Behavioural dissociation of the enkephalinergic systems of nucleus accumbens and nucleus caudatus.
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Animals↗
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Alterations of spontaneous neuronal activity in the caudate-putamen, nucleus accumbens and amygdaloid complex of rats produced by D-amphetamine.
Changes in spontaneous neuronal activity in the caudate-putamen, accumbens nucleus and amygdaloid complex of immunobilized, locally anesthetized rats were recorded following intraperitoneal injection of 2.5 mg/kg d-amphetamine sulfate. In each site, d-amphetamine typically produced a prolonged depression of firing rate which, in most cases, occurred after an inital, brief potentiation of activity. However, the onset of the amphetamine-induced depression occurred signficantly later in the amygdala. Subsequent IP administration of either 5.0 mg/kg chlorpromazine or 2.0 mg/kg haloperidol reversed, to varying degrees, the amphetamine-induced depression of neuronal activity in each area. These results are discussed in terms of the known biochemical effects of amphetamine on catecholaminergic transmission and the alleged role of the nigro-neostriatal mesolimbic dopamine systems in the amphetamine behavioral response.
Amygdala↗
Self-stimulation of the nucleus accumbens and ventral tegmental area of Tsai attenuated by microinjections of spiroperidol into the nucleus accumbens.
The contribution of dopaminergic neurons to self-stimulation of the ventral tegmental area, nucleus accumbens and prefrontal cortex was investigated. The ventral tegmental area is the site of non-striatal dopaminergic neurons and their axons project to the nucleus accumbens and prefrontal cortex. Injections of spiroperidol, a dopamine antagonist, into the nucleus accumbens significantly reduced self-stimulation of the ipsilateral ventral tegmental area but did not influence self-stimulation of the contralateral ventral tegmental area. Injections of spiroperidol into the prefrontal cortex did not reduce self-stimulation of the ipsilateral or contralateral ventral tegmental area. Electrical stimulation of sites in the nucleus accumbens positive for self-stimulation antidromically activated neurons of the ventral tegmental area, and a reduction of discharge of these neurons following administration of apomorphine suggested that they were dopaminergic neurons. These observations provide additional evidence implicating dopaminergic neurons in brain-stimulation reward and suggest that dopaminergic neurons contribute to self-stimulation of the nucleus accumbens but not the prefrontal cortex.
Animals↗
Inhibition of prolactin release in conscious sheep following stimulation of nucleus accumbens and caudate nucleus.
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Animals↗
Dopamine-dependent hyperactivity in the rat following manipulation of GABA mechanisms in the region of the nucleus accumbens.
The effect of manipulation of GABA mechanisms in the region of the nucleus accumbens on dopamine-dependent locomotor hyperactivity in the rat has been studied. Two models of hyperactivity were used: (1) the injection of dopamine into the region of the nucleus accumbens in nialamide-pretreated animals and (2) the systemic administration of d-amphetamine. Both GABA and the GABA agonist 3-aminopropane sulphonic acid (3-APS) depressed hyperactivity in a dose-related manner. High concentrations of GABA (greater than 100 micrograms) were required to produce a significant effect and the response was short-lived possibly reflecting the efficient GABA inactivating mechanisms. 3-APS proved to be approximately 10 times more potent as compared to GABA in the dopamine-accumbens hyperactivity model. Conversely GABA receptor antagonism with low doses of either picrotoxin or bicuculline enhanced the mild locomotor response induced by a low dose of dopamine injected into the nucleus accumbens. However such results were difficult to evaluate fairly as higher doses of the GABA antagonists resulted in varying degrees of generalized seizures. Blockade of GABA uptake systems with cis-1, 3-aminocyclohexane carboxylic acid (ACHC), nipecotic acid or beta-alanine within the region of the nucleus accumbens produced dose-related depression of dopamine-dependent hyperactivity in both models. GABA uptake blockade (nipecotic acid) significantly enhanced the GABA-mediated depression of hyperactivity induced by bilateral injection of dopamine into the nucleus accumbens. The results demonstrate an inhibitory action of GABA and drugs facilitating GABA-ergic transmission on dopamine-dependent hyperactivity in the rat. Although open to criticisms of not being able to distinguish between true GABA effects and the results of non-specific neuronal depression the hyperactivity model underlines the potency of the GABA uptake blocking compounds and their possible potential for future clinical use.
Amino Acids↗
Connections of the nucleus accumbens.
Reports from previous works has given different classifications for the nucleus accumbens. There also appears to be a general lack of information regarding the fiber connections of the nucleus. The present investigation was undertaken to clarify the connections of this structure. Silver impregnation methods were used to discern some of the afferent fibers of the nucleus, and autoradiographic techniques were used to locate target areas of efferent projections. Afferents were found to be predominately from the septum. Other sources of possible afferents were the mid cingulate gyrus and the ventral nucleus of the diagonal band. No argyrophilia was observed in the nucleus accumbens following transection of the fornix body, lesions of the anterior orbital frontal cortex or anterior cingulate gyrus. On the basis of grain counts made from autoradiographic studies, the nucleus accumbens projects predominately to the lateral hypothalamus. Counts above background were found in the cingulate gyrus, septum, ventral nucleus of the diagonal band, midline thalamic nuclei, habenula, caudate and substantia nigra. Thus, efferent projections appear to distribute to both limbic and extrapyramidal structures. Considering these connections and the functions reported by various workers the nucleus accumbens may serve as bridge between limbic and extrapyramidal motor systems effecting limbic influence in some movements.
Animals↗
Dopamine metabolism in the nucleus accumbens: the effect of clozapine.
Dopamine metabolism in the nucleus accumbens of the rat was studied by gas chromatographic quantitation of 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). The ratio of DOPAC/HVA in the nucleus accumbens was significantly greater than the same ratio in the striatum. Dose-response curves for the increase in DOPAC and HVA in the nucleus accumbens and striatum 2 h after clozapine were generated. The effect of clozapine on dopamine metabolism was similar in both structures.
3,4-Dihydroxyphenylacetic Acid↗
Effect of thioridazine, clozapine and other antipsychotics on the kinetic state of tyrosine hydroxylase and on the turnover rate of dopamine in striatum and nucleus accumbens.
In rats, a single injection of antipsychotic drugs produced a transitory change in the kinetic state of tyrosine hydroxylase (TH) in striatum and nucleus accumbens. The affinity of TH for 2-amino-4-hydoxy-6,7-dimethyl-5,6,7,8-tetrahydropterine (DMPH4) and the Vmax with respect ot tyrosine were increased. The relative potencies of anti-psychotics to change the kinetics of TH in striatum and nucleus accumbens when injected into rats were measured in the presence of 0.4 mM DMPH4. The doses of methiothepin, pimozide and halopridol which increased the affinity for DMPH4 of striatal TH were lower than those required to produce a similar change in nucleus accumbens. In contrast, thioridazine and clozapine were more effective in nucleus accumbens than in striatum. Chlorpromazine was equally active in these two tissues. Haloperidol increased the turnover rate of dopamine in striatum with doses that are relatively smaller than those required in the nucleus accumbens. Clozapine was more active in increasing turnover rate of dopamine in nucleus accumbens; the activity of chlorpromazine in these two tissues was equal. These results suggest that antipsychotics with high incidence of extrapyramidal side effects affect the nigrostriatal dopaminergic pathway selectively.
Adenylyl Cyclases↗
A functional effect of dopamine in the nucleus accumbens and in some other dopamine-rich parts of the rat brain.
Dopamine (5 to 50 mug) applied bilaterally to the nucleus accumbens of reserpine-nialamide pretreated rats produced a marked dose-dependent rise in coordinated locomotor activity, devoid of stereotypies such as gnawing, rearing and licking seen after dopamine application (50 mug) to the neostriatum. The locomotor activity was completely blocked by pimozide, but not by phenoxybenzamine. The effects of apomorphine or d-noradrenaline was similar to those of dopamine. In contrast, l-noradrenaline produced a "convulsive" syndrome devoid of coordinated locomotor activity, and this convulsive syndrome could be completely blocked by phenoxybenzamine but not by pimozide. Release of endogenous dopamine by d- or l-amphetamine (10 and 50 mug) in the nucleus accumbens produced a rise in coordinated activity, the d-isomer was about 4 times as potent as the l-isomer, and the effect of the d-isomer was blocked completely by alpha-methyltyrosine. Bilateral application of trifluoperazine (2.5 mug) to the nucleus accumbens completely blocked the effect of systemically administered d-amphetamine (1.5 and 3.0 mg/kg), but similar application to the area of the central nucleus of the amygdala or the neostriatum was much less effective. Partial protection of the endogenous dopamine stores against the depleting action of reserpine by local application of metatyramine to the nucleus accumbens resulted in a higher level of basal activity than in control animals. Application of dopamine or noradrenaline to the area of the central nucleus of the amygdala or to the olfactory tubercles did not lead to any consistent changes in locomotor activity. The nucleus accumbens and olfactory tubercles contained most of the dopamine in the limbic forebrain, with noradrenaline more evenly distributed. These data suggest that the nucleus accumbens plays an important role in the locomotor activity in rats.
Amphetamine↗
The effect of long-term ethanol treatment on the sensitivity of the dopamine receptors in the nucleus accumbens.
The effect of local application of dopamine into the nucleus accumbens on locomotor activity was studied in rats during and after withdrawal of long-term ethanol treatment. The bilateral application of dopamine into the nucleus accumbens of both the ethanol and withdrawal rats produced a pronounced increase in coordinated locomotor activity, which was 8-10 times higher than that of untreated water control rats. This effect of dopamine was antagonized by intraperitoneally administered haloperidol indicating a specific effect on dopamine receptors. It is concluded that prolonged ethanol administration may produce an increased sensitivity of the dopamine receptors in the nucleus accumbens and further support the contention that central catecholamine mechanisms are involved in the mediation of the withdrawal syndrome observed after long-term treatment with ethanol.
Animals↗
The effect of long-term penfluridol treatment on the sensitivity of the dopamine receptors in the nucleus accumbens and in the corpus striatum.
The effect of local application of dopamine to the nucleus accumbens or corpus striatum on locomotor activity was studied in rats 4 days after withdrawal from a 6 weeks term of penfluridol medication. The bilateral application of dopamine into the nucleus accumbens of penfluridol-treated rats produced a very marked increase in coordinated locomotor activity which was 3-5 times higher than that of rats not treated with penfluridol. This effect of dopamine in both penfluridol-treated and control rats was antagonized by intraperitoneally administered haloperidol. The bilateral application of dopamine into the corpus striatum of penfluridol-treated animals produced a marked stereotyped behavioural syndrome in all rats studied, whereas no signs of stereotyped behaviour were observed in any of the rats not treated with penfluridol. The results indicate that long-term treatment of rats with the dopamine receptor blocking agent penfluridol produces an increase in the sensitivity of the dopamine receptors in the nucleus accumbens and corpus striatum and that the nucleus accumbens may play a role in locomotor activity.
Animals↗
Studies on the pharmacology of neurones in the nucleus accumbens of the rat.
A study was made of the effects of iontophoretically applied drugs on single neurones in the nucleus accumgens and caudate nucleus of rats anaesthetized with urethane. Neurones in the caudate nucleus were inhibited by dopamine, dibutyryl cyclic AMP, ADTN and ergometrine. Acetylcholine and homocysteic acid caused excitation of striatal neurones. In the nucleus accumbens neurones were inhibited by dopamine, ADTN, ergometrine, dibutyryl cyclic AMP, glycine and gamma-aminobutyric acid. The responses of glycine and gamma-aminobutyric acid were antagonised by strychnine and picrotoxin, respectively. Acetylcholine and homocysteic acid caused excitation of neurones in the nucleus acumbens; the effects of acetylcholine were blocked by atropine. The results are consistent with the suggestion that dopamine is an inhibitory transmitter in the nucleus accumbens and in the caudate nucleus and support the hypothesis that the effects of dopamine are mediated by cyclic AMP. The locomotor stimulants ADTN and ergometrine mimicked the inhibitory actions of dopamine in both the striatum and in the nucleus accumbens. These results support the suggestion that dopamine receptors in the nucleus accumbens are involved in the actions of locomotor stimulant drugs.
Acetylcholine↗
Possible GABA-mediated control of dopamine-dependent behavioural effects from the nucleus accumbens of the rat.
The effect of elevating GABA levels in the region of the nucleus accumbens on various dopamine-dependent behaviours in the rat has been studied. The GABA-transaminase inhibitor, ethanolamine O-sulphate (EOS) was injected bilaterally (through a needle angled at 45 degrees) into the nucleus accumbens. This resulted in a 4-5 fold increase in the GABA concentrations in the mesolimbic areas on day 1, a 2-fold increase on day 3, and a return to normal by day 7. Moderate increases in striatal and cortical GABA levels were also seen on days 1 and 3. At all times animals exhibited normal spontaneous activity and exploratory behaviour in a hold-board apparatus. However, on day 1, when mesolimbic GABA levels were maximal, a low dose of systematically administered amphetamine (0.5 mg/kg) did not induce the increased locomotor activity seen in a control group of animals. Similarly on day 1, the direct injection of dopamine into the nucleus accumbens of rats previously injected with EOS did not evoke the usual hyperactivity response. This response returned to normal on day 7. Apomorphine-induced stereotyped behaviour patterns observed on days 1 and 2 did not significantly differ in those rats previously injected with EOS with animals of a control group. A possible GABA-mediated control of dopaminergic mechanisms in the nucleus accumbens is suggested, and the possible site of interaction discussed.
4-Aminobutyrate Transaminase↗
The effect of electric stimulation of caudate nucleus and nucleus accumbens septi on serotonergic neurons in the rat brain.
Nucleus caudatus--putamen (CP) or nucleus accumbens septi (A) were stimulated electrically for 30 min in free moving rats. Immediately or 30 min after the stimulation we studied the level of 5-HTP and DOPA accumulated in the mesencephalon+pons+medulla oblongata, after inhibition of activity of aromatic amino acids decarboxylase by NSD 1015, and intensity of histofluorescence of serotonin in the midbrain raphe nuclei. The electrical stimulation of either structure did not significantly change the content of 5-HTP and DOPA, but stimulation of nucleus accumbens depressed the level of serotonin in the neurocytes of dorsal and ventral raphe nuclei.
5-Hydroxytryptophan↗
Ergometrine and its biphasic action at dopaminergic receptors in the nucleus accumbens of rats.
Bilateral administration of ergometrine into the nucleus accumbens of rats pretreated 40 min earlier with apomorphine (0.9 mg/kg, s.c.) resulted in a shift from a predominant licking score to a predominant gnawing score. Bilateral administration of ergometrine or (3.4-dihydroxyphenylamino)-2-imidazoline into the brain of rats treated 20 min later with apomorphine (2.0 mg/kg, s.c.) resulted in a shift from a predominant licking and gnawing score to a predominant walking and sniffing score. These and related data suggest a biphasic action at a certain group of dopamine receptors within the nucleus accumbens of rats: a short-term activation and along-term inhibition following this initial activation. The predictive value of the behavioural profile triggered by ergometrine for the evaluation of antidepressant effects of centrally acting drugs is discussed.
Animals↗
Increased utilization of dopamine in the nucleus accumbens but not in the cerebral cortex after dorsal raphe lesion in the rat.
Dihydroxyphenylacetic acid (DOPAC) and dopamine (DA) levels were estimated in the frontal cortex, the nucleus accumbens and the striatum of the rat after electrolytical lesion of the dorsal raphe nucleus. The efficiency of this lesion was tested by measuring the decline in serotonin (5-HT) levels in the striatum. 5-HT levels were reduced by 90% when compared to those of sham-operated rats 11 days after the lesion. As revealed both by the increase in DOPAC levels and in the DOPAC/DA ratio, the rate of DA utilization was markedly increased in the nucleus accumbens, slightly enhanced in the striatum and in contrast remained unaffected in the frontal cerebral cortex 4 days after the lesion. Changes in DOPAC levels in the nucleus accumbens were also seen 11 and 30 days after the lesion but they were less pronounced than those observed at 4 days. These results suggest that neurons originating from the dorsal raphe and projecting to the ventro-tegmental area are regulating the activity of the meso-nucleus accumbens dopaminergic neurons but not that of the meso-cortical dopaminergic neurons.
3,4-Dihydroxyphenylacetic Acid↗
Apparent lack of a dopaminergic-cholinergic link in the rat nucleus accumbens septi-tuberculum olfactorium.
The nucleus accumbens septi and tuberculum olfactorium (NAS-TO), which from part of the mesolimbic dopaminergic system, and the striatum, which is part of the nigrostriatal dopamingeric system, contain high levels of both dopamine (DA) and acetylcholine and resemble each other in some other biochemical properties. We determined whether blockade or stimulation of DA receptors by agonists or antagonists affects the cholinergic neurons in this brain structure. The DA receptor antagonists haloperidol, pimozide, chlorpromazine and clozapine had no effect on the acetylcholine level in the NAS-TO even at 2-8 times the minimum dose required to maximally decrease striatal acetylcholine. Similarly, D-amphetamine and bromocriptine (CB 154), DA receptor stimulating drugs, had no effect on the acetylcholine level in this brain area at doses up to 3 times higher than those that produced a maximum increase in the striatum. Piribedil (15-120 mg/kg) and apomorphine (4 mg/kg) did increase acetylcholine in the NAS-TO but the action was not blocked by pimozide and is therefore not attributable to DA receptor action. The data thus indicate an apparent lack of a dopaminergic-cholinergic link in the NAS-TO.
Acetylcholine↗
Thyrotrophin releasing hormone stimulates release of [3H]-dopamine from slices of rat nucleus accumbens in vitro.
Thyrotrophin releasing hormone (TRH) (25 to 100 microM) was found to stimulate the efflux of [3Hu-dopamine from small slices of rat nucleus accumbens, but not from similar slices of rat caudate nucleus. Uptake inhibition was not responsible for this action, since at 10 and 50 microM TRH had no effect on the ability of small slices of nucleus accumbens to accumulate radioactivity when incubated with 10(-7) M [3H]-dopamine. In addition the hormone had no effect on basal or dopamine-stimulated adenylate cyclase, nor did it displace [3H]-spiperone binding, in membrane preparations from nucleus accumbens.
Adenylyl Cyclases↗