Does treatment with haloperidol for 3 weeks produce depolarization block in midbrain dopamine neurons of unanaesthetized rats?

Treatment of rats with haloperidol, 0.5 mg/kg SC daily for 3 weeks, did not increase the concentration of dopamine in the dopamine-rich nuclei of the forebrain apart from a small effect in the olfactory tubercle. Cessation of the nerve impulse flow in the ascending dopamine neurons induced by gamma-butyrolactone caused an approximately twofold increase in the dopamine levels of both haloperidol-treated and control rats. The results are hard to reconcile with the notion of haloperidol-induced depolarization block, i.e., cessation of impulse flow in the majority of midbrain dopamine neurons of unanaesthetized rats.

Ritanserin, a 5-HT2 receptor antagonist, activates midbrain dopamine neurons by blocking serotonergic inhibition.

The effect of systemic administration of ritanserin (R 55667), a 5-hydroxytryptamine (5-HT2) receptor antagonist, on midbrain dopamine (DA) neurons was studied with single cell recording techniques in the chloral hydrate anesthetized male rat. Dopamine cells of the zona compacta, substantia nigra (ZC-SN) and the ventral tegmental area (VTA) were identified by established criteria. Ritanserin (0.5-2.0 mg/kg, IV) dose-dependently increased both the burst firing and firing rate of the midbrain DA neurons. These effects were prevented by endogenous 5-HT depletion through pretreatment with the 5-HT synthesis inhibitor para-chlorophenylalanine (PCPA, 300 mg/kg, IP, x3), which did not significantly alter the firing characteristics of the midbrain DA cells when given alone. These results suggest that 5-HT exerts an inhibitory control of midbrain DA cell activity mediated by 5-HT2 receptors. The stimulatory effect of ritanserin on midbrain DA systems might contribute to some of its clinical effects, such as improvement of mood, drive and motivation as well as its therapeutic actions in parkinsonism and type II schizophrenia.

Decreased sensory responsiveness of noradrenergic neurons in the rat locus coeruleus following phencyclidine or dizocilpine (MK-801): role of NMDA antagonism.

The effects of the schizophrenomimetic compound phencyclidine (PCP) on baseline activity and sensory-evoked responses of noradrenergic locus coeruleus neurons were studied with extracellular single-cell recording techniques in the chloral hydrate-anaesthetized male albino rat. PCP dose-dependently decreased firing rate, induced a more regular firing pattern of the neurons, and decreased neuronal responses to a peripheral sensory stimulus (electrical stimulation of the hindpaw). These effects of PCP were significantly decreased by pretreatment with reserpine or yohimbine, indicating that the effects of PCP were largely indirect and mediated through noradrenaline, i.e. by inhibition of its re-uptake, resulting in stimulation of alpha 2 autoreceptors. The effects of PCP were, however, mimicked by dizocilpine (MK-801), a selective non-competitive antagonist at excitatory amino acid receptors of the N-methyl-D-aspartate (NMDA) sub-type, suggesting a role also for NMDA receptors in the suppression of sensory responsiveness of locus coeruleus neurons by PCP. In view of the purported physiological role of the locus coeruleus, this effect of PCP may well contribute to the psychotomimetic properties of the drug.

Role of alpha7 nicotinic receptors in nicotine dependence and implications for psychiatric illness.

It has previously been shown that the reinforcing and dependence-producing properties of nicotine depend to a great extent on activation of nicotinic receptors within the ventral tegmental area (VTA), i.e. the site of origin of the mesolimbocortical dopaminergic projection. Based on the data reviewed in the present study, it is suggested that nicotine by stimulating presynaptic alpha7 nicotinic receptors within the VTA, that are probably localized on glutamatergic afferents from the medial prefrontal cortex, produces sequentially an increase in glutamate concentrations, stimulation of NMDA receptors found on dopamine (DA)-containing neurons in the VTA, enhanced firing activity of VTA-DA neurons, augmented DA release in the nerve terminal regions, and enhanced c-fos expression in the dopaminergic projection areas through activation of D1-DA receptors. In addition, it appears that alpha7 nicotinic receptors within the VTA are directly involved in nicotine-related reward and withdrawal responses. These data may be instrumental in understanding how nicotine interacts with the mesolimbocortical dopaminergic system, which is perhaps the most important component of the neural mechanisms underlying nicotine dependence. These results may also contribute to unraveling the cellular basis of nicotine's association with neuropsychiatric disorders, thereby offering the prospect of new therapeutic advances for their treatment.

Chronic continuous nicotine treatment causes decreased burst firing of nigral dopamine neurons in rats partially hemitransected at the meso-diencephalic junction.

Chronic continuous administration of nicotine (0.125 mg/kg/h, 14 days) to male Sprague-Dawley rats with a partial hemitransection at the meso-diencephalic junction caused a significant reduction in burst firing of remaining dopamine (DA) neurons in the zona compacta, substantia nigra, whereas neither the firing rate nor the number of spontaneously active DA cells per track were altered in comparison with saline-treated, hemitransected controls. The reduced functional activity of the remaining DA cells subjected to nicotine treatment provides a physiological correlate to the previously observed, reduced DA utilization in these neurons. It may also help to explain the increased nigral DA cell survival found after chronic nicotine treatment in similar lesion experiments.

Prazosin modulates the firing pattern of dopamine neurons in rat ventral tegmental area.

Previous studies have indicated a noradrenergic modulation of midbrain dopamine cell activity. The effects of systemic administration of the alpha 1-adrenoceptor antagonist prazosin and the alpha 2-antagonist idazoxan on midbrain dopamine cell firing were now studied with extracellular recording from single dopamine neurons in the ventral tegmental area of chloral hydrate-anaesthetized male rats. Prazosin (0.15-0.6 mg/kg i.v.) dose dependently decreased burst firing and regularized the firing pattern of dopamine neurons, while the firing rate was unaffected. The prazosin-induced effects were abolished by pretreatment with reserpine. Idazoxan (0.5-2.0 mg/kg i.v.) increased firing rate and burst firing and made the firing pattern less regular, probably by increasing adrenergic transmission via blockade of presynaptic alpha 2-adrenoceptors. The effects of idazoxan were blocked by prazosin. The present results indicate that noradrenergic neurons modulate the dopamine cell firing pattern via excitatory postsynaptic alpha 1-adrenoceptors. This mechanism might be involved in the pathogenesis and pharmacological treatment of schizophrenia.

Clonidine modulates dopamine cell firing in rat ventral tegmental area.

The effect of clonidine (5-20 micrograms/kg i.v.) on the activity of single, identified dopamine neurons in the ventral tegmental area of the mesencephalon was studied in chloral hydrate-anesthetized male rats. Clonidine regularized cell firing without affecting the firing rate of the neurons. This effect was blocked by idazoxan (0.5 mg/kg i.v.) or yohimbine (1.0 mg/kg i.v.), but not by phentolamine (1.0 mg/kg i.v.), indicating that clonidine acts at central alpha 2-adrenoceptors. Idazoxan or yohimbine alone produced deregularization and excitation of cell firing. Pretreatment with reserpine (5 mg/kg s.c.) 4 h before the experiment abolished the neuromodulatory effect of clonidine. Thus, the regularization of ventral tegmental area dopamine cell firing by clonidine is indirect and dependent on endogenous monoamines in brain, and, in principle, a tonic adrenergic control of DA cell firing pattern is indicated. The regularization of DA cell activity produced by clonidine may underlie certain therapeutic neuropsychiatric actions of the drug.

Prefrontal cortex regulates burst firing and transmitter release in rat mesolimbic dopamine neurons studied in vivo.

The influence of the medial prefrontal cortex (PFC) on mesolimbic dopamine activity was studied with electrophysiological techniques and in vivo voltammetry in the chloral hydrate-anesthetized male rat. Glutamate injected into the PFC selectively increased burst firing of single dopamine cells in the ventral tegmental area and enhanced the release of dopamine from nerve terminals in the nucleus accumbens. PFC injection of the local anesthetic lidocaine produced the opposite effects on burst firing and terminal release. This selective modulation of the dynamic activity of mesolimbic dopamine neurons by the prefrontal cortex might be important in motivation, learning and schizophrenia.

Nicotinic and muscarinic components of rat brain dopamine synthesis stimulation induced by physostigmine.

The role of a putative cholinergic control of ascending midbrain dopamine neurons was studied with biochemical methods in the unanaesthetized male albino rat. Post-mortem catechols were measured with high performance liquid chromatography with electrochemical detection. The acetylcholinesterase inhibitor physostigmine (0.5 mg/kg s.c.) enhanced L-dihydroxyphenylalanine (DOPA) and 3,4-dihydroxyphenylacetic acid (DOPAC) levels in both the corpus striatum and limbic areas (nucleus accumbens) after inhibition of aromatic amino acid decarboxylase with NSD-1015, indicating an enhanced synthesis of dopamine in these brain regions. The effect of physostigmine was blocked both in the corpus striatum and in limbic areas by the centrally penetrating muscarinic antagonist scopolamine (1.0 mg/kg s.c.). In contrast, the nicotinic antagonist mecamylamine (1.0 mg/kg s.c.) significantly reduced the stimulatory effect of physostigmine in limbic areas, but not in the corpus striatum. The present results suggest that ascending dopamine neurons are influenced by cholinergic synaptic transmission being mediated mainly by muscarinic receptors as regards the nigrostriatal system, and by both nicotinic and muscarinic receptors as regards the mesolimbic system. The nicotinic influence appears to primarily control phasic activity of the dopamine neurons.

Clonidine regularizes substantia nigra dopamine cell firing.

The effects of clonidine on the activity of single substantia nigra dopamine neurons were studied in the chloral hydrate anesthetized rat. Although clonidine did not affect the firing rate of the cells, it regularized the firing pattern and decreased burst firing at 2-8 micrograms kg-1 i.v. These effects were antagonized by the alpha 2-antagonist yohimbine. Yohimbine (1.0 mg kg-1) deregularized the firing pattern and increased the firing rate as well as the burst firing. The regularization produced by clonidine is discussed in terms of synaptic efficacy. The results might explain the therapeutic effects of clonidine in certain neuropsychiatric disorders.

[Neuropharmacology of smoking: basic research opens new therapeutic possibilities]. / Tobaksrökningens neurofarmakologi: Grundforskning öppnar nya terapimöjligheter.

Cigarette smoking and other forms of tobacco usage may be described as pharmacological nicotine-dependence. In the article are reviewed recent findings regarding nicotine dependence and its neuropharmacological basis. Nicotine acts via nicotinic receptors, and its dependence-promoting properties appear to be chiefly mediated by stimulation of noradrenaline and dopamine neurons in the brain, which may help to explain the excessive tobacco consumption associated with certain psychiatric disorders. Pharmacological treatment with nicotine substitution has been shown to improve prognosis significantly in smoking cessation programmes. New forms of non-addictive treatment are suggested by recent neuropharmacological findings.

Pharmacology of nicotine.

In recent years progress in basic neuropsychopharmacology and clinical addiction research have allowed the conclusion that tobacco smoking essentially represents an addiction to nicotine. Parallel to this work, experimental research in biochemistry, physiology and pharmacology has provided detailed descriptions of the structure and function of the nicotinic receptor, the biologic mediator of the many actions of nicotine. This article reviews current knowledge of nicotinic mechanisms in the peripheral and central nervous systems as well as some implications for the notion of smoking as an addiction to nicotine. In particular this review will focus on the effects of nicotine on brain dopamine and noradrenaline systems since these neuronal systems appear to be crucially involved in the rewarding and stimulant effects of addictive drugs.

Alpha 1-adrenergic effects on dopamine neurons recorded intracellularly in the rat midbrain slice.

Previous studies have indicated excitatory adrenergic effects on midbrain dopamine systems. To investigate the cellular mechanisms, intracellular recordings were made from neurons in perfused, oxygenated slices of male rat midbrain. Electrophysiological and pharmacological parameters were used to identify cells as principal (presumably dopaminergic) neurons as opposed to secondary (presumably GABAergic) neurons in the substantia nigra zona compacta and the ventral tegmental area. Noradrenalin (10-100 microM) hyperpolarized 57% of all principal cells and depolarized 36%. Sulpiride (100-1000 nM), a dopamine D2 receptor antagonist, completely blocked noradrenalin-induced hyperpolarizations (six of six cells). In sulpiride, noradrenalin depolarized 58% of all principal neurons and had no effect in 42%; this effect was mimicked by the alpha-adrenergic agonist phenylephrine (10-30 microM) which depolarized 43 of 72 cells. The alpha 1 receptor antagonist prazosin (30-100 nM) completely blocked the membrane depolarization produced by either noradrenalin or phenylephrine in all cells tested, whereas alpha 2- and beta-adrenergic agents had no effect. In voltage clamp, phenylephrine evoked an inward current (at -60 mV) and reduced cord conductance by 0.81 +/- 0.14 nS (n = 4). Inward current evoked by phenylephrine became outward at -96 +/- 8 mV, which is near the membrane reversal potential for potassium as predicted by the Nernst equation. Phenylephrine also depolarized secondary cells and increased the frequency of spontaneous GABAA receptor-mediated postsynaptic potentials recorded in both principal and secondary cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of nicotine on dynamic function of brain catecholamine neurons.

Burst firing in the mesolimbocortical dopamine (DA) neurons, originating in the ventral tegmental area (VTA), is facilitated by systemic administration of nicotine. Pharmacological results show that bursting in VTA-DA cells is critically dependent on a tonic, excitatory amino acid drive, probably originating from the medial prefrontal cortex. Cold inactivation of the prefrontal cortex caused pacemaker-like firing of VTA-DA cells, an effect partly antagonized by systemic nicotine. Clinically, hypofrontality has been associated with negative symptoms in chronic schizophrenia and with chronic alcoholism. Thus, smoking may provide a means to partially restore the dynamics of the VTA-DA system in such disorders. Intravenous nicotine also induces a selective activation of bursting in noradrenaline neurons of the pontine nucleus locus ceruleus. Pharmacological and physiological experiments clearly suggest that this effect is indirect, e.g. peripherally elicited and relayed to the locus ceruleus through its excitatory amino acid input from the paragigantocellular nucleus. The locus ceruleus activation is rapid in onset, dose dependent, short lasting and can be repeated within minutes. This effect of nicotine, which would imply an instant coping response, may be relevant to nicotine dependence, particularly in depressive states.

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

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 mumol 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.

Nicotinic effects on the firing pattern of midbrain dopamine neurons.

The effects of systemic administration of nicotine or the nicotinic antagonist mecamylamine on the midbrain dopamine (DA) systems of the rat were studied with single cell recording techniques. Dopamine cells of the zona compacta, substantia nigra (ZC-SN) and the ventral tegmental area (VTA) were identified by their characteristic action potentials, antidromic stimulation methodology and conventional histological procedures. Firing rates as well as firing patterns were determined from computer-generated interspike interval histograms describing burst-firing in relation to single-spike firing. A larger proportion of burst-firing DA cells was found in the VTA when compared with the ZC-SN area. (-)-Nicotine bitartrate (0.5 mg kg-1 i.p.) not only increased the firing rate of ZC-SN neurons but also the amount of burst firing of the ZC-SN neurons and VTA neurons, respectively. Mecamylamine HCl (4.0 mg kg-1 i.p.) decreased the firing rate of VTA cells which, in principle, indicates a tonic nicotinic input in this area. The increase in firing rate of central DA neurons following nicotine administration was found to be associated with increased bursting of the burst firing cells whereas, in contrast, the non-bursting neurons did not respond with burst-firing. Generally, the correlation between nicotine induced changes in firing rate and in burst-firing activity, respectively, was found to be low for midbrain DA neurons. These observations, in conjunction with the previous demonstration of nicotinic receptors in these areas, indicate the existence of a nicotinic input, specifically regulating the firing pattern of these central DA cells. This neuromodulatory effect of nicotine may be significant for its behavioural stimulant action.(ABSTRACT TRUNCATED AT 250 WORDS)

Firing patterns of midbrain dopamine neurons: differences between A9 and A10 cells.

Dopamine neurons of the substantia nigra (A9) and the ventral tegmental area (A10), giving rise to the nigrostriatal and mesolimbic dopamine pathways, respectively, are commonly supposed to show similar electrophysiological activity. There are, however, instances where the two systems are differently modulated. To assess possible physiological differences in the neuronal activity of A9 and A10 neurons, randomly sampled single cells were extracellularly recorded in the chloral hydrate-anaesthetized male rat. In addition to firing rate, the degree of burst firing and the regularity of firing were quantitatively analysed. Our results show that although A9 and A10 do not differ in firing rates, A10 neuronal activity is markedly less regular and shows a higher degree of burst firing, as judged from analysis of inter-spike time interval histograms. Mean burst firing values were 3% for the A9, and 23% for the A10 neurons. Regularity was described by variation coefficients of inter-spike time interval histograms. The mean variation coefficient was 38.4% in the A9 group and 63.8% in the A10 group, i.e. the A10 neuronal firing was less regular. The difference in regularity is partly, but not fully, dependent on the difference in burst firing. Previous biochemical and physiological studies strongly support the functional significance of modulatory changes in midbrain dopamine-cell firing patterns. Since the firing pattern of midbrain dopamine cells seems to be controlled by synaptic inputs, our results indicate a higher tonic modulatory influence on the A10 than on the A9 neurons. Thus the present results imply the pharmacological possibility of preferentially affecting A10 versus A9 dopamine cell function.

Serotonin inhibits synaptic glutamate currents in rat nucleus accumbens neurons via presynaptic 5-HT1B receptors.

Neurons in the nucleus accumbens septi in brain slices from adult male rats were studied with patch clamp recording in the whole-cell conformation. Cells filled with Lucifer Yellow were identified as medium spiny neurons. Electrical stimulation close to the recorded cell evoked excitatory and inhibitory synaptic currents. In the presence of picrotoxin or bicuculline, stimulation at a holding potential of -90 mV evoked an inward excitatory current that was blocked by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 10 microM), identifying it as an excitatory postsynaptic current (EPSC) mediated by glutamate acting at AMPA/kainate receptors. Serotonin (5-hydroxytryptamine, 5-HT; 3-100 microM in the bath) decreased the EPSC in about 90% of the cells. The action of 5-HT was mimicked by N-(3-trifluoromethylphenyl)-piperazine HCl (TFMPP), but not by (+/-)-8-hydroxydipropylaminotetralin (8-OH-DPAT) or (+/-)-2,5-dimethoxy-4-iodoamphetamine HCl (DOI). The 5-HT effect was antagonized by pindolol or cyanopindolol, but not by spiperone, ketanserin or tropisetron. Taken together, these results indicate that 5-HT acts at 5-HT1B receptors. The effect of 5-HT was potentiated by cocaine (0.3-3 microM) or the selective serotonin reuptake inhibitor citalopram. Miniature synaptic currents recorded in the presence of tetrodotoxin were inhibited by CNQX, identifying them as spontaneous miniature EPSCs. 5-HT reduced the frequency of these miniature EPSCs without affecting their amplitude, which indicates a presynaptic site of action. This presynaptic inhibition by 5-HT might be involved in the behavioural effects of cocaine.