Jean-Pol Tassin

Blockade by benzodiazepines of the selective high increase in dopamine turnover induced by stress in mesocortical dopaminergic neurons of the rat

The effects of electrical foot shock on the activity of the ascending dopaminergic neurons were estimated in the rat by measuring the changes in DOPAC and DA levels in discrete brain areas. DOPAC and DA levels were estimated with a radioenzymatic method in microdiscs of tissues punched out from serial frontal sections of the brain. A marked rise in the ratio of DOPAC/DA levels resulting from an increase of DOPAC and a decrease of DA levels was found in the cerebral frontal cortex at the end of a 20 min stress. The effect was less pronounced in stress of shorter duration from 3 to 10 min and was only related to a reduction of DA levels. Using the DOPAC/DA ratio as an index of the activity of the neurons, the mesocortical dopaminergic neurons were found to be selectively activated under stress since this ratio was increased in the frontal and cingular cortices but not in limbic structures such as the septum, the amygdala and the nucleus accumbens or in the striatum. Finally, pretreatment of the rats with diazepam (5 mg/kg i.p.) or chlordiazepoxide (10 mg/kg i.p.) prevented the increase in the DOPAC/DA ratio in the frontal cerebral cortex of rats submitted to the 20 min stress.

Relationship between the locomotor hyperactivity induced by A10 lesions and the destruction of the frontocortical dopaminergic innervation in the rat

Bilateral high frequency lesions of the ventral tegmental area (VTA) in the rat induce a behavioral syndrome characterized by a permanent locomotor hyperactivity and a reduction of attention capacities. The VTA contains the cell bodies of the mesocortical and mesolimbic dopaminergic (DA) systems but is also rich in serotoninergic (5-HT) fibers which originate from the raphe nuclei and innervate the forebrain. In order to establish possible correlation(s) between the destruction of specific aminergic system(s) and some of the behavioral effects of VTA lesions, rat locomotor activities were recorded and DA, 5-HT and norepinephrine (NE) were estimated in discrete areas of the forebrain using specific and sensitive radioenzymatic methods. VTA lesions greatly affected DA and 5-HT levels in the forebrain but only induced minor effects on cortical NE. No significant correlations were found between the changes in locomotor activity and the reduction of 5-HT levels in the parietal and rhinal cortices, the striatum and the hippocampus. On the other hand, a very good correlation was observed between the increase in locomotor activity and the decrease in DA content in the frontal cortex (r= −0.82,n= 20, P < 0.01). Although not as striking, a correlation was also found between the changes in locomotor activity and those of DA levels in the nucleus accumbens, a structure innervated by the mesolimbic DA system (r= −0.47,n= 24, P < 0.05). A comparison between changes in DA levels in the frontal cortex and the nucleus accumbens after VTA lesions suggested that cell bodies of the mesocortical and mesolimbic DA systems, although very close, are not the same. It cannot be excluded that the mesolimbic DA system plays a role in the ‘VTA syndrome’. However, it is clear that the disappearance of DA in the frontal cortex is critical for the development of the non-vicarious locomotor hyperactivity. This suggests that the dopaminergic neurons which innervate the frontal cortex exert an inhibitory role on locomotor behavior.

Inhibitory effects of ventral tegmental area stimulation on the activity of prefrontal cortical neurons: Evidence for the involvement of both dopaminergic and GABAergic components

The medial prefrontal cortex of the rat receives dopamine and non-dopaminergic projections from the ventral tegmental area. Both electrical stimulation of the ventral tegmental area and local application of dopamine induce an inhibition of the spontaneous activity of most prefrontal cortical neurons, including efferent neurons. In the present study, the techniques of extracellular recording and microiontophoresis were used in anesthetized rats in order to determine whether these dopamine- and ventral tegmental area-induced inhibitory responses involve GABAergic components. Prefrontal cortex output neurons were identified by antidromic activation from subcortical structures. The inhibitory responses evoked by the local application of dopamine were blocked by the iontophoretic application of the D2 antagonist sulpiride, and the GABAA antagonist bicuculline in 89 and 57% of the cases, respectively. In addition, sulpiride and bicuculline abolished the inhibition induced by ventral tegmental area stimulation in 54 and 51% of the prefrontal cortical cells tested, respectively. The implication of a non-dopaminergic mesocortical system in the ventral tegmental area-induced inhibition was further analysed using rats pre-treated with alpha-methylparatyrosine to deplete dopamine stores. The proportion of prefrontal cortical cells inhibited by ventral tegmental area stimulation was markedly reduced (39%) in alpha-methylparatyrosine-treated rats, when compared to controls (86%). Remaining ventral tegmental area-induced inhibition was no longer affected by sulpiride, but in all cases blocked by the local microiontophoretic application of bicuculline. The present results suggest that: (1) the dopamine-induced inhibition of prefrontal cortex neurons could involve cortical GABAergic interneurones; (2) the non-dopaminergic mesocortical system exerts also an inhibitory influence on prefrontal cortical cells and appears to be GABAergic.

The mesocortico-prefrontal dopaminergic neurons.

The mesocortico-prefrontal dopaminergic neurons represent a dopaminergic subsystem which is distinct from other ascending dopaminergic pathways. Via their inhibitory modulatory influence on cortical efferent neurons, they can indirectly regulate DA transmission in subcortical structures and hence may participate in the control of motor activity, emotional responses and cognitive processes.

Integrity of the mesocortical dopaminergic system is necessary for complete expression of in vivo hippocampal-prefrontal cortex long-term potentiation.

The prefrontal cortex receives dopaminergic inputs from the ventral tegmental area and excitatory inputs from the hippocampus. Both afferent pathways target in close proximity dendritic spines of pyramidal cells in layer V-VI of the prefrontal cortex. In view of the prominent role of dopamine in cognitive functions we examined the effects of ventral tegmental area stimulation on the induction of long-term potentiation in the hippocampal-prefrontal cortex pathway of anesthetized rats. Stimulation of the ventral tegmental area at a frequency known to evoke dopamine overflow in the prefrontal cortex produces a long-lasting enhancement of the magnitude of the hippocampal-prefrontal cortex long-term potentiation. The role of dopamine was further examined by investigating the effects of prefrontocortical dopamine depletion induced by an electrolytic ventral tegmental area lesion. A significant correlation (r = 0.8; P < 0.001; n = 14) was obtained between cortical dopamine levels and cortical long-term potentiation amplitude, a depletion of more than 50% of cortical levels corresponding to a dramatic decrease in hippocampal-prefrontal cortex long-term potentiation. However, a recovery to normal long-term potentiation was observed 1 h after tetanic stimulation. In contrast to the effects on long-term potentiation, ventral tegmental area stimulation, when applied at low or high frequency, decreases the amplitude of the hippocampal-prefrontal cortex postsynaptic synaptic response. The present study demonstrates the importance of the integrity of the mesocortical dopaminergic system for long-term potentiation to occur in the hippocampal-prefrontal cortex pathway and suggests a frequency-dependent effect of dopamine on hippocampal-prefrontal cortex transmission.

Topographical distribution of dopaminergic innervation and of dopaminergic receptors in the rat striatum. I. Microestimation of [3H]dopamine uptake and dopamine content in microdiscs

Topographical variations in the uptake of [3H] dopamine (DA) and in the endogenous content of DA were estimated in the striatum of the rat. For this purpose, microdiscs were punched out in serial 500 mum sections. [3H] DA uptake was measured in 0.25 M sucrose homogenates prepared from microdiscs punched out from frozen slices (--7C). This uptake was similar to that observed in fresh tissues. It was unaffected by desmethylimipramine (5 X 10(-7) M), inhibited by benztropine (10(-6) M) and no longer detectable after 6-hydroxydopamine-induced degeneration of the nigrostriatal dopaminergic pathway. Both [3H] DA uptake and DA content decreased regularly from the rostral to the caudal part of the structure. In contrast, no important differences could be found in the dorso-ventral plane. These results suggest that the extent of dopaminergic innervation is heterogenous within the structure.

Extensive Co-localization of neurotensin with dopamine in rat meso-cortico-frontal dopaminergic neurons

In mammalian brain, dopaminergic (DA) cell bodies located in the ventral mesencephalon give rise to meso-cortical, meso-limbic and meso-striatal systems. Among these, the meso-cortical DA pathway is particularly involved in the processing of emotional and cognitive responses. We demonstrate that the rat meso-cortical neurons specifically contain, in addition to DA, another transmitter, Neurotensin. If this co-localization exists in man, it may provide an anatomical substratum for the biological theory of schizophrenia as well as an indication that potential anti-psychotic drugs which act differentially on the DA ascending transmissions can be developed.

Biochemical investigation on the localization of the cholecystokinin octapeptide in dopaminergic neurons originating from the ventral tegmental area of the rat

Abstract This study was undertaken to verify immunohistochemical data (10,11) which have indicated that a cholecystokinin -like peptide coexists with dopamine (DA) in some neurons of the ventral tegmental area (VTA). For this purpose we examined the effects of bilateral 6-hydroxydopamine (6-OHDA) lesions of the VTA on the contents of the cholecystokinin octapeptide-like immunoreactivity (CCK 8) and DA in the anterior cerebral cortex, the nucleus accumbens and the anterior part of the striatum. Such lesions induced a selective pronounced decrease in CCK 8 levels in the posterior part of the nucleus accumbens similar to that observed for DA, confirming the presence of a composite VTA-nucleus accumbens CCK 8-DA pathway. Although CCK 8 levels in the prefrontal cortex were not affected by 6-OHDA lesions, bilateral electrolytic lesions of the VTA induced a slight significant decrease in CCK 8 levels in this cortical area. This latter result is in favor of the existence of a non-DA pathway containing CCK 8 which originate or pass through the VTA and innervate the ventral part of the prefrontal cortex.

5-HT2A and α1b-adrenergic receptors entirely mediate dopamine release, locomotor response and behavioural sensitization to opiates and psychostimulants

Addictive properties of drugs of misuse are generally considered to be mediated by an increased release of dopamine (DA) in the ventral striatum. However, recent experiments indicated an implication of α1b‐adrenergic receptors in behavioural responses to psychostimulants and opiates. We show now that DA release induced in the ventral striatum by morphine (20 mg/kg) is completely blocked by prazosin (1 mg/kg), an α1‐adrenergic antagonist. However, morphine‐induced increases in DA release in the ventral striatum were found to be similar in mice deleted for the α1b‐adrenergic receptor (α1b‐AR KO) and in wild‐type (WT) mice, suggesting the presence of a compensatory mechanism. This acute morphine‐evoked DA release was completely blocked in α1b‐AR KO mice by SR46349B (1 mg/kg), a 5‐HT2A antagonist. SR46349B also completely blocked, in α1b‐AR KO mice, the locomotor response and the development of behavioural sensitization to morphine (20 mg/kg) and d‐amphetamine (2 mg/kg). Accordingly, the concomitant blockade of 5‐HT2A and α1b‐adrenergic receptors in WT mice entirely blocked acute locomotor responses but also the development of behavioural sensitization to morphine, d‐amphetamine or cocaine (10 mg/kg). We observed, nevertheless, that inhibitory effects of each antagonist on locomotor responses to morphine or d‐amphetamine were more than additive (160%) in naïve WT mice but not in those sensitized to either drug. Because of these latter data and the possible compensation by 5‐HT2A receptors for the genetic deletion of α1b‐adrenergic receptors, we postulate the existence of a functional link between these receptors, which vanishes during the development of behavioural sensitization.

Opposed behavioural outputs of increased dopamine transmission in prefrontocortical and subcortical areas : a role for the cortical D-1 dopamine receptor

The possibility that the dopaminergic neurons innervating the medial prefrontal cortex (mPFC) can inhibit locomotor behaviour has been suggested in several studies. The evidence remains indirect, however, because the manipulations tested aimed exclusively at permanently depleting mPFC dopamine. Here we demonstrate in rats that acute increases in dopamine transmission in this site by local injections of amphetamine inhibit the known locomotor‐activating effects of amphetamine in the nucleus accumbens (N.Acc). Further, intra‐mPFC injections of the D‐1 dopamine receptor antagonist SCH‐23390, but not other dopamine antagonists with greater affinities for noradrenergic, serotonergic and D‐2 dopamine receptors, enhanced the locomotion induced by intra‐N.Acc. amphetamine. These findings provide direct evidence for the inhibition of locomotor activity by mPFC dopamine and suggest that it is acting at D‐1 dopamine receptors in this site.