Acute and prolonged effects of ibogaine on brain dopamine metabolism and morphine-induced locomotor activity in rats.

Ibogaine, an indolalkylamine, proposed for use in treating opiate and stimulant addiction, has been shown to modulate the dopaminergic system acutely and one day later. In the present study we sought to systematically determine the effects of ibogaine on the levels of dopamine (DA) and the dopamine metabolites 3,4 dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in tissue at several time points, between 1 h and 1 month post-injection. One hour after ibogaine-administration (40 mg/kg i.p.) a 50% decrease in DA along with a 37-100% increase in HVA were observed in all 3 brain regions studied: striatum, nucleus accumbens and prefrontal cortex. Nineteen hours after ibogaine-administration a decrease in DOPAC was seen in the nucleus accumbens and in the striatum. A week after administration of ibogaine striatal DOPAC levels were still reduced. A month after ibogaine injection there were no significant neurochemical changes in any region. We also investigated the effects of ibogaine pretreatment on morphine-induced locomotor activity, which is thought to depend on DA release. Using photocell activity cages we found that ibogaine pretreatment decreased the stimulatory motor effects induced by a wide range of morphine doses (0.5-20 mg/kg, i.p.) administered 19 h later; a similar effect was observed when morphine (5 mg/kg) was administered a week after ibogaine pretreatment. No significant changes in morphine-induced locomotion were seen a month after ibogaine pretreatment. The present findings indicate that ibogaine produces both acute and delayed effects on the tissue content of DA and its metabolites, and these changes coincide with a sustained depression of morphine-induced locomotor activity.     

Depletion of dopamine in the caudate nucleus but not in nucleus accumbens impairs reaction-time performance in rats

Impairment of the dopaminergic system in the brain induced by dopamine-receptor antagonists or by specific neurotoxin terminal lesions results in motor disturbances in rats. In order to specify further the role of the different dopamine pathways in the brain on motor function, the performance of rats trained in an operant reaction-time task was examined after systemic administration of a dopamine-receptor antagonist, alpha-flupenthixol, and after specific destruction of dopamine neurons by 6-hydroxydopamine perfusion into the nucleus accumbens or caudate nucleus. Rats were trained to press a lever and release it as quickly as possible after a light-cue conditioned stimulus (CS). Reaction time was measured from the CS to the release of the lever for each trial. alpha-Flupenthixol (0.2 and 0.4 mg/kg) injected intraperitoneally impaired the reaction-time performance of the rats. While disruption of dopamine activity in the nucleus accumbens did not affect the performance of the rats, lesions of the dopamine terminals of the nigrostriatal pathway in the corpus striatum (59% decrease in posterior striatal dopamine) significantly impaired reaction-time performance. These results show that moderate decreases in dopamine function restricted to the corpus striatum can disrupt sensitive motor performance, and support the hypothesis that dopamine in the corpus striatum has a role in the initiation of complex goal-directed responses.     

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.     

Suppression of conditioned avoidance behavior by the local application of (-)sulpiride into the ventral, but not the dorsal, striatum of the rat

The local application of (-)sulpiride, 200 ng side-1, into the nucleus accumbens produced a suppression of conditioned avoidance behavior in male rats, 10 and 90 min after injection. The decrease in avoidance behavior was accompanied by a decrease in motor activity, as evidenced by changes in the number of intertrial crosses. When injected into the dorsolateral neostriatum, or the amygdala, (-)sulpiride produced a suppression of conditioned avoidance behavior at the 90-min time interval only. Considering diffusion from the injection site, as indicated by an increase in local dopamine turnover [(DO-PAC + HVA) DA-1], the effects obtained in the dorsolateral neostriatum, and possibly also the amygdala, 90 min after injection could be due to diffusion to the nucleus accumbens. The local application of (-)sulpiride into the posterior neostriatum, or into the prefrontal cortex, produced no statistically significant effect on conditioned avoidance behavior 10 or 90 min after injection. It is concluded that the performance of conditioned avoidance behavior in the rat is critically dependent on an intact dopaminergic neurotransmission in the nucleus accumbens or adjacent areas of the ventral striatum.     

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.     

Behavioural and biochemical effects of dopamine and noradrenaline depletion within the medial prefrontal cortex of the rat

The effects of 6-hydroxydopamine (6-OHDA) lesions of catecholamine terminals within the medial prefrontal cortex on spontaneous motor activity, dopamine (DA)-dependent stereotyped behaviour and subcortical dopamine turnover were investigated in the rat. Two types of lesions were examined, bilateral injection of 6-OHDA into the medial prefrontal cortex of untreated rats (6-OHDA alone), and bilateral injection of 6-OHDA into the medial prefrontal cortex of animals pretreated with the noradrenaline (NA) uptake blocking agent desmethylimipramine (6-OHDA/-DMI). Ten days after surgery the 6-OHDA lesions produced no significant change in spontaneous motor activity and had no overall effects on stereotyped behaviour induced by apomorphine or (+)-amphetamine. This lesion caused gross depletion of NA within the medial prefrontal cortex and curiously, elevated DA concentrations within this site. No changes in DA concentration were recorded within subcortical sites, although concentrations of DA metabolites within striatum and nucleus accumbens were reduced. In contrast, the 6-OHDA/DMI lesion of the medial prefrontal cortex significantly enhanced spontaneous motor activity and amphetamine-induced stereotyped behaviour. Apomorphine-induced stereotypy, on the other hand, was significantly reduced. Biochemically the lesion caused a large depletion of DA with relatively little loss of NA within the medial prefrontal cortex. In addition, from this and another study (ref. 33), increases in DA and its metabolite concentrations were measured in striatum and nucleus accumbens, together with an apparent increased in DA turnover within these subcortical sites. It is thus apparent that in the absence of a substantial portion of the DA innervation of the medial prefrontal cortex, with a largely intact NA innvervation, there is an increase in motor activity and amphetamine-induced stereotypy which may be related to functional changes in DA activity within subcortical telecephalic structures. Such a finding might suggest that DA within the frontal cortex has a behaviourally inhibitory role in the rat, although further work is required to substantiate this.     

Lead exposure and dorsomedial striatum mediation of fixed interval schedule-controlled behavior

Prior studies demonstrate a critical role for mesolimbic dopamine systems, particularly nucleus accumbens, in the mediation of fixed interval (FI) schedule-controlled behavior and an enhancement of nucleus accumbens dopamine activity as a mechanism of chronic postweaning lead (Pb)-induced increases in Fl response rates. Since dorsomedial striatum, like nucleus accumbens, receives limbic input, it could also conceivably contribute to Pb-related effects on FI performance. Therefore, changes in FI schedule-controlled behavior were examined following administration of dopamine or the non-specific irreversible dopamine antagonist N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) into dorsomedial striatum of rats exposed from weaning to 0, 50 or 500 ppm Pb acetate drinking solutions. The 500 ppm exposure increased baseline FI response rates relative to both 0 and 50 ppm. Intra-dorsomedial striatum EEDQ and dopamine had no effects when examined across all animals. However, both compounds produced rate-dependent effects, i.e. increases or decreases in rate in different subjects, depending upon baseline Fl overall rates. The rate-increasing effects of intra-dorsomedial striatum dopamine actually mimicked Pb effects, increasing Fl overall and run rates and shortening postreinforcement pause times. Further, Pb exposure modulated effects of dopamine and EEDQ in dorsomedial striatum. While these collective findings conceivably suggest dorsomedial striatum as another potential site through which postweaning Pb exposure influences FI performance, this possibility is not supported by other studies that show that chronic postweaning Pb alters dopamine binding sites and evoked dopamine release in nucleus accumbens but not in dorsomedial striatum even over a year exposure period. Thus, while both regions may play a role in mediating Fl performance under normal conditions, it appears that alterations in nucleus accumbens dopamine activity may be sufficient to induce chronic postweaning Pb-induced increases in FI response rates.     

Behavioral cross-sensitization between cocaine and enkephalin in the A10 dopamine region

The motor stimulant effect produced by cocaine and the injection of opioids onto A10 dopamine neurons is thought to be mediated by an increase in dopaminergic transmission in mesolimbic dopamine terminal fields such as the nucleus accumbens. Following daily administration, the behavioral stimulant effect of both cocaine and intra-A10 injection of opioids is augmented. The data in this report demonstrate that rats receiving daily injection of enkephalin analogue into the A10 have an enhanced motor stimulant response to intraperitoneal cocaine, but not to saline. Conversely, rats receiving daily injection of intraperitoneal cocaine have an enhanced motor stimulant response to intra-A10 injection of enkephalin analogue.     

Dopamine and homovanillic acid concentrations in striatal and limbic regions of human brain

In an attempt to further define the dopaminergic nature of the limbic nucleus accumbens from the morphologically similar striatal caudate and putamen, the levels of dopamine (DA), homovanillic acid (HVA), and HVA/DA ratios, an index of dopamine turnover, were measured in these three structures of human brain. The levels of dopamine in the accumbens (2.49 ng/mg), caudate (2.39 ng/mg), and putamen (3.00 ng/mg) were similar. The homovanillic acid concentration in the accumbens (7.44 ng/mg) and putamen (6.54 ng/mg) were comparable, while its concentration was considerably lower in the caudatae (3.61 ng/mg). The most striking difference between the limbic accumbens and the striatum was observed in the HVA/DA ratio. This index of turnover was significantly higher in the accumbens (3.64) when compared to the caudate (1.80), and was 59% higher than that found in the putamen (2.53). The data provide evidence for differences in dopamine activity in the mesolimbic versus the nigrostriatal pathways.     

Cortical cholinergic deficiency enhances amphetamine-induced dopamine release in the accumbens but not striatum

Cholinergic dysfunction has been implicated as a putative contributing factor in the pathogenesis of schizophrenia. Recently, we showed that cholinergic denervation of the neocortex in adult rats leads to a marked increase in the behavioral response to amphetamine. The main objective of this study was to investigate if the enhanced locomotor response to amphetamine seen after cortical cholinergic denervation was paralleled by an increased amphetamine-induced release of dopamine in the nucleus accumbens and/or striatum. The corticopetal cholinergic projections were lesioned by intraparenchymal infusion of 192 IgG-saporin into the nucleus basalis magnocellularis of adult rats. Amphetamine-induced dopamine release in the nucleus accumbens or striatum was monitored by in vivo microdialysis 2 to 3 weeks after lesioning. We found that cholinergic denervation of the rat neocortex leads to a significantly increased amphetamine-induced dopamine release in the nucleus accumbens. Interestingly, the cholinergic lesion did not affect amphetamine-induced release of dopamine in the striatum. The enhanced amphetamine-induced dopamine release in the nucleus accumbens in the cholinergically denervated rats could be reversed by administration of the muscarinic agonist oxotremorine, but not nicotine, prior to the amphetamine challenge, suggesting that loss of muscarinic receptor stimulation is likely to have caused the observed effect. The results suggest that abnormal responsiveness of dopamine neurons can be secondary to cortical cholinergic deficiency. This, in turn, might be of relevance for the pathophysiology of schizophrenia and provides a possible link between cholinergic disturbances and alteration of dopamine transmission.     

Injection of the protein kinase C inhibitor Ro31-8220 into the nucleus accumbens attenuates the acute response to amphetamine: tissue and behavioral studies

The ability of amphetamine to produce heightened locomotor activity is thought to be due to its ability to enhance dopamine release from mesolimbic dopamine neurons. The mechanism by which amphetamine increases dopamine release is not well understood, but is thought to involve exchange diffusion with synaptosomal dopamine through the dopamine transporter. We recently reported that amphetamine-mediated dopamine release in the striatum is also dependent on protein kinase C activity. In the current study, we investigated the role of protein kinase C activity in the acute neurochemical and behavioral response to amphetamine in the nucleus accumbens. Consistent with previous results in the striatum, amphetamine-stimulated dopamine release from nucleus accumbens tissue was inhibited by the specific protein kinase C inhibitor Ro31-8220, but not by the relatively inactive analog bisindoylmaleimide V. In addition, the effects of protein kinase C activity on the acute behavioral response to amphetamine was examined by injecting Ro31-8220 into the nucleus accumbens 15 min prior to intra-accumbens amphetamine. Pretreatment with Ro31-8220 attenuated the motor-stimulant effects of intra-accumbens amphetamine relative to control subjects pretreated with vehicle. Bisindoylmaleimide V did not significantly inhibit the motor-stimulant effects of intra-accumbens amphetamine. These results suggest that the action of amphetamine in the nucleus accumbens in increasing dopamine release and locomotor activity is dependent on protein kinase C activity.     

Microinjection of cocaine into the nucleus accumbens elicits locomotor activation in the rat

Cocaine is believed to exert its psychostimulant effects through activation of the mesocorticolimbic system. Although the nucleus accumbens, in particular, has been hypothesized as the site of action of cocaine's stimulating effects, there is no direct evidence that microinjection of cocaine into this region produces behavioral activation. The present experiments investigated the locomotor response to microinjection of cocaine (0, 10, 30, 100 micrograms/0.5 microliter) into the nucleus accumbens in rats. Cocaine elicited a pronounced, dose-dependent motor activation of approximately 60 min duration. This stimulant effect was blocked by prior administration of a dopamine (DA) receptor antagonist, cis-flupenthixol. The response to cocaine was differentiated from nucleus accumbens microinjections of procaine and lidocaine, compounds that have potent local anesthetic effects but little affinity for the dopamine-uptake site. Neither procaine nor lidocaine (0, 10, 30, 100 micrograms/0.5 microliter) had any overall effect, although activity was somewhat decreased in the initial part of the test session and increased at the end, relative to control activity. Cocaine injected into the anterior dorsal or ventrolateral striatum (100 micrograms) also increased motor activity; procaine and lidocaine had no effect. Cocaine injected into the ventrolateral striatum significantly increased stereotypy. The amplitude of motor activation following cocaine injection into nucleus accumbens was much greater than that elicited at the other striatal sites. Further, observation of the time course of motor activation following cocaine injection into the anterior dorsal and ventrolateral striatum suggested that the motor effect was due to diffusion, most likely to the nucleus accumbens.(ABSTRACT TRUNCATED AT 250 WORDS)     

Lesions of the superior colliculus in the rat differentiate between nigrostriatal and mesolimbic dopamine systems

Bilateral electrolytic lesions of the superior colliculus in rats increased spontaneous locomotor activity, enhanced amphetamine-induced hyperactivity and attenuated apomorphine-induced biting. These lesions were associated with an increased rate of turnover of dopamine in the nucleus accumbens, but not in the striatum. Similarly concentrations of the dopamine metabolites homovanillic acid and 3,4-dihydroxyphenylacetic acid were elevated in accumbens tissue but not in striatum in rats with bilateral collicular lesions. The results indicate that lesions of the superior colliculus cause differentiation between hyperactivity and stereotypy, and that this may be related to blockade of a nigrostriatal outflow, and relief of inhibition on mesolimbic systems.     

Effects of Nicotine and Footshock Stress on Dopamine Release in the Striatum and Nucleus Accumbens

We have used a microdialysis technique to analyze the effects of nicotine administration on the release of dopamine in the striatum and the nucleus accumbens (NAC) in rats under footshock stress. In the striatum, neither chronic systemic nicotine administration alone nor stress alone changed the extent of dopamine release. During stress application, however, chronic nicotine administration significantly increased dopamine release. In the NAC, stress did not induce increase in dopamine release in rats given nicotine chronically. However, in rats subjected to stress alone, dopamine release in the NAC was significantly increased after stress. In the striatum, the local infusion of 1.0 mM nicotine increased dopamine release. Furthermore, stress significantly increased nicotine-induced dopamine release. The local infusion of 1.0 mM nicotine into the NAC significantly increased dopamine release, but the levels returned to the baseline 30 min later. On the other hand, stress alone induced the release of dopamine 30 min later and the combination of stress and nicotine induced the release of dopamine during the stress and the effects lasted for 30 min. These results suggest that the responses of nicotine-induced dopamine release were different in the striatum and in the NAC under the stress. Stress and nicotine (systematically or locally administered) induced an immediate effect on dopamine release in the striatum, but in the nucleus accumbens stress alone and the combination of stress and nicotine induced a lasting release of dopamine (DA).     

Neurotensin increases extracellular striatal dopamine levels in vivo.

This study employed intracranial microdialysis to assess the effects of neurotensin (NT) infusion on extracellular dopamine (DA) and DA metabolite concentrations in the rat striatum and nucleus accumbens, and the effects of NT on alterations in extracellular DA levels induced by cocaine and the DA D-2 receptor agonist, quinpirole. Direct NT infusion (.10, 1.0, 10.0 microM) did not significantly affect extracellular DA in the nucleus accumbens, but did produce a significant increase in the DA metabolite homovanillic acid (HVA). In contrast, direct NT infusion produced an increase in striatal DA levels, without altering DA metabolites. Neurotensin infusion (.10 microM) into the striatum significantly attenuated the peak DA increase induced by an intraperitoneal (IP) injection of a low dose (10.0 mg/kg) but not a high dose (30.0 mg/kg) of cocaine. Neurotensin infusion (.10 microM) did not affect the decrease in DA and its metabolites induced by an IP injection of a low dose of quinpirole (.03 mg/kg), but did alter the decrease in HVA induced by a high dose of quinpirole (.10 mg/kg). These results suggest that NT differentially affects in vivo DA release in the striatum and nucleus accumbens, and further strengthens the assertion that NT is an important modulator of dopaminergic function.     

Differential tonic influence of lateral habenula on prefrontal cortex and nucleus accumbens dopamine release

Conditions of increased cognitive or emotional demand activate dopamine release in a regionally selective manner. Whereas the brief millisecond response of dopamine neurons to salient stimuli suggests that dopamine's influence on behaviour may be limited to signalling certain cues, the prolonged availability of dopamine in regions such as the prefrontal cortex and nucleus accumbens is consistent with the well described role of dopamine in maintaining motivation states, associative learning and working memory. The behaviourally elicited terminal release of dopamine is generally attributed to increased excitatory drive on dopamine neurons. Our findings here, however, indicate that this increase may involve active removal of a tonic inhibitory control on dopamine neurons exerted by the lateral habenula (LHb). Inhibition of LHb in behaving animals transiently increased dopamine release in the prefrontal cortex, nucleus accumbens and dorsolateral striatum. The inhibitory influence was more pronounced in the nucleus accumbens and striatum than in the prefrontal cortex. This pattern of regional dopamine activation after LHb inhibition mimicked conditions of reward availability but not increased cognitive demand. Electrical or chemical stimulation of LHb produced minimal reduction of extracellular dopamine, suggesting that in an awake brain the inhibition associated with tonic LHb activity represents a near-maximal influence on dopamine neurotransmission. These data indicate that LHb may be critical for functional differences in dopamine neurons by preferentially modulating dopamine neurons that project to the nucleus accumbens over those neurons that primarily project to the prefrontal cortex.     

Differential responses in central dopaminergic activity induced by apomorphine in IPL nude rat

The IPL nude rat, derived by spontaneous mutation from the Sprague-Dawley strain, presents alterations in the prolactin synthesis and secretion due to an increased dopaminergic inhibition. However, there are no reports concerned to central dopamine activity. The corpus striatum is a brain area involved in the development of stereotyped behavior after the activation of mesolimbic and/or nigro-striatal dopamine pathways. In order to identify possible mesolimbic and/or nigro-striatal dysfunctions in the IPL nude rat, we study the spontaneous oral behaviors and the effects of apomorphine-induced dopaminergic activation on stereotyped behavior and neurochemical changes. Males from both strains were injected with saline or apomorphine (2 and 5 mg/kgs.c.) and evaluated during 30 min in a stereotypes oral tests. The corpus striatum and nucleus accumbens were used to measure dopamine (DA), 3,4-dihydroxyphenylalanine (DOPA) and 3,4-dihydroxyphenylacetic acid (DOPAC) by HPLC. The concentrations were expressed as synthesis rate (DA/DOPA) and turnover rate (DOPAC/DA). We observed that the spontaneous gnaw movements were significantly different between the untreated IPL nude and Sprague-Dawley (SD) rats. Apomophine injection decreased the amount of stereotyped gnawing in IPL nude rats at the two doses used, but it induced an increase in SD rats. Apomorphine also caused an enhancement in the number of biting and sniffing without modifying the licking behavior. In addition, modifications of the dopaminergic activity were also observed. Synthesis rate in the striatum of IPL nude rats was higher than in SD rats after the injection of saline. Apomorphine caused a reduction of the synthesis rate in both strains. Turnover rate was significantly lower in the striatum of IPL nude rats than in the SD rats injected with saline. Apomorphine caused an increase in the turnover rate in both strains. Contrary to observed in the striatum, the 2 mg/kg dose of apomorphine caused a significant increase in the DA synthesis rate in nucleus accumbens, while 5 mg/kg decrease it in both strains. The DA turnover rate in the same area was lower in IPL nude than in SD rats after saline injection. Apomorphine enhances the DA turnover rate in both strains. We conclude that the modifications of the oral spontaneous and induced stereotypical patterns observed in the IPL nude rats could be related to the differential responses in dopaminergic activity in the two brain areas examined.     

Action of apomorphine,bromocriptine and lergotrile onγ-aminobutyric acid and acetylcholine release in nucleus accumbens and corpus striatum

The effect of three dopamine agonists, apomorphine, bromocriptine and lergotrile, was tested on the release of gamma-aminobutyric acid, (GABA) and acetylcholine (ACh) from tissue slices of rat nucleus accumbens and striatum. All three agents in vitro caused a dose dependent depression of the K+-evoked release of [14C]-GABA in corpus striatum. This effect was also obtained following in vivo drug application and when endogenous GABA release was determined. A similar depression of GABA release was obtained in the nucleus accumbens. Both dopamine and dibutyryl adenosine-3':5'-cyclic monophosphoric acid inhibited the K+-evoked release of [14C]-GABA in corpus striatum. This inhibitory effect was not reversed by sulpiride. Bromocriptine and lergotrile also depressed the K+-evoked release of [3H]-acetylcholine from tissue slices of corpus striatum but not nucleus accumbens, as has previously been demonstrated for dopamine and apomorphine. In contrast, sulpiride enhanced the release of [3H]-acetylcholine and molindone reversed the apomorphine inhibition of [3H]-acetylcholine release. These results indicate that dopaminergic agents may influence the release of both GABA and ACh in the corpus striatum but only GABA in the nucleus accumbens.     

Chronic desipramine treatment selectively potentiates somatostatin-induced dopamine release in the nucleus accumbens

Dopamine and somatostatin have been implicated in the pathophysiology of depression. We have employed in vivo microdialysis to investigate the regulation of dopamine release by somatostatin in the nucleus accumbens and the striatum of awake, freely moving rats, and to ascertain how this regulation may be affected by desipramine treatment. Somatostatin-14 (10(-4) M) infusion induced an increase in the release of dopamine and a decrease in the release of its metabolites in both the nucleus accumbens (568% of basal) and the striatum (546% of basal). Chronic desipramine treatment resulted in an exaggerated somatostatin-induced increase of dopamine levels, specifically in the nucleus accumbens (3542% compared with 564% of basal in the striatum), whereas acute desipramine treatment had no effect (582% of basal) compared with saline treated rats. Basal concentrations of dopamine and metabolites were not influenced by either chronic or acute treatment of desipramine in either brain area. These results demonstrate that somatostatin regulates dopamine release in the nucleus accumbens and the striatum. Chronic antidepressant treatment influences somatostatin's actions on dopamine function selectively in the nucleus accumbens.     

Evidence for, and nature of, the tonic inhibitory influence of habenulointerpeduncular pathways upon cerebral dopaminergic transmission in the rat

The potential role of the habenula in the transsynaptic regulation of the activity of ascending dopaminergic systems has been investigated in the rat by studying the effect of an acute interruption of impulse traffic in the diencephalic conduction system (stria medullaris-habenula-fasciculus retroflexus) and of pharmacological manipulation of various neurotransmitter systems in the interpeduncular nucleus on dopamine metabolism in several dopaminergic projection fields. The bilateral infusion of tetrodotoxin into the fasciculus retroflexus (which conveys the habenulointerpeduncular tract) of conscious rats markedly increased homovanillic acid levels and dopamine synthesis and utilization in the medial prefrontal cortex, nucleus accumbens, olfactory tubercle and striatum. Similar changes in dopamine metabolism were observed in these areas after bilateral infusion of tetrodotoxin into the stria medullaris (which conveys most of the afferents to the habenula). Infusion of atropine (0.4-1 micrograms) into the interpeduncular nucleus increased homovanillic acid concentrations and dopamine utilization in the medial prefrontal cortex and nucleus accumbens but not in the olfactory tubercle and striatum. Moreover, intra-interpeduncular injection of oxotremorine (17 micrograms) antagonized the increase in dopamine utilization in the nucleus accumbens (but not in the olfactory tubercle) induced by an intrafasciculus retroflexus infusion of tetrodotoxin. Local infusion of naloxone (20 micrograms) into the interpeduncular nucleus increased homovanillic acid concentrations in the nucleus accumbens and olfactory tubercle but not in the medial prefrontal cortex and striatum. In contrast, intra-interpeduncular nucleus infusion of the substance P antagonist D-Arg1, D-Pro2, D-Trp7,9, Leu11-substance P or of substance P antiserum failed to alter homovanillic acid levels in the 4 dopamine-rich areas investigated. Finally, intraraphé medianus (but not intraraphé dorsalis) infusion of muscimol (25 ng) moderately increased dopamine synthesis in the nucleus accumbens and striatum. The present findings suggest that the habenulointerpeduncular pathways exert a tonic inhibitory influence on mesocortical, mesolimbic and mesostriatal dopaminergic neurons. Cholinergic and/or opioid peptidergic neurons coursing through the fasciculus retroflexus as well as ascending serotonergic neurons originating in the raphé medianus could take part in this inhibitory control of ascending dopaminergic neurons.