergic and cholinergic mechanisms for ethanol reinforcement. This was done by comparing the effects of nicotine on locomotor activity and release of dopamine in the nucleus accumbens of the alcohol-preferring Alko Alcohol (AA) and alcohol-avoiding alko non-alcohol (ANA) rats. Nicotine was administered acutely (0.25, 0.50 or 0.75 mg/kg, s.c.) or repeatedly once daily (0.5 mg/kg, s.c.) for 8 days. An acute dose of nicotine increased locomotor activity and the extracellular levels of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) measured with in vivo microdialysis suggesting stimulation of dopamine release by nicotine. No difference in the stimulation of locomotor activity or in the increase in the extracellular concentrations of dopamine or its metabolites by nicotine was found between the rat lines. The concentrations of nicotine in the plasma were also identical. The rats treated repeatedly with nicotine showed a progressive increase in locomotion. On the challenge day, 1 week after termination of nicotine or saline injections, rats previously treated with nicotine were activated more by nicotine than saline-treated rats. This behavioral sensitization was not accompanied by an increase in the amplitude of the neurochemical response to nicotine, but the duration of the increase in the levels of DOPAC was longer in the nicotine than saline-treated animals. The increases in locomotor activity and metabolite levels were, however, similar in both rat lines. These data suggest that differences in the interaction of central dopaminergic and cholinergic mechanisms probably do not contribute to the difference in ethanol self-administration between the AA and ANA rat lines.

Alcohol Drinking↗
PubMed2000

The effects of acute nicotine on the body temperature and striatal dopamine metabolism of mice during chronic nicotine infusion.

The effects of acute nicotine administration on body temperature and striatal dopamine metabolism of mice during chronic subcutaneous nicotine infusion were investigated. On the 7th day of nicotine infusion the hypothermic effect of 1 mg/kg nicotine s.c. but not that of 2 mg/kg was weakened suggesting that tolerance developing to nicotine's hypothermic effect during chronic nicotine can be overcome by increasing the dose of nicotine. In saline-infused control mice 1 mg/kg nicotine increased striatal 3, 4-dihydroxyphenylacetic acid (DOPAC) but not homovanillic acid (HVA) concentration whereas 2 mg/kg increased both DOPAC and HVA. On the 7th day of nicotine infusion DOPAC and HVA concentrations were similar to control; and acute nicotine did not increase them suggesting that nicotinic acetylcholine receptors (nAChRs) regulating striatal dopamine metabolism were desensitized. The results suggest that the nAChRs mediating nicotine's effects on thermoregulation and brain dopamine metabolism differ.

Animals↗
PubMed2000

Comparison of the effects of epibatidine and nicotine on the output of dopamine in the dorsal and ventral striatum of freely-moving rats.

The effects of the nicotinic acetylcholine receptor (nAChR) agonist epibatidine on the extracellular concentrations of dopamine (DA) and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the dorsal (caudate-putamen) and the ventral striatum (nucleus accumbens) of freely-moving male Wistar rats were studied by in vivo microdialysis. In the dorsal striatum, epibatidine (3.0 microg/kg s.c.) significantly elevated the extracellular concentrations of DA, DOPAC and HVA. In contrast, epibatidine did not alter the extracellular DA concentration in the ventral striatum, but elevated significantly the concentration of DOPAC and also tended to elevate that of HVA. In parallel experiments, nicotine (0.5 mg/kg s.c.) significantly increased DA output in the ventral striatum whereas only a modest and non-significant increase of extracellular DA concentration was found in the dorsal striatum. Earlier studies have shown that the doses of epibatidine and nicotine used in the present study are about equieffective at least with respect to the analgesia-producing or hypothermic effects of the drugs. Comparison of the effects of epibatidine and nicotine suggests that the responses of the mesolimbic and nigrostriatal dopaminergic systems to the two nicotinic receptor agonists differ. Epibatidine, in contrast to nicotine, preferentially stimulates the nigrostriatal vs. the mesolimbic dopaminergic system. Therefore, novel nicotinic AChR ligands structurally related to epibatidine may have low abuse potential.

Animals↗
PubMed2000

Effect of acute nicotine on Fos protein expression in rat brain during chronic nicotine and its withdrawal.

To study the cholinergic regulation of hypothalamic paraventricular (PVN) and supraoptic (SON) nuclei and interpeduncular nucleus (IPN) we investigated the effects of acute nicotine (0.5 mg/kg, SC, 60 min) on Fos-like immunostaining (IS) during chronic nicotine and its withdrawal in rats. Nicotine or saline was infused to rats via osmotic minipumps (4 mg/kg/day) for 7 days; on the seventh day, the minipumps were removed surgically. In control rats, acute nicotine increased Fos IS significantly in all three brain areas studied. On the seventh day of nicotine infusion this effect partially persisted in IPN but was abolished in PVN and SON. After 72-h withdrawal nicotine-induced elevation of Fos IS was similar to that of control rats in all three areas. The observed attenuation of the response to acute nicotine during constant nicotine infusion in PVN and SON may be attributable to the desensitization of nicotinic acetylcholine receptors (nAChRs) mediating the effects of nicotine in these areas or in their input areas. IPN is connected to midbrain limbic system, so in agreement with our earlier observations, it seems that limbic nicotinic receptors do not very readily desensitize during chronic nicotine infusion. These findings support the suggestions that there are differences in the level of desensitization of nAChRs.

Adrenocorticotropic Hormone↗
PubMed2000

Chronic nicotine administration in the drinking water affects the striatal dopamine in mice.

Although tobacco contains a large variety of substances, its addictive properties are most probably due to the reinforcing actions of nicotine that motivates continued tobacco use. Animals and humans self-administer nicotine, a response that appears to involve the mesolimbic dopamine system and to be common to other abused drugs. The present article reviews animal models to administer nicotine chronically. We also describe a new animal model in which nicotine is given to mice in drinking water as their sole source of fluid. This treatment produced nicotine plasma concentrations comparable to or above those found in smokers. We found that mice withdrawn from nicotine were tolerant to the effects of nicotine challenge on striatal dopamine metabolism as well as on body temperature and locomotor activity. Furthermore, 3H-nicotine binding in the cortex and midbrain was significantly increased in mice withdrawn from nicotine. The last part of the article will focus on the effects of this chronic nicotine treatment on striatal dopamine. Dopamine and its metabolites and locomotor activity were increased in the forenoon in mice still drinking nicotine solutions. We also report recent data in which chronic nicotine administration in the drinking water enhanced the effect of dopamine receptor agonist, quinpirole, on striatal metabolism. The animal model described appears to be a relevant method for studying the mechanisms that are thought to be involved in nicotine dependence.

Animals↗
PubMed2000

Effects of repeated morphine on cerebral dopamine release and metabolism in AA and ANA rats.

Cerebral dopaminergic mechanisms were studied in the nucleus accumbens and caudate-putamen of alcohol-preferring AA (Alko Alcohol) and alcohol-avoiding ANA (Alko Non-Alcohol) rats after 4-day repeated morphine treatment. This treatment has been shown to enhance the locomotor activity stimulating effect of morphine in the AA but not in the ANA rats. Morphine (1 or 3 mg/kg) or saline was administered subcutaneously once daily and the extracellular concentrations of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were measured, in freely moving rats by in vivo microdialysis on days 1 and 4. Morphine increased accumbal DA, DOPAC and HVA similarly in rats of both lines, and no sensitization of DA release or metabolism was seen in rats of either line given morphine repeatedly. In the caudate-putamen, morphine increased DA, DOPAC and HVA significantly only in the AA rats. During repeated treatment, the morphine-induced elevation of DA metabolites, but not that of DA, was enhanced similarly in rats of both lines. These results suggest that the effects of acute morphine administration on nigrostriatal dopaminergic mechanisms are stronger in the AA than in the ANA rats, whereas the effects of morphine on mesolimbic dopaminergic systems do not differ. Furthermore, in rats of both lines, repeated morphine treatment enhanced the responses of the nigrostriatal dopaminergic systems similarly, but no enhancement occurred in the mesolimbic systems of rats of either line. These findings do not support the critical role of accumbal dopaminergic systems in morphine-induced behavioural sensitization.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2000

Effects of chronic oral nicotine treatment and its withdrawal on locomotor activity and brain monoamines in mice.

The effects of chronic nicotine and its withdrawal on locomotor activity and brain monoamines were studied using a new animal model of administering nicotine in the drinking water to male NMRI mice as the sole source of fluid. Locomotor activity as well as cerebral concentrations of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 5-hydroxytryptamine (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), noradrenaline (NA) and 3-methoxy-4-hydroxyphenylethyleneglycol (MOPEG) were measured post mortem on the 50th day of nicotine administration or at 12-14 or 23-25 h after withdrawal. On the 50th day of drug administration the chronically nicotine-treated mice were more active than the control mice drinking tap water and after withdrawal from nicotine the locomotor activity dropped to the level of the controls. In chronically nicotine-treated mice the striatal concentrations of DOPAC, HVA and 5-HIAA, hypothalamic 5-HIAA and NA as well as cortical NA were elevated. The concentrations of DOPAC, HVA and 5-HIAA reversed to control levels within 23-25 h after withdrawal from nicotine. The nicotine-induced elevation of the hypothalamic NA concentration was still significant at 23-25 h after withdrawal. At 12-14 h after withdrawal the hypothalamic concentration of MOPEG was increased. In conclusion, our findings on locomotor activity suggest that administration of nicotine in the drinking water to mice for several weeks seems to be a relevant method to study nicotine dependence. Furthermore, the alterations found in cerebral DA, NA and 5-HT metabolism during chronic nicotine administration indicate that all three cerebral transmitter monoamines might be involved in nicotine dependence and withdrawal.

Animals↗
PubMed2000

Effect of acute nicotine administration on striatal dopamine output and metabolism in rats kept at different ambient temperatures.

1. The effect of ambient temperature on the nicotine-induced (0.3, 0.5 or 0.8 mg kg(-1) s.c.) changes of the striatal concentrations of dopamine (DA) and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) was studied in freely-moving rats by in vivo microdialysis. 2. At the ambient temperature of 30 - 33 degrees C, but not at 20 - 23 degrees C, nicotine doses of 0.5 (P<0. 01) and 0.8 mg kg(-1) (P<0.05) significantly increased the extracellular DA concentration. The nicotine doses of 0.5 and 0.8 mg kg(-1) increased the DA metabolite levels similarly at both ambient temperatures studied (P</=0.0001), but the dose of 0.3 mg kg(-1) only at 30 - 33 degrees C (DOPAC: P<0.05; HVA: P<0.01). 3. At 30 - 33 degrees C, dihydro-beta-erythroidine (DHbetaE 2.8 mg kg(-1) i.p.) blocked the nicotine-induced (0.5 or 0.8 mg kg(-1)) increases of extracellular DA concentration but only tended to antagonize the increases of DA metabolites. Mecamylamine (5.0 mg kg(-1) i.p.) blocked the increase of DA output induced by 0.5 mg kg(-1) but not that induced by 0.8 mg kg(-1) of nicotine and fully prevented the nicotine-induced elevations of DOPAC and HVA. 4. Elevation of ambient temperature did not affect the cerebral concentration of nicotine or the nicotine-induced elevation of serum corticosteroids. Also, the rectal temperatures of rats given nicotine at either ambient temperature did not significantly change. 5. Our results show that the nicotine-induced output of striatal DA is enhanced at high ambient temperature. Further, our findings suggest that the nicotinic cholinoceptors mediating the effects of nicotine on striatal DA release are different from those mediating nicotine's effects on DA metabolism.

Animals↗
PubMed1999

The effects of acute nicotine on the metabolism of dopamine and the expression of Fos protein in striatal and limbic brain areas of rats during chronic nicotine infusion and its withdrawal.

The effects of acute nicotine (0.5 mg/kg, s.c.) on dopamine (DA) metabolism and Fos protein expression in striatal and limbic areas of rats on the seventh day of chronic nicotine infusion (4 mg. kg(-1). d(-1)) and after 24 or 72 hr withdrawal were investigated. In saline-infused rats, acute nicotine elevated striatal and limbic 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) concentrations significantly. During the nicotine infusion, no such increases were seen in the striatum, but limbic HVA was somewhat elevated. After 24 hr withdrawal when no nicotine was found in the plasma, acute nicotine elevated striatal DOPAC and HVA and limbic HVA. However, the limbic DOPAC was unaffected. Acute nicotine increased Fos immunostaining (IS) in the caudate-putamen (CPU), the core of nucleus accumbens (NAcc), the cingulate cortex (Cg), and the central nucleus of amygdala (ACe) significantly. During nicotine infusion the nicotine-induced responses were attenuated in CPU and NAcc, whereas in ACe and Cg Fos immunostaining was increased as in saline-infused rats. After 24 hr withdrawal, acute nicotine did not increase Fos immunostaining in CPU, NAcc, and Cg, but increased it clearly in ACe. After 72 hr withdrawal, nicotine's effects were restored. Our findings suggest that the nicotinic receptors in the striatal areas are desensitized more easily than those in the limbic areas. Furthermore, the effects of nicotine on various DA metabolites differ. We also found evidence for long-lasting inactivation of nicotinic receptors in vivo regulating limbic dopamine metabolism and Fos expression in striatal and limbic areas. These findings might be important for the protective effects of nicotine in Parkinson's disease and in its dependence-producing properties.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1999

Effects of morphine in rats withdrawn from repeated nifedipine administration.

The effects of withdrawal from repeated nifedipine treatment on morphine-induced analgesia, hyperthermia and catalepsy as well as on cerebral [3H]nitrendipine binding and on morphine-induced changes in striatal and limbic dopamine and 5-hydroxytryptamine metabolism were studied in rats. Repeated administration of nifedipine (5 mg/kg i.p., twice daily for 14 days) decreased [3H]nitrendipine binding in several brain areas of the rats at 24 h after the last dose but did not change the nociceptive response or rectal temperature of the animals. Further, the antinociceptive potency of acute morphine (2.5 mg/kg s.c.) was significantly reduced in rats withdrawn for 24 h from repeated nifedipine treatment. However, withdrawal from repeated nifedipine treatment failed to affect either the hyperthermia induced by this dose of morphine or the catalepsy and the elevation of dopamine or 5-hydroxytryptamine metabolites induced by 15 mg/kg of morphine. Taken together, these data show that withdrawal from repeated treatment with dihydropyridine calcium channel antagonists selectively reduces the effects of opioids on the nociceptive response.

Animals↗
PubMed1999

Enhanced morphine- and cocaine-induced behavioral sensitization in alcohol-preferring AA rats.

Locomotor stimulation and behavioral sensitization induced by acute and repeated treatment with alcohol, cocaine or morphine were studied in the alcohol-preferring AA (Alko, Alcohol), alcohol-avoiding ANA (Alko, Non-Alcohol) rats and non-selected Wistar rats. Daily treatment with alcohol (ethanol, 0.4 or 1.0 g/kg, IP) for 6 days had no effect on locomotor activity either in the AA or ANA rats. Acute cocaine (5, 10 or 20 mg/kg, IP) produced a locomotor stimulation in the animals of all lines studied, and there was no difference in this effect between the AA and ANA rats. During a 4-day repeated cocaine treatment, the AA rats became sensitized with the 10 mg/kg dose, while the ANA rats did not show any sensitization with this dose. With the 20 mg/kg cocaine dose, in addition to locomotor stimulation, the rats of all lines studied showed stereotyped behavior, which response was enhanced during repeated treatment. Morphine-induced locomotor stimulation was larger in the AA rats than in the ANA or Wistar rats both with 1.0 and 3.0 mg/kg doses and only the AA rats were sensitized during 4-day treatment with the 1 mg/kg dose. With the 3.0 mg/kg morphine dose, only the AA rats showed a weak sensitization evident only during the initial 30 min after morphine injection. As the drug-induced behavioral sensitization is an important factor in the development of drug addiction, it is possible that mechanisms underlying the enhanced susceptibility of the AA rats to morphine- and cocaine-induced sensitization contribute to the high intake of alcohol and other abused drugs by these animals.

Alcohol Drinking↗
PubMed1999

Involvement of opioid mu1-receptors in opioid-induced acceleration of striatal and limbic dopaminergic transmission.

The role of mu1-opioid receptors in the acceleration of cerebral dopaminergic transmission induced by morphine and the putative mu1-opioid agonist, etonitazene, was studied in rats by measuring the tissue levels of dopamine (DA) and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the dorsal striatum and nucleus accumbens. The striatal extracellular concentrations of DA and its metabolites in freely moving rats were estimated as well. Morphine (3 mg/kg) and etonitazene (2.5 microg/kg) increased the striatal and accumbal dopamine metabolism as measured by the tissue ratios of DOPAC/DA and HVA/DA. The mu1-opioid receptor antagonist, naloxonazine (15 mg/kg), significantly antagonized these elevations except the morphine-induced elevation of striatal HVA/DA ratio. Both morphine (3 mg/kg) and etonitazene (1, 2.5, and 5 microg/kg) elevated the striatal extracellular DA, DOPAC, and HVA. Naloxonazine antagonized the effects of morphine and etonitazene on striatal extracellular DA concentration as well as etonitazene's effects on DOPAC and HVA, but not morphine's effects on DOPAC and HVA. As we previously showed concerning morphine, the conditioned place preference induced by etonitazene was inhibited by naloxonazine. These findings emphasize the role of mu1-opioid receptors in opioid reward, in which the mesolimbic dopaminergic system is considered to be importantly involved. Our results clearly show that in addition to the mesolimbic dopaminergic system the mu1-opioid receptors are also involved in the control of nigrostriatal DA release and metabolism. However, the effects of etonitazene on the striatal DA differ from those of morphine, suggesting that the opioid mechanisms regulating these two DA systems differ.

3,4-Dihydroxyphenylacetic Acid↗