Behavioural and biochemical responses following activation of midbrain dopamine pathways by receptor selective neurokinin agonists.

Preferential activation of mesolimbic and nigro-striatal dopamine (DA) pathways by receptor-selective and peptidase-resistant neurokinin (NK) agonists is reported. The DA cell body region of the mesolimbic pathway appears to be activated by NK agonists selective for NK-1 and NK-3 receptors whereas the DA cell bodies in the substantia nigra are under an excitatory NK-2 receptor-mediated influence. Stimulation of the mesolimbic DA pathway by NK-1 (Ava[L-Pro9,N-Me-Leu10]SP (7-11) [GR73632]) or NK-3 (Senktide) agonists increase locomotor activity. Additional studies showed that this elevated motor response observed after intra-VTA infusion of GR73632 was accompanied by a corresponding increase in DA turnover in the terminal fields of this pathway. Similarly, unilateral activation of the nigro-striatal DA pathway by NK-2 selective agonists (Ava (D-Pro9) SP (7-11) [GR51667] or [Lys3,Gly8,R-Lac-Leu9]NKA (3-10) [GR64349]) elicit contralateral rotational activity and an increase in DA turnover in the ipsilateral striatum. The rotational response was attenuated by prior administration of an NK-2 antagonist (cyclo (Gln, Trp, Phe, Gly, Leu, Met)] L-659877]) into the nigra. Peripheral injection of haloperidol, a DA antagonist, also blocked the NK-2 agonist induced rotations.     

Neurotensin modulates autoreceptor mediated dopamine effects on midbrain dopamine cell activity.

Interactions of neurotensin (NT) with midbrain dopamine (DA) neurons were studied in rats using microiontophoretic techniques. Local ejection of NT significantly increased (greater than 30%) the firing rate of a few DA cells (12/106). In most cases, however, iontophoretic NT produced no significant change in spontaneous activity. On the other hand, in these same cells, NT significantly attenuated the inhibition induced by either DA or quinpirole, a specific D2 agonist. Inhibition induced by DA was not attenuated by either glutamate or cholecystokinin, although both of them increase the firing rate of DA cells. The effect of NT appears to be selective as NT attenuated DA-induced inhibition without a measurable effect on either GABA-induced inhibition or glutamate-induced excitation of the same DA cells. Combined, these results suggest that NT's effect on DA cell activity is primarily a neuromodulatory one. As both NT and D2 receptors in midbrain DA cell areas are primarily located on DA cells, the above results also suggest that the observed interaction between NT and DA occurred at the DA cell level.     

Book Review - On acute oral dyskinesia. Behavioural effects of dopamine receptor agonists and antagonists in humans and primates

Henning Paikin giver i denne artikel en kort oversigt over forskellen mellem den biologisk-naturvidenskabelige og den humanvidenskabelige måde at anskue psykiske fæomener. På basis heraf beskriver han forskellen mellem at bruge psykofarmaka og benytte psykoterapeutiske metoder. Til slut diskuteres konsekvenserne af at benytte de fundamentalt forskellige behandlingsmetoder i kombination.     

Behavioral effects of selective midbrain raphe lesions in the rat.

Lesions were produced in the median (n = 8), dorsal (n = 7) or both (n = 7) midbrain raphe nuclei and their effects on behavior (days 16-54 postoperatively) compared to that of controls (n = 9). In addition, forebrain 5-hydroxytryptamine (5-HT) concentration were determined. Only the median and combined lesion groups showed increased running wheel and open field activity, as well as enhanced reactivity to novel stimuli and environmental change. None of the lesion groups, however, showed changes in home cage activity on postoperative day 21. Although all lesion groups were deficient in the acquisition and retention of one-way avoidance, the deficits were of a greater magnitude in the median and combined lesion groups. The latter two groups, furthermore, were impaired in forced extinction of the one-way avoidance response, but only the combined lesion group evidenced facilitation of two-way avoidance acquistion. Thus, in contrast to the effects of median or combined raphe lesions, lesions in the dorsal raphe nucleus affected few of the behavioral parameters studied. These results suggest that the dorsal raphe nucleus plays a different behavioral role than the median raphe nucleus. The median nucleus appears to be involved in the regulation of activity level, the reaction to novelty and environmental change, and the response to aversive stimuli. Possible mechanisms for the observed behavioral changes are discussed, as well as their apparent similarity to the effects of other mesencephalic and limbic lesions. Lastly, the median, dorsal and combined raphe lesions lowered forebraine 5-HT but 26, 65, and 77%, respectively, versus controls. These reductions differed significantly from each other, and with previously reported data indicate that the dorsal raphe nucleus in the principal origin of forebrain 5-HT. It is suggested, furthermore, that the behavioral effects of midbrain raphe lesions are not due primarily to their associated reduction in forebrain 5-HT.     

Striatal tachykinin biosynthesis: regulation of mRNA and peptide levels by dopamine agonists and antagonists

The effects of dopamine agonists and antagonists on rat basal ganglia substance P, substance K, and preprotachykinin mRNA were examined. Chronic administration of the prototypical dopamine antagonist haloperidol decreased striatal preprotachykinin mRNA and nigral tachykinin peptides. Chronic treatment with the dopamine D2 receptor antagonist L-sulpiride (but not the inactive D-isomer) mimicked the effect of haloperidol. In contrast, the atypical neuroleptic clozapine did not decrease tachykinin mRNA or peptides. The potent indirect dopamine agonist methamphetamine rapidly increased preprotachykinin mRNA, substance P, and substance K although the direct agonist apomorphine was without effect. Methamphetamine-stimulated changes in preprotachykinin mRNA were prevented by prior haloperidol administration. These data demonstrate that alterations in dopaminergic transmission significantly alter striatonigral tachykinin biosynthesis in vivo.     

Met-enkephalin levels in midbrain dopamine regions of inbred mouse strains which differ in the number of dopamine neurons

The Met-enkephalin content in tissue micropunches of the substantia nigra zona compacta, ventral tegmental area and the caudate nucleus in BALB/c and CBA mouse strains was measured by radioimmunoassay. The CBA strain had significantly higher Met-enkephalin levels in all 3 regions than the BALB/c strain. These differences should be taken into account when relating the intensity of dopamine-induced behaviors to the number of dopamine neurons.     

Electrophysiological effects of tachykinin agonists on sympathetic ganglia of spontaneously hypertensive rats

This study investigated the cellular basis for the enhanced ganglionic responsiveness to NK1 agonists in the spontaneously hypertensive rat (SHR) in comparison to their normotensive counterpart, the Wistar-Kyoto (WKY) rat. Rats for in vivo studies were anesthetized with pentobarbital and treated with chlorisondamine (10.5 micromol/kg). Extracellular recordings from the external carotid nerve showed a greater responsiveness of decentralized SHR superior cervical ganglia (SCG) to intravenous injection of SP (32 nmol/kg). Blood pressure and heart rate were increased in SHRs, whereas WKY rats responded with a decrease in blood pressure and only slight tachycardia. Membrane properties of SCG neurons, as shown by intracellular microelectrode recordings, were similar between strains. Picospritzer application of the NK1 agonist GR-73632 (100 microM, 1 s) evoked slow depolarization and increased neuron excitability. Spontaneous firing was evoked only in some neurons. Depolarization amplitudes were similar between strains; however, the NK1 agonist depolarized a greater number of neurons in hypertensive rats. In conclusion, SHRs are more responsive to ganglion stimulation by NK1 agonists due to a greater number of responsive cells within the SCG rather than an enhanced responsiveness of individual neurons.     

Antidepressant-like effects of dopamine agonists in an animal model of depression.

Chronic exposure to mild unpredictable stress (CMS) has previously been found to cause an antidepressant-reversible decrease in the consumption of palatable sweet solutions. There is evidence that the effect of antidepressants in this model is mediated by an increase in transmission at dopamine (DA) synpases. The present study investigated whether another treatment known to increase the functional responsiveness of DA systems, intermittent administration of DA agonists, would have antidepressant-like effects. In three experiments in rats, CMS-induced decreases in sucrose consumption were reversed by three to four twice-weekly injections of quinpirole (100-200 micrograms/kg) or bromocriptine (2.5 mg/kg). The effects lasted for several weeks, and when they waned, could be reinstated by a single additional injection of quinpirole. As with tricyclic antidepressants, the effect of quinpirole was reversed by raclopride, administered acutely immediately prior to a sucrose consumption test; there were no changes in sucrose intake in nonstressed control animals. The results suggest that intermittent administration of DA agonists merits investigation as a novel strategy for the treatment of depression.     

Differential effects of three dopamine receptor agonists in MPTP-treated monkeys

Summary The behavioral effects of cabergoline, pergolide and bromocriptine were investigated in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned parkinsonian cynomolgus monkeys with attention to the induction of hyperactivity, as evidenced by irritability, excitability and aggressiveness. All three drugs improved the parkinsonism in a dose-dependent fashion following a single injection. Among the three dopamine (DA) receptor agonists used, the antiparkinsonian effect of pergolide was the strongest and had an immediate effect, while cabergoline showed the longest duration of the antiparkinsonian effect and was least potent in inducing hyperactivity.     

Diet and chronic haloperidol effects on rat midbrain dopamine neurons

The effects of dietary glucose (chow containing 0%, 10%, 20%, or 40% glucose, w/w) on chronic haloperidol-induced changes in dopamine (DA) neuronal activity were tested. Rats were treated daily by oral gavage for 21 days with either water or 0.5 mg/kg haloperidol, then anesthetized for in vivo electrophysiological recording. The numbers of spontaneously active DA neurons in the substantia nigra (A9) and ventral tegmental area (A10) regions of the midbrain were estimated with the cells-per-track sampling method. In rats fed standard chow, haloperidol significantly reduced the number of active neurons in both regions compared to water controls. In water controls there were no differences in DA cells per track between rats fed standard chow or chow containing 10% or 20% glucose, whereas these glucose diets significantly attenuated the effects of chronic haloperidol on DA cells per track. The 40% glucose diet itself nonsignificantly reduced cells per track and, in turn, nonsignificantly attenuated the effects of haloperidol. The results demonstrate that dietary glucose content can alter haloperidol-induced changes in the activity of midbrain DA neurons.     

Diazepam antagonizes effects on dopamine metabolism produced by PCP receptor agonists.

1. Male rats were injected with either saline, diazepam, MK-801, or diazepam plus MK-801. 2. In previous work with phencyclidine (PCP), diazepam significantly reduced the increase in homovanillic acid (HVA) in olfactory tubercle and prefrontal cortex. 3. Diazepam also lowered the HVA increase following MK-801 in caudate, olfactory tubercle, and prefrontal cortex. 4. Benzodiazepine receptors may modify dopaminergic function at PCP receptors that affect dopamine neurotransmission.     

Opposing effects of striatonigral feedback pathways on midbrain dopamine cell activity

The existence of a striatonigral GABAergic pathway has been well established both anatomically and biochemically. During intracellular recording from identified DA neurons in vivo, stimulation of the striatum (100 microA, 50 microseconds pulses) elicits an inhibitory postsynaptic potential (IPSP) and a rebound depolarization. The IPSP is a short latency (1.8-2.2 ms) conductance increase to chloride, since: the reversal potential is near the chloride reversal potential reported for other cells (-68 mV); intracellular chloride injection progressively reverses the IPSP into a depolarization with a similar time course; and the response of DA cells to systemic injection of the chloride channel blocker, picrotoxin, also exhibits a similar reversal potential. In contrast, during extracellular recording, stimulation of the striatum at low levels of intensity (e.g. 20 microA at 10 Hz) increases the firing rate of DA cells. Stimulation of the striatum will, in addition, elicit IPSPs in a subclass of substantia nigra zona reticulata neurons at the same latency as the IPSPs triggered in DA cells. These IPSPs also reverse with intracellular chloride injection. However, their amplitude is larger and their duration longer than observed in DA cells, and there is no depolarizing rebound. The late component of the IPSP in the zona reticulata neurons corresponds temporally to the rebound depolarization seen in DA cells in response to striatal stimulation. In addition, when recorded extracellularly, striatal stimulation will inhibit the firing of this class of zona reticulata interneurons at the same stimulation parameters that will excite DA cells. These data suggest that striatal cells may send branched fast-conducting GABAergic projections to zona reticulata cells and DA cells. Furthermore, low levels of striatal stimulation can excite DA cells by preferentially inhibiting interneurons in the zona reticulata which are more sensitive to the inhibitory effects of GABA than are DA neurons.     

D1 and functionally selective dopamine agonists as neuroprotective agents in Parkinson's disease

Parkinson's disease (PD) is a progressive neurodegenerative disorder that results in major motor disturbances due primarily to loss of midbrain dopamine neurons. The mainstream treatment has been dopaminergic replacement therapy aimed at symptomatic relief, with the gold standard drug being the dopamine precursor levodopa. The general dogma has been that levodopa works primarily by indirectly activating the D(2) family of dopamine receptors. Recently, a number of direct dopamine agonists that target the D(2) and D(3) dopamine receptors have been used as dopaminergic replacement strategies. Although these direct D(2) and D(3) drugs cause only modest improvement in motor function compared to levodopa, they can delay the initiation of levodopa and can act synergistically with levodopa. In addition, they can delay the onset of levodopa-related motor complications. Recent imaging data also suggest that they may have neuroprotective effects. Whereas D(2)/D(3) agonists have received much attention as several drugs are available for clinical trials and usage, there has been a large body of data showing that the D(1) receptor actually may play a larger role in restoration of normal motor function. This review examines the current use of dopamine D(2)/D(3) agonists in treatment of PD and their potential for providing neuroprotection. Furthermore, we also examine the potential that D(1) agonists might have in neuroprotective actions in the disease progression.     

Effects of chronic treatment with selective agonists on the subtypes of dopamine receptors

The effects of chronic administration of selective dopaminergic agonists on D1 and D2 receptor density, affinity and function were measured in Sprague-Dawley rats. Animals received daily injections (i.p.) of the D1-selective agonist SKF-38393 (10 mg/kg), the D2-selective agonist quinpirole (1 mg/kg), SKF-38393 plus quinpirole, or saline for 14 days. Quantitative autoradiographic analysis revealed that the density of D2 receptors was decreased following chronic treatment with quinpirole alone or in combination with SKF-38393 whereas SKF-38393 by itself had no effect on this receptor. In contrast, the density of D1 receptors was increased following treatment with SKF-38393. Although quinpirole by itself had no effect on D1 receptors, co-administration with SKF-38393 attenuated the up-regulation of D1 receptors produced by SKF-38393 in the caudate-putamen and nucleus accumbens but not in the substantia nigra. The up-regulation of D1 receptors in response to chronic SKF-38393 may be attributed to the partial agonist properties of SKF-38393 which may not provide sufficient D1 receptor stimulation to down-regulate the receptor. Quinpirole-induced hypothermia and SKF-38393-induced hyperthermia were measured before and after chronic agonist treatments to examine the effects of these treatments on thermoregulatory functions mediated by each receptor subtype. Treatment with quinpirole or quinpirole plus SKF-38393 resulted in desensitization of quinpirole-induced hypothermia, whereas treatment with SKF-38393 alone had no effect. All of the chronic treatments produced sensitization of SKF-38393-induced hyperthermia. Since not all treatments result in an increase in the density of D1 receptors, up-regulation of D1 receptors is not the sole mechanism for this sensitization.     

Evidence for the functional compartmentalization of spike generating regions of rat midbrain dopamine neurons recorded in vitro

The regulation of spike generation in rat midbrain dopamine (DA) neurons was investigated using in vitro intracellular recordings. DA neurons fired long (greater than 1.8 ms) action potentials that exhibited comparatively depolarized spike thresholds (approx. -35 to -45 mV). Depolarization of the DA neuron increased the duration and the threshold of subsequent action potentials. The action potential was composed of two distinct components, a fast (0.8-1.5 ms duration) initial segment (IS) spike which triggered a slow (1.5-3 ms duration) somatodendritic (SD) component. Cobalt application (2 mM) blocked the SD spike component and revealed fast TTX-sensitive spikes. These fast spikes were also observed in untreated neurons following large hyperpolarizing pulses, and showed consistent changes in threshold and amplitude during membrane depolarization. Administration of 4-aminopyridine decreased the threshold of this TTX-sensitive spike, whereas tetraethylammonium (TEA) had no effect. When the fast spike was blocked by TTX, depolarization was ineffective in triggering further spike activity. However, after the administration of TEA (but not 4-AP), high threshold cobalt-sensitive spike activity could be triggered by relatively small depolarizations. TEA increased the duration of the SD portion of the action potential without altering the action potential threshold. The effect of 4-AP on spike threshold and the increase in SD spike duration caused by TEA were similar in nature to the changes in action-potential waveforms produced by polarizing the DA neuron membrane. Drawing from evidence gathered here and in previous in vivo studies, the properties of the TTX-sensitive fast spike are consistent with those of the IS spike component of the action potential, whereas the SD component is similar in nature to the high threshold calcium spike. One hypothesis that can be drawn from these studies is that dendritic and axonal spiking regions may exist in different functional subcompartments of the DA neuron, and may be independently modulated by pharmacologically distinct conductances. Under these conditions, synaptic influences could exist to modulate dendritic excitability and thus regulate putative dendritic spike-dependent functions, such as neuronal activity state, electrical coupling, and dendritic DA synthesis and release.     

Dystonia-Parkinson syndrome: differential effects of levodopa and dopamine agonists

Eleven patients who presented with predystonic syndrome later developed pure dystonic syndromes and later developed parkinsonism. This suggests that dystonic syndromes can be the precursor to a mixed syndrome including both dystonia and parkinsonism. While the parkinsonian features in such patients respond to either levodopa or direct-acting agonists, levodopa often exacerbates the underlying dystonia. Direct acting agonists appear to be less liable to do this.     

Validation of the l-dopa-induced dyskinesia in the 6-OHDA model and evaluation of the effects of selective dopamine receptor agonists and antagonists

Current treatments for Parkinson's disease (PD) rely on a dopamine replacement strategy and are reasonably effective, particularly in the early stages of the disease. However, chronic dopaminergic therapy is limited by the development of a range of side effects, including dyskinesia. This has led to a search for alternative treatments. Transplantation of foetal nigral dopamine neurons is a rational approach and many studies have shown that it can improve motor functions in parkinsonian rodents, primates and man. Recently, however, two clinical trials have reported an exacerbation of dyskinesias in some transplanted patients, raising concerns about the safety of the transplantation strategy. To study this issue, we have reproduced the l-dopa-induced dyskinesia model developed by Cenci et al. [M.A. Cenci, C.S. Lee, A. Bjorklund, l-DOPA-induced dyskinesia in the rat is associated with striatal overexpression of prodynorphin- and glutamic acid decarboxylase mRNA, Eur. J. Neurosci. 10 (1998) 2694-2706] in the rat. We find that their abnormal involuntary movements rating scale is easy to apply and consistent to use. Moreover, the Schallert forelimb placing test has been used to assess l-dopa-induced recovery of function and we find that the rats continue to show good recovery on this test, even while they are exhibiting abnormal dyskinetic side effects. To further evaluate this model, we have studied the effects of selective dopamine receptor antagonists and agonists for D1, D2 and D3 receptors. Antagonists of all three receptors are able to block the l-dopa-induced dyskinesia without interfering with the beneficial effects of l-dopa on the placing test. This indicates that the effects of chronic l-dopa on recovery of parkinsonian symptoms and on induction of dyskinetic side effects can be dissociated, which may provide the basis for developing novel combination treatments, e.g. using grafts while blocking the unwanted adverse effects of the drugs.     

Kynurenate blocks the acute effects of haloperidol on midbrain dopamine neurons recorded in vivo

Summary The acute effect of systemic administration of the antipsychotic drug haloperidol on the activity of midbrain dopamine (DA) neurons was investigated with extracellular single cell recording in the chloral hydrate anaesthetized male rat. DA cells in the zona compacta-substantia nigra (SN) and ventral tegmental area (VTA) were excited by low doses of haloperidol. This excitation, which included increased firing rate and burst firing, was no longer present after treatment with the excitatory amino acid (EAA) antagonist kynurenate (1 mol ICV). Kynurenate alone profoundly regularized the activity and abolished burst firing in VTA-DA neurons, while SN-DA neuronal activity was unaffected by this treatment. Thus, VTA-DA neurons, but not SN neurons, appear to be dependent on a tonic EAA input for their normal varied, burst-firing activity. The antagonism of haloperidol-induced effects by kynurenate suggests that the acute excitatory action of haloperidol on midbrain DA neurons is executed via EAA neurons, in the case of the VTA probably via a corticofugal EAA pathway from the medial prefrontal cortex.