Microiontophoretic studies of the effects of D-1 and D-2 receptor agonists on type I caudate nucleus neurons: lack of synergistic interaction.

Several lines of evidence have suggested there may be a physiologically relevant form of synergistic interaction between D-1 and D-2 dopamine (DA) receptors located on postsynaptic neurons in the forebrain that receive a dopaminergic innervation. Because of the theoretical importance of such an interaction with respect to understanding the normal physiology of dopaminergic systems, we evaluated effects of D-1 and D-2 selective agonists, applied microiontophoretically, on the spontaneous electrical activity of a single, identifiable subpopulation of neurons within the caudate nucleus, the type I striatal neuron, in locally anesthetized, gallamine-paralyzed rats. It was observed that the D-2 receptor agonist quinpirole (QUIN) produced biphasic effects on cell firing rate. Low ejection currents significantly increased firing rate, while higher currents produced an inhibition. Similar effects were observed for the D-1 agonists SKF 38393; however, the overall excitations observed at low ejection currents were far less than those observed for QUIN. When these two agonists were applied concurrently, a simple additive effect (but not synergism) was always observed. The acute reduction of striatal levels of DA, by as much as 84% (with pretreatment with alpha-methyl-p-tyrosine, AMPT), did not alter the responsiveness of type I striatal neurons to the DA receptor agonists applied alone or in combination. These observed effects were not altered either by chloral hydrate anesthesia (in which glutamate-driven activity was studied) or by a more severe depletion of striatal DA levels (98% depletion produced by combined pretreatment with AMPT and reserpine).

Motor effects of globus pallidus stimulation in the rat: lesions to corticofugal fibers block the motor effects.

Unilateral electrical stimulation of the globus pallidus (GP) in anesthetized male rats was used to determine the nature of the activity driven in muscles of the neck and shoulder by GP output. In 6 groups of animals stimulation was coupled with lesions to sites that interrupted corticofugal fibers or GP output. Interruption of corticofugal fibers blocked the driven activity while lesions that compromised GP output left the activity unaffected.

Pedunculopontine tegmental nucleus-induced inhibition of muscle activity in the rat.

The connections of the pedunculopontine tegmental nucleus (PPN) have led us to propose that this structure mediates striatally induced inhibition of muscle activity by directing basal ganglia output to an inhibitory reticulospinal system (nucleus reticularis gigantocellularis and ventralis, nrGi-V). We conducted experiments in order to examine the effects of electrical stimulation of the PPN on the activity of selected neck and shoulder muscles. PPN stimulation at low rates (0.1 Hz) elicited bilateral muscle excitation. As the rate of stimulation was increased (e.g. to 10 Hz), less excitation was observed. Anodal DC current inactivation of the nrGi-V during concurrent 10 Hz PPN stimulation resulted in an augmentation of muscle activity above the levels observed during 10 Hz PPN stimulation alone. PPN stimulation (10 Hz) also profoundly inhibited cortically-induced muscle activity. Further support for our proposal stems from increased baseline activity (0.1 Hz PPN-induced excitation) in animals with ibotenic acid lesions of the PPN as compared to normal animals. Apparently, destruction of the PPN releases the musculature from tonic and/or phasic inhibition. A model is discussed which attempts to account for both the rate-dependent changes in excitation and the inhibition of cortically induced muscle activity.

Inhibition and excitation of neck and shoulder muscles during unilateral electrical stimulation of the rat neostriatum.

Electrical stimulation of the caudate-putamen (Cd-Pt) in anesthetized adult male rats was used to determine the nature and extent of the control exerted by the Cd-Pt over the following neck and shoulder muscles: the trapezius, biventer cervicis, rectus capitis and scalenus dorsalis. Unilateral Cd-Pt stimulation resulted in a pattern of muscle responses marked by immediate inhibition of ipsilateral spontaneous activity and subsequent excitation of contralateral activity. Lesions of the substantia nigra pars reticulata blocked the excitation in 3 of the 4 muscles, while globus pallidus lesions had equivocal results. However, control ablations of the frontoparietal motor cortex, which blocked excitation in all muscles, and kainic acid lesions of the Cd-Pt, which had no effect on excitation, suggested that the excitation of muscle activity can only be attributed to the stimulation of corticofugal fibers passing through this region (i.e. the Cd-Pt). The inhibition of spontaneous activity does appear to be attributable to stimulation of the Cd-Pt.

Asymmetric behavior induced by enkephalinergic agents in the basal ganglia.

The caudate-putamen (CDp) and the globus pallidus (GP) are sites rich in both leucine (LEU) and methionine-enkephalin (MET-ENK) and in ENK receptors. Since chemical and electrolytic lesions of the CDp and GP result in a reduction in ENKs and their receptors and in motor asymmetry, there may be a role for CDp and GP ENKs in rotational behavior and bodily asymmetry. To test this possibility, various doses of D-ALA-2-LEU-ENK, D-ALA-2-MET-ENK, naloxone and naltrexone were injected into the CDp and GP through chronically implanted cannulae. The injections of MET and LEU-ENK caused dose-dependent ipsiversive rotations while injections of naloxone and naltrexone caused contraversive rotations. All of the drug injections also caused bodily asymmetries which were in the same direction as the circling. Intraperitoneal injections of naloxone dose-dependently blocked the rotational behavior induced by the most effective dose of the ENKs used. ENK injections into sites adjacent to the CDp and GP (i.e., cortex, nucleus accumbens and the region bordering the bed nucleus of the stria terminalis and the bed nucleus of anterior commissure) failed to produce any significant circling. These results clearly suggest that CDp and GP ENKs cause ipsiversive rotational behavior and bodily asymmetry and must be considered as one element of the control exerted by the basal ganglia over the motor system.

Circling and bodily asymmetry induced by injection of GABA agonists and antagonists into the superior colliculus.

The observation that ipsiversive circling follows unilateral lesions of the deep layers of the superior colliculus (DLSC), combined with the recent demonstration of an ipsilateral inhibitory GABAergic projection from substantia nigra pars reticulata (SNr) to the DLSC suggests a role for tectal GABA in circling behavior. In the present experiment, GABA, the GABA agonist muscimol, and the GABA antagonists picrotoxin and bicuculline were injected into the DLSC through chronic cannulae. GABA and muscimol produced significantly higher ipsiversive circling and bodily asymmetry than saline injections. Picrotoxin and bicuculline resulted in significantly higher contraversive circling and asymmetry than saline injections. All drugs except bicuculline produced dose-dependent circling. GABA injections were also made into the mesencephalic reticular formation (MRF) and the periaqueductal gray (PAG). The MRF injections produced the same degree of circling and asymmetry as the DLSC injections. The PAG injections resulted in significantly lower amounts of circling than the DLSC GABA injections, but they resulted in equivalent measures of asymmetry. These results demonstrate that DLSC GABA produces circling and asymmetry, and suggest that the DLSC as well as the MRF serve as output stations for the expression of circling behavior initiated at the striatum.

Impairment in a T-maze task following unilateral lateral hypothalamic lesions.

Rats with unilateral LH lesions showed great difficulty performing a contraversive turn to escape shock in a T-maze. Rats that were required to turn to the side ipsilateral to the side of their lesion did not show this performance deficit. The impairment in contraversive responding was shown to dissipate over time. It is proposed that animals with LH lesions do not suffer learning disabilities in escape-avoidance tasks, but can not activate motor behavior directed toward the side contralateral to their lesion.

Active avoidance in rats with unilateral hypothalamic and optic nerve lesions.

During the height of the contralateral sensorimotor deficit that follows unilateral hypothalamic lesions, rats demonstrate severe performance deficits when tested on a two-way active avoidance task which utilizes a visual conditioned stimulus. This deficit is observed whether or not the ipsilateral or contralateral optic nerve is sectioned in conjunction with the unilateral hypothalamic lesion. With the return of sensorimotor function contralateral to the lesion, animals that had been unable to avoid shock during their debillitated phase demonstrated significant savings when tested on the original task.

Viewing and sectioning the rat's optic nerve using cheap retractors.

A technique for sectioning the optic nerve in rats is described which permits direct viewing of the nerve during surgery. The technique results in no damage to the front of the eye. A procedure for constructing cheap, effective retractors is described.

Entrainment of the rat's activity rhythm by cyclic light following lateral geniculate nucleus lesions.

The rhythmic running-wheel activity of rats is entrained by sensory input via the visual system. The retinal projection transmitting visual information essential for entrainment of the activity rhythm is unknown. Lesions of the lateral geniculate nucleus (LGN) disrupt two projections, the primary optic tract (POT) and the superior accessory optic tract (AOT-SF). It was found that activity remained entrained to a light cycle following LGN lesions. This indicates that the POT and the AOT-SF are not necessary for entrainment. The two remaining projections, the retinohypothalamic pathway and the inferior accessory optic tract (AOT-IF), are sufficient to maintain entrainment. In light of other investigations, it is suggested that the retinohypothalamic pathway is the key projection for synchrony of the activity rhythm with environmental illumination. It was also found that LGN lesions severely impaired the subjects' ability to learn a brightness discrimination.