Arthur S. Freeman

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.

(+/-)-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.

Effects of administration of cholecystokinin into the VTA on DA overflow in nucleus accumbens and amygdala of freely moving rats

The carboxyterminal octapeptide of cholecystokinin (CCK-8) coexists with dopamine (DA) in mesolimbic neurons of the ventral tegmental area (VTA). In the present study, in vivo microdialysis in freely moving rats was used to assess the relative effects of sulfated CCK-8 (CCK-8S), unsulfated CCK-8 (CCK-8US) and CCK tetrapeptide (CCK-4), focally injected into the VTA, on DA overflow in two mesolimbic DA/CCK-8S terminal regions, the nucleus accumbens and the amygdala. Consistent with electrophysiological findings, microinjection of CCK-8S, but not CCK-8US or CCK-4, elicited increases in DA overflow in both terminal regions. In the absence of anatomical evidence of CCK-containing fibers in the VTA region, it seems reasonable to conclude that the modulation of terminal DA overflow by CCK-8S through actions at the somatodendritic region represents a form of autoregulation of these cells. Whereas CCK-8US and CCK-4 are preferential CCK-B receptor agonists, CCK-8S binds non-selectively to CCK-A and CCK-B receptors. Thus, these results implicate CCK-A receptors in the stimulatory effects of CCK-8S on VTA DA neurons.

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.

Overflow of dopamine and cholecystokinin in rat nucleus accumbens in response to acute drug administration.

Cholecystokinin octapeptide (CCK‐8) coexists with dopamine (DA) in rat mesencephalic neurons that project to the nucleus accumbens. To obtain indices of corelease, microdialysis probes were placed in the posterior nucleus accumbens of anesthetized rats, which were then injected acutely (s.c.) with drugs that exert known effects on DA neuronal function. Microdialysis samples were assayed for DA and CCK‐8 to determine the differential overflow of these cotransmitters in response to drug treatment. Haloperidol (0.5 mg/kg), d‐amphetamine (1 mg/kg), and TCP (5 mg/kg) preferentially increased DA overflow, whereas morphine (5 mg/kg) elicited marked increases in the overflow of both DA and CCK‐8. These results suggest that the release of accumbal DA and CCK‐8 can be differentially regulated by drug treatment. Synapse 38:238–242, 2000.

The effects of the phencyclidine analogs BTCP and TCP on nigrostriatal dopamine neuronal activity.

Extracellular single unit recording techniques were used to evaluate the effects of two phencyclidine (PCP) derivatives. N-[1-(2-benzo(b)thiophenyl)cyclohexyl]piperidine (BTCP) and N-[1-(2-thiophenyl)cyclohexyl]piperidine (TCP) on the electrophysiological activity of antidromically identified nigrostriatal dopamine (DA) neurons in chloral hydrate-anesthetized rats. I.v. BTCP produced a dose-dependent decrease in the firing rate of identified nigrostriatal DA neurons whereas TCP elicited a dose-dependent biphasic effect which was characterized by an activation of cell firing at low doses followed by a reversal of the response with larger doses. A hemitransection of the brain anterior to the substantia nigra significantly reduced the inhibitory effect of BTCP while this surgical procedure did not affect the response to TCP. However, iontophoretic application of BTCP induced a current-dependent inhibition of the spontaneous activity of cells while local application of TCP had no effect on the firing rate of these cells. These data indicate that PCP analogs are able to interact with the nigrostriatal DAergic pathway through distinct and opposing mechanisms. The results are discussed in light of recent observations that BTCP is selective for the DA uptake site while TCP is selective for the high affinity PCP binding site.

Effect of glucose on antipsychotic drug-induced changes in dopamine neuronal activity

The effect of glucose on antipsychotic drug-induced changes in the spontaneous activity of rat midbrain dopaminergic neurons was tested with the cells-per-track extracellular electrophysiology method. After daily s.c. treatment with vehicle, haloperidol (0.5 mg/kg), or clozapine (20 mg/kg) for 21 days, rats were anesthetized and recordings performed on one side of the brain. Then, glucose (250 mg/kg, i.v.) was administered and recordings were made from the contralateral midbrain. Glucose significantly reduced the number of spontaneously active A9 and A10 dopaminergic cells per track in control rats, but significantly attenuated the chronic haloperidol- and clozapine-induced reductions in dopaminergic cells per track. These results suggest that caloric intake may influence antipsychotic drug-induced changes in the population activity of midbrain dopaminergic neurons.

Effects of the CCK-A receptor antagonist CR 1409 on the activity of rat midbrain dopamine neurons

Previous studies have shown that acute intravenous treatment with sulfated cholecystokinin octapeptide (CCK-8S) but not unsulfated CCK-8 increases the number of spontaneously active midbrain dopamine (DA) neurons. This suggested that a peripheral-type (CCK-A) CCK receptor mediates this effect. Proglumide does not discriminate between CCK-A and CCK-B (central-type) receptors. In the present study, rats were treated acutely or repeatedly (14 days) with the selective CCK-A antagonist CR 1409. Repeated treatment with 5 mg/kg (IP) increased the number of spontaneously active DA cells in the A10 (ventral tegmental area) but not the A9 (substantia nigra zona compacta) region, which suggests that these DA populations are differentially affected by prolonged CCK-A receptor blockade. The sensitivity of impulse-regulating DA autoreceptors to the DA agonist quinpirole was not altered by CR 1409.