Michael Wu

Injections of dopaminergic, cholinergic, serotoninergic and gabaergic drugs into the nucleus accumbens: effects on locomotor activity in the rat

Abstract Locomotor activity was elicited by injecting dopamine into the nucleus accumbens of the chronically cannulated rat. Dopamine was also injected together with cholinergic, serotoninergic and GABAergic agonists and antagonists to investigate the possible contribution to locomotor activity of these putative neurotransmitters. Carbachol elicited a transient enhancement of dopamine-stimulated activity. Atropine attenuated carbachol-stimulated enhancement but did not attenuate dopamine-stimulated activity. Serotonin attenuated dopamine-stimulated activity. The peripheral serotonin antagonist, methysergide, also attenuated locomotion. The administration of GABA elicited a bimodal response in locomotion, the lower dose eliciting a small increase in locomotion and the larger dose eliciting a reduction. The GABA antagonist, picrotoxin, elicited only increases in locomotion at all doses. These results suggest that there is not a cholinergic interneuron on the dopamine-stimulated pathway subserving locomotion but that both cholinergic and serotoninergic projections may modulate locomotor activity. Further they suggest that such modulation must be at least one inhibitory interneuron away from the dopamine synapse on the locomotor pathway. In addition, these results suggest a direct influence of GABAergic interneurons on the pathway subserving locomotor activity within the nucleus accumbens.

Evidence that projections from substantia innominata to zona incerta and mesencephalic locomotor region contribute to locomotor activity

A series of anatomical, electrophysiological and behavioral experiments was carried out in the rat to investigate the possible functional significance of a recently demonstrated neural pathway from the substantia innominata of the subpallidal forebrain to the mesencephalic locomotor region. Following injections of the anterogradely transported lectin PHA into the substantia innominata labeled fibers with terminal boutons were observed in the zona incerta, dorsal to the medial part of the subthalamic nucleus, and some appeared to continue on to the pedunculopontine nucleus. Electrophysiological recordings of action potentials were made from neurons in the substantia innominata and some of these neurons were activated antidromically by single-pulse stimulation of the zona incerta and/or by single-pulse stimulation of the pedunculopontine nucleus as well. Neurons in the zona incerta responded orthodromically to stimulation of the substantia innominata. Locomotor activity was initiated by injecting picrotoxin, a GABA antagonist, unilaterally into the substantia innominata through chronic cannulae, as reported previously. This picrotoxin-initiated locomotor activity was reduced significantly when procaine (a neuronal blocker) was injected into the ipsilateral zona incerta. Injecting procaine into the contralateral zona incerta had little or no effect on the picrotoxin-initiated locomotor activity. Taken together these observations suggest the tentative working hypothesis that projections from the substantia innominata to the zona incerta as well as the pedunculopontine nucleus may contribute to the locomotor component of adaptive behaviors resulting from limbic forebrain integrative activities, an hypothesis that can now be investigated further.

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.

Locomotor activity initiated by microinfusions of picrotoxin into the ventral tegmental area.

Ambulatory activity in rats was increased in a dose-related manner by microinjections of picrotoxin, a GABA antagonist, bilaterally into the ventral tegmental area. Microinjections of strychnine, a glycine antagonist, had no effect on activity. The ambulatory activity induced by microinjections of picrotoxin into the ventral tegmental area was significantly attenuated when the nucleus accumbens was pretreated with spiroperidol, a dopamine antagonist. These findings provide additional evidence that dopaminergic (A10) neurons projecting from the ventral tegmental area to the nucleus accumbens, contribute to locomotor activity. It is suggested that picrotoxin disinhibits the A10 dopaminergic neurons projecting to the nucleus accumbens.

Ventral pallidum projections to mediodorsal nucleus of the thalamus: an anatomical and electrophysiological investigation in the rat.

Horseradish peroxidase (HRP) and single unit recording experiments were done in rats to investigate neural connections from the ventral pallidal region to the mediodorsal nucleus of the thalamus (MD). In the first series, following the diffusion or iontophoretic injection of HRP into the MD, retrogradely labeled neurons were observed throughout the rostrocaudal extent of the ipsilateral ventral pallidum. Most of the labeled neurons were found in an area between the nucleus of the diagonal band and the ventral aspect of the substantia innominata subcommissuralis. Additional labeled neurons were found in the ventral aspect of the globus pallidus and substantia innominata sublenticularis. In the second series, the region shown to contain labeled neurons was explored for single units antidromically activated by single pulse stimulation of the MD in urethane anesthetized rats. One hundred and fifty-nine single units in the subpallidal area were antidromically activated with latencies corresponding to conduction velocities of 0.2-3.9 m/s. A greater percentage of units in the subcommissural region (50.3%) were activated antidromically as compared to the sublenticular region (27.4%). In the third series, the MD was explored for single units which responded orthodromically to stimulation of the ventral pallidum. Fifty-eight percent (40/69) of MD units responded to stimulation of the subcommissural substantia innominata, whereas 90% (72/80) MD units responded to stimulation of the sublenticular substantia innominata. The most frequent type of orthodromic response observed in MD neurons was inhibition with short onset latencies (less than 10 ms). These data provide anatomical and electrophysiological evidence for the existence of direct pathways from the ventral pallidum to the MD and suggest that this projection is part of a corticosubcortical loop through which the frontal cortex with the ventral striatum and pallidum may contribute to motor function.

Differential effects on locomotor activity of injections of procaine into mediodorsal thalamus and pedunculopontine nucleus

A comparison was made of the contributions to locomotor activity of output projections of the subpallidal region to the mediodorsal thalamus (MD) and to the pedunculopontine nucleus (PPN). Locomotor activity elicited by injections of picrotoxin into the subpallidal region was reduced by the administration of procaine to the pedunculopontine nucleus but not by the administration of procaine to mediodorsal thalamus. Since the pedunculopontine nucleus is part of the mesencephalic locomotor region (MLR) it appears that subpallido-pedunculopontine projections contribute to the locomotor component of adaptive behaviors associated with limbic integrative activities.

Modulation of locomotor activity induced by injections of carbachol into the tegmental pedunculopontine nucleus and adjacent areas in the rat

The pedunculopontine nucleus (PPN) is a major component of the mesencephalic locomotor region. There is little known, however, about neurotransmitters in the PPN associated with locomotor activity. The purpose of the present study was to investigate a possible modulatory effect of the cholinergic system on locomotion. The effects of application of carbachol (CCh) into the PPN on locomotor activity of freely moving rats were studied. Unilateral injections of CCh into the PPN decreased spontaneous locomotor activity of rats. On the other hand, an increase in locomotor activity resulted from CCh injections into sites surrounding the PPN. These CCh-induced changes in locomotion were no longer observed after pretreatment of the PPN with atropine. Locomotor activity induced by injections of amphetamine into the nucleus accumbens was also reduced to control levels by ipsilateral injections of CCh into the PPn, whereas contralateral injections of CCh were ineffective. The results suggest that the muscarinic cholinergic system has a modulatory influence on locomotor activity presumably by affecting PPN cells involved in relaying locomotion-associated signals. The PPN receives signals from higher structures involved in initiation of locomotion while the muscarinic system seems to play a role in attenuation or inhibition of locomotor behaviour.

Subpallidal-pedunculopontine projections but not subpallidal-mediodorsal thalamus projections contribute to spontaneous exploratory locomotor activity

The contribution of the pedunculopontine nucleus to exploratory locomotion was investigated in rats. Locomotor activity recorded in a standard open-field apparatus was increased more than two-fold when wooden panels were inserted. This novelty-elicited locomotion was reduced significantly when procaine was injected bilaterally into the pedunculopontine nucleus but not when procaine was injected bilaterally into the mediodorsal thalamus, a second major projection site of the subpallidal area. These results support observations from earlier studies implicating hippocampal-accumbens-subpallidal-pedunculopontine projections in exploratory locomotion.

Effects of administration of dopamine D2 agonist quinpirole on exploratory locomotion

Injections of the dopamine D2 agonist quinpirole (LY 171555) into the nucleus accumbens reduced exploratory locomotion in a dose-dependent manner. Injections of the dopamine D1 agonist SKF 38393 had no effect on exploratory locomotion. The results are consistent with observations from recent electrophysiological and behavioral experiments which suggest a presynaptic action of the D2 agonist. It is proposed that quinpirole activates D2 receptors on the axon terminals of glutamatergic hippocampal-accumbens neurons that are associated with exploratory locomotion.

Disruption of food hoarding by injections of procaine into mediodorsal thalamus, GABA into subpallidal region and haloperidol into accumbens

The contributions of accumbens-subpallido-mediodorsal thalamus (MD) projections to food hoarding were investigated. The number of food pellets hoarded was reduced by bilateral injections of haloperidol into the accumbens, by bilateral injections of GABA into the subpallidal region and by bilateral injections of procaine into the mediodorsal thalamus. Food hoarding was not reduced by bilateral injections of procaine into the pedunculopontine nucleus. It appears that subpallido-mediodorsal thalamus projections are associated with hoarding behavior but not subpallido-pedunculopontine projections.