Neuronal nitric oxide synthase inhibition decreases cocaine self-administration behavior in rats

RATIONALE: Inhibitors of nitric oxide synthase (NOS) have been shown to alter behaviors related to cocaine addiction, including its self-administration. However, previous studies have largely used mixed-action NOS inhibitors and have not examined the effects of a neuronal NOS inhibitor on cocaine self-administration. OBJECTIVES: Pretreatment with the neuronal NOS inhibitor 7-nitroindazole (7-NI) was used and its effects on cocaine self-administration were compared with those produced by pretreatment with an indirect dopamine receptor agonist (cocaine) and a D(1)-like dopamine receptor antagonist (SCH 23390). METHODS: Rats were trained to self-administer 1 mg/kg cocaine under a second-order schedule of drug delivery, which measures drug-seeking behavior independently from drug intake. Pretreatment with various doses of 7-NI, cocaine, and SCH 23390 were tested in combination with the training dose of cocaine followed by studies examining the effects of a selected dose of each pretreatment drug in combination with a range of cocaine doses. Other rats were trained under a second-order schedule of food pellet delivery and pretreated with 7-NI, cocaine, or SCH 23390 to determine the behavioral specificity of the effects of these drugs for cocaine-maintained responding. RESULTS: The results demonstrated that 7-NI reduced responses maintained by the cocaine training dose and produced a downward shift in the cocaine dose-response curve. Changes in drug intake were minor by comparison. Cocaine pretreatment produced effects similar to 7-NI, while the changes observed after SCH 23390 pretreatment were different from 7-NI and cocaine. The reductions in cocaine-maintained responding after 7-NI pretreatment were behaviorally specific because there was no effect of 7-NI on food-maintained responding within the dose range examined. CONCLUSIONS: By selectively reducing drug-seeking behavior, these data suggest that 7-NI may enhance the reinforcing effects of cocaine.     

The role of monoamine uptake in the discriminative stimulus effects of cocaine and related compounds

The involvement of monoamine neurotransmitter uptake in the discriminative stimulus effects of cocaine was examined in rats (n = 48) trained to discriminate 10mg/kg of this substance from saline in a two-level, water-reinforced (FR 20), drug discrimination situation. Compounds that act primarily by inhibiting dopamine (DA) uptake substituted for the cocaine cue; the order of potency was mazindol > nomifensine > GBR 12909 > bupropion, although efficacy was lowest with GBR 12909. Desipramine, which inhibits norepinephrine (NE) uptake, substituted partially for cocaine while two drugs that inhibit serotonin (5-HT) uptake, citalopram and fluoxetine, did not mimic cocaine. When given in combination with cocaine, cis flupenthixol and SCH 23390 reduced responding on the cocaine-appropriate lever significantly and to a greater extent than either haloperidol, (+/-) sulpiride or (-) sulpiride; neither (+) sulpiride nor metergoline had significant effects. Cocaine substitutions with DA uptake inhibitors were also attenuated to varying extents by cis-flupenthixol, SCH 23390 and haloperidol, but not by metergoline. These data, in conjunction with results reported previously, suggest that inhibition of DA uptake is involved to a greater extent than either NE or 5-HT uptake in the discriminative stimulus properties of cocaine and related compounds. Since both the cocaine cue and its substitution by DA uptake inhibitors appear to be blocked most effectively, reliably and potently by compounds that act either non-selectively at DA receptors (cis-flupenthixol) or primarily at D1 receptors (SCH 23390), D1 mechanisms may play a particularly important role in the neuronal substrates of these behavioral effects.     

Nitric oxide synthase inhibitors cause motor deficits in mice.

We investigated possible motor effects of 7-nitroindazole (7-NI), an neuronal nitric oxide synthase (nNOS) inhibitor, and N(G)-nitro-L-arginine methyl ester (L-NAME), an non-selective NOS inhibitor in mice using catalepsy and pole tests in comparison with dopamine D(2) receptor antagonist, haloperidol. We also studied the change in dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) contents of these compounds. The administration of 7-NI and L-NAME (40-160 mg/kg, s.c.) dose-dependently induced motor deficit in both catalepsy and pole tests. The motor deficit induced by 7-NI was more pronounced than the one produced by L-NAME. In contrast, haloperidol showed a marked motor deficit in mice. Haloperidol showed a marked motor deficit as compared with 7-NI and L-NAME. For dopamine, DOPAC and HVA contents, haloperidol exhibited a significant decrease in dopamine content and a significant increase in DOPAC and HVA content in the striatum. In contrast, 7-NI showed a significant increase in the striatal dopamine content. However, 7-NI had no significant change in the striatal DOPAC and HVA contents. On the other hand, no significant change in the striatal dopamine, DOPAC and HVA contents was observed in L-NAME-treated mice. The present study also showed that the motor deficit induced by 7-NI or L-NAME was significantly attenuated by the treatment with L-arginine. These results demonstrate that NOS inhibitors as well as dopamine D(2) receptor antagonist haloperidol can induce motor deficit in mice. The present study also suggests that the mechanism in the motor deficit caused by NOS inhibitors may be different from that in the motor deficit induced by haloperidol. Furthermore, our findings suggest that nNOS may play some role in control of motor behavior.     

Discriminative stimulus properties of ethanol in rats: studies on the role of nitric oxide

The present study examined the role of the L-arginine-nitric oxide pathway in mediation of the ethanol interoceptive (discriminative) cue. Adult male Wistar rats (n = 16) were trained to discriminate ethanol (1 g/kg, 10% v/v) from saline under a fixed-ratio 10 (FR10) schedule of sweetened milk reinforcement. A nonselective nitric oxide synthase (NOS) inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME; 10-540 mg/kg) did not substitute for ethanol. Similarly, a relatively selective neuronal NOS inhibitor, 7-nitroindazole (7-NI; 10-80 mg/kg), did not mimic the ethanol cue. However, both L-NAME and 7-NI produced significant reduction in the rate of operant responding. A nitric oxide precursor, L-arginine (100-500 mg/kg) neither substituted for nor antagonize the ethanol stimulus. Taken together, these results suggest that the L-arginine-nitric oxide pathway is not involved in mediation of the discriminative stimulus effects of ethanol in the rat.     

Blockade of the discriminative stimulus effects of cocaine in rhesus monkeys with the D1 dopamine antagonist SCH 23390

To investigate the role of D₁ dopamine receptors in the discriminative stimulus effects of cocaine, two rhesus monkeys were trained in a two-lever, food-reinforced, drug discrimination paradigm to discriminate cocaine (0.2 mg/kg, IM) from saline. Administration of various doses of cocaine resulted in a dose-related increase in the percentage of responses that occurred on the drug-appropriate lever. Administration of the D₁ antagonist SCH 23390 20 min before cocaine reduced drug-appropriate responding from 100% to 0% in all subjects and increased by 4–8-fold the cocaine dose necessary to induce drug-appropriate responding. A mutual antagonism of the rate-decreasing effects of cocaine and SCH 23390 was also observed. These findings suggest that D₁ receptors play a significant role in the discriminative stimulus and rate-decreasing effects of cocaine.     

Discriminative stimulus properties of cocaine: modulation by dopamine D1 receptors in the nucleus accumbens

Dopamine (DA) D₁ and D₂ receptors are involved in mediating the behavioral effects of cocaine, including its discriminative stimulus properties. The purpose of the present study was to investigate the role of the nucleus accumbens and, in particular, accum bens DA D₁ receptors in modulating the stimulus effects of cocaine. Thus, rats were trained to discriminate cocaine (10 mg/kg, IP) from saline using a two-lever, water-reinforced FR 20 drug discrimination task. In substitution tests, systemic (IP) administration of cocaine (0.625–20 mg/kg) produced a dose-related increase in cocaine-appropriate responding. Microinjections of cocaine (2.5–40 µg) into the nucleus accumbens also engendered dose-dependent and complete substitutions (> 80% drug-lever responding) for the systemic training dose of cocaine, whereas intra-accumbens artificial cerebrospinal fluid (1 µl/side) produced primarily saline-appropriate responding. In antagonism tests, pretreatment with the DA D₁ antagonist SCH 23390 (3–12 µg/kg) completely antagonized (<20% drug-lever responding) a dose of cocaine (5 mg/kg) that produced greater than 90% cocaine-lever responding when given alone. Additionally, intra-accumbens injections of SCH 23390 (0.025–0.4 µg) prior to systemic cocaine (5 mg/kg) also significantly blocked the cocaine stimulus. The present results confirm the importance of the nucleus accumbens in mediating the discriminative stimulus properties of cocaine and suggest a primary role of accumbens DA D₁ receptors in modulating this behavior.Some of these data were presented at the annual FASEB Experimental Biology meeting in New Orleans (1993)     

Modulation of cocaine's discriminative stimulus effects by dopamine D(1) agonists in rhesus monkeys

Dopamine (DA) D(1) agonists are classified as high- or low-efficacy on the basis of in vitro functional measures as compared to DA. In monkeys self-administering cocaine, high-efficacy D(1) agonists have been shown to have reinforcing effects, while low-efficacy agonists do not. However, the relationship between D(1) agonist efficacy and cocaine-like discriminative stimulus effects, particularly in rhesus monkeys, is not clear. The present study investigated the discriminative stimulus effects of a high- (SKF 81297) and a low-efficacy (SKF 38393) D(1) agonist in rhesus monkeys (n=4) trained to discriminate cocaine from saline using a two-lever drug discrimination procedure. In a second experiment, the effects of agonist pretreatments, as well as pretreatment with a D(1) antagonist, on cocaine's discriminative stimulus effects were evaluated. SKF 81297 (0.01-1.7 mg/kg) fully substituted for cocaine in three of four animals (> 80% cocaine-appropriate responding), while SKF 38393 (0.3-10 mg/kg) occasioned < 50% cocaine-appropriate responding in all subjects. When given as a pretreatment, neither agonist altered cocaine's discriminative stimulus effects at the doses tested. In contrast, the D(1) antagonist SCH 23390 attenuated cocaine's discriminative stimulus effects. These results indicate that D(1) agonists have cocaine-like discriminative stimulus effects in rhesus monkeys that are consistent with their in vitro efficacies. However, when given in combination with cocaine, D(1) agonist efficacy does not appear to be a major factor in modifying cocaine's discriminative stimulus effects.     

The discriminative stimulus effects of methamphetamine in pigeons

This experiment was designed to elucidate the neurotransmitter systems that mediate the discriminative stimulus effects of methamphetamine. Four pigeons were trained to peck one key following saline injections and a second key following methamphetamine injections (1.0 or 1.7 mg/kg, IM). Substitution tests revealed drug-appropriate responding following administration of the psychomotor stimulants methamphetamine, amphetamine and cocaine, the dopamine (DA) reuptake inhibitor bupropion, norepinephrine (NE) reuptake inhibitors imipramine and tomoxetine, and the serotonin (5-HT) releaser fenfluramine. Salinekey responding occurred following administration of the D₁ agonist SKF-38393, the D₁ antagonist SCH-23390, the α₂ receptor agonist clonidine, the α₁ antagonist prazosin, a nonselective β-antagonist propranolol and the selective 5-HT reuptake inhibitor fluoxetine. The D₂/D₃ agonist quinpirole produced drug-appropriate responding in two pigeons and partial substitution in the remaining two pigeons. The 5HT_1A agonist 8-OH-DPAT produced drug-appropriate responding at higher doses (0.3–1.0 mg/kg), whereas much lower doses (0.003–0.1 mg/kg) antagonized the methamphetamine stimulus. The stimulus effects of methamphetamine were attenuated by pretreatment with prazosin, SCH-23390 and eticlopride, whereas pretreatment with propranolol and the 5-HT₃ antagonist, MDL 72222, failed reliably to attenuate drug key responding. These results suggest that NE and DA reuptake inhibition and 5-HT release mediate the discriminative stimulus effects of methamphetamine as do the 5-HT_1A and DA D₁ and D₂ receptors.     

Monoamine reuptake inhibitors enhance the discriminative state induced by cocaine in the rat

Cocaine inhibits the reuptake of dopamine (DA), norepinephrine (NE), and serotonin (5-HT). To investigate the relative role of such reuptake processes in the discriminative stimulus properties of cocaine, male rats (N=16) were trained to discriminate cocaine (10 mg/kg) from saline in a two-lever, water-reinforced drug discrimination task and were administered neuroactive compounds during substitution or combination tests. The DA reuptake inhibitor GBR 12909 (2–16 mg/kg) completely mimicked cocaine. The reuptake inhibitors for NE (desipramine; 2–8 mg/kg) and 5-HT (fluoxetine; 0.625–5 mg/kg) did not substitute for the training drug. A low dose of either desipramine (3 mg/kg), fluoxetine (1.25 mg/kg), or GBR 12909 (2 mg/kg) coadministered with low doses of cocaine (0.625–2.5 mg/kg) enhanced the discriminative stimulus properties of this psychostimulant. The dose predicted to elicit 50% drug-lever responding is reduced (ED₅₀) in the presence of desipramine (0.38 mg/kg), fluoxetine (0.79 mg/kg) or GBR 12909 (0.84 mg/kg) compared to the ED₅₀ for cocaine (1.57 mg/kg) in the absence of any reuptake inhibitor. The finding that GBR 12909 mimics the cocaine cue corroborates the hypothesis that the stimulus properties of cocaine are mediated predominantly by DA systems. The potentiation of the stimulus effects of cocaine by monoamine reuptake inhibitors in rats suggests that these drugs could also amplify the subjective effects of cocaine in humans, a possibility that should be considered given the current use of antidepressants in the treatment of cocaine abusers.     

Modification of behavioral effects of cocaine by selective serotonin and dopamine uptake inhibitors in squirrel monkeys

Modification of the behavioral effects of cocaine by the selective serotonin (5-HT) uptake inhibitors citalopram and fluoxetine and the selective dopamine (DA) uptake inhibitor GBR 12909 was investigated in squirrel monkeys trained under a fixed-interval schedule of reinforcement or a two-lever cocaine-discrimination procedure. Under the fixed-interval schedule cocaine (0.03–1.78 mg/kg) produced dose-related increases in response rate, reaching an average maximum of 215% of control after a dose of 0.3 mg/kg. Similar rate-increasing effects were seen with GBR 12909 (3.0 or 10.0 mg/kg), but not citalopram (10.0 or 17.8 mg/kg) or fluoxetine (10.0 mg/kg). Pretreatment with citalopram or fluoxetine attenuated the rate-increasing effects of cocaine and produced an overall downward shift in the cocaine dose-response function. Pretreatment with GBR 12909, on the other hand, produced an overall leftward shift in the cocaine dose-response function. Under the drug-discrimination procedure cocaine (0.03–1.78 mg/kg) engendered dose-related increases in the percentage of cocaine-appropriate responses, as did GBR 12909 (1.0–17.8 mg/kg) but not citalopram (1.0–17.8 mg/kg). Pretreatment with citalopram attenuated the discriminative stimulus effects of cocaine and produced an overall rightward shift in the cocaine dose-response function, whereas pretreatment with GBR 12909 produced an overall leftward shift in the cocaine dose-response function. The results show that selective 5-HT and DA uptake inhibitors can modify the rate-altering and discriminative stimulus effects of cocaine in qualitatively different ways and suggest a modulatory role for 5-HT uptake inhibition in the behavioral effects of cocaine.     

Nitric oxide modulation affects the tissue distribution and toxicity of bupivacaine

We have previously demonstrated that inhibition of nitric oxide synthase (NOS) alters the toxicity of local anesthetics including bupivacaine. Because significant changes in blood distribution are associated with the use of nonselective NOS inhibitors, the purpose of this study was to determine whether modification of bupivacaine toxicity by nonselective NOS inhibition is due to alteration in tissue disposition of bupivacaine. Rats were anesthetized with halothane and pretreated with either: 1) a nonselective NOS inhibitor, N(omega)-nitro-L-arginine methyl ester (L-NAME, 2 mg/kg/min, IV for 30 min); 2) a neuronal NOS inhibitor, 7-nitroindazole (7-NI, 30 mg/kg, IP); or 3) vehicle (control). Thirty minutes later, bupivacaine 2 mg/kg/min IV was infused until onset of seizures, arrhythmias, or asystole. L-NAME caused a rapid increase in plasma bupivacaine concentrations (3-4 times faster than in the other groups), which was associated with markedly lower bupivacaine doses (mg/kg) required to produce arrhythmias in L-NAME (4.2 +/- 0.5) vs. control (26 +/- 3, p < 0.01) and 7-NI groups (17 +/- 3, p < 0.01). Myocardial bupivacaine concentrations at arrhythmia onset were slightly lower in the L-NAME group. Bupivacaine seizure doses in 7-NI and L-NAME pretreated animals were similar to control but significantly different from each other. Brain bupivacaine concentrations at seizure onset were similar among the groups. There were no significant differences between 7-NI and control groups in any parameter observed. We conclude that enhanced cardiotoxicity of bupivacaine by nonselective NOS inhibition is primarily due to rapid increases in plasma and myocardial distribution of bupivacaine.     

Differential involvement of dopamine in mediating the discriminative stimulus effects of low and high doses of caffeine in rats

The hypothesis that low and high doses of caffeine produce effects that are differentially mediated by dopamine (DA) receptor mechanisms was investigated in rats trained to discriminate either 10 or 56 mg/kg of caffeine from saline. Rats trained to discriminate 56 mg/kg of caffeine acquired the discrimination in an average of 74 sessions, whereas rats trained to discriminate 10 mg/kg of caffeine required an average of 108 sessions. The DA D1 receptor agonist SKF 81297 and the DA D2 receptor agonist R(-)-propylnorapomorphine (NPA) generalized partially (50-75%) in rats trained to discriminate 10 mg/kg of caffeine, but produced predominantly saline-appropriate responding (< 40%) in rats trained to discriminate 56 mg/kg of caffeine. When SKF 81297 and NPA were combined, stimulus generalization was no greater than it was when either agonist was tested alone. The DA uptake inhibitors cocaine and GBR 12909 produced predominantly saline-appropriate responding in both groups of rats. Neither the DA D1 receptors antagonists SCH 23390 and SCH 31966, nor the DA D2 receptor antagonists eticlopride and sulpiride, generalized in rats trained to discriminate 10 or 56 mg/kg of caffeine. When administered in combination with caffeine, both the DA D1 and DA D2 antagonists antagonized completely the discriminative stimulus effects of the low training dose of caffeine, but did not alter the discriminative stimulus effects of the high training dose. These results suggest that the discriminative stimulus effects of 10 mg/kg of caffeine, but not 56 mg/kg of caffeine, are dependent on, but not limited to, DA D1 and D2 receptor mechanisms.     

Involvement of dopamine D3 and D4 receptors in the discriminative stimulus properties of cocaine in the rat

The present study was carried out to determine the involvement of dopamine receptor subtypes D3 and D4, in the discriminative stimulus effects of cocaine in the rats trained to discriminate 10 mg/kg of cocaine from vehicle. The discriminative stimulus effects of cocaine (1-10 mg/kg) were dose-dependent. The dopamine D2 receptor agonist bromocriptine (1.25-20 mg/kg) and the dopamine D3 receptor agonist R(+)-7-OH-DPAT (0.0001-0.3 mg/kg) produced cocaine (10 mg/kg)-like discriminative stimulus effects. Both the dopamine D3 receptor antagonist GR103691 (1 mg/kg) and the dopamine D4 receptor antagonist L745870 (1 mg/kg) partially antagonized the discriminative stimulus effects of cocaine (10 mg/kg) and the cocaine (10 mg/kg)-like discriminative stimulus effects of R(+)-7-OH-DPAT (0.3 mg/kg). L745870 (0.001 mg/kg) inhibited the antagonistic effects of GR103691 (1 mg/kg) on the discriminative stimulus effects of cocaine (10 mg/kg), whereas the drug (0.001 mg/kg) enhanced the antagonistic effects of GR103691 (1 mg/kg) on the cocaine (10 mg/kg)-like discriminative stimulus effects of R(+)-7-OH-DPAT (0.3 mg/kg). GR103691 (1 mg/kg) in combination with L745870 (0.001 mg/kg) did not markedly affect the cocaine (10 mg/kg)-like discriminative stimulus effects of bromocriptine (20 mg/kg). These results suggest that the discriminative stimulus effects of cocaine are different from the cocaine-like discriminative stimulus effects of bromocriptine or R(+)-7-OH-DPAT, in terms of dopamine D3 and D4 receptors.     

Protection from inorganic mercury effects on the in vivo dopamine release by ionotropic glutamate receptor antagonists and nitric oxide synthase inhibitors

The possible role of ionotropics glutamate receptors on the HgCl(2)-induced dopamine (DA) release from rat striatum was investigated by using in vivo brain microdialysis technique after administration of selective NMDA and AMPA/Kainate receptors antagonists dizocilpine (MK-801), D (-)-2-amino-5-phoshonopentanoic acid (AP5), and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). Moreover, we have also studied the effects of nitric oxide synthase (NOS) inhibitors L-nitro-arginine methyl ester (L-NAME) and 7-nitro-indazol (7-NI) on HgCl(2)-induced DA release. Intraestriatal infusion of 1mM HgCl(2) increased striatal DA to 1717.2+/-375.4% respect to basal levels. Infusion of 1mM HgCl(2) in 400 microM MK-801 pre-treated animals produced an increase on striatal DA levels 61% smaller than that induced in non-pre-treated animals. In the case of AP5, this treatment reduced 92% the increase produced by HgCl(2) as compared to non-pre-treated rats. Nevertheless, the administration of CNQX did not produce any effect on HgCl(2)-induced dopamine release. Intrastriatal infusion of 1mM HgCl(2) in 100 microM L-NAME pre-treated animals produced an increase on extracellular DA levels 82% smaller than produced by HgCl(2) alone. In addition, the pre-treatment with 7-NI reduced 90% the increase produced by infusion of HgCl(2) alone in rats. Thus, HgCl(2)-induced DA release could be produced at last in part, by overstimulation of NMDA receptors with NO production, since administration of NMDA receptor antagonists and NOS inhibitors protected against HgCl(2) effects on DA release.     

Effects of the putative dopamine D3 receptor agonist 7-OH-DPAT in rhesus monkeys trained to discriminate cocaine from saline

These studies were designed to evaluate the effects of the putative dopamine D₃ receptor agonist 7-hydroxy-N,N-di-n-propyl-2-aminotetraline (7-OH-DPAT), alone and in combination with cocaine, in four rhesus monkeys trained to discriminate cocaine (0.4 mg/kg, IM) from saline under a fixed-ratio 30 schedule of food presentation. Under these conditions, cumulative doses of cocaine (0.013–1.3 mg/kg) produced a dose-dependent and complete generalization to the training dose of cocaine in all monkeys, while producing only minimal effects on response rates. The discriminative stimulus effects of cocaine were antagonized by the non-selective dopamine receptor antagonist flupenthixol (0.018 mg/kg, IM) in all four monkeys. The effects of 7-OH-DPAT (0.01–1.8 mg/kg) were inconsistent across monkeys. In two of the four monkeys (monkeys L990 and L958), 7-OH-DPAT consistently and completely generalized to cocaine and decreased response rates in a dose-dependent manner. Both the cocaine-like discriminative stimulus effects and rate-decreasing effects of 7-OH-DPAT were antagonized by flupenthixol in these two monkeys. Pretreatment with low doses of 7-OH-DPAT (0.01–0.032 mg/kg) had no effect on the cocaine dose-effect curve in monkeys L990 and L958; however, higher doses of 7-OH-DPAT (0.032–0.32 mg/kg) shifted the cocaine dose-effect curve to the left. In the other two monkeys (monkeys 150F and 89B036), 7-OH-DPAT produced a dose-dependent decrease in response rates but did not consistently generalize to cocaine. Flupenthixol did not antagonize the rate-decreasing effects of 7-OH-DPAT in these two monkeys, and pretreatment with 7-OH-DPAT (0.1–0.32 mg/kg) produced a decrease in response rates but had no effect on the cocaine dose-effect curve. Time-course experiments revealed that 7-OH-DPAT (0.32 mg/kg) displayed a slower onset and a longer duration of effect than the training dose of cocaine. Finally, the D₃/D₂ dopamine agonist quinpirole completely generalized to cocaine in three monkeys, and partially in the fourth monkey. Quinpirole showed the highest potency in those monkeys in which 7-OH-DPAT consistently generalized to cocaine. The results of the present study suggest that, in rhesus monkeys, 7-OH-DPAT produces cocaine-like effects and may modulate the discriminative stimulus effects of cocaine in some monkeys.This paper is dedicated to the memory of Xavier Lamas, who died on 26 August 1995 on Mount Everest     

Failure of cholecystokinin antagonists to modify the discriminative stimulus effects of cocaine.

Enhancement of brain dopamine (DA) activity is believed to be an important mechanism underlying the discriminative stimulus effects of cocaine in animals and the subjective effects of cocaine in people. Cholecystokinin (CCK) receptors, which are colocalized with DA receptors in several brain regions, have been implicated as modulators of DA activity, leading to speculation that CCK-based drugs might be developed as therapeutics for cocaine abuse. In the present study, the effects of cocaine alone and after pretreatment with the selective CCKA antagonist devazepide and the selective CCKB antagonist CI 988 were determined in squirrel monkeys trained to discriminate cocaine (1.0 mg/kg) from saline. When tested alone, cocaine engendered dose-related increases in the percentage of cocaine-appropriate responses, reaching virtually exclusive responding on the cocaine-associated lever after doses of 1.0 mg/kg or greater. Pretreatment with a wide range of doses of either devazepide (0.01-3.0 mg/kg) or CI 988 (0.3-30 mg/kg) did not systematically alter the discriminative stimulus effects of any dose of cocaine. The results do not support a role for CCK antagonists in the pharmacotherapy of cocaine abuse.     

Nitric oxide modulates apomorphine-induced recognition memory deficits in rats

Nitric oxide (NO) is an important intracellular messenger in the brain. The implication of NO in schizophrenia is well documented although it is not yet clear whether net over or underproduction of NO is typical of this disease. In line with this, either NO donors or NO synthase (NOS) inhibitors were found to abolish psychotomimetic effects, including cognition deficits, produced by N-methyl-d-aspartate (NMDA) receptor hypofunction. In addition, there is poor experimental evidence concerning the efficacy of NO to modulate memory deficits produced by dopamine (DA) dysfunction. The present study was designed to investigate the ability of NO modulators (NO donors and NOS inhibitors to reverse recognition memory impairments produced by the DA D₁/D₂ mixed receptor agonist apomorphine in rats. For these studies, the novel object recognition test (NORT) was used as the memory test. Apomorphine (0.05, 0.1, 0.5 and 1.0 mg/kg), dose-dependently, disrupted performance in this recognition memory procedure in rats. The NO donors molsidomine (2.0 and 4.0 mg/kg) and SNP (0.3 and 1.0 mg/kg), reversed the impairing effects of apomorphine (1.0 mg/kg) in the NORT. Administration of the NOS inhibitors L-NAME (1.0 and 3.0 mg/kg) or 7-NI (1.0 and 3.0 mg/kg) produced similar results. The present findings indicate a) that apomorphine dose-dependently impaired recognition memory and b) that a cognitive deficit produced by DA dysfunction is sensitive to NO.     

Selective D1 and D2 dopamine antagonists decrease response rates of food-maintained behavior and reduce the discriminative stimulus produced by heroin

Animals were trained to discriminate heroin from saline in a two-lever food-reinforced paradigm. Tests with the heroin metabolites O6-monoacetylmorphine and morphine suggest that the heroin discriminative stimulus was mediated by monoacetylmorphine. The heroin discriminative stimulus was not blocked by pretreatment with low doses of the D1 dopamine antagonist SCH23390 or the D2 antagonist spiperone; higher doses of the antagonists produced decreases both in selection of the drug-appropriate lever after heroin, and in food-maintained responding. The data suggest that dopamine may mediate the heroin discriminative stimulus. When administered in the absence of opioids, the D2 antagonist spiperone did not have rate-decreasing effects, whereas SCH23390 did. Heroin partially reversed the rate-decreasing effects of SCH23390, possibly as a result of the ability of opioids to release dopamine.     

Protection of methylmercury effects on the in vivo dopamine release by NMDA receptor antagonists and nitric oxide synthase inhibitors

The possible protective effects of NMDA receptor antagonists dizocilpine (MK-801) and D(-)-2-amino-5-phosphonopentanoic acid (AP5), and nitric oxide synthase (NOS) inhibitors L-nitro-arginine methyl ester (L-NAME) and 7-nitro-indazol (7-NI) on the methylmercury (MeHg)-induced dopamine (DA) release from rat striatum were investigated using in vivo microdialysis. Intrastriatal infusion of 400 microM or 4 mM MeHg increased the extracellular DA levels to 1941+/-199 and 7971+/-534% with respect to basal levels. Infusion of 400 microM or 4 mM MeHg in 400 microM MK-801 pretreated animals, increased striatal DA levels to 677+/-126 and 2926+/-254%, with respect to basal levels, these increases being 65 and 63% smaller than those induced by MeHg in non-pretreated animals. Infusion of 400 microM or 4 mM MeHg in 400 microM AP5 pretreated animals, increased striatal DA levels to 950+/-234 and 2251+/-254% with respect to basal levels, these increases being 51 and 72% smaller than those induced by MeHg in non-pretreated animals. Infusion of 400 microM MeHg in 100 microM L-NAME or 7-NI pretreated animals, increased the extracellular DA levels to 1159+/-90 and 981+/-292%, with respect to basal levels, these increases being 40 and 50% smaller than those induced by MeHg in non-pretreated animals. In summary, MeHg acts, at last in part, through an overstimulation of NMDA receptors with possible NO production to induce DA release, and administration of NMDA receptor antagonists and NOS inhibitors protects against MeHg-induced DA release from rat striatum.     

Effects of H(1)-antagonists on discriminative stimulus effects of cocaine and methamphetamine in rats

The effects of H(1)-antagonists, such as tripelennamine, chlorpheniramine and pyrilamine, on the discriminative stimulus effects of cocaine and methamphetamine in rats were examined. Rats were trained to discriminate between cocaine (10mg/kg, i.p.) or methamphetamine (1.0mg/kg, i.p.) and saline, with responses maintained under a fixed-ratio 10 (FR10) schedule of food delivery. In generalization tests, tripelennamine generalized to the discriminative stimulus effects of cocaine and methamphetamine, while chlorpheniramine only generalized to cocaine. These generalizations of tripelennamine and chlorpheniramine were attenuated by the dopamine receptor antagonist haloperidol. Furthermore, tripelennamine and chlorpheniramine, but not pyrilamine, potentiated the discriminative stimulus effects of cocaine and methamphetamine. These results suggest that some H(1)-antagonists possess cocaine- and/or methamphetamine-like discriminative stimulus effects which may be mediated by the dopaminergic system, and as a result the discriminative stimulus effects of cocaine and methamphetamine were potentiated by these H(1)-antagonists.