Effect of Y-516 on the hyperactivity induced by dopamine injected bilaterally into the nucleus accumbens

The effect of Y-516 on the hyperactivity induced by dopamine injected bilaterally into the nucleus accumbens was compared with those of clocapramine (CCP), haloperidol (HPD) and chlorpromazine (CPZ). Dopamine (5-50 micrograms) injected into the nucleus accumbens induced a dose-dependent hyperactivity following pretreatment with nialamide (100 mg/kg, i.p., 2 hr). The hyperactivity induced by 10 micrograms of dopamine was antagonized by the i.p. administration of Y-516 (0.5-1.0 mg/kg), CCP (5-25 mg/kg), HPD (0.05-0.5 mg/kg) and CPZ (1-5 mg/kg) in a dose-dependent manner. The ED50 values of Y-516, CCP, HPD and CPZ were 0.85, 16.5, 0.098 and 2.53 mg/kg, respectively. These results suggest that Y-516 has a potential inhibitory effect on the mesolimbic dopaminergic system and may be a beneficial neuroleptic drugs.     

Hyperactivity induced by N-methyl-d-aspartate injections into nucleus accumbens: lack of evidence for mediation by dopaminergic neurons

To test the hypothesis that the motor hyperactivity associated with intra-accumbens injections of N-methyl-d-aspartate (NMDA) results from stimulation (direct or indirect) of nucleus accumbens dopaminergic mechanisms, the behavioral effects of intra-accumbens and intraventricular NMDA were compared to those of the prototypic dopaminergic releasing agent, amphetamine, and the competitive NMDA receptor antagonist, 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP). Drugs were injected into the right lateral ventricle, or bilaterally into the nucleus accumbens of rats. Locomotor activity was monitored electronically and by direct observation for 40 min prior to, and 1 hour after, drug treatment. Intra-accumbens injections of NMDA (0.4, 1.2 and 2.0 micrograms/side) produced dose-related increases in distance traveled, but had no significant effect on movement time or vertical movements. The NMDA-induced increase in distance traveled was temporally correlated with convulsive wild running, but not with exploratory behavior, suggesting that this increase may have been secondary to seizure-like activity. Intra-accumbens injections of amphetamine (10, 20 and 40 micrograms) or CPP (0.1 microgram) produced dose-related increases in all three measures. By the intraventricular route, the effects of NMDA were similar to those of intra-accumbens administration, whereas intraventricularly administered d-amphetamine had no effect. The behavioral effects of intra-accumbens NMDA cannot be explained by an NMDA receptor-mediated facilitation of dopaminergic neurotransmission; rather, this type of facilitation may be associated with competitive NMDA receptor antagonism.     

Modulation of feeding and drinking behaviour by catecholamines injected into nucleus accumbens in rats

Nucleus accumbens is proposed as one of the centers in the neural circuitry involved in the regulation of feeding and drinking behaviour in rats. Injection of dopamine and angiotensin-II into this nucleus has been documented to affect water and food intake in rats. Reports on the effect of intracerebral injection of catecholamines on feeding and drinking behaviour in animal models are conflicting. Therefore, in the present study the effect of adrenaline and noradrenaline injected into nucleus accumbens on food and water intake in rats was assessed. 24 h basal food and water intakes were recorded in Wistar rats and were found to be 12.3 +/- 0.46 g and 21.7 +/- 1.03 ml respectively. Stainless steel cannulae were implanted stereotaxically into the nucleus accumbens. Four different doses (0.1 microgram, 0.5 microgram, 1 microgram, and 2 micrograms) of adrenaline and noradrenaline were injected into the nucleus accumbens through the implanted cannulae in different group of animals and their 24 h food and water intakes were recorded following these injections. No change in food and water intake was observed following the administration of different doses of adrenaline. A significant increase in 24 h water intake reaching a maximum of 28.88 +/- 1.45 ml at 1 microgram dose, without change in food intake was observed following administration of different doses of noradrenaline. The noradrenaline-facilitated water intake was blocked when noradrenaline was injected following injection of phentolamine, an alpha-receptor blocker. The bilateral lesions of nucleus accumbens resulted in a significant and sustained inhibition of water intake (16.61 +/- 0.67 ml) without change in food intake. These observations suggest that noradrenaline facilitates water intake without affecting food intake when injected into the nucleus accumbens in rats and the dipsogenic effect of noradrenaline is mediated by alpha-receptors. Adrenaline does not affect these ingestive behaviours when injected into the nucleus accumbens in rats.     

Desipramine given repeatedly enhances behavioural effects of dopamine and d-amphetamine injected into the nucleus accumbens

The effect of desipramine (DMI) was studied after its repeated administration (10 mg/kg p.o., twice daily, 14 days) to rats, on the action of dopamine and d-amphetamine injected bilaterally into the nucleus accumbens. DMI, applied repeatedly but not acutely, prevented the sedative effect of dopamine and enhanced its stimulating action, as assessed by the open-field test. Repeated administration of DMI also enhanced d-amphetamine-induced locomotor hyperactivity. The number of [3H]SCH 23390 binding sites (D-1) in the limbic system decreased while the number of [3H] spiperone ones (D-2) remained unchanged. The results indicate that, like other antidepressant drugs studied earlier, DMI enhances neurotransmission in the dopamine mesolimbic system (nucleus accumbens) of the rat.     

Changes in social behaviour of rats following chronic treatment with gamma-endorphin antiserum injected into the nucleus accumbens

Treatment with gamma-endorphin antiserum twice daily for 12 days, by injection into the nucleus accumbens did not change the basal level of social activity or explorative behaviour when pairs of rats were tested in a social interaction test. The decrease in social interactions due to increased light level as observed in placebo-treated rats, was not present in animals treated with gamma-endorphin antiserum. Significantly more freezing and fly-responses were observed in the rats treated with antiserum, as reactions to penetrating sound stimuli. These changed responses to light and sound stimuli persisted for at least 3 days following discontinuation of treatment. It is concluded that treatment with gamma-endorphin antiserum, injected into the nucleus accumbens results in disturbances in the integration of environmental stimuli in social behaviour and in enhanced responsiveness to stressful stimuli. It is suggested that these effects may be related to increased dopaminergic transmission in some dopaminergic systems in the nucleus accumbens, implicating these systems in the environmental control over social behaviour.     

Place conditioning with dopamine D1 and D2 agonists injected peripherally or into nucleus accumbens

The conditioned place preference technique was used to assess the affective properties of the direct dopamine D1 agonist, SKF38393, and the direct D2 agonist, LY171555 (quinpirole). A three compartment apparatus was used: the animals' pre-experimental preference for the two choice compartments was equal and, within each experimental group, half the rats received drug pairings in each choice compartment. Intraperitoneal injections of SKF38393 produced conditioned place aversions at all doses tested (1.0–4.0 mg/kg); LY171555 produced weak conditioned place preferences at 1.0 and 2.0 mg/kg, but no reliable effect at 4.0 mg/kg. Bilateral intra-accumbens microinjections of SKF38393 produced strong preferences at all doses tested (0.5–2.0 µg/side); LY171555 produced strong preferences at two doses (0.5 and 1.0 µg/side) and no effect at a third dose (2.0 µg/side). These results suggest that activation of either D1 or D2 receptors in the nucleus accumbens can produce reward, and that D1 receptors (and possibly also D2 receptors) located elsewhere in the brain or in the periphery may mediate aversive effects.     

Effects of muscimol, amphetamine, and DAMGO injected into the nucleus accumbens shell on food-reinforced lever pressing by undeprived rats

Previous studies have shown that large increases in food intake in nondeprived animals can be induced by injections of both the GABA_A agonist muscimol and the μ-opioid agonist DAMGO into the nucleus accumbens shell (AcbSh), while injections of the catecholamine agonist amphetamine have little effect. In the current study we examined whether injections of these drugs are able to increase food-reinforced lever pressing in nondeprived rats. Twelve subjects were trained to lever press on a continuous reinforcement schedule while food deprived and were then tested after being placed back on ad libitum feeding. Under these conditions, responding was markedly increased by injections of either muscimol or DAMGO, although the onset of the effects of the latter drug was delayed by 30-40 min. In contrast, amphetamine injections failed to increase reinforced lever pressing, although they did enhance responding on a non-reinforced lever, presumably reflecting alterations in behavioral activation. These results demonstrate that stimulation of GABA_A and μ-opioid receptors within the AcbSh is able to promote not only food intake, but also food-directed operant behavior. In contrast, stimulation of AcbSh dopamine receptors may enhance behavioral arousal, but does not appear to specifically potentiate behaviors directed toward food procurement.     

Self-administration of methionine enkephalin into the nucleus accumbens

Microinfusions of the endogenous opiate neurohumor, methionine enkephalin, into the nucleus accumbens initiated a reinforcing stimulus in a dose-related manner. The reinforcing nature of this intracranial self-administration was evaluated with intermittent schedules of reinforcement and a two-lever discrimination procedure. Opiate receptors are likely responsible for the initiation of this reinforcing stimulus since naloxone effectively blocked self-administration. These data suggest the mediation of opiate reinforcement through interactions with opiate receptors in brain regions outside the ventral tegmental area, questioning the current dopamine hypothesis for the initiation of these reinforcement processes.     

The influence of oxaprotiline enantiomers given repeatedly on the behavioural effects of d-amphetamine and dopamine injected into the nucleus accumbens

The effects of (+)- and (-)-oxaprotiline, given repeatedly (10 mg/kg p.o., twice daily, 14 days), on the behavioural action of d-amphetamine and dopamine injected bilaterally into the nucleus accumbens were studied in rats. Repeated but not acute treatment with (+)- or (-)-oxaprotiline enhanced the d-amphetamine-induced locomotor hyperactivity. Both enantiomers, given repeatedly but not acutely, attenuated the inhibition of exploration activity induced by dopamine and potentiated the stimulating effect of dopamine as assessed in the open field test. The results indicate that, like other antidepressants studied previously, both oxaprotilines increase the responsiveness of the dopamine mesolimbic system (nucleus accumbens) of the rat.     

Characterisation of the mechanisms for hyperactivity induction from the nucleus accumbens by phenylethylamine derivatives

A wide variety of phenylethylamine derivatives were injected bilaterally into the nucleus accumbens of rat following a nialamide pretreatment and hyperactivity was recorded. 2-Phenylethylamine was shown to induced a low intensity hyperactivity but the inrroduction of hydroxyl functions on to the phenyl ring at the 3- and/or 4-positions enhanced activity and m- and p-tyramine and dopamine each caused marked hyperactivity in the 0.4–25 g dosage range. Methylation of one hydroxyl function reduced activity (3-methoxy-4-hydroxy- and 3-hydroxy-4-methoxy-phenylethylamine); 2(3,4-methylenedioxyphenyl) ethylamine was inactive. Agents with substitution of the side chain, such as noradrenaline, d-amphetamine and -methyldopamine, were all shown to induced marked hyperactivity at doses of 1.6–25 g. Alterations in the chain length markedly reduced activity (4-(3,4-dihydroxyphenyl) butylamine, 3,4-dihydroxybenzylamine). A variety of N-substituted compounds were shown to be potent inducers of hyperactivity from the nucleus accumbens (adrenaline, epinine, N-ethyldopamine, N-isopropyldopamine, isoprenaline) (0.2–25 g). However, N-methyl-N-isopropyldopamine showed only weak activity and N,N-dimethyldopamine was inactive. All hyperactivity effects were shown to be dose-dependent. The hyperactivities induced by dopamine, noradrenaline and isoprenaline were each inhibited in a dose-dependent manner by subsequent injections of fluphenazine (1.25–25 g) into the nucleus accumbens, although no reductions were recorded following similar injections of saline, solvent, 2% procaine, 50 g propranolol or 50 g piperoxan.     

Effects of hypothalamic self-stimulation of drugs influencing dopaminergic neurotransmission injected into nucleus accumbens and corpus striatum of rats

The role of the nucleus accumbens septi (ACB) and corpus striatum (CPU) in self-stimulation were investigated by injecting directly or indirectly acting stimulant drugs or a dopamine-(DA-) receptor blocking agent into each site bilaterally. d-Amphetamine (68 nmol) facilitated hypothalamic self-stimulation when injected into either site. Apomorphine (40 nmol) depressed or facilitated responding, the direction and magnitude of this effect being contingent (C=0.52) on the effect of systemic injection (0.3 mg/kg i.p.), and correlated with the difference between the effects of d-and l-amphetamine (0.5 mg/kg i.p.) but not with injection site. Haloperidol (6.6 nmol) in either site depressed self-stimulation. Tyramine (730 nmol), an agent believed to cause noncontingent displacement of transmitter from catecholamine terminals, depressed self-stimulation when injected into CPU, but facilitated it when injected into ACB. The sitespecific effects found with tyramine but not with apomorphine may have been due to release by tyramine of transmitters other than DA.     

Drug-induced modulation of locomotor hyperactivity induced by picrotoxin in nucleus accumbens

Locomotor hyperactivity was induced in rats by bilateral injection of picrotoxin (PIC) into the nucleus accumbens (NAC) followed by intraperitoneal (IP) or intra-accumbens (IA) injection of agents affecting dopamine (DA), acetylcholine, serotonin, or GABA receptors. IP injection of haloperidol and diazepam attenuated PIC-induced hypermotility in a dose-dependent manner. Low (sedative) doses of the DA agonists apomorphine (APO) and lisuride, or pretreatment with reserpine abolished PIC-induced hypermotility. Independent of a preceding IA injection of PIC, higher IP doses of APO produced the well-known locomotor effect. LSD, and the atypical neuroleptic, sulpiride, potentiated PIC-induced hypermotility strongly whereas clozapine was ineffective. IA injection of carbachol or haloperidol, in doses which antagonized hypermotility induced by APO IP, did not influence PIC-induced hypermotility. The atypical neuroleptics, clozapine and sulpiride, and the benzodiazepine, diazepam, inhibited PIC-induced hypermotility. The results suggest that there is a complex involvement of GABA, DA and serotonin functions in the effectuation of PIC-induced hypermotility and that PIC-induced hypermotility may be affected by DA-sensitive structures situated outside the NAC.     

The behavioral effects of CCK8 injected into the medial nucleus accumbens are dependent on the motivational state of the rat

The effects of CCK8 injected into the rat median nucleus accumbens on exploration and locomotion were measured in the four hole box and open-field tests. CCK8 (1 fmol to 100 pmol) induced hypoexploration in the four hole box (duration, frequency), with the pattern of the responses remaining unchanged compared to those of the control group. These effects were reversed by injection of the CCK antagonist proglumide (20 micrograms) into the nucleus accumbens. In the open-field test, CCK8 (100 pmol) only decreased locomotion and rearing when the rats were not habituated to the environment. These results show that the behavior of rats exposed to a novel external stimuli is highly sensitive to CCK8.     

Effects of GABA ligands injected into the nucleus accumbens shell on fear/anxiety-like and feeding behaviours in food-deprived rats

In an attempt to establish a relationship between food intake and fear/anxiety-related behaviours, the goal of this study was to investigate the effect of bilateral injections of GABAA (Muscimol, MUS, doses 25 and 50 ng/side) and GABAB (Baclofen, BAC, doses 32 and 64 ng/side) receptor agonists in the nucleus accumbens shell (AcbSh) on the level of fear/anxiety-like and feeding behaviours in 24 h food-deprived rats. The antagonists of GABAA (Bicuculline, BIC, doses 75 and 150 ng/side) and GABAB (Saclofen, SAC, doses 1.5 and 3 μg/side) were also tested. The results indicated that the total number of risk assessment behaviour decreased after the injection of both doses of GABAA agonist (MUS) into the AcbSh of 24 h food-deprived rats exposed to elevated plus maze. Similar results were obtained after treatment with both doses of GABAB (BAC) agonist in the AcbSh. These data indicated that the activation of both GABAA and GABAB receptors within the AcbSh caused anxiolysis in 24 h food-deprived rats. In addition, feeding behaviour (food intake, feeding latency and feeding duration) remained unchanged after treatment with both GABA agonists. In contrast, both food intake and feeding duration decreased after injections of both doses of BIC (GABAA antagonist), while the feeding latency remained unchanged after treatment with both GABA antagonists in the AcbSh of 24 h food-deprived rats. The treatment with SAC (GABAB antagonist) did not affect feeding behaviour. Collectively, these data suggest that emotional changes evoked by pharmacological manipulation of the GABA neurotransmission in the AcbSh are not linked with changes in food intake.     

The response of apomorphine administered into the accumbens in rats with bilateral lesions of the nucleus accumbens, induced with 6-hydroxydopamine

Bilateral lesions of the nucleus accumbens, induced with 6-hydroxydopamine, reduced motor activity and produced a 20-35% depletion of the concentrations of dopamine (DA) and its main metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). Small doses of apomorphine (1-10 ng), injected into the nucleus accumbens of sham-lesioned rats, decreased motor activity, while larger doses (1-10 micrograms) produced hyperactivity. In rats lesioned with 6-hydroxydopamine, apomorphine caused hyperactivity only, and this apomorphine-induced response was more pronounced than in sham-lesioned rats. Large doses of apomorphine decreased, only in sham-lesioned animals, the levels of DOPAC and HVA. These data suggest that the apomorphine-induced hypomotility is mediated by presynaptically located DA receptor systems in the nucleus accumbens, whereas the apomorphine-induced hypermotility is likely to be mediated by postsynaptically located DA receptor systems.     

Nonserotonergic control of nucleus accumbens dopamine metabolism by the median raphe nucleus.

Injections of the GABA agonist muscimol into the median raphe nucleus (MR) have been shown to result in an acceleration of dopamine metabolism within the nucleus accumbens. To examine whether serotonergic mechanisms play a role in this effect, muscimol or its vehicle was injected into the MR of either control subjects or of rats that had received prior injections of the serotonin-depleting agent p-chlorophenylalanine (PCPA). Although PCPA treatments produced massive depletions of forebrain serotonin, they failed to alter the effect of muscimol infusions on dopamine metabolism. This finding suggests that the effects of intra-MR injections of muscimol on accumbens dopamine turnover do not result entirely from an interaction between serotonergic and dopaminergic systems.