Search

The acute effects of systemic administration of the anti-obesity agent sibutramine on extracellular dopamine (DA) in the nucleus accumbens of freely moving rats were studied using in vivo microdialysis and compared with the actions of phentermine and d-amphetamine at doses 1x and 3x their respective 2 h ED(50) values to reduce food intake in rats. At the lower dose, sibutramine did not elevate extracellular DA concentrations; however, at the higher dose (6.0 mg kg(-1), i.p.) it caused a modest and prolonged increase in extraneuronal DA. A maximal rise was observed at 60 min post-sibutramine treatment (+231% compared to controls) with DA levels remaining elevated for up to 160 min post treatment. In contrast, phentermine and d-amphetamine significantly enhanced DA efflux at both the lower and higher doses. These elevations of DA levels were significantly greater than that seen with the corresponding dose of sibutramine over 0-80 min post treatment. Maximal rises in DA levels resulting from the higher dose of each drug were +733% (phentermine, 3.9 mg kg(-1), i.p.) and +603% (d-amphetamine, 1.5 mg kg(-1), i.p.) compared to controls 40 min post treatment. The highest doses of phentermine and d-amphetamine increased rat locomotor activity up to 100 min and 160 min post treatment, respectively, whereas the equivalent sibutramine dose had no effect. These findings therefore suggest that dopaminergic reward mechanisms are not involved in the reduction of food intake by sibutramine. Furthermore, they are consistent with the view that sibutramine lacks abuse potential., (Copyright 2000 Wiley-Liss, Inc.)

The acute effects of systemic administration of the antipsychotic drug, zotepine, on extracellular dopamine (DA) in the frontal cortex of freely-moving rats were studied using in vivo microdialysis and compared with the actions of clozapine, olanzapine and haloperidol. Treatment with zotepine (1.0 mg/kg, i.p.) resulted in a prolonged elevation of cortical DA levels for up to 180 min post-drug. A maximal rise of +333% was observed at 120 min post-zotepine treatment. Clozapine (10.0 mg/kg, i.p.) also evoked a rise in extracellular DA which was similar in duration (200 min) to that resulting from treatment with zotepine. A maximal rise of +223% was observed at 100 min post-clozapine treatment. Olanzapine (1.0 mg/kg, i.p.) resulted in an immediate increase in DA levels which was maximal 40 min post-treatment (+280%) with levels returning to pre-injection values by 100 min after dosing. In contrast, haloperidol (0.1 mg/kg, i.p.) had no measurable influence on cortical DA levels. Local perfusion with the NA uptake inhibitor, nisoxetine (10 microM), resulted in an increase in cortical DA levels which was maximal at 100 min post-onset of perfusion (+257% above baseline). Administration of zotepine (1.0 mg/kg, i.p.) during nisoxetine perfusion elevated DA levels to a maximum of +301% above baseline, 60 min post-zotepine. These results show that acute administration of each of three drugs with an atypical antipsychotic profile causes an elevation of cortical DA in freely-moving rats at doses relevant to those derived from animal models which predict antipsychotic activity. As a dysfunction in cortical DA is thought to be involved in both the negative symptoms of schizophrenia and cognitive deficits in schizophrenic patients, it is possible that zotepine's ability to elevate cortical DA levels may underlie its effectiveness in successfully treating these components of schizophrenia. Furthermore, the ability of zotepine to elevate cortical DA is more likely to derive from its inhibition of the NA transporter rather than DA receptor blockade in this region.

1. The influence of (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) on haloperidol-induced increases in the dopamine metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and 4-hydroxy-3-methoxyphenylacetic acid (HVA), was measured in three microdissected brain regions of the rat following a quantitative assessment of catalepsy. 2. Haloperidol alone (2.66 mumol kg-1, i.p.) caused a robust cataleptic response. Given 30 min after haloperidol, 8-OH-DPAT (76 or 760 nmol kg-1, s.c.) prevented catalepsy in 30% and 100% of rats, respectively. 3. Haloperidol significantly increased the DOPAC (by 2 to 4 fold) and HVA (by 3 to 7 fold) contents of the caudate-putamen, nucleus accumbens and medial prefrontal cortex. Given alone, only the lower dose of 8-OH-DPAT caused a significant biochemical change, a doubling of cortical DOPAC. 4. In the cases where catalepsy was prevented by either dose of 8-OH-DPAT, the haloperidol-induced increases in DOPAC and HVA were consistently lower in the caudate-putamen. This pattern was true for the rise in cortical HVA but only in response to the lower dose of 8-OH-DPAT. In contrast, neither dose of 8-OH-DPAT was able to influence the haloperidol-induced rises in cortical DOPAC. In the nucleus accumbens, 8-OH-DPAT did not affect the haloperidol-induced increases in the dopamine metabolites, irrespective of the dose employed or the resulting behaviour. When catalepsy was not prevented, 8-OH-DPAT did not alter the neurochemical responses to haloperidol in any region. 5. These results suggest that part of the mechanism by which 8-OH-DPAT prevents haloperidol-induced catalepsy is reflected by a reversal of the compensatory increase in meso-striatal and/or meso-cortical dopamine neuronal activity that normally accompanies postsynaptic dopamine receptor blockade with haloperidol.

The present study assessed the role of postsynaptic dopamine (DA) receptors in mediating the actions of focal injections of the classical antipsychotic drug, haloperidol, on DA metabolism in the rat amygdala (AMYG) and caudate-putamen (CP) using a high-performance liquid chromatographic assay. One hour after unilateral injection of haloperidol into either site, significant elevations of the DA metabolite, homovanillic acid, were observed in both ipsilateral (+33%) and contralateral (+81%) hemispheres of the CP and in the ipsilateral (+107%) and contralateral AMYG (+121%). Such increased DA metabolism persisted in these regions if focal injections of muscimol (intended to eliminate transmission in postsynaptic output neurones) had been made into either brain area immediately prior to the focal haloperidol injection. It is argued that neurones lying postsynaptic to DA terminals in both the AMYG and CP are unnecessary for the ability of haloperidol to increase DA metabolism in these regions.

The present study investigated the actions of single and repeated injections of the classical antipsychotic drug, haloperidol (1 mg.kg-1 IP), on dopamine (DA) metabolism in three distinct rat brain regions, namely the prefrontal cortex, amygdala and caudate-putamen (CP), using a high-performance liquid chromatographic assay. Acute administration of the drug caused significant elevations in concentrations of two major DA metabolites in all three areas studied. Less marked acute increases were seen in the CP following 10 days of repeated haloperidol treatment. However, in both the prefrontal cortex and the amygdala, the development of such "tolerance" was somewhat delayed in comparison, occurring only after a 22-day treatment schedule. The amygdala displayed the greatest degree of neurochemical tolerance, returning to control values by day 22 of chronic treatment. When allowance was made for the withdrawal effects of antipsychotic drug administration, a genuine tolerance phenomenon was observed in all three areas examined. These data suggest that if neurochemical tolerance is a prerequisite for functional DA receptor blockade and hence therapeutic efficacy, then both the prefrontal cortex and amygdala should be considered as potential therapeutic targets of haloperidol and perhaps antipsychotic drugs in general.

Experiments employing a rodent circling model were conducted to test the predictive capacity of the theory which states that striatonigral gamma-aminobutyrate neurones transmit striatal information influencing the animal's locomotion and orientation. In agreement with this proposal, blocking nerve conduction in one substantia nigra with procaine, or nigral gamma-aminobutyrate receptors with bicuculline administered stereotaxically, frequently forced rats to move ipsiversively to systemic apomorphine, as though the treatment had impaired striatonigral transmission on that side of the brain. Attempts to reverse the direction of apomorphine circling by stimulating gamma-aminobutyrate receptors with muscimol, by facilitating the amino acid's action with flurazepam, or by increasing its synaptic concentration either with a breakdown inhibitor (ethanolamine O-sulphate or 4-amino-hex-5-enoic acid) or an uptake blocker (cis-1,3-aminocyclohexane carboxylic acid) in one nigra, proved unsuccessful. In fact, ethanolamine O-sulphate, flurazepam and muscimol all gave the appearance of hindering rather than enhancing the passage of striatal-derived motor information through the nigra. Broadly speaking, these drugs gave predictable behavioral responses from the ventromedial thalamus, suggesting they were acting in accordance with known mechanisms. The anomalous behaviour with ethanolamine O-sulphate may be attributed to its elevating gamma-aminobutyrate levels in other brain areas, since similar ipsiversive rotations occurred if gamma-aminobutyrate catabolism was prevented at a wide variety of extranigral sites. A simple explanation for the paradoxical ipsiversive behaviours produced by intranigral flurazepam or muscimol in combination with systemic or intracerebral injection of dopamine agonists, is that they act via presynaptic receptors to inhibit the release of endogenous gamma-aminobutyrate and thereby impede striatonigral outflow ipsilaterally.

A neurochemical response of four dopamine-rich brain regions to unilateral electrical stimulation of the parafascicular thalamic nucleus was examined in the halothane-anaesthetized rat. Tissue concentrations of dopamine and its two major metabolites, 3,4-dihydroxyphenylacetic acid and 4-hydroxy-3-methoxyphenylacetic acid, were assayed by a high performance liquid chromatographic technique in samples of caudate-putamen complex, nucleus accumbens, prefrontal cortex and substantia nigra. The ratios of metabolite to parent amine concentrations were taken as indices of dopamine utilization. Halothane anaesthesia alone evoked significant bilateral increases of dopamine utilization in every brain region studied. Electrical stimulation of one parafascicular nucleus produced further bilateral elevations of dopamine utilization in the caudate-putamen complex without altering these parameters in the substantia nigra. In the prefrontal cortex, however, thalamic stimulation resulted in significant bilateral decreases of dopamine utilization. Electrical stimulation of cortical or other thalamic areas did not evoke this regional pattern of dopamine utilization. It is argued that these indices of dopamine utilization together serve as reliable indicators of synaptic dopamine release and it is concluded that the parafascicular thalamus is capable of facilitating dopaminergic neurotransmission in the caudate-putamen by a mechanism that is probably independent of changes in dopamine cell firing rate. An anatomical analysis suggests that a thalamo-cortical-striatal route is most likely to mediate this function.

Infusion of a low dose (5 microM) of the cell-selective chemical excitant quisqualic acid (QUIS) into rostral ventromedial globus pallidus (GP) had no immediate effect on DA utilization (assessed as [DOPAC]:[DA] and [HVA]:[DA] ratios) in either the medial bank of the prefrontal cortex (FCx) or the agranular insular cortex (AgCx). In contrast, a larger dose (630 microM) of another excitant sodium ibotenate (IBO) produced an immediate bilaterally symmetrical increase in both indices of DA utilization in FCx. There was also a marked trend towards a bilateral increase in these indices of DA utilization in AgCx. In order to determine whether these effects on cortical DA utilization are mediated by a direct cortical route or via the thalamic mediodorsal nucleus (lateral division, MDL), infusions of IBO into GP were repeated in animals with a 1-week-old N-methyl-D-aspartate lesion of MDL. The increase in DA utilization of FCx following infusion of IBO into GP was abolished, although the trend towards increased DA utilization in AgCx was still maintained. Since MDL innervates FCx but not AgCx and since we have previously shown that MDL lesions alone have no effect on DA utilization in either cortical region, the present results suggest that the changes in cortical DA utilization are probably mediated via MD. Thus in addition to the well-documented control exerted by the thalamus over brain DA function, this has now been extended in the present study to include GP, which projects both directly and indirectly to the thalamus.

Dopaminergic terminals have been identified in the primary visual cortex with three techniques; immunocytochemistry with an anti-dopamine antiserum, retrograde axonal transport techniques using unconjugated wheat germ agglutinin and HPLC determination of catecholamines and metabolites in microdissected sub-regions of occipital cortex in the rat. The results demonstrate a specific dopaminergic innervation, arising from the ventral tegmental area, which is found mainly in laminae VI and V, but with minor innervation also in lamina I. Dopaminergic innervation to adjacent cortical regions is also described. Neurochemical data from post-mortem human material suggests that a similar innervation exists in man. An analysis of the distribution of dopaminergic fibres in relation to the known connections and possible functions of the deep laminae of visual cortex suggests that dopaminergic axons may participate in the corticofugal control of visual afferent pathways.

Dopamine (DA) utilisation (expressed as homovanillic acid:DA) was compared in the medial prefrontal cortex (FCx), the agranular insular cortex (AgCx), the caudate-putamen (medial, CPM and lateral, CPL divisions) and the nucleus accumbens (NAc). DA utilisation in these regions decreased in the order AgCx greater than FCx greater than CPM, CPL, NAc, whilst the concentration of DA decreased in the reverse order. Thus, although fewer DA neurones appear to innervate AgCx compared with FCx, the rate of DA utilisation/release is much greater in AgCx. It is suggested that this apparently more marked activity in DA neurones innervating AgCx may reflect a relative lack of autoreceptor control.

Stereotaxic injection of muscimol into a restricted region of one substantia nigra of the rat provoked robust circling and a concomitant rise in ipsilateral nigrostriatal dopamine activity, as revealed by a greater accumulation of 3,4-dihydroxyphenylacetic acid and homovanillic acid in the caudate-putamen together with depleted nigral dopamine concentrations. Considered with earlier evidence, these data are taken to indicate that dopamine may be involved in the mediation of this particular rotational behaviour. On the other hand, focal application of bicuculline to the substantia nigra or ventromedial thalamus, or intrathalamic kainate, all evoked a closely similar and vigorous hypermotility (not circling) that could not be correlated with the assorted changes in dopamine utilisation occurring in the substantia nigra, caudate-putamen or nucleus accumbens, either uni- or bilaterally. These changes were therefore probably casually rather than causally related to the mechanisms underlying the behaviour of the animals. Whilst the regional concentrations of noradrenaline were unaltered by these focal drug treatments, the induction of halothane anaesthesia coupled with a unilateral intranigral saline injection produced bilateral elevations in regional dopamine utilisation when assessed 15 min after injection. Such changes were not apparent in tissue taken 30 or 60 min post-injection. We conclude that dopamine cell activity and/or other indices of dopamine utilisation cannot be used to predict the behavioural state of the individual and that an imbalance between the dopamine systems in the two hemispheres does not per se lead to postural or locomotor asymmetry.

We have investigated the role of the parafascicular-intralaminar thalamus in the regulation of dopaminergic function in the caudate-putamen by making unilateral injections of the excitotoxin, ibotenic acid, into the thalamus of the halothane-anaesthetized rat. Dopamine utilization was measured at 4 h, 18 h, and 7 days after operation in microdissected tissue from caudate-putamen, substantia nigra, and nucleus accumbens. High performance liquid chromatography with electrochemical detection was used to simultaneously determine dopamine, 3,4-dihydroxyphenylacetic acid and homovanillic acid. Dopamine utilization was recorded as a ratio of metabolite to its parent amine. At 4 h following injection large bilateral increases in dopamine utilization were recorded in both medial and lateral sectors of caudate-putamen. The percentage increases found for homovanillic acid-based ratios were larger than those found for 3,4-dihydroxyphenylacetic acid-based ratios. These results probably reflect increased dopamine release resulting from the acute effects of ibotenic acid. These changes were independent of dopamine utilization ratios recorded in the substantia nigra, which showed no change either ipsilateral or contralateral to the injection. In contrast to these findings, at 7 days following injection, dopamine utilization ratios were reduced both ipsilateral and contralateral to the injection, although only the ipsilateral reductions were significant. Again, no change was found for this survival time in the substantia nigra. At 18 h survival an intermediate pattern between the 4 h and 7 day result was found. In the nucleus accumbens, ibotenic acid injection produced similar results to those found in caudate-putamen, i.e. a bilateral increase in dopamine utilization at early time intervals and a unilateral ipsilateral decrease at long intervals following injection. These results show that dopamine release in the caudate-putamen is sensitive to experimentally induced changes in neural activity and lesions of its thalamic input. Since the effect of presumed stimulation is markedly greater than lesion, it would appear that, under the conditions employed in these experiments, the thalamus is relatively silent; a suggestion consistent with other evidence. Furthermore, since the changes found occurred in the absence of changes in utilization ratios in the substantia nigra, the mechanisms whereby thalamus regulates dopamine release may be exerted via a local circuit and/or a presynaptic mechanism in the region of dopamine terminals. The anatomical routes responsible for these effects are discussed.(ABSTRACT TRUNCATED AT 400 WORDS)

Dopamine (DA) utilisation has been assessed in the medial bank of the prefrontal cortex (FCx) and the agranular insular cortex (AgCx) of the rat in response to unilateral manipulations of the thalamic mediodorsal nucleus (MD). The ratios of 3,4-dihydroxyphenylacetic acid (DOPAC):DA and 4-hydroxy-3-methoxyphenylacetic acid (homovanillic acid, HVA):DA are used as indices of DA utilisation and were shown to increase in the ipsilateral FCx following electrical stimulation of lateral MD. A similar response was observed 1 hr after an infusion of the excitotoxin sodium ibotenate into lateral MD, although in this case the increase in DA utilisation in FCx was bilateral. Longer periods of recovery after ibotenate treatment (2 day and 1 week) produced DA utilisation ratios that had returned to near control values and by 1 week a significant decrease was detected in HVA:DA of the contralateral FCx. All treatments had little effect on DA utilisation in AgCx, although there was a tendency towards enhanced ratios after electrical stimulation and short-term ibotenate injection. These findings suggest that stimulation of MD neurones may tend to activate the DA system in their convergent terminal regions of cortex. It is argued that these influences result from interactions at the level of the DA terminal rather than at the cell bodies of mesocortical DA neurones.

The effects of unilateral treatments applied to non-dopamine containing output neurones of the thalamic paraventricular nucleus and adjacent midline nuclei (PV-MLT) were observed on dopamine (DA) utilisation of the nucleus accumbens (NAc). The ratios of [metabolite]: [parent amine] were used as indices of DA utilisation. In general, these indices were observed to increase in NAc in a bilaterally symmetrical fashion immediately after infusion of low doses (5 microM) of a cell-selective chemical excitant (quisqualic acid, QUIS) into either rostral or caudal PV-MLT. Moreover, the increases appeared to be entirely due to changes in the tissue content of metabolite. Electrical stimulation of caudal PV-MLT also enhanced DA utilisation ratios in NAc but appeared to do so by decreasing the tissue content of DA itself. Attempts to lesion caudal PV-MLT neurones by infusion of a higher dose of QUIS (50 mM) followed by long-term recovery (7 days) produced ratios of DA utilisation in NAc that were no different from those of controls. DA utilisation ratios in NAc were no different from control values immediately after infusion into caudal PV-MLT of an 'intermediate' dose (10 mM) of another chemical excitant (N-methyl-D-aspartic acid, NMDA). Since DA utilisation ratios in this area were also unaffected by histologically verifiable lesions of caudal PV-MLT neurones produced 7 days after infusion of high doses (100 mM) of NMDA it is argued that the former treatment may lead to an acute firing inactivation of PV-MLT neurones.(ABSTRACT TRUNCATED AT 250 WORDS)

Dopamine receptor binding in the caudate-putamen was studied following bilateral lesions of the thalamostriatal pathway. Receptor binding was assayed using [3H]spiperone and defined with both (+)-butaclamol and S(-)-sulpiride. Radiofrequency lesions resulted in an increase in the Bmax of [3H]spiperone binding defined with both (+)-butaclamol and S(-)-sulpiride between 7 and 14 days following surgery. At longer survival times a fluctuating response was seen in which a decrease in receptor binding was observed at 28 days following lesion and a further rise again at 70 days. At no time point was significant change in Kd recorded. Further experiments were carried out to control for the possible effects of damage to fibres of passage and for inadvertent damage to habenula, as well as to define the receptor subtype involved. Ibotenic acid lesions resulted in similar effects to those reported with the radiofrequency method. Thus, 7 days following lesion, Bmax for (+)-butaclamol-defined [3H]spiperone binding increased by approximately 14-20% over that recorded in sham-lesioned animals. Using S(-)-sulpiride to define binding, Bmax was found to increase 13-17% in the same membrane preparations. Similar results were obtained in experiments at 14 days following ibotenic acid induced lesions. Again, no change in Kd was recorded. When radiofrequency lesions were made, which were largely restricted to habenula and associated fibres of passage, only small [(+)-butaclamol defined] or insignificant [S(-)-sulpiride defined] changes in Bmax were recorded. Combined radiofrequency lesions of habenula and ibotenic acid lesions of the thalamus resulted in a larger increase in Bmax for (+)-butaclamol defined binding than with S(-)-sulpiride defined binding. Our interpretation of these findings, in the light of the histology of the lesions, is that the predominant effect of removing thalamic input to the caudate-putamen is an increase in the number of D2 receptors, but without any change of affinity. A small component of the change in Bmax defined with (+)-butaclamol found with radiofrequency lesions may be due to a response at non-dopamine sites (possibly a 5-hydroxytryptamine receptor subtype) following damage to other caudate-putamen afferents which pass near the habenula or fasciculus retroflexus. Following unilateral ibotenic acid lesions of the thalamus, the number of high affinity uptake sites for dopamine was increased at long survival times.(ABSTRACT TRUNCATED AT 400 WORDS)

Dopamine (DA) utilisation has been determined in the medial bank of the prefrontal cortex (FCx) and the agranular insular cortex (AgCx) of the rat in response to a unilateral reduction of gamma-aminobutyric acid (GABA)-mediated inhibition in the thalamic mediodorsal nucleus (MD). The ratios of 3,4-dihydroxyphenylacetic acid (DOPAC): DA and 4-hydroxy-3-methoxyphenylacetic acid (homovanillic acid, HVA): DA were used as indices of DA utilisation. A bilateral increase in both ratios was found in FCx and AgCx following unilateral infusion of GABA antagonists (1 mM) into MDc. When this concentration was infused into one MDL no change was detected in DA utilisation of FCx, although a bilateral increase was observed in AgCx. However, a correspondence with the known anatomical connections was attained following infusion of lower concentrations (0.5 mM) into MDL in that a significant bilateral elevation of DA utilisation was shown in FCx. The changes induced in these ratios by the above treatments were, in general, due to increases in the concentration of metabolite and slight decreases in that of DA. However, unilateral lesions to the presumed GABA-containing neurones of the rostrodorsal thalamic reticular nucleus (TRNd), which topographically innervate MDL, produced increases in both metabolite and DA concentrations in FCx of both hemispheres, whilst those in AgCx were unaffected. Despite the slightly different results obtained using these two experimental approaches, it is argued that a reduction of tonic GABA-mediated inhibition in MD may tend to activate the DA system in cortical target regions.

Dopamine (DA) utilisation has been assessed in medial and lateral segments of the caudate-putamen complex (CPM and CPL, respectively) in response to unilateral manipulations aimed at the thalamic mediodorsal nucleus, lateral division (MDL). The ratios of 3,4-dihydroxyphenylacetic acid (DOPAC):DA and 4-hydroxy-3-methoxyphenylacetic acid (homovanillic acid, HVA):DA are used as indices of DA utilisation and, in the case of HVA:DA, may also reflect DA release. Neither electrical stimulation nor ibotenate (IBO) treatment followed by long recovery periods (2 days or 1 week) had any significant effect on DA utilisation in CPM or CPL. Cell-specific activation of neurones produced by short-term (1 h recovery) infusions of IBO aimed unilaterally at MDL (right side) resulted in bilateral increases of DA utilisation in both CP sectors. These changes tended to be slightly more marked in the hemisphere ipsilateral to the side of IBO infusion. Unilateral infusions of IBO were then aimed at MDL of either (1) the left or right hemisphere of animals which had already received a 1-week-old unilateral (right side) prefrontal cortex (FCx) lesion or (2) the right hemisphere of animals which had previously received a 1 week-old bilateral FCx lesion. The pattern of changes, when expressed relative to the 'sham-operated' animals which received the FCx lesion alone, were similar to those described above following intra-MDL infusions of IBO into animals with an intact cortex. The FCx lesions themselves were shown to have no significant effect on DA utilisation in any CP sector. In view of the known neuroanatomical connections, it is likely that the effects observed in CP are not due to activation of MDL neurones themselves but are more likely the result of activation of neurones in the intralaminar nuclei which border MDL. Nevertheless, these findings support the concept that activation of thalamic nuclei will enhance DA function in a variety of forebrain areas in the rat.