Region-specific reductions of intracranial self-stimulation after uncontrollable stress: Possible effects on reward processes

Rates of responding for intracranial self-stimulation from the medial forebrain bundle, nucleus accumbens and substantia nigra were evaluated in mice that had been exposed to either escapable shock, yoked inescapable shock or no shock treatment. Whereas performance was unaffected by escapable shock, marked reductions of responding from the medial forebrain bundle and nucleus accumbens were evident following the uncontrollable shock treatment. Responding from the substantia nigra was unaffected by the stress treatment. Uncontrollable shock is thought to reduce the rewarding value of responding for electrical brain stimulation from those brain regions in which stressors are known to influence dopamine activity.     

Dopaminergic terminal excitability following arrival of the nerve impulse: The influence of amphetamine and haloperidol

Variations in the excitability of the axons and terminal fields of dopaminergic neurons of the substantia nigra were examined as a function of time following the nerve impulse in urethane-anesthetized, immobilized rats. Excitability was measured by determining the threshold, defined as the minimum current required to consistently activate dopaminergic neurons antidromically. Threshold currents were maximal immediately following the action potential and declined exponentially to a plateau. The interval during which threshold current declined, the phasic period, was significantly longer for stimulation of neostriatal terminal fields as contrasted to stimulation of axons along the medial forebrain bundle. A positive correlation was observed between antidromic response latency and the duration of this phasic period for both sites of stimulation, an observation consistent with the view that the site of initiation of the antidromic action potential is of smaller diameter in the neostriatum than in the medial forebrain bundle Amphetamine, which promotes dopamine release and/or re-uptake blockade, reduced dopaminergic terminal excitability in the neostriatum at all intervals examined. This effect increased at successively shorter intervals during the phasic portion of the excitability curve. Haloperidol, a dopamine antagonist, increased the excitability of dopaminergic terminal fields, an effect which was also more marked earlier in the phasic interval. Neither amphetamine nor haloperidol had a significant effect on the excitability of dopaminergic axons in the medial forebrain bundle. Variations in dopaminergic terminal excitability after impulse arrival, and the effects of amphetamine and haloperidol on this phenomenon suggest that terminal excitability is determined by events related to arrival of the nerve impulse including activation of presynaptic 'autoreceptors' by dopamine released from the synaptic ending.     

Utility of a tripolar stimulating electrode for eliciting dopamine release in the rat striatum

The present study evaluated tripolar stimulating electrodes for eliciting dopamine release in the rat brain in vivo. Stimulating electrodes were placed either in the medial forebrain bundle or in the ventral mesencephalon associated with the ventral tegmental area and substantia nigra. The concentration of extracellular dopamine was monitored in dopamine terminal fields at 100-ms intervals using fast-scan cyclic voltammetry at carbon-fiber microelectrodes. To characterize the stimulated area, recordings were collected in several striatal regions including the caudate putamen and the core and shell of the nucleus accumbens. The tripolar electrode was equally effective in stimulating dopamine release in medial and lateral regions of the striatum. In contrast, responses evoked by a bipolar electrode were typically greater in one mediolateral edge versus the other. The added size of the tripolar electrode did not appear to cause complications as signals were stable over the course of the experiment (3 h). Subsets of mesostriatal dopamine neurons could also be selectively activated using the tripolar electrode in excellent agreement with previously described topography. Taken together, these results suggested that the tripolar stimulating electrode is well suited for studying the regulation of midbrain dopamine neurons in vivo.     

Spreading depression in the cortex differently modulates dopamine release in rat mesolimbic and nigrostriatal terminal fields

The effects of cortical spreading depression (SD) on evoked dopamine release in mesolimbic (nucleus accumbens) and nigrostriatal (nucleus caudatus) terminal fields were studied by in vivo voltammetry in anesthetized rats. Dopamine release was evoked by electrical stimulation of medial forebrain bundle (20 Hz, 100 pulses). Local application of 3 M KCl on the dura initiated SD in the cortex. It was found that SD modulated evoked dopamine release in subcortical structures at the same time when the wave of depression of cortical activity reached reciprocally connected subcortical areas. This cortical depression increased stimulated dopamine release in the nucleus accumbens and decreased dopamine release in the nucleus caudatus. In agreement with these results, electrical stimulation of the prefrontal cortex at 20 Hz, synchronized with medial forebrain bundle stimulation, decreased evoked dopamine release in the nucleus accumbens. Areas of the cortex which modulated dopamine release in these two terminal fields were spatially separated by at least 5 mm from each other. It is proposed that depression and activation of evoked dopamine release in the nucleus caudatus and nucleus accumbens following SD are indicative of tonic activation of the nigrostriatal and tonic inhibition of the mesolimbic dopaminergic terminals by cortex in normal conditions. SD in the cortex, modulating neurotransmitter release in subcortical structures, may have a general impact on redistribution of oxygen supply in these subcortical areas and on behavior associated with brain trauma, migraine, insult or seizures, i.e. the kind of neuropathology which may cause SD type phenomena also in human brain.     

Time window of autoreceptor-mediated inhibition of limbic and striatal dopamine release

Forebrain dopamine release is under the local control of D2 family (D2 and D3) autoreceptors. In this study, autoreceptor-mediated modulation of forebrain dopamine release was investigated using amperometry in brain slices following local electrical stimulation. 350 microm-thick slices of nucleus accumbens or dorsolateral neostriatum were prepared from male Wistar rats (150-200 g) and superfused with artificial cerebrospinal fluid at 32 degrees C. Dopamine release was evoked by electrical pulses (0.1 ms, 10 mA) across bipolar tungsten stimulating electrodes and measured at carbon fibre microelectrodes using fixed potential amperometry (+300 mV vs. Ag/AgCl). Peak dopamine release on stimulation (single pulse) was 0.75 microM (neostriatum) and 1.37 microM (nucleus accumbens). Metoclopramide (1 microM) had no significant effect on DA efflux from a single pulse in either region. Using paired pulse stimuli, dopamine release on the second pulse varied according to the interval between the two pulses. At very long intervals (>20 sec), dopamine release was similar to that for the first pulse. At shorter intervals, dopamine efflux was attenuated. Metoclopramide had no effect on second pulse dopamine release when the pulse was applied at short (<0.1 sec) or long (>5.0 sec) intervals after the first. At intermediate intervals, metoclopramide significantly increased second pulse dopamine release. The peak dopamine autoreceptor effect occurred at approximately 550 ms in neostriatum and approximately 700 ms in nucleus accumbens. The onset time is due both to diffusion of dopamine from the release sites to the autoreceptors and receptor-effector mechanisms. These findings may have implications for the local control of forebrain dopamine function in physiological and pathological states.     

Real-time measurement of dopamine release in rat brain

Dopamine release at the submicromolar level has been observed in the striatum of an anesthetized rat on a millisecond time scale. Fast-scan cyclic voltammetry with Nafion-coated microelectrodes has been synchronized with electrical stimulation of the medial forebrain bundle, and synaptic overflow is observed following a burst of 15 impulses. The rapid appearance of dopamine following this stimulus indicates that the source of dopamine is very close (approximately 10 micron) to the electrode. The rapid disappearance of released dopamine reflects the potency of cellular uptake for dopamine. Inhibition of dopamine uptake with nomifensine allows the measurement of dopamine overflow as a result of a single stimulus impulse or with low-frequency stimulations, both comparable to physiological dopaminergic impulse flow.     

Stress-induced increase in extracellular dopamine in striatum: role of glutamatergic action via N-methyl-D-aspartate receptors in substantia nigra

There is considerable support for an influence of excitatory amino acids released from corticofugal neurons on dopaminergic activity in the basal ganglia. However, the relative importance of cortico-striatal and cortico-mesencephalic projections remains unclear, particularly with respect to the nigro-neostriatal pathway. We have therefore examined the influence of endogenous excitatory amino acids in substantia nigra on stress-induced dopaminergic activity in neostriatum. Microdialysis probes were implanted unilaterally into substantia nigra and ipsilateral neostriatum, and dopamine release in neostriatum was monitored by measuring changes in extracellular dopamine. In separate animals, neostriatal dopamine synthesis was assessed by measuring extracellular DOPA in the presence of 3-hydroxylbenzylhydrazine (NSD-1015; 100 microM), an inhibitor of aromatic amino acid decarboxylase. Thirty minutes of intermittent foot shock increased both dopamine release (+41%) and synthesis (+37%) in neostriatum. Infusion of 2-amino-5-phosphonovalerate (APV; 100 microM), an inhibitor of N-methyl-D-aspartate (NMDA) receptors, into substantia nigra greatly attenuated the stress-induced increase in neostriatal dopamine release, while having no effect on the apparent increase in stress-induced dopamine synthesis. These data suggest that excitatory amino acids such as glutamate act on NMDA receptors in substantia nigra to increase striatal dopamine release produced by exposure to stress, but that the increase in dopamine synthesis is mediated through a separate mechanism.     

Gender difference in dopamine concentration and postischemic neuronal damage in neostriatum after unilateral dopamine depletion.

Most neurons in the dorsal neostriatum die 1 day after 30 min of cerebral ischemia. Dopamine may play a role in the pathogenesis of neuronal injury in neostriatum following ischemia. It has been shown that the number of surviving neurons in the right neostriatum dramatically increased following ischemia after lesions were made in the right substantia nigra (SN), whereas no such protective effect was observed in the left neostriatum after left SN lesion. Using a voltammetric technique, the present study measured the dopamine concentration in neostriatum during ischemia after unilateral dopamine depletion and correlated it with the postischemic neuronal damage in neostriatum of male and female rats. In both genders, dopamine concentrations in the neostriatum of the intact side increased to 50-60 microM during ischemia while those of the lesion side were 15-30 microM. No difference in dopamine concentration was detected between animals with lesions in the left SN and those with lesions in right SN. In male rats, the number of surviving neurons in the right neostriatum (approximately 80% as control) was significantly greater than that in the left neostriatum (approximately 20%) after ipsilateral dopamine depletion, whereas in female animals, the number of surviving neurons in the right neostriatum (approximately 40%) was about the same as that in the left neostriatum (approximately 35%) after dopamine depletion. These results indicate that the asymmetry in ischemic outcome after unilateral dopamine depletion in male rats is not due to the difference in residual dopamine in neostriatum. The lateralization of D2 receptors in male rats may be responsible for the asymmetry of survivability of striatal neurons after transient forebrain ischemia.     

Persistence of the releasable pool of CCK in the rat nucleus accumbens and caudate-putamen following lesions of the midbrain

Previous studies have identified populations of dopamine neurons in the midbrain that colocalize cholecystokinin some of which project to the nucleus accumbens and caudate-putamen. The contribution of dopamine-colocalized peptide to the total releasable pool of cholecystokinin in these brain regions was investigated using microdialysis. Dopamine, dihydroxyphenylacetic acid and cholecystokinin immunoreactive levels in dialysates of the posterior medial nucleus accumbens and medial caudate-putamen were determined following 6-hydroxydopamine lesions of the ventral tegmental area and substantia nigra or transection of the medial forebrain bundle. An 89–99% depletion in basal extracellular dihydroxyphenylacetic acid and an 87–99% decrease in veratridine-evoked extracellular dopamine levels was observed in the nucleus accumbens and caudate-putamen, 4 weeks after 6-hydroxydopamine lesion. No statistically significant difference was observed between lesioned and control animals in the basal or veratridine-evoked extracellular level of cholecystokinin immunoreactivity in either region. Similarly, transection of the medial forebrain bundle failed to significantly deplete the releasable pool of cholecystokinin immunoreactivity in the nucleus accumbens or caudate nucleus despite 89–99% depletions of dopamine and its metabolite. These data suggest that midbrain dopamine or non-dopaminergic cells are not the primary source of releasable cholecystokinin in the posterior medial nucleus accumbens and medial caudate-putamen measured by microdialysis.     

Stress-induced increase in extracellular dopamine in striatum: role of glutamatergic action via N-methyl- -aspartate receptors in substantia nigra

There is considerable support for an influence of excitatory amino acids released from corticofugal neurons on dopaminergic activity in the basal ganglia. However, the relative importance of cortico-striatal and cortico-mesencephalic projections remains unclear, particularly with respect to the nigro-neostriatal pathway. We have therefore examined the influence of endogenous excitatory amino acids in substantia nigra on stress-induced dopaminergic activity in neostriatum. Microdialysis probes were implanted unilaterally into substantia nigra and ipsilateral neostriatum, and dopamine release in neostriatum was monitored by measuring changes in extracellular dopamine. In separate animals, neostriatal dopamine synthesis was assessed by measuring extracellular DOPA in the presence of 3-hydroxylbenzylhydrazine (NSD-1015; 100 μM), an inhibitor of aromatic amino acid decarboxylase. Thirty minutes of intermittent foot shock increased both dopamine release (+41%) and synthesis (+37%) in neostriatum. Infusion of 2-amino-5-phosphonovalerate (APV; 100 μM), an inhibitor of N-methyl- -aspartate (NMDA) receptors, into substantia nigra greatly attenuated the stress-induced increase in neostriatal dopamine release, while having no effect on the apparent increase in stress-induced dopamine synthesis. These data suggest that excitatory amino acids such as glutamate act on NMDA receptors in substantia nigra to increase striatal dopamine release produced by exposure to stress, but that the increase in dopamine synthesis is mediated through a separate mechanism.