Differential inhibitory effects of a 5-HT3 antagonist on drug-induced stimulation of dopamine release

The effects of a potent and specific antagonist of 5-HT3 receptors, ICS 205-930, on the dopamine (DA)-releasing properties of morphine (1.0 mg/kg s.c.), nicotine (0.6 mg/kg s.c.), ethanol (1.0 g/kg i.p.) and amphetamine (0.25 and 1.0 mg/kg s.c.) were studied in rats. DA release was estimated by trans-cerebral dialysis in the nucleus accumbens of freely moving rats. ICS 205-930 (15-30 micrograms/kg s.c.) failed to modify the basal output of DA and its metabolites, however, ICS 205-930 dose dependently reduced the stimulation of DA release by morphine, nicotine and ethanol. Thus, at doses of 30 micrograms/kg s.c., ICS 205-930 completely prevented the morphine-, nicotine- and ethanol-induced stimulation of DA release in the nucleus accumbens; doses of 15 micrograms/kg s.c. partially prevented the morphine-, nicotine- and ethanol-induced stimulation of DA release while doses of 7.5 micrograms/kg s.c. were ineffective. In contrast, ICS 205-930 (up to 30 micrograms/kg s.c.) failed to affect the amphetamine-induced stimulation of DA release in the nucleus accumbens. The inhibitory effects of ICS 205-930 (15 and 30 micrograms/kg s.c.) on the drug-induced stimulation of DA release could also be extended to the neuroleptic haloperidol (0.1 mg/kg s.c.). The results indicate that blockade of 5-HT3 receptors selectively prevents the stimulation of DA release induced by drugs known to stimulate the firing activity of DA neurons.     

Increased levels of extracellular dopamine in neostriatum and nucleus accumbens after histamine H1 receptor blockade

The dopaminergic system plays a central role in the processing of reward or reinforcement since drugs that have reinforcing properties all share the ability to elevate dopamine (DA) levels in the nucleus accumbens or neostriatum. Histamine H1 receptor antagonists are known to have reinforcing effects in humans and laboratory rats. Here, we examined the effect of systemic (i.p.) treatment with two H1 antagonists, chlorpheniramine and pyrilamine, on the extracellular levels of DA and its metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the neostriatum and nucleus accumbens of urethane-anesthetized rats. Dopamine and metabolites were measured using in vivo microdialysis and HPLC with electrochemical detection. Saline injections did not produce significant effects on DA, DOPAC, or HVA levels in the neostriatum or nucleus accumbens. In the neostriatum, chlorpheniramine administration (5 and 20 mg/kg) produced a sustained increase in DA to approximately 140 and 180% of pre-injection baseline levels, respectively. In the nucleus accumbens, chlorpheniramine (20 mg/kg) produced a transient increase in DA levels to about 300% of baseline. In both the neostriatum and nucleus accumbens, DOPAC and HVA decreased after chlorpheniramine treatment. Pyrilamine administration (10 and 20 mg/kg) produced a sustained increase in neostriatal DA levels to 140 and 165%, respectively, and accumbens DA increased transiently to 230% after a dose of 20 mg/kg. Levels of neostriatal and accumbens DOPAC and HVA decreased after pyrilamine treatment. These results show that H1 antagonists can potently enhance DA levels in the neostriatum and nucleus accumbens of urethane-anesthetized rats. The neurochemical effects on DA and its metabolites seen here (increased DA, decreased DOPAC and HVA) are similar to those commonly observed with drugs of abuse (e.g. psychostimulants). The interaction of H1 antagonists with dopaminergic transmission may explain the reinforcing effects and abuse potential associated with these compounds. Received: 29 December 1997 / Accepted: 18 June 1998     

Acamprosate suppresses the expression of morphine-induced sensitization in rats but does not affect heroin self-administration or relapse induced by heroin or stress

Acamprosate (calcium-acetyl homotaurinate) is a new compound used in the treatment of alcohol abuse. Because of the putative link between alcoholism and the endogenous opioid systems in both humans and laboratory animals, we tested in rats the effects of acamprosate on behavioral and neurochemical effects of opioid drugs related to their abuse potential. These included sensitization to the behavioral effects of morphine, morphine-induced dopamine (DA) release in the nucleus accumbens (NAS), intravenous (IV) heroin self-administration and relapse to heroin seeking in drug-free rats. In experiment 1, rats were injected daily with either morphine (10 mg/kg, SC) or saline for 14 days. Three days later in a test for the expression of sensitization, an injection of morphine (10 mg/kg) resulted in increased locomotor activity and enhanced DA release in the NAS in rats previously exposed to morphine. Acamprosate (two injections of 200 mg/kg; 12 h apart; IP) suppressed the expression of the sensitized responses, but did not alter the effects of morphine in drug-naive control rats. In experiment 2, it was found that acamprosate (two injections of 50–200 mg/ kg; IP) had no consistent effects on IV heroin self-administration (50–100 μg/kg per infusion) and, in experiment 3, that acamprosate (100–200 mg/ kg, IP) did not alter reinstatement of drug seeking induced by priming injections of heroin (0.25 mg/kg, SC) or a footshock stressor (15 min; 0.5 mA) after a 5- to 8-day period of extinction. Thus, although acamprosate attenuated the expression of sensitized locomotor activity and DA release in the NAS, it did not have any consistent effect on either the intake of heroin during the maintenance phase or the relapse to heroin seeking in a drug-free state. Thus, to the extent that the self-administration and the reinstatement procedures provide valid preclinical models for drug use and relapse in humans, our data suggest that acamprosate may not be effective in altering drug-taking behavior in heroin users. Received: 4 November 1997/Final version: 25 January 1998     

Attenuation of the reinforcing efficacy of morphine by 18-methoxycoronaridine

In previous studies, 18-methoxycoronaridine, a novel iboga alkaloid congener, has been reported to decrease the self-administration of morphine, cocaine, ethanol and nicotine, and to attenuate naltrexone-precipitated signs of morphine withdrawal. In the present study, the nature of the interaction between 18-methoxycoronaridine and morphine was further investigated. Using in vivo microdialysis, 18-methoxycoronaridine pretreatment (40 mg/kg i.p., 19 h beforehand) was found to markedly inhibit morphine-induced (5 mg/kg, i.p.) dopamine release in the nucleus accumbens and striatum; 18-methoxycoronaridine also enhanced morphine-induced increases in extracellular levels of dopamine's metabolites. These effects, which were more prominent in the nucleus accumbens than in the striatum, suggest that 18-methoxycoronaridine selectively interferes with morphine-induced dopamine release, without altering morphine-induced stimulation of dopamine synthesis. In intravenous morphine self-administration experiments, the effects of acute 18-methoxycoronaridine treatment (40 mg/kg, p.o.) were assessed in rats responding for one of several different unit infusion dosages of morphine (0.01-0.16 mg/kg/infusion). 18-Methoxycoronaridine produced a downward shift in the entire morphine dose-response curve without any displacement to the left or right. These results suggest that 18-methoxycoronaridine reduced the reinforcing efficacy of morphine without altering its apparent potency. Together, the microdialysis and self-administration data suggest that 18-methoxycoronaridine profoundly alters mechanisms crucial to the development and maintenance of opioid addiction.     

Benzodiazepine-induced decreases in extracellular concentrations of dopamine in the nucleus accumbens after acute and repeated administration

In vivo microdialysis was used to assess the effects of acute and repeated injections of the benzodiazepine midazolam on extracellular dopamine (DA) concentrations in the nucleus accumbens. Acute administration of midazolam (5 mg/kg, SC) elicited a 22% decrease in extracellular DA in the nucleus accumbens but failed to affect DA concentrations in the striatum. Similarly, six spaced intravenous infusions of midazolam, at a dose that has previously been found to support self-administration (0.05 mg per infusion), produced a 50% decrease in extracellular DA in the nucleus accumbens. In order to assess the effects of subchronic midazolam injections, two groups of rats were given injections of saline or midazolam (5 mg/kg, SC) for 14 days (two injections per day). A subsequent challenge injection of midazolam (5 mg/kg) decreased extracellular DA in the nucleus accumbens by 25% in both groups, indicating that neither tolerance nor sensitization occurred during the repeated drug administration. These experiments indicate (1) that midazolam differentially affects meso-accumbens and nigrostriatal DA neurons, and (2) that the midazolam-induced decrease in extracellular DA in the nucleus accumbens is not affected by repeated drug administration. The data further suggest that the rewarding effects of midazolam are not associated with increased release of DA in the nucleus accumbens.     

Long-term opiate effects on amphetamine-induced dopamine release in the nucleus accumbens core and conditioned place preference

Withdrawal following chronic exposure to opiates or other drugs of abuse, administered as frequent doses, or a chronic infusion can cause reductions in mesolimbic dopamine (DA) transmission. However, mesolimbic DA transmission can be enhanced by opiates or psychostimulants administered intermittently as a single daily injection. Both enhanced and attenuated responsiveness of the mesolimbic DA system may have important implications for substance abuse disorders. Previous studies have shown that procedures that use electrical stimulation or drug treatments to augment neurotransmitter release are more effective for demonstrating declines in mesolimbic DA transmission that persist for extended periods following opiate withdrawal. The present study evaluated the effects of pretreatment with noncontingent morphine on amphetamine-induced DA release in the nucleus accumbens core and conditioned place preference (CPP). Morphine pretreatment was administered as a constant infusion, which was gradually increased to a dose of 50 mg/kg/day over a 1-week period in Wistar rats. At 10 days after cessation of morphine pretreatment, baseline dialysate DA levels in the nucleus accumbens core were unchanged, but amphetamine-induced increases in DA were attenuated by greater than 50% in morphine-pretreated animals. Morphine pretreatment did not modify locomotor activity during conditioning sessions, expressed as absolute values or change in activity counts between saline and morphine injections. Place preference, conditioned by two morphine pairings at 10 and 11 days after the onset of opiate withdrawal, was enhanced by opiate pretreatment between 12 and 33 days after the onset of withdrawal. In conclusion, morphine pretreatment delivered as a constant infusion can have pronounced and long-lasting effects on DA release and CPP, which may have important implications for drug-seeking behavior and treatment of substance abuse disorders.     

Diazepam alters cocaine self-administration, but not cocaine-stimulated locomotion or nucleus accumbens dopamine

Cocaine is known to enhance nucleus accumbens dopamine (NAcc DA), to serve as a positive reinforcer and to produce negative effects, such as anxiety. The influence of diazepam on cocaine intake, cocaine-stimulated behavioral activity and NAcc DA was investigated using self-administration and experimenter-administered intravenous (i.v.) cocaine. In Experiment 1, rats were pretreated with diazepam (0.25 mg/kg) or saline (0.1 ml) 30 min prior to 20 daily 1-hour cocaine (0.75 mg/kg/injection) self-administration sessions. Cocaine intake increased for all animals across sessions, but was highest in diazepam-pretreated animals. Diazepam rats also self-administered their first cocaine injection of each session faster than controls. Experiment 2 utilized in vivo microdialysis to assess NAcc DA levels before and after experimenter-administered i.v. cocaine injections (0.75 mg/kg/injectionx2; 10-min interval) in diazepam- and saline-pretreated rats. Group differences were not revealed across basal and cocaine-stimulated NAcc DA assessments, indicating that diazepam did not decrease NAcc DA during cocaine self-administration. Findings that diazepam enhances cocaine self-administration and decreases cocaine response latency support the notion that cocaine-induced anxiety limits voluntary cocaine intake. It is further suggested that individual variations in cocaine-induced aversive effects may determine whether cocaine use is avoided or repeated.     

Comparative effects of dextromethorphan and dextrorphan on morphine, methamphetamine, and nicotine self-administration in rats.

The effects of dextromethorphan and its metabolite dextrorphan on morphine, methamphetamine and nicotine self-administration and on responding for a nondrug reinforcer (water) were assessed in rats. Both dextromethorphan and dextrorphan decreased morphine self-administration at 10-30 mg/kg, s.c., decreased methamphetamine self-administration at 20 and 30 mg/kg, s.c., and decreased nicotine self-administration at 5-30 mg/kg, s.c.; doses of both drugs less than 40 mg/kg, s.c. did not affect responding for water. The equal potencies of dextromethorphan and dextrorphan suggest mediation of these effects by a non-NMDA receptor mechanism, possibly involving blockade of alpha3beta4 nicotinic receptors. The results also suggest that dextromethorphan should be tested extensively as a potential treatment for diverse populations of drug-abusing patients.     

Central serotonin4 receptors selectively regulate the impulse-dependent exocytosis of dopamine in the rat striatum: in vivo studies with morphine,amphetamine and cocaine

In vivo microdialysis and single-cell extracellular recordings were used to assess the involvement of serotonin(4) (5-HT(4)) receptors in the effects induced by morphine, amphetamine and cocaine on nigrostriatal and mesoaccumbal dopaminergic (DA) pathway activity.The increase in striatal DA release induced by morphine (2.5 mg/kg, s.c.) was significantly reduced by the selective 5-HT(4) antagonists GR 125487 (0.1 and 1 mg/kg, i.p.) or SB 204070 (1 mg/kg, i.p.), and potentiated by the 5-HT(4) agonist prucalopride (5 mg/kg, i.p.). Neither of these compounds affected morphine-stimulated DA release in the nucleus accumbens. In both regions, amphetamine (2 mg/kg, i.p.) and cocaine (15 mg/kg, i.p.) induced DA release was affected neither by GR 125487 nor by prucalopride. None of the 5-HT agents used modified basal DA release in either brain region. Finally, GR 125487 (445 microg/kg, i.v.), whilst not affecting basal firing of DA neurons within either the substantia nigra pars compacta nor the ventral tegmental area, significantly reduced morphine (0.1-10 mg/kg, i.v.) stimulated firing of nigrostriatal DA neurons only.These results confirm that 5-HT(4) receptors exert a state-dependent facilitatory control restricted to the nigrostriatal DA pathway, and indicate that 5-HT(4) receptors selectively modulate DA exocytosis associated with increased DA neuron firing rate.     

Mid- to late gestational morphine exposure does not alter the rewarding properties of morphine in adult male rats

Prenatal exposure to drugs of abuse often leads to physiological and neurobiological abnormalities including decreased brain and body weight, cognitive deficits and behavioral alterations. A handful of studies showed increased vulnerability to drug abuse in prenatally drug-exposed offspring. Our work also demonstrated that prenatal exposure to analgesic doses of morphine during gestation days 11-18 increases mu-opioid receptor density in the nucleus accumbens and central amygdala of adult male rats. Both the nucleus accumbens and central amygdala play important roles in modulating drug-induced reward via the mesolimbic dopaminergic system. Therefore, two types of behavioral paradigms were used to test the hypothesis that the same prenatal morphine exposure would enhance the rewarding effects of morphine, making drug-exposed offspring more vulnerable to abuse this drug in adulthood. All experiments were performed with adult male offspring of saline-injected, morphine-injected or non-injected (control) dams. (1) The unbiased conditioned place preference (CPP) paradigm was used to investigate whether prenatal morphine exposure sensitizes adult male rats to non-contingent morphine reward. These adult animals were conditioned with 0.1, 0.3, 1, 3 or 5 mg/kg morphine. All control, prenatally saline- and morphine-exposed male rats preferred the morphine-paired compartment relative to the saline-paired compartment. However, the magnitude of morphine CPP in adult male rats was not dependent on the conditioning dose of morphine or prenatal morphine exposure. (2) Intravenous morphine self-administration was used to assess the behavioral response to contingent morphine reward. Each rat self-administered one of four doses of morphine (0.3, 1, 2 or 3 mg/kg/infusion). Morphine self-administration was not altered in prenatally morphine-exposed adult male offspring. Control males self-administered significantly less morphine at the lowest dose of morphine than both prenatally saline- and morphine-exposed males. Although our data show that prenatal exposure to an analgesic dose of morphine during the time of opioid receptor appearance does not enhance morphine CPP or self-administration, they do not exclude the possibility that this prenatal morphine exposure enhances the rewarding properties of other drugs of abuse.     

The effects of a novel nicotinic receptor antagonist N,N-dodecane-1,12-diyl-bis-3-picolinium dibromide (bPiDDB) on acute and repeated nicotine-induced increases in extracellular dopamine in rat nucleus accumbens

The present study examined the effects of the novel nicotinic acetylcholine receptor (nAChR) antagonist, N,N'-dodecane-1,12-diyl-bis-3-picolinium dibromide (bPiDDB), after acute and repeated nicotine treatment on extracellular dopamine (DA) levels in rat nucleus accumbens (NAcc), using in vivo microdialysis. Acute nicotine (0.4mg/kg, sc) injection produced an increase (232% of basal) in extracellular DA, which was attenuated by pretreatment with the nAChR antagonist mecamylamine (4mg/kg, sc). Pretreatment with bPiDDB (1 or 3mg/kg, sc) dose-dependently reduced the increase in extracellular DA produced by nicotine (0.4mg/kg, sc), but not by amphetamine (0.5mg/kg, sc). Basal levels of NAcc DA increased in animals that had been pretreated with nicotine (0.4mg/kg, sc) for 5 days compared to saline. In addition, nicotine challenge further increased extracellular DA (237% of basal). The increase in DA in NAcc following repeated nicotine was blocked by pretreatment with mecamylamine (4mg/kg, sc) and bPiDDB (1 or 3mg/kg, sc). These results indicate that bPiDDB likely acts as an antagonist at neuronal nAChRs to inhibit DA release in NAcc after acute or repeated nicotine administration. The ability of bPiDDB to inhibit the effect of nicotine in NAcc, combined with previous studies showing decreased nicotine self-administration in rats provides support for bPiDDB as a potential lead compound for the development of a novel pharmacotherapy for nicotine dependence.     

A TRH analog (DN-1417). Effects on the levels of monoamines and the metabolites in the various brain regions in rats

The effects of a TRH (thyrotropin-releasing hormone) analog, DN-1417 (gamma-butyrolactone-gamma-carbonyl-L-histidyl-L-prolinamide citrate), on the levels of norepinephrine (NE), dopamine (DA), serotonin (5-HT) and the metabolites in the various brain regions of rats were determined by means of high performance liquid chromatography with electrochemical detection. DN-1417 (20 mg/kg, i.p.) produced marked decreases in the levels of NE, DA and 5-HT, especially in the nucleus accumbens, striatum and hypothalamus. The maximum effect was observed at 15 min after the administration. DA metabolites, 3,4-dihydroxyphenylacetic acid and homovanillic acid, increased significantly in the nucleus accumbens, striatum and hypothalamus, whereas 3-methoxy-4-hydroxyphenylglycol and 5-hydroxyindoleacetic acid remained unchanged. 3-Methoxytyramine increased significantly in the nucleus accumbens and striatum. Two week chronic administration of DN-1417 (20 mg/kg, i.p.) increased the levels of DA and NE in the nucleus accumbens and DA in the striatum. These results suggest that DN-1417 stimulates the turnover of the cerebral monoamines, especially the release of DA from the nucleus accumbens and striatum in the mesolimbic and nigro-striatal DAergic systems.     

Behavioral and neurochemical responses to cocaine in periadolescent and adult rats.

Although recreational drug use by human adolescents is a well-known and long-standing problem, relatively little is known regarding differences in behavioral and physiological responses to abused substances in adolescent vs adult animals. The present study compared effects of the psychomotor stimulant, cocaine, in periadolescent (postnatal days 37-52) and adult (postnatal days 75-90) male Wistar rats. Locomotion and motor stereotypy were recorded after acute and repeated cocaine injections (0, 10, or 20 mg/kg cocaine, intraperitoneal (i.p.), four injections spaced 5 days apart). Spontaneous acquisition of intravenous (i.v.) cocaine self-administration was investigated in two dose groups ( approximately 0.37 or 0.74 mg/kg/infusion) over 14 days. Dopamine levels in the nucleus accumbens were recorded under basal conditions (no net flux method) and after cocaine administration ( approximately 0.37, 0.74, and 2.92 mg/kg/i.v. infusion or 20 mg/kg i.p.) using in vivo microdialysis. The locomotor data are in partial agreement with previous reports of hyposensitivity to acute cocaine in periadolescent vs adult rats; periadolescents were less active overall than adults. Moreover, adult rats exhibited significant locomotor sensitization after repeated injection of 10 mg/kg cocaine, whereas periadolescents required the high dose of 20 mg/kg cocaine to demonstrate sensitization. Neither age group showed sensitization of motor stereotypies. No age-related difference was observed in acquisition of cocaine self-administration, or in basal or cocaine-stimulated nucleus accumbens dopamine. These experiments imply a developmental dissociation between the motor activating and reinforcing effects of cocaine. Similarities in dopamine levels across age groups suggest that age-specific motor responses to cocaine are not mediated by dopamine in the nucleus accumbens.     

Effects of high-dose methadone maintenance on cocaine place conditioning, cocaine self-administration, and mu-opioid receptor mRNA expression in the rat brain.

Methadone maintenance at appropriate doses can effectively reduce cocaine abuse in heroin-dependent individuals. In the present studies, we investigated the effect of high-dose methadone maintenance cocaine conditioned place preference (CPP) and cocaine intravenous self-administration. Rats implanted with methadone-filled osmotic mini-pumps (20 and 55 mg/kg/day, SC) and conditioned with cocaine (1, 5, and 20 mg/kg, i.p.) did not express cocaine CPP. Similarly, rats implanted with methadone pumps (55 mg/kg/day) after cocaine conditioning (20 mg/kg) displayed neither spontaneous nor cocaine-precipitated (20 mg/kg, i.p.) CPP. In contrast, methadone maintenance (30 and 55 mg/kg/day, SC) did not alter the intravenous self-administration (continuous schedule of reinforcement) of various doses of cocaine (0.1, 0.5, and 2.0 mg/kg/inf). To explore neuropharmacological interactions between methadone maintenance and cocaine conditioning, we quantitatively measured mRNA levels of mu-opioid receptor (MOR) and proopiomelanocortin genes 10 days after methadone maintenance. MOR mRNA levels in both the nucleus accumbens core and frontal cortex were significantly elevated in rats exposed to cocaine during CPP conditioning. However, upregulation of MOR mRNA levels in the nucleus accumbens core were reduced by methadone maintenance in a dose-dependent manner. In conclusion, our results suggest that high-dose methadone maintenance does not alter the direct reinforcing effect of cocaine, but blocks spontaneous and cocaine-precipitated cocaine-seeking, possibly by preventing MOR alterations in the nucleus accumbens core induced by cocaine conditioning.     

Differential impact of pavlovian drug conditioned stimuli on in vivo dopamine transmission in the rat accumbens shell and core and in the prefrontal cortex

Rationale Conditioned stimuli (CSs) by pavlovian association with reinforcing drugs (US) are thought to play an important role in the acquisition, maintenance and relapse of drug dependence. Objective The aim of this study was to investigate by microdialysis the impact of pavlovian drug CSs on behaviour and on basal and drug-stimulated dopamine (DA) in three terminal DA areas: nucleus accumbens shell, core and prefrontal cortex (PFCX). Methods Conditioned rats were trained once a day for 3 days by presentation of Fonzies filled box (FFB, CS) for 10 min followed by administration of morphine (1 mg/kg), nicotine (0.4 mg/kg) or saline, respectively. Pseudo-conditioned rats were presented with the FFB 10 h after drug or saline administration. Rats were implanted with microdialysis probes in the shell, core and PFCX. The effect of stimuli conditioned with morphine and nicotine on DA and on DA response to drugs was studied. Results Drug CSs elicited incentive reactions and released DA in the shell and PFCX but not in the core. Pre-exposure to morphine CS potentiated DA release to morphine challenge in the shell but not in the core and PFCX. This effect was related to the challenge dose of morphine and was stimulus-specific since a food CS did not potentiate the shell DA response to morphine. Pre-exposure to nicotine CS potentiated DA release in the shell and PFCX. Conclusion The results show that drug CSs stimulate DA release in the shell and medial PFCX and specifically potentiate the primary stimulant drug effects on DA transmission.     

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.     

Agmatine modulates neuroadaptations of glutamate transmission in the nucleus accumbens of repeated morphine-treated rats

It has been proved that agmatine inhibits opioid dependence, yet the neural mechanism remains unclear. In the present study, the effect of agmatine on the neuroadaptation of glutamate neurotransmission induced by morphine dependence, including changes of the extracellular glutamate level and glutamate receptors in the nucleus accumbens was investigated.We found that agmatine (2.5–20 mg/kg, s.c.) inhibited development of morphine dependence, which was consistent with our previous report. In rats repeatedly treated with morphine, the glutamate level in the nucleus accumbens dialysate was markedly increased after naloxone-precipitated withdrawal. When agmatine (20 mg/kg, s.c.) was co-pretreated with morphine or was applied before naloxone-precipitated withdrawal, this elevation of the extracellular glutamate level was inhibited. In the synaptosome model, repeated morphine treatment and naloxone precipitation induced an increase in glutamate release, while agmatine (20 mg/kg, s.c.) co-pretreated with morphine reversed the increase of glutamate release. However, neither morphine or agmatine treatment alone nor morphine and agmatine co-administration had any influence on [3H]-glutamate uptake. It indicated that the elevation of the glutamate level in the nucleus accumbens might be caused by the increase of glutamate release of synaptosome in the withdrawal conditions of morphine-dependent rat. Furthermore, agmatine concomitant treatment with morphine entirely abolished the up-regulation of the NR1 subunit of N-methyl-d-aspartate (NMDA) receptors in the nucleus accumbens in repeated morphine-treated rats.Taken together, the present study demonstrated that agmatine could modulate the neuroadaptations of glutamate transmission in the nucleus accumbens in the case of morphine dependence, including modulating extracellular glutamate concentration and NMDA receptor expression.     

Acute administration of amitriptyline and mianserin increases dopamine release in the rat nucleus accumbens: possible involvement of serotonin2C receptors

Previous studies of conventional tricyclic and non-tricyclic antidepressants have suggested that a number of these drugs display considerable pharmacological activity at 5-HT2C receptors in the brain. There is evidence that 5-HT2C receptors are involved in the control of the activity of the central dopaminergic system. Therefore, the effects of amitriptyline (5 mg/kg and 10 mg/kg i.p.) and of the atypical antidepressant mianserin (2.5 mg/kg and 5 mg/kg i.p.) were studied on the extracellular concentration of dopamine (DA) in the nucleus accumbens of chloral hydrate-anesthetized rats, using intracerebral microdialysis. Amitriptyline and mianserin significantly increased DA release (+31.1 +/- 7.9% and +33.6 +/- 4.3%, respectively) at the higher doses. In addition, lower doses of mianserin (2.5 mg/kg i.p.) and amitriptyline (5 mg/kg i.p.) blocked the inhibitory action of RO 60-0175 (1 mg/kg i.p.), a selective 5-HT2C receptor agonist, on DA release. The effect of RO 60-0175 (1 mg/kg i.p.) was completely blocked by SB 242084 (2.5 mg/kg i.p.), a selective and powerful 5-HT2C receptor antagonist. Taken together, these data indicate that amitriptyline and mianserin increase DA release in the nucleus accumbens by blocking 5-HT2C receptors.     

Decreased accumbens dopamine release after cocaine challenge in behaviorally sensitized female rats

The effects of the competitive NMDA receptor antagonist CPP on the initiation of behavioral sensitization to acute cocaine and basal and acute cocaine-induced dopamine (DA) release in the nucleus accumbens (NAC) were assessed in female Sprague-Dawley rats. Cocaine pretreated rats (30 mg/kg IP, once daily for 7 days) challenged with cocaine (10 mg/kg) on day 8 displayed increased motor activity relative to controls challenged with cocaine on day 8. This effect was blocked in rats receiving CPP (2 mg/kg) 15 min prior to all cocaine pretreatments. Basal DA levels in the NAC of both cocaine-pretreated and CPP plus cocaine-pretreated rats were higher on day 8 compared to controls. Acute cocaine challenge on day 8 resulted in increased extracellular DA concentrations in the NAC in control rats, no increase in rats pretreated with CPP plus cocaine, and a decrease in rats pretreated with cocaine only. These data demonstrate that development of behavioral sensitization to cocaine in female Sprague-Dawley rats can be completely blocked by a peripherally administered competitive NMDA receptor antagonist and that an increase in DA release in the NAC after a cocaine challenge is not an absolute requirement for expression of motor sensitization to cocaine in female rats.     

Release of dopamine is reduced by diazepam more in the nucleus accumbens than in the caudate nucleus of conscious rats

The effects of 1-20 mg/kg diazepam were studied on the extracellular concentrations of dopamine (DA), dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the nucleus accumbens and striatum of conscious rats, using intracerebral microdialysis. Five, but not 1 mg/kg diazepam significantly reduced extracellular DA, DOPAC and HVA in the nucleus accumbens. Twenty mg/kg diazepam significantly reduced extracellular DA, DOPAC and HVA in the striatum. A significant effect on striatal DOPAC, but not on DA and HVA, was seen with 10 mg/kg diazepam, while no changes were found with 5 mg/kg diazepam. The results suggest that diazepam reduces the release and metabolism of DA in the nucleus accumbens more than in the striatum.