David N. Ruskin

Correlated multisecond oscillations in firing rate in the basal ganglia: modulation by dopamine and the subthalamic nucleus.

Previous studies from this laboratory have shown that many neurons in the basal ganglia have multisecond (<0.5 Hz) periodicities in firing rate in awake rats. The frequency and regularity of these oscillations are significantly increased by systemically injected dopamine (DA) agonists. Because oscillatory activity should have greater functional impact if shared by many neurons, the level of correlation of multisecond oscillations was assessed by recording pairs of neurons in the globus pallidus and substantia nigra pars reticulata in the same hemisphere, or pairs of globus pallidus neurons in opposite hemispheres in awake, immobilized rats. Cross-correlation (90-180 s lags) and spectral analysis were used to characterize correlated oscillations. Thirty-eight percent of pairs recorded in baseline (n=50) demonstrated correlated multisecond oscillations. Phase relationships were near 0 or 180 degrees. DA agonist injection significantly increased the incidence of correlation (intra- and interhemispheric) to 94% (n=17). After DA agonist injection, phase relationships of globus pallidus/substantia nigra neuron pairs were exclusively concentrated near 180 degrees, and phases of interhemispheric pairs of globus pallidus neurons were concentrated near 0 degrees. After subthalamic nucleus lesion (n=8), the incidence of correlated multisecond oscillations (or of multisecond oscillations per se) was not changed, although the consistent phase relationship between the globus pallidus and substantia nigra pars reticulata was disrupted. Subthalamic lesion also blocked apomorphine-induced decreases in oscillatory period and increases in oscillation amplitude, and significantly attenuated apomorphine-induced changes in mean firing rate. The data demonstrate that multisecond oscillations in the basal ganglia can be correlated between nuclei, and that DA receptor activation increases the level of correlation and organizes internuclear phase relationships at these multisecond time scales. While the subthalamic nucleus is not necessary for generating or transmitting these slow oscillations, it is involved in DA agonist-induced modulation of mean firing rate, oscillatory period, and internuclear phase relationship. These data further support a role for DA in modulating coherent oscillatory activity in the basal ganglia, and for the subthalamic nucleus in shaping the effects of DA receptor stimulation on basal ganglia output.

Pre- and postsynaptic aspects of dopamine-mediated transmission

Dopamine agonist administration induces changes in firing rate and pattern in basal ganglia nuclei that provide an insight into the role of dopamine in basal ganglia function. These changes support a more complex, integrated basal ganglia network than envisioned in early models. Functionally important effects on basal ganglia output involve alterations in burstiness, synchronization and oscillatory activity,as well as rate. Multisecond oscillations in basal ganglia firing rates are markedly affected by systemic administration of dopamine-receptor agonists. This suggests that coordinated changes in neuronal activity at time scales longer than commonly investigated play a role in the cognitive and motor processes that are modulated by dopamine.

Dopamine agonist-mediated rotation in rats with unilateral nigrostriatal lesions is not dependent on net inhibitions of rate in basal ganglia output nuclei

Current models of basal ganglia function predict that dopamine agonist-induced motor activation is mediated by decreases in basal ganglia output. This study examines the relationship between dopamine agonist effects on firing rate in basal ganglia output nuclei and rotational behavior in rats with nigrostriatal lesions. Extracellular single-unit activity ipsilateral to the lesion was recorded in awake, locally-anesthetized rats. Separate rats were used for behavioral experiments. Low i.v. doses of D1 agonists (SKF 38393, SKF 81297, SKF 82958) were effective in producing rotation, yet did not change average firing rate in the substantia nigra pars reticulata or entopeduncular nucleus. At these doses, firing rate effects differed from neuron to neuron, and included increases, decreases, and no change. Higher i.v. doses of D1 agonists were effective in causing both rotation and a net decrease in rate of substantia nigra pars reticulata neurons. A low s.c. dose of the D1/D2 agonist apomorphine (0.05 mg/kg) produced both rotation and a robust average decrease in firing rate in the substantia nigra pars reticulata, yet the onset of the net firing rate decrease (at 13-16 min) was greatly delayed compared to the onset of rotation (at 3 min). Immunostaining for the immediate-early gene Fos indicated that a low i.v. dose of SKF 38393 (that produced rotation but not a net decrease in firing rate in basal ganglia output nuclei) induced Fos-like immunoreactivity in the striatum and subthalamic nucleus, suggesting an activation of both inhibitory and excitatory afferents to the substantia nigra and entopeduncular nucleus. In addition, D1 agonist-induced Fos expression in the striatum and subthalamic nucleus was equivalent in freely-moving and awake, locally-anesthetized rats. The results show that decreases in firing rate in basal ganglia output nuclei are not necessary for dopamine agonist-induced motor activation. Motor-activating actions of dopamine agonists may be mediated by firing rate decreases in a small subpopulation of output nucleus neurons, or may be mediated by other features of firing activity besides rate in these nuclei such as oscillatory firing pattern or interneuronal firing synchrony. Also, the results suggest that dopamine receptors in both the striatum and at extrastriatal sites (especially the subthalamic nucleus) are likely to be involved in dopamine agonist influences on firing rates in the substantia nigra pars reticulata and entopeduncular nucleus.

Cocaine or Selective Block of Dopamine Transporters Influences Multisecond Oscillations in Firing Rate in the Globus Pallidus

Previous studies have shown that direct-acting dopamine agonists modulate the multisecond oscillations which are present in globus pallidus spike trains in vivo in awake rats. To investigate possible modulation by endogenous dopamine and by other monoamines, and by drugs with abuse potential, cocaine or selective monoamine uptake blockers were injected systemically during extracellular recording of single globus pallidus neurons and the results analyzed with spectral and wavelet methods. Both cocaine and the selective dopamine uptake blocker GBR-12909 significantly shortened the period of multisecond oscillations, as well as increasing overall firing rate. Cocaine effects were blocked by dopamine antagonist pretreatment, as well as by N-methyl-D-aspartate receptor antagonist (MK-801) pretreatment. Desipramine and fluoxetine (blockers of norepinephrine and serotonin uptake, respectively) had no significant effects on multisecond oscillations. The results suggest that dopamine has a primary role among monoamines in modulating multisecond oscillations in globus pallidus activity, and that tonic dopaminergic and glutamatergic transmission is necessary for normal slow oscillatory function.

N-methyl-D-aspartate receptor blockade attenuates D1 dopamine receptor modulation of neuronal activity in rat substantia nigra

It has been proposed that dopamine and glutamate affect basal ganglia output, in part, through interactions between D1 receptors and NMDA receptors. The present study examined whether N‐methyl‐D‐aspartate (NMDA) receptor antagonists affect the neurophysiological responses of substantia nigra pars compacta (SNpc; dopaminergic) and pars reticulata (SNpr; non‐dopaminergic) neurons to a systemically administered D1 dopamine agonist in two animals models of Parkinsons disease, reserpine treatment and nigrostriatal lesion. Previous studies using extracellular single unit recording techniques have shown that the D1 dopamine agonist SKF 38393 (10 mg/kg) exerts different effects on the firing rates of SNpr neurons after these two dopamine‐depleting treatments, suggesting the involvement of multiple mechanisms. SKF 38393 consistently increased the firing rates of SNpr neurons in rats treated subchronically with reserpine, and markedly decreased SNpr firing rates in rats with nigrostriatal damage. Pretreatment with the non‐competitive NMDA antagonist MK‐801 (0.15 mg/kg i.v.) blocked, and the competitive NMDA antagonist (±)‐CPP (30 mg/kg i.p.) attenuated, the rate effects of SKF 38393 in both dopamine‐depleted preparations. SKF 38393 consistently inhibited the firing rate of SNpc dopamine neurons after acute reserpine treatment (10 mg/kg, 4–7 hours), an effect specifically mediated by D1 receptors. Pretreatment with MK‐801 (0.1 mg/kg i.v.) or the competitive NMDA antagonist (+)‐HA‐966 (30 mg/kg i.v.) also effectively attenuated SKF 38393s inhibitory effect on SNpc dopamine neurons. Therefore, NMDA receptor blockade markedly reduces the ability of D1 receptor stimulation to modulate firing rates of both dopaminergic and non‐dopaminergic cells in the substantia nigra. Although multiple mechanisms appear to underlie D1‐mediated effects on substantia nigra firing rates in reserpine and 6‐OHDA‐treated rats, these results demonstrate a common dependence on glutamatergic transmission and a permissive role for NMDA receptor activation in the ability of D1 receptor stimulation to both enhance and reduce neuronal activity in the substantia nigra. Synapse 30:18–29, 1998. Published 1998 Wiley‐Liss, Inc.

Effects of Dopamine Receptor Stimulation on Basal Ganglia Activity

The importance of dopamine in the regulation of basal ganglia function and the control of movement has been appreciated for several decades. In the mid 1960s, histochemical studies established the presence of a dopaminergic nigrostriatal pathway, and neuropathological investigations demonstrated a correlation between dopamine cell loss and Parkinsons disease (PD) (Anden et al., 1964; Dahlstrom and Fuxe, 1964; Hornykiewicz, 1966; Poirier and Sourkes, 1966). In the intervening years, a large body of research has provided support for dopamines critical role in a range of cognitive and motor functions. In particular, evidence that changes in dopamine receptor stimulation can affect the balance between hypoand hyperkinetic states has led to considerable interest in how dopamine receptor stimulation ultimately modulates basal ganglia output to permit effective motor control. One strategy for gaining insight into how dopamine-mediated transmission regulates activity in the basal ganglia nuclei has involved investigation of effects of systemically administered dopamine agonists on neuronal activity in these areas. The beneficial effect of dopamine replacement therapy in PD suggests that tonic, agonist-induced stimulation of dopamine receptors can provide much of the same regulation of postsynaptic systems as normal dopaminergic transmission. Thus, studies of the effects of systemically administered dopamine agonists on firing rate, pattern, and synchronization of activity in basal ganglia nuclei have the potential to shed light on the role of dopamine-mediated transmission in basal ganglia function. Early studies of the in vivo effects of dopamine agonists on basal ganglia activity nuclei postsynaptic to the nigra dopamine projection were conducted in monkeys with electrolytic lesions of the nigrostriatal pathway and in intact rats. Subsequently, similar studies were carried out in I-methyl-4-phenyl-l,2,3,6tetrahydropyridine (MPTP)-treated monkeys and rats with 6-hydroxydopamine (60HDA)induced unilateral lesions of the nigrostriatal dopamine system animal models of PD.

The Relationship of Dopamine Agonist-Induced Rotation to Firing Rate Changes in the Basal Ganglia Output Nuclei

Pharmacological manipulations of brain dopamine (DA) systems modify motor behavior. Current models of basal ganglia function predict that dopamine agonist-induced motor activation, such as rotation or stereotypic behavior, is mediated by decreases in activity in the output nuclei of the basal ganglia, the substantia nigra pars reticulata (SNPR) and entopeduncular nucleus (EPN), brought about by activation of striatal DA receptors. These decreases in activity are thought to lead to disinhibition in motor thalamocortical and tectofugal circuits. Electrophysiology has provided some support for these models: in animals with nigrostriatal lesions, the D1/D2 agonist apomorphine or high doses of the partial D1 agonist SKF 38393 cause decreases in firing rate in most neurons of the SNPR19,20 or the primate homolog of the EPN.3

Effects of Dopamine Receptor Stimulation on Single Unit Activity in the Basal Ganglia

In the past decade, research directed toward determining how dopamine receptor stimulation affects information processing in the basal ganglia has found the familiar “dual circuit” model3,4,16 of the basal ganglia a very useful tool. This dual circuit view of the basal ganglia system emerged from investigations of the effects of dopamine cell lesion on GABA receptor changes at the sites of termination of the two types of striatal efferents: the striatonigral and striatopallidal neurone3,35. Also critical were studies that mapped the distribution of the two main dopamine receptor subtypes in the striatum with respect to these striatal efferents18–32. The conclusions drawn from these observations have been supported by additional biochemical and inununohistochemical data18,19,36 and they led to the view that dopamine acts primarily to inhibit activity in the so-called ”indirect“ pathway through stimulation of the D2 receptors expressed by the striatopallidal neurons, and to enhance activity in the ”direct“ pathway through the D1 receptors expressed by the striatal neurons projecting to the substantia nigra pars reticulata (SNpr) and internal globus pallidus (GPi) or, in the rat, the entopeduncular nucleus (EPN).