J. Grenhoff

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.

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.

Noradrenergic modulation of midbrain dopamine cell firing elicited by stimulation of the locus coeruleus in the rat

Electrical stimulation techniques were employed in the chloral hydrate anaesthetized male rat to evaluate if the pontine noradrenergic nucleus locus coeruleus can influence the activity of midbrain dopamine neurons in the ventral tegmental area and zona compacta, substantia nigra. Single-pulse locus coeruleus stimulation evoked an excitation, followed by an inhibition, of the electrical activity of single midbrain dopamine neurons. Neither of these responses were observed in animals pretreated with reserpine, implicating noradrenaline as a mediator. The α1-adrenoceptor antagonist prazosin decreased the excitation, while other adrenoceptor antagonists were without general effect. Burst-type stimulation produced only a more long-lasting inhibition. The influence from the locus coeruleus on midbrain dopamine neurons could be important in behavioural situations involving novelty and reward, and might also be of importance for the actions of psychotropic drugs.

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.

Effects of dizocilpine (MK-801) on rat midbrain dopamine cell activity: differential actions on firing pattern related to anatomical localization

The effects of the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine ((+)-MK-801) on the firing pattern of midbrain dopamine neurons were studied with single cell recording techniques in male albino rats anaesthetized with chloral hydrate. The extracellularly recorded electrical activity of single, identified dopamine neurons was studied with respect to firing rate, burst firing and regularity of firing. MK-801 (0.01–1.0 mg/kg IV) induced different effects in different subgroups of midbrain dopamine neurons. In the substantia nigra, firing rate was increased while the pattern was regularized and burst firing slightly increased. In the ventral tegmental area, firing rate and regularity of firing was also increased while effects on burst firing were bidirectional. Histological inspections revealed that neurons which responded with an increase in burst firing were mainly located in the nucleus paranigralis subdivision of the ventral tegmental area, while cells responding with a decrease were predominantly found in the nucleus parabrachialis pigmentosus subdivision. The effects of MK-801 were similar to previously described effects of phencyclidine, another non-competitive NMDA antagonist. The present effects of MK-801 might shed some light on the mechanisms involved in psychotic symptoms induced by phencyclidine and other non-competitive NMDA antagonists.

Role of α7 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 nicotines association with neuropsychiatric disorders, thereby offering the prospect of new therapeutic advances for their treatment.

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 μm), identifying it as an excitatory postsynaptic current (EPSC) mediated by glutamate acting at AMPA/kainate receptors. Serotonin (5‐hydroxytryptamine, 5‐HT; 3–100 μm 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‐hydroxy‐dipropylaminotetralin (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 μm) 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.

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.

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 Μmol 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.