Mark D. Kelland

Ascending afferent regulation of rat midbrain dopamine neurons

Standard, extracellular single-unit recording techniques were used to examine the electrophysiological and pharmacological responsiveness of midbrain dopamine (DA) neurons to selected, ascending afferent inputs. Sciatic nerve stimulation-induced inhibition of nigrostriatal DA (NSDA) neurons was blocked by both PCPA (5-HT synthesis inhibitor) and 5,7-DHT (5-HT neurotoxin), suggesting mediation by a serotonergic (5-HT) system. Direct stimulation of the dorsal raphe (which utilizes 5-HT as a neurotransmitter and inhibits slowly firing NSDA neurons) inhibited all mesoaccumbens DA (MADA) neurons tested. Paradoxically, DPAT, a 5-HT1A agonist which inhibits 5-HT cell firing, enhanced sciatic nerve stimulation-induced inhibition of NSDA neurons. MADA neurons were not inhibited by sciatic nerve stimulation and, therefore, could not be tested in this paradigm. In contrast to the dorsal raphe, electrical stimulation of the pedunculopontine tegmental nucleus preferentially excited slowly firing NSDA and MADA neurons. Thus, both excitatory and inhibitory ascending afferents influence the activity of midbrain DA neurons, and intact 5-HT systems are necessary for sciatic nerve stimulation to alter DA cell activity. However, the role that 5-HT plays in mediating peripheral sensory input remains unclear.

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.

Medial Forebrain Bundle Stimulation or D‐2 Dopamine Receptor Activation Increases Preproenkephalin mRNA in Rat Striatum

Abstract: Electrical stimulation of the medial forebrain bundle, in a manner that augmented the release of dopamine in the forebrain, rapidly increased the striatal content of preproenkephalin (but not preprotachykinin) mRNA. This effect was mimicked by administration of either the indirect (do‐pamine‐releasing) agonist methamphetamine or by the D‐2 dopamine receptor agonist quinpirole, but not by the D‐1 agonist SKF 38393. These data suggest that D‐2 receptors, which mediate a stimulatory effect on enkephalin gene expression, may be subsaturated under basal conditions and, therefore, responsive to increases in synaptic dopamine.

(+/-)-3,4-Methylenedioxymethamphetamine-induced changes in the basal activity and pharmacological responsiveness of nigrostriatal dopamine neurons.

The present study examined the effects of methylenedioxymethamphetamine (MDMA) on the basal activity and pharmacological responsiveness of rat nigrostriatal dopamine (DA) neurons. Under standard in vivo extracellular single-unit recording conditions, acute MDMA administered alone (i.v.) inhibited the firing rate of nigrostriatal DA neurons in a dose-dependent fashion. The potency of MDMA to elicit this inhibition was significantly reduced following depletion of either serotonin or DA. Acute MDMA pretreatments (10 mg/kg i.v., 90 s) also profoundly enhanced the sensitivity of nigrostriatal DA neurons to the rate-inhibitory effects of the D-2 DA receptor agonist quinpirole but not apomorphine. It has previously been demonstrated that the ability of quinpirole and apomorphine to inhibit nigrostriatal DA neuronal activity is dependent on the basal firing rate of the cell. Both acute MDMA and a single dose of MDMA (15 mg/kg i.p.) one week prior eliminated the rate dependency of quinpirole- and apomorphine-induced inhibition of the firing rate of these cells. These data suggest that, although MDMA is known to be a serotonergic neurotoxin, this compound may also exert direct functional effects on the nigrostriatal DA system.

Repeated amphetamine: reduced dopamine neuronal responsiveness to apomorphine but not quinpirole

Extracellular recordings from single nigrostriatal dopamine (DA) neurons in rats revealed significantly reduced neuronal sensitivity to the inhibitory effects of i.v. apomorphine following repeated amphetamine (4 mg/kg per day i.p., 14 days). This effect was reversed by acute SCH 23390. Quinpirole sensitivity was reduced in amphetamine-treated rats only following acute SKF 38393 pretreatment. These results suggest that, in amphetamine-treated animals, D-1 receptor activation is important for the expression of reduced nigrostriatal DA neuron sensitivity to apomorphine.

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.

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.

Repeated SKF 38393 and nigrostriatal system neuronal responsiveness: functional down-regulation is followed by up-regulation after withdrawal

SummaryThe effects of chronic administration of the D1 dopamine (DA) agonist SKF 38393 on the basal activity and electrophysiological and pharmacological responsiveness of nigrostriatal DA neurons were examined by means of extracellular, single-unit recording techniques. Chronic D1 stimulation failed to alter either the basal activity of DA neurons or the potency of quinpirole to induce inhibition of these cells. However, 28-day SKF 38393 treatment (but not 14-day treatment) eliminated the ability of subsequent (24 h later) acute SKF 38393 to alter the rate-dependent nature of quinpirole-induced inhibition. In contrast, one week after a 28-day SKF 38393 treatment we found that quinpirole-induced inhibition by itself was no longer rate-dependent, an effect which was reversed by acute pretreatment with the D1 antagonist SCH 23390. This latter finding is suggestive of enhanced endogenous D1 tone. Similarly, 28-day SKF 38393 treatment eliminated the effect of subsequent acute SKF 38393 on sciatic nerve stimulation-induced inhibition of nigrostriatal DA neurons, whereas one week after the chronic D1 regimen these cells were highly sensitive to acute D1 enhancement of the response to sciatic nerve stimulation.In order to address the postsynaptic effects of chronic D1 stimulation, the influence of iontophoretically administered SKF 38393 was examined on type I caudate neurons. Again, 28-day SKF 38393 treatment resulted in reduced sensitivity of caudate neurons tested 24 h later, and an enhanced sensitivity was observed one week after the completion of chronic SKF 38393 administration. Thus, chronic SKF 38393 induced functional desensitization of D1 receptors, but one-week withdrawal was followed by sensitization.

Effect of ketamine-anesthesia on N-methyl-D-aspartate-induced activation of type I nucleus accumbens neurons

Extracellular single-unit recording and microiontophoretic techniques were used to determine the effects of ketamine-anesthesia on N-methyl-D-aspartate (NMDA)-induced excitation of Type I nucleus accumbens neurons. NMDA increased the firing rate of most neurons in this preparation. Thus, it may be concluded that ketamine-anesthesia does not result in blockade of central NMDA receptors. The excitation caused by NMDA was readily reversed in all cases by co-iontophoresis of MK 801, but was generally unaffected by coiontophoresis of ketamine. However, ketamine-anesthesia did significantly increase the current levels necessary for, and limited the magnitude of, NMDA-induced activation of these cells (as compared to urethane-anesthetized rats), suggesting that ketamine is not without effect on NMDA-receptors in vivo.