Louis A. Chiodo

Interactions between dopamine and amino acid-induced excitation and inhibition in the striatum

Iontophoretic techniques were used to examine the effect of dopamine on glutamate-induced excitation and gamma-aminobutyric acid (GABA)-induced inhibition of single striatal neurons in rat brain. When dopamine was applied at concentrations that produced little or no inhibition of spontaneous firing rate, both glutamate-induced excitation and GABA-induced inhibition were enhanced. In contrast, when dopamine was applied at doses that significantly decreased spontaneous firing, glutamate-induced excitation was greatly reduced, though GABA-mediated inhibition remained enhanced. Thus, dopamine acts to modulate the efficacy of other neurotransmitters impinging on striatal neurons, but has a qualitatively different effect on the excitatory activity of striatal cells depending on its concentration.

Electrophysiological effects of MK-801 on rat nigrostriatal and mesoaccumbal dopaminergic neurons☆

The electrophysiological effects of the non-competitive N-methyl-D-aspartate (NMDA) antagonist (+)-MK-801 (MK-801) on nigrostriatal and mesoaccumbal dopaminergic (DA) neurons were evaluated in chloral hydrate-anesthetized rats. MK-801 (0.05-3.2 mg/kg, i.v.) stimulated the firing rates of 14 (74%) of 19 nigrostriatal DA (NSDA) neurons and all 16 mesoaccumbal DA (MADA) neurons tested. Stimulatory effects of the drug were more prominent on MADA neurons. Interspike interval analysis revealed that MK-801 also regularized DA neuronal firing pattern. Acute brain hemitransection between the midbrain and forebrain attenuated the stimulatory effects of MK-801 on firing rate and blocked the effects on firing pattern. Similar to MK-801, hemitransection itself increased NSDA and MADA cell firing rates and regularized firing pattern. Both i.v. and iontophoretic MK-801 blocked the excitatory effects of iontophoretic NMDA but did not affect excitations caused by the non-NMDA glutamatergic receptor agonists quisqualate and kainate. Iontophoretic MK-801 had no effect alone. These results suggest that the excitatory effects of i.v. MK-801 on DA neuronal activity are not due to direct actions on DA neurons. Glutamatergic projections originating anterior to the hemitransection appear to play a role in the effects of MK-801 on DA neuronal activity.

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.

Effects of phencyclidine, MK-801 and 1,3-di(2-tolyl)guanidine on non-dopaminergic midbrain neurons.

The effects of i.v. administration of the noncompetitive NMDA receptor antagonists, phencyclidine and MK-801, and the sigma receptor ligand, 1,3-di(2-tolyl)guanidine (DTG), on the firing rates of non-dopaminergic mid brain neurons were evaluated in chloral hydrate-anesthetized rats. Phencyclidine and MK-801 inhibited the activity of putative gamma-aminobutyric acid (GABA)-containing interneurons identified by their response to foot-pinch. DTG did not significantly alter neuronal activity. These results suggest that the reported excitatory effects of non-competitive NMDA receptor antagonists on dopamine neuronal activity are due, in part, to disinhibition secondary to the inhibition of interneuron 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.

Electrophysiological effects of cholecystokinin octapeptide on identified rat nigrostriatal dopaminergic neurons

Cholecystokinin octapeptide (CCK-8) exists in a subpopulation of midbrain dopaminergic (DA) neurons and has been shown to affect the activity of unidentified DA cells. This study describes the effects of the sulfated (CCK-8S) and unsulfated (CCK-8US) peptides (8 micrograms/kg, i.v.) on the ability of apomorphine to inhibit the firing rate of nigrostriatal DA cells identified by antidromic activation from the caudate nucleus of anesthetized rats. CCK-8S excited 9/25 DA cells while CCK-8US was without effect on firing rate (n = 9). CCK-8S pretreatment resulted in complex changes in the sensitivity of nigrostriatal DA cells to apomorphine which were related to whether an initial excitatory response was elicited by CCK-8S. CCK-8US did not alter apomorphine sensitivity. These results suggest that CCK-8S can exert modulatory effects on DA cells independent of a direct excitatory action. The effect of acute CCK-8 injection on the number of spontaneously active DA cells in stereotaxically defined regions of the substantia nigra and ventral tegmental area was also determined. CCK-8S doubled the number of active cells in these areas; CCK-8US did not alter the population activities.

(+/-)-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.

Release of cholecystokinin from rat midbrain slices and modulatory effect of D2 DA receptor stimulation

Cholecystokinin octapeptide (CCK-8) is colocalized within a majority of dopamine (DA)-containing neurons of the rat midbrain. Exogenous CCK-8 can modulate the electrophysiological activity of DA neurons, at least in part, by direct actions on the somatodendritic region of these cells. If CCK-8 is somatodendritically released from DA neurons, it may influence DA cell function as has been shown for DA itself. In the present study, radioimmunoassay was used to determine if CCK-8 is released in vitro from slices of rat midbrain under basal and depolarizing (30 mM potassium) conditions. Low levels of CCK-8 were detected in the basal incubation medium. Thirty mM potassium caused about a 3-fold increase in the release of CCK-8. This stimulated release was abolished in calcium-free medium. The D2 receptor agonist quinpirole, but not the D1 agonist SKF 38393, attenuated the potassium-stimulated release of CCK-8 but did not affect basal release. These results show that CCK-8, like DA, can be released from midbrain slices, presumably from DA/CCK-8-containing neurons. This finding is in accordance with the possibility that CCK-8 plays a role in the regulation of DA neuronal function at the level of the cell body, where it might influence the excitability of the DA cell membrane.

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.

The effects of in utero ethanol administration on the electrophysiological activity of rat nigrostriatal dopaminergic neurons.

Iontophoresis and single-unit extracellular recording techniques were utilized to study the effects of in utero ethanol administration on nigrostriatal dopaminergic (NSDA) neurons in adult rats. Pregnant Sprague-Dawley rats consumed an ethanol-containing liquid diet providing 0%, 17.5%, or 35% ethanol-derived calories (EDC) from gestation day 8 until parturition. A separate group was fed standard rat chow as an ad lib, diet control. The dose-response curves of intravenously administered apomorphine on the spontaneous activity of NSDA neurons were shifted to the right in animals exposed to a liquid diet containing 17.5% or 35% EDC compared to 0% EDC or ad lib. control groups. The responsiveness of NSDA neurons to microiontophoretic application of the D-2 DA receptor agonist, quinpirole, was not altered following in utero ethanol exposure. These results suggest that in utero ethanol exposure may produce a down-regulation in the function of DA receptors distinct from the somatodendritic impulse-regulating D-2 autoreceptors. The firing pattern of NSDA neurons was also found to be altered after in utero ethanol exposure. There was a dissociation between the firing rate and burst activity in neurons that displayed burst-firing patterns in animals with in utero ethanol exposure. These observations agree with biochemical and behavioral studies that in utero ethanol exposure produces a long-lasting effect on the development of electrophysiological and pharmacological characteristics of midbrain DA systems in adulthood.