Nucleus Accumbens Of Conscious Rats Research Articles

Pharmacokinetics of N-ethylpentylone and its effect on increasing levels of dopamine and serotonin in the nucleus accumbens of conscious rats.

N-Ethylpentylone (NEP) is one of the most confiscated synthetic cathinones in the world. However, its pharmacology and pharmacokinetics remain largely unknown. In this study, the pharmacokentics of NEP in rat nucleus accumbens (NAc) was assessed via brain microdialysis after the intraperitoneal (ip) administration of NEP (20 or 50mg/kg). The concentrations of dopamine (DA) and serotonin (5-HT) and their metabolites, including 3,4-dihydroxyphenylacetic acid (DOPAC), 3-methoxytyramine (3-MT), and 5-hydroxyindoleacetic acid (5-HIAA), were simultaneously monitored to elucidate the pharmacological effect of NEP. In addition, the plasma levels of NEP were also assessed. The pharmacokinetics of NEP showed a dose-related pattern, with NEP rapidly passing through the blood-brain barrier and reaching a maximum concentration (Cmax ) at approximately 40-minutes postdose. Approximately 4% of plasma NEP was distributed to the NAc, and considering a homogeneous brain distribution, over 90% of plasma NEP was potentially distributed to the brain. High values of area under curve (AUC) and mean residence time (MRT) of NEP were observed in both the NAc and plasma, indicating large and long-lasting effects. NEP elicited dose-related increases in microdialysate DA and 5-HT and increased the concentration of 3-MT in a dose-related manner. However, the rate of DA converted into 3-MT was unaffected. NEP had a negative effect on the rates of which DA and 5-HT were transformed into DOPAC and 5-HIAA, respectively. In summary, NEP rapidly entered the NAc and showed a long-lasting effect. In addition, DA increased more significantly than 5-HT, indicating a large potential for NEP abuse.

The synthetic cathinones, butylone and pentylone, are stimulants that act as dopamine transporter blockers but 5-HT transporter substrates

Synthetic cathinones continue to emerge in recreational drug markets worldwide. 1-(1,3-Benzodioxol-5-yl)-2-(methylamino)butan-1-one (butylone) and 1-(1,3-benzodioxol-5-yl)-2-(methylamino)pentan-1-one (pentylone) are derivatives of the cathinone compound, 1-(1,3-benzodioxol-5-yl)-2-(methylamino)propan-1-one (methylone), that are being detected in drug products and human casework. The purpose of the present study was to examine the neuropharmacology of butylone and pentylone using in vitro and in vivo methods. In vitro uptake and release assays were carried out in rat brain synaptosomes and in cells expressing human dopamine transporters (DAT) and 5-HT transporters (SERT). In vivo microdialysis was performed in the nucleus accumbens of conscious rats to assess drug-induced changes in neurochemistry. Butylone and pentylone were efficacious uptake blockers at DAT and SERT, though pentylone was more DAT-selective. Both drugs acted as transporter substrates that evoked release of [3H]5-HT at SERT, while neither evoked release at DAT. Consistent with the release data, butylone and pentylone induced substrate-associated inward currents at SERT but not DAT. Administration of butylone or pentylone to rats (1 and 3mg/kg, i.v.) increased extracellular monoamines and motor activity, but pentylone had weaker effects on 5-HT and stronger effects on motor stimulation. Our data demonstrate that increasing the α-carbon chain length of methylone creates "hybrid" transporter compounds which act as DAT blockers but SERT substrates. Nevertheless, butylone and pentylone elevate extracellular dopamine and stimulate motor activity, suggesting both drugs possess significant risk for abuse.

Oxytocin attenuates phencyclidine hyperactivity and increases social interaction and nucleus accumben dopamine release in rats.

The pituitary neuropeptide oxytocin promotes social behavior, and is a potential adjunct therapy for social deficits in schizophrenia and autism. Oxytocin may mediate pro-social effects by modulating monoamine release in limbic and cortical areas, which was investigated herein using in vivo microdialysis, after establishing a dose that did not produce accompanying sedative or thermoregulatory effects that could concomitantly influence behavior. The effects of oxytocin (0.03-0.3 mg/kg subcutaneous) on locomotor activity, core body temperature, and social behavior (social interaction and ultrasonic vocalizations) were examined in adult male Lister-hooded rats, using selective antagonists to determine the role of oxytocin and vasopressin V1a receptors. Dopamine and serotonin efflux in the prefrontal cortex and nucleus accumbens of conscious rats were assessed using microdialysis. 0.3 mg/kg oxytocin modestly reduced activity and caused hypothermia but only the latter was attenuated by the V1a receptor antagonist, SR49059 (1 mg/kg intraperitoneal). Oxytocin at 0.1 mg/kg, which did not alter activity and had little effect on temperature, significantly attenuated phencyclidine-induced hyperactivity and increased social interaction between unfamiliar rats without altering the number or pattern of ultrasonic vocalizations. In the same rats, oxytocin (0.1 mg/kg) selectively elevated dopamine overflow in the nucleus accumbens, but not prefrontal cortex, without influencing serotonin efflux. Systemic oxytocin administration attenuated phencyclidine-induced hyperactivity and increased pro-social behavior without decreasing core body temperature and selectively enhanced nucleus accumbens dopamine release, consistent with activation of mesocorticolimbic circuits regulating associative/reward behavior being involved. This highlights the therapeutic potential of oxytocin to treat social behavioral deficits seen in psychiatric disorders such as schizophrenia.

The effect of Gly–Gln [ß-endorphin30–31] on morphine-evoked serotonin and GABA efflux in the nucleus accumbens of conscious rats

Glycyl-L-glutamine (Gly–Gln; β-endorphin30–31) is an endogenous dipeptide synthesized through the post-translational processing of β-endorphin1–31. Central Gly–Gln administration inhibits the rewarding properties of morphine and attenuates morphine tolerance, dependence and withdrawal although it does not interfere with morphine analgesia. In an earlier study, we found that Gly–Gln inhibits morphine-induced dopamine efflux in the nucleus accumbens (NAc), consistent with its ability to inhibit morphine reward. To further investigate the mechanism responsible for its central effects we tested whether i.c.v. Gly–Gln administration influences the rise in extracellular serotonin and GABA concentrations evoked by morphine in the NAc. Conscious rats were treated with Gly–Gln (100nmol/5μl) or saline i.c.v. followed, 2min later, by morphine (2.5mg/kg) or saline i.p. and extracellular serotonin and GABA concentrations were analyzed by microdialysis and HPLC. Morphine administration increased extracellular serotonin and GABA concentrations significantly within 20min, as shown previously. Unexpectedly, Gly–Gln also increased extracellular serotonin concentrations significantly in control animals. Combined treatment with Gly–Gln+morphine also elevated extracellular serotonin concentrations although the magnitude of the response did not differ significantly from the effect of Gly–Gln or morphine, given alone suggesting that Gly–Gln suppressed morphine induced serotonin efflux. Gly–Gln abolished the morphine-induced rise in extracellular GABA concentrations but had no effect on extracellular GABA when given alone to otherwise untreated animals. These data show that Gly–Gln stimulates NAc serotonin efflux and, together with earlier studies, support the hypothesis that Gly–Gln inhibits the rewarding effects of morphine by modulating morphine induced dopamine, GABA and serotonin efflux in the NAc.

Differential effects of methamphetamine and cocaine on behavior and extracellular levels of dopamine and 3,4-dihydroxyphenylalanine in the nucleus accumbens of conscious rats

The central dopamine system plays a prominent role in the effect of psychostimulants such as methamphetamine, cocaine and nicotine. l-3,4-Dihydroxyphenylalanine (DOPA), a precursor of dopamine, has been proposed as a neurotransmitter in the central nervous system. We have studied the effects of these psychostimulants on the release of DOPA and dopamine from the nucleus accumbens shell in conscious rats using in vivo microdialysis. Methamphetamine and cocaine increase the extracellular levels of dopamine. The effect of methamphetamine (1 mg/kg s.c.) on the release of dopamine was almost comparable to that of cocaine (10 mg/kg i.p.). However, methamphetamine increases, but cocaine decreases the extracellular levels of DOPA. In a behavioral study, methamphetamine (1 mg/kg s.c.) induced chewing, walking and sniffing behavior. Cocaine (10 mg/kg i.p.) produces weak effects on these behavioral parameters, when compared to the effects of methamphetamine (1 mg/kg s.c.). The behavioral changes produced by methamphetamine are suppressed by DOPA cyclohexyl ester (30 mg/kg i.p.), a competitive DOPA antagonist. Endogenous DOPA in the nucleus accumbens thus appears to be in involved in the behavioral responses to these psychomotor stimulants.

Characterization of β-phenylethylamine-induced monoamine release in rat nucleus accumbens: a microdialysis study

In vivo microdialysis was used to investigate the effect of β-phenylethylamine on extracellular levels of monoamines and their metabolites in the nucleus accumbens of conscious rats. At all doses tested (1, 10 and 100 μM), infusion of β-phenylethylamine through the microdialysis probe significantly increased extracellular levels of dopamine in the nucleus accumbens. These increases were dose-related. The increase in dopamine levels induced by 100 μM β-phenylethylamine was not affected by co-perfusion of 4 μM tetrodotoxin. The ability of 100 μM β-phenylethylamine to increase the extracellular level of dopamine was comparable to that of the same dose of methamphetamine. On the other hand, β-phenylethylamine had a much less potent enhancing effect on 5-hydroxytryptamine (5-HT) than dopamine levels. Only the highest dose (100 μM) caused a statistically significant effect on 5-HT levels. Over the dose range tested (1, 10 and 100 μM), β-phenylethylamine had no effect on extracellular metabolite levels of dopamine and 5-HT. The results suggest that β-phenylethylamine increases the efflux of monoamines, preferentially dopamine, without affecting monoamine metabolism, in the nucleus accumbens.

NMDA- and MK801-induced changes in dopamine release are attenuated in kainic acid-lesioned nucleus accumbens of conscious rats: an in vivo microdialysis study

Local application of N-methyl- d-aspartate (NMDA) and a NMDA receptor antagonist, MK801 through the dialysis membrane into the nucleus accumbens (NAC) caused a significant decrease and increase in extracellular dopamine (DA) in the NAC of conscious rats, respectively. These neurochemical changes were significantly smaller in the kainic acid (KA)-lesioned NAC than in the intact NAC. These findings show that locally applied NMDA and MK801 into the NAC modulate DA release mainly through indirect mechanism involving putative GABA neuron of the NAC.

P2.15 Effect of epibatidine on the extracellular concentrations of dopamine and its metabolites in the nucleus accumbens of conscious rats: A microdialysis study : I Bednar∗ & A Nordberg Div. of Nicotine Res., Karolinska Inst., Huddinge Univ. Hospital, B 84, S-141 86 Huddinge

P2.15 Effect of epibatidine on the extracellular concentrations of dopamine and its metabolites in the nucleus accumbens of conscious rats: A microdialysis study : I Bednar∗ & A Nordberg Div. of Nicotine Res., Karolinska Inst., Huddinge Univ. Hospital, B 84, S-141 86 Huddinge

P2-278 - Nicotine releases transmitter-like L-DOPA from the nucleus accumbens of conscious rats — its involvement in the nicotine-induced locomotor activities

P2-278 - Nicotine releases transmitter-like L-DOPA from the nucleus accumbens of conscious rats — its involvement in the nicotine-induced locomotor activities

Biphasic effect of ethanol on extracellular accumulation of glutamate in the hippocampus and the nucleus accumbens

The effect of systemic ethanol administration on the extracellular levels of glutamate in the hippocampus and nucleus accumbens of conscious rats was assessed using microdialysis. At 0.5 g/kg, ethanol caused a sustained increase in the levels of glutamate in both regions. Following 1.0 g/kg. response was observed in the nucleus accumbens while a trend towards a decrease in glutamate levels occurred in hippocampus. Injection of 2.0 g/kg ethanol decreased these levels in both regions. These findings suggest a relationship between the previously reported biphasic behavioral consequence of ethanol and its effect on glutamatergic neurotransmission.

Effect of acute and daily neurotensin and enkephalin treatments on extracellular dopamine in the nucleus accumbens

The injection of neurotensin or the enkephalin analog Tyr-D-Ala-Gly-MePhe-Gly(ol) (DAMGO) into the A10 region of rats produces a motor stimulant effect that is associated with an increase in the postmortem levels of dopamine metabolites in the nucleus accumbens. These behavioral and neurochemical effects are augmented following daily administration. In vivo dialysis in the nucleus accumbens of conscious rats was used to determine if the acute and augmented behavioral responses following neurotensin or DAMGO administration are associated with an increase in extracellular dopamine concentrations. The acute injection of DAMGO produced a dose-dependent (0.03-3.3 nmol) elevation in extracellular dopamine and its metabolites in the nucleus accumbens. Neurotensin also produced a dose-related (0.1-3.3 nmol) increase in dopamine and its metabolites. The elevation in extracellular dopamine produced by DAMGO, but not by neurotensin, was positively correlated with the increase in motor activity. Following daily treatment of either neurotensin (1.0 nmol X 4 d) or DAMGO (0.03 nmol X 4 d), a significant elevation in extracellular dopamine levels occurred in the nucleus accumbens compared to an acute injection. The time course of the change in extracellular dopamine after daily injections was similar to the time course of the behavioral stimulation for both compounds. These data demonstrate that enhanced dopamine release in the nucleus accumbens mediates the acute behavioral effect of DAMGO but does not entirely explain the motor effects of neurotensin. However, enhanced dopamine release may mediate the behavioral sensitization produced by daily injection of both peptides into the A10 region.

Effects of acute and chronic clozapine on dopamine release and metabolism in the striatum and nucleus accumbens of conscious rats

1. The effect of single and repeated (once daily for 23 days) oral doses of 20 and 60 mg kg-1 clozapine on dopamine release and metabolism were studied by intracerebral dialysis in the striatum and nucleus accumbens of conscious rats. 2. The basal output of dopamine, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the striatum and nucleus accumbens of rats given clozapine 20 or 60 mg kg-1 chronically, measured one day after the last drug dose, was not significantly different from that of vehicle-treated animals. 3. Challenge doses of 20 or 60 mg kg-1 clozapine produced similar increases in dopamine levels in the striatum and nucleus accumbens of animals which had received vehicle or clozapine 20 or 60 mg kg-1 once daily for 23 days, except that 1 h after administration 60 mg kg-1 clozapine had a greater effect in the nucleus accumbens. 4. In animals treated chronically with clozapine 20 and 60 mg kg-1 or vehicle, DOPAC levels in the striatum and nucleus accumbens were increased to the same extent by challenge doses of clozapine (20 or 60 mg kg-1). In animals treated chronically with clozapine, a challenge dose of 60 mg kg-1 had significantly greater effect on HVA only in the nucleus accumbens. 5. When DOPAC and HVA were measured post mortem in the striatum and nucleus accumbens 2 h after various oral doses of clozapine, it was found that 10 mg kg-1 significantly increased dopamine metabolites only in the nucleus accumbens whereas 100 mg kg-1 had this effect in both regions. Clozapine, 30mgkg-' significantly raised DOPAC levels in both regions but HVA was elevated only in the nucleus accumbens. 6. There appeared to be no appreciable changes in dopamine release and metabolism nor any reduction in the effect of clozapine in the nucleus accumbens after chronic drug treatment. In fact the effect was greater in chronically treated rats, particularly in the nucleus accumbens of animals given 60mgkg' clozapine. 7. It was confirmed that measurement of dopamine metabolites in post mortem tissue provides no valuable information on changes in the availability of synaptic dopamine.

Effect of acute and daily cocaine treatment on extracellular dopamine in the nucleus accumbens

The behavioral stimulant effect of peripheral cocaine injection into rats is augmented following daily administration. In vivo dialysis in the nucleus accumbens of conscious rats was used to determine if the increased behavioral response following daily cocaine administration is associated with an increase in extracellular dopamine concentration. Acute injection of cocaine (15 mg/kg, ip) produced an elevation in extracellular dopamine concentration in the nucleus accumbens. Following daily pretreatment with cocaine (15 mg/kg, ip X 4 days), a subsequent acute injection of cocaine (15 mg/kg, ip) significantly elevated the extracellular dopamine levels compared to that produced by a single acute injection. Although the levels of extracellular dopamine metabolites was significantly lowered by both acute cocaine and daily cocaine, no difference between these two groups of animals was measured. The increase in extracellular dopamine following a single acute injection of cocaine was not correlated to the motor stimulant response. However, after daily pretreatment with cocaine the motor stimulant response to acute cocaine was positively correlated with the increased extracellular concentration of dopamine in the nucleus accumbens. These data demonstrate that enhanced dopamine release into the nucleus accumbens may mediate the behavioral sensitization produced by daily injections of cocaine, but that other neural systems are influential in mediating the acute motor stimulant effect of cocaine.

Dopamine receptors in rat striatum and nucleus accumbens; conformational studies using rigid analogues of dopamine.

A study was made of the actions of dopamine and of some 2-amino-1,2,3,4-tetrahydronaphthalenes on dopamine-sensitive adenylate cyclase in homogenates of rat striatum and nucleus accumbens. The compounds were also tested for their ability to stimulate motor activity following bilateral injection into the nucleus accumbens of conscious rats. The most active compounds on adenylate cyclase from both striatum and nucleus accumbens were dopamine and 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene(6,7-diOHATN). The 5,6-dihydroxy analogue (5,6-diOHATN) was 50 times less active than 6,7-diOHATN in striatal homogenates and 350 times less active in homogenates of nucleus accumbens. All dihydroxy compounds tested were active in causing stimulation of motor activity, the most active compounds being 6,7-and5,6diOHATN. Both dimethoxy derivatives tested were inactive on the adenylate cyclase and as locomotor stimulants.