Firing Rate Of Dopaminergic Neurons Research Articles

No Effect of Morphine on Ventral Tegmental Dopamine Neurons during Withdrawal

Substantial evidence indicates that the ventral tegmental area (VTA) of the mesocorticolimbic dopaminergic (DA) system has a key role in mechanisms of opiate dependence. Although DA neurons have been studied extensively, little is known about their activity and their response to acute morphine during morphine dependence. We recorded the activity of VTA DA neurons in five groups of anesthetized rats: drug-naive (naive) rats, morphine-dependent [(MD) implanted with pellets] rats, and three groups of withdrawn rats. Withdrawals either were precipitated by naltrexone or occurred spontaneously 24 h or 15 d after pellet removal. We confirmed that acute morphine in naive rats produced a marked increase in the firing of VTA DA neurons. We also found that the basal firing rate of VTA DA neurons was markedly higher in MD than in naive rats; however, in MD rats, acute morphine failed to increase DA activity. We confirmed inhibition of VTA DA activity in MD rats in response to precipitated withdrawal; however, this inhibition resulted only in a normalization of the firing rate to that of naive animals. In rats that had spontaneous withdrawal after 24 h or 15 d, the activity of VTA DA neurons was similar to that of naive rats, and an acute injection of morphine failed to alter their activity. Our results indicate that VTA DA neurons show long-lasting tolerance to the acute effect of morphine after withdrawal. These findings show that VTA DA neural activity is unlikely to be a factor in the altered behavioral responses that occur with acute morphine or naltrexone administration after chronic opiate exposure.

Nociceptive responses of midbrain dopaminergic neurones are modulated by the superior colliculus in the rat

Midbrain dopaminergic neurones exhibit a short-latency phasic response to unexpected, biologically salient stimuli. In the rat, the superior colliculus is critical for relaying short-latency visual information to dopaminergic neurones. Since both collicular and dopaminergic neurones are also responsive to noxious stimuli, we examined whether the superior colliculus plays a more general role in the transmission of short-latency sensory information to the ventral midbrain. We therefore tested whether the superior colliculus is a critical relay for nociceptive input to midbrain dopaminergic neurones. Simultaneous recordings were made from collicular and dopaminergic neurones in the anesthetized rat, during the application of noxious stimuli (footshock). Most collicular neurones exhibited a short-latency, short duration excitation to footshock. The majority of dopaminergic neurones (92/110; 84%) also showed a short-latency phasic response to the stimulus. Of these, 79/92 (86%) responded with an initial inhibition and the remaining 14/92 (14%) responded with an excitation. Response latencies of dopaminergic neurones were reliably longer than those of collicular neurones. Tonic suppression of collicular activity by an intracollicular injection of the local anesthetic lidocaine reduced the latency, increased the duration but reduced the magnitude of the phasic inhibitory dopaminergic response. These changes were accompanied by a decrease in the baseline firing rate of dopaminergic neurones. Activation of the superior colliculus by the local injections of the GABA A antagonist bicuculline also reduced the latency of inhibitory nociceptive responses of dopaminergic neurones, which was accompanied by an increased in baseline dopaminergic firing. Aspiration of the ipsilateral superior colliculus failed to alter the nociceptive response characteristics of dopaminergic neurones although fewer nociceptive neurones were encountered after the lesions. Together these results suggest that the superior colliculus can modulate both the baseline activity of dopaminergic neurones and their phasic responses to noxious events. However, the superior colliculus is unlikely to be the primary source of nociceptive sensory input to the ventral midbrain.

Involvement of the endogenous cannabinoid system in the effects of alcohol in the mesolimbic reward circuit: electrophysiological evidence in vivo

Several lines of evidence indicate that the endogenous cannabinoid system is involved in the pharmacological and behavioural effects of alcohol. The mesolimbic dopaminergic (DA) system and the nucleus accumbens (NAc) process rewarding properties of drugs of abuse, including alcohol and cannabinoids, whereas endocannabinoids in these regions modulate synaptic function and mediate short- and long-term forms of synaptic plasticity. The present study was designed to investigate the contribution of the endogenous cannabinoid system in alcohol electrophysiological effects in the mesolimbic reward circuit. We utilized extracellular single cell recordings from ventral tegmental area (VTA) DA and NAc neurons in anesthetized rats. DA neurons were antidromically identified as projecting to the shell of NAc, whereas NAc putative medium spiny neurons were identified by their evoked responses to basolateral amygdala (BLA) stimulation. Alcohol stimulated firing rate of VTA DA neurons and inhibited BLA-evoked NAc neuron spiking responses. The cannabinoid type-1 receptor (CB1) antagonist rimonabant (SR141716A) fully antagonized alcohol effect in both regions. In the NAc, either inhibition of the major catabolic enzyme of the endocannabinoid anandamide, the fatty-acid amyd hydrolase, with URB597 or a pretreatment with the CB1 receptor agonist WIN55212-2 significantly depressed alcohol-induced effects in the NAc. These results corroborate the notion of the involvement of endocannabinoids and their receptors in the actions of alcohol and highlight the endocannabinoid system as a valuable target in the therapy for alcoholism.

BP 897, a selective dopamine D3 receptor ligand with therapeutic potential for the treatment of cocaine-addiction.

BP 897 is a potent (K(i) = 0.92 nM) dopamine D(3) receptor compound developed for the treatment of cocaine abuse and craving. BP 897 has a high selectivity for the dopamine D(3) versus D(2) receptors (70-fold) and a moderate affinity for 5-HT(1A) receptors, (K(i) = 84 nM), adrenergic-alpha(1) (K(i) = 60 nM) and -alpha(2) adrenoceptors (K(i) = 83 nM). BP 897 displays significant intrinsic activity at the human dopamine D(3) receptor by decreasing forskolin-stimulated cAMP levels and by stimulating mitogenesis of dopamine D(3)-expressing NG108-15 cells. Although these findings suggest that BP 897 is a partial agonist, recent studies in Chinese Hamster Ovary (CHO) cells with expressed dopamine D(3) receptors demonstrated that BP 897 is devoid of any intrinsic activity but potently inhibits dopamine agonist effects (pIC(50) = 9.43 and 9.51) in agonist-induced acidification rate or increase of GTPgammaS binding, respectively. In addition, BP 897 inhibits in vivo (EC(50) = 1.1 mg/kg, i.v.) agonist-induced decrease of firing rate of dopaminergic neurons in the substantia nigra. It has been clearly shown that BP 897, 1 mg/kg, i.p., reduces cocaine-seeking behavior in rats, without producing reinforcement on its own. In rhesus monkeys, BP 897 is not self-administered (up to 30 microg/kg, i.v.) but reduces cocaine self-administration. The potential usefulness of BP 897 in the treatment of drug-seeking behavior is further supported by its effects in drug conditioning models. Although BP 897 reduces L-DOPA-induced dyskinesia in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys, it provokes a return of parkinsonian symptoms. At high doses BP 897 has been reported to produce catalepsy in rats. Pharmacokinetic and toxicological data have not yet been published. These interesting preclinical findings with BP 897 provide additional validation for dopamine D(3) receptor as a therapeutic target for the treatment of cocaine abuse and its associated central nervous system (CNS) disorders. BP 897 recently entered phase II clinical studies.

Presynaptic action of neurotensin on cultured ventral tegmental area dopaminergic neurones

Dopamine-containing neurones of the ventral tegmental area express neurotensin receptors which are involved in regulating cell firing and dopamine release. Although indirect evidence suggests that some neurotensin receptors may be localised on the nerve terminals of dopaminergic neurones in the striatum and thus locally regulate dopamine release, a clear demonstration of such a mechanism is lacking and a number of indirect sites of action are possible. We have taken advantage of a simplified preparation in which cultured rat ventral tegmental area dopaminergic neurones establish nerve terminals that co-release glutamate to determine whether neurotensin can act at presynaptic sites. We recorded glutamate-mediated synaptic currents that were generated by dopaminergic nerve terminals as an index of presynaptic function. The neurotensin receptor agonist NT(8–13) caused an inward current and an enhancement of the firing rate of dopaminergic neurones together with an increase in the frequency of spontaneous glutamate receptor-mediated excitatory postsynaptic currents (EPSCs). Incompatible with a direct excitatory action on nerve terminals, NT(8–13) failed to change the amplitude of individual action potential-evoked EPSCs or the frequency of miniature EPSCs recorded in the presence of tetrodotoxin. However, NT(8–13) reduced the ability of terminal D2 dopamine receptors to inhibit action potential-evoked EPSCs in isolated dopaminergic neurones. Taken together, our results suggest that in addition to its well-known somatodendritic excitatory effect leading to an increase in firing rate, neurotensin also acts on nerve terminals. The main effect of neurotensin on nerve terminals is not to produce a direct excitation, but rather to decrease the effectiveness of D2 receptor-mediated presynaptic inhibition.

Effects of naltrexone on the accumulation of l-3,4-dihydroxyphenylalanine and 5-hydroxy- l-tryptophan and on the firing rate induced by acute ethanol administration

In order to characterize the effects of naltrexone, a μ-opioid receptor antagonist, on acute ethanol-induced functional modification of dopaminergic neurons in the nigrastriatal and mesolimbic dopamine systems, the accumulation of l-3,4-dihydroxyphenylalanine ( l-DOPA) in the cerebral cortex, dorsal striatum and nucleus accumbens and of 5-hydroxy- l-tryptophan (5-HTP) in the hippocampus was measured in normal rats using the μ-hydroxybenzylhydrazine dihydrochloride (NSD-1015) enzymatic inhibition method. In addition, the firing rates of dopaminergic neurons were recorded in the substantia nigra and ventral tegmental area. Naltrexone resulted in a decrease in the dopaminergic neuronal firing rates activated by ethanol and eventually in a reduction of the dopamine synthesis induced by ethanol in the dorsal striatum and nucleus accumbens, but not in the cerebral cortex. Mesolimbic dopamine neurons were slightly more sensitive to ethanol and naltrexone than were nigrostriatal dopamine neurons. The widespread inhibitory action of naltrexone also decreased the ethanol-induced stimulation of hippocampal serotonin synthesis.

Different mechanisms for dopaminergic excitation induced by opiates and cannabinoids in the rat midbrain

1. 1. The mechanism underlying morphine and cannabinoid-induced excitation of meso-accumbens and nigro-striatal dopaminergic neurons was investigated by extracellular single unit recording techniques coupled with antidromic activation from the nucleus accumbens and striatum respectively, in unanesthetized rats. 2. 2. The intravenous administration of cumulative doses (1–4 mg/kg) of morphine, dose-dependently increased the firing rate of dopaminergic neurons projecting to the nucleus accumbens and neostriatum, while the same doses inhibited the activity of pars reticulata neurons of the substantia nigra. Both effects were antagonized by naloxone (0.1 mg/kg i.v.) but not by the selective CB1 receptor antagonist SR 141716A (1 mg/kg i.v.). 3. 3. The intravenous administration of cumulative doses (0.125–0.5 mg/kg) of Δ 9-tetrahydrocannabinol ( Δ 9-THC) also increased the firing rate of meso-accumbens and nigro-striatal dopaminergic neurons; this effect was antagonized by SR 141716A (1 mg/kg i.V.), but not by naloxone. 4. 4. Furthermore, nor Δ 9-THC up to a dose of 1 mg/kg, maximally effective in stimulating dopamine neurons, neither SR 141716A (1 mg/kg i.v.) at a dose able to reverse the stimulatory effect of Δ 9-THC on dopamine cells, did alter the activity of SNr neurons. 5. 5. The results indicate that morphine and Δ 9-THC activate dopaminergic neurons through distinct receptor-mediated mechanisms; morphine may act by removing the inhibitory input from substantia nigra pars reticulata neurons (an effect mediated by μ-opioid receptors). Alternatively, the Δ 9-THC-induced excitation of dopaminergic neurons seems to be mediated by CB1 cannabinoid receptors, while neither μ-opioid receptors nor substantia nigra pars reticulata neurons are involved.

Mechanism of the antialcohol effect of gamma-hydroxybutyric acid

Treatment with gamma-hydroxybutyric acid has been reported to effectively decrease alcohol craving and consumption as well as alcohol withdrawal symptoms in alcoholics. We describe the results of animal studies demonstrating the ability of gamma-hydroxybutyric acid to reduce (1) the severity of ethanol withdrawal signs in rats rendered physically dependent on ethanol and (2) voluntary ethanol intake in selectively bred Sardinian alcohol-preferring rats. Furthermore, we review experimental data suggesting that gamma-hydroxybutyric acid and ethanol have several pharmacological effects in common. Relevant similarities are: (1) stimulation of firing rate of dopaminergic neurons and dopamine release in specific rat brain areas; (2) development of cross-tolerance to the motor-impairing effects after repeated administration in rats; 3) abuse potential, as indicated by self-administration of pharmacologically relevant doses of gamma-hydroxybutyric acid in rats and mice; (4) induction of anxiolytic effects in rats; and (5) induction of similar discriminative stimulus effects, as evidenced by symmetrical generalization in a drug discrimination study in rats. These lines of evidence are discussed in relation to gamma-hydroxybutyric acid exerting its antialcohol effects by a substitution mechanism.

Preferential modulation of mesolimbic vs. nigrostriatal dopaminergic function by serotonin(2C/2B) receptor agonists: a combined in vivo electrophysiological and microdialysis study.

Electrophysiological and in vivo microdialysis were used to investigate and compare the effect of tonic activation of serotonin(2C/2B) (5-HT(2C/2B)) receptors on nigrostriatal and mesolimbic dopaminergic (DA) function. Thus, extracellular single unit recordings of neurochemically-identified DA neurons in the SNc and the VTA, as well as simultaneous monitoring of striatal and accumbal DA release were performed following the administration of the unselective 5-HT(2C/2B) agonists, mCPP (m-chlorophenylpiperazine) and MK 212 [6-chloro-2-(1-piperazinyl)piperazine]. Both mCPP (5-320 microg/kg i. v.) and MK 212 (5-320 microg/kg i.v.) dose-dependently decreased the firing rate of VTA DA neurons. The maximal effect was reached at the cumulative dose of 320 microg/kg mCPP and MK 212, which caused a decrease of 42.6 +/- 12.8% and 56.4 +/- 12.6%, respectively. In addition, the total number of events in bursts and the number of bursts of VTA DA cells were significantly reduced by both mCPP and MK 212. On the other hand, mCPP (5-320 microg/kg i.v.) and MK 212 (5-320 microg/kg i.v.) induced a slight decrease in the basal firing rate, but not in bursting activity of SNc DA neurons. Consistent with electrophysiological data, dialysate DA levels in the nucleus accumbens decreased significantly, reaching the maximum of 26.6 +/- 9.6% below baseline levels 120 min after mCPP (1 mg/kg i.p.) administration, and of 25.2 +/- 5.5% 140 min after MK 212 (1 mg/kg i. p.) injection. DA outflow in the striatum was unaffected by both drugs. The inhibitory effect of both mCPP and MK 212 on VTA DA cell activity was blocked completely by pretreatment with the selective 5-HT(2C) antagonist SB 242084 ¿6-chloro-5-methyl-1-[2-(2-methylpyridyl-3-oxy)-pyrid-5-yl carbamoyl] indoline¿ (200 microg/kg), given intravenously 10 min before the first injection of the 5-HT(2C/2B) agonists. SB 242084 (2. 5 mg/kg i.p.) antagonized also the decrease in DA release induced by mCPP and MK 212 in the nucleus accumbens. Taken together, these data indicate that mCPP and MK 212 selectively inhibit mesolimbic dopaminergic function by acting on 5-HT(2C) receptors. Therefore, selective 5-HT(2C) receptor agonists might be useful in clinical conditions where it is necessary to reduce the mesolimbic dopaminergic activity without affecting the nigrostriatal function.

The role of beta 2-subunit-containing nicotinic acetylcholine receptors in the brain explored with a mutant mouse.

Neuronal nicotinic receptors comprise a family of pentameric oligomers made up of a combination of 10 different subunits. The beta 2 subunit has the widest pattern of expression in the brain and is thus likely to form a significant fraction of neuronal nicotinic receptors. Using mice lacking the beta 2 subunit, we have shown that nAChRs containing this subunit are responsible for most of the high-affinity binding sites for nicotine, cytisine, and epibatidine in the brain. Functional receptors containing the beta 2-subunit are found in the somatodendritic compartment as well as the axonal compartment of neurons. We have examined the contribution of these receptors to the effects of nicotine on the mesolimbic DA system, which mediates the reinforcing properties of many addictive drugs (including nicotine). Submicromolar doses of nicotine, corresponding to the concentrations of nicotine in vivo in self-administration paradigms, increased the firing rate of dopaminergic neurons in vitro in normal mice but not in mice lacking the beta 2 subunit. Consistently, systemic injection of nicotine induced an increase in extracellular dopamine in normal mice but not in mutant mice, and nicotine self-administration was reduced or suppressed in mutant mice. These data support the view that the beta 2-containing receptors are involved in mediating the reinforcing properties of nicotine.

Induction of burst firing in ventral tegmental area dopaminergic neurons by activation of serotonin (5-HT)1A receptors: WAY 100,635-reversible actions of the highly selective ligands, flesinoxan and S 15535.

This study examined the influence of the highly selective 5-HT1A receptor ligands, flesinoxan, S 15535, and WAY 100,635, upon the electrical activity of dopaminergic neurons in the ventral tegmental area (VTA), as compared to serotonergic neurons in the dorsal raphe nucleus (DRN) of anesthetized rats. Flesinoxan, a high-efficacy agonist at both pre- and postsynaptic 5-HT1A receptors, dose-dependently (inhibitory dose (ID)50 = 19.5 microg/kg, i.v.) inhibited the firing of DRN serotonergic neurons. This action was abolished by WAY 100,635 (31 microg/kg i.v.) which is an antagonist at pre- and postsynaptic 5-HT1A receptors. S 15535, which behaves as an agonist and partial agonist at pre- and postsynaptic 5-HT1A receptors, respectively, similarly abolished DRN firing in a WAY 100,635-reversible fashion with an ID50 of 6.1 microg/kg, i.v. In contrast to these actions, both flesinoxan (> or = 500 microg/kg, i.v.) and S 15535 (> or = 125 microg/kg, i.v.) dose-dependently and monophasically increased the firing rate of dopaminergic neurons in the VTA, with maximal effects of 70.1 +/- 17.2% and 33.7 +/- 5.3%, respectively. Further, VTA dopaminergic neurons displaying a regular firing pattern were transformed into a bursting mode. This influence of flesinoxan and S 15535 on VTA cells was abolished by WAY 100,635. Administered alone, WAY 100,635 did not significantly modify the activity of either serotonergic or dopaminergic neurons. In conclusion, the present findings show that selective activation of 5-HT1A receptors not only inhibits serotonergic neurones but also elicits a (possibly related) increase in VTA dopaminergic output. A facilitatory influence of flesinoxan, S 15535, and other selective 5-HT1A receptor ligands upon mesocortical dopaminergic pathways may contribute to their putative antidepressant properties.

Selective serotonin reuptake inhibitors reduce the spontaneous activity of dopaminergic neurons in the ventral tegmental area

Electrophysiological techniques were used to study the effects of paroxetine, sertraline, and fluvoxamine on the basal activity of dopaminergic neurons in the ventral tegmental area (VTA) of rats. Acute i.v. administrations of paroxetine (20–1280 μg/kg), sertraline (20–1280 μg/kg), and fluvoxamine (20–1280 μg/kg) caused a slight but significant reduction in the firing rate of the VTA dopaminergic cells studied. Paroxetine produced a maximal inhibitory effect of 10 ± 11% at the cumulative dose of 160 μg/kg. Sertraline induced a dose-related inhibition of VTA dopaminergic neurons, which reached its maximum (10 ± 7%) at the cumulative dose of 1280 μg/kg. The effect of fluvoxamine on the basal firing rate of VTA dopaminergic neurons was more pronounced as compared to that of paroxetine and sertraline, in that it produced a maximal inhibition of 17 ± 12% at the cumulative dose of 1280 μg/kg. Acute i.v. injections of paroxetine (20–1280 μg/kg), sertraline (20–1280 μg/kg), and fluvoxamine (20–5120 μg/kg) caused a dose-dependent decrease in the basal firing rate of serotonergic neurons in the dorsal raphé nucleus (DRN). Paroxetine and sertraline stopped the spontaneous firing of serotonergic neurons at the cumulative dose of 1280 μg/kg, whereas fluvoxamine reached the same effect only at the cumulative dose of 5120 μg/kg. Pretreatment with the 5-HT 1A receptor antagonist tertatolol (1 mg/kg, i.v.) reduced the inhibitory effects of paroxetine, fluvoxamine, and sertraline on the basal activity of serotonergic neurons in the DRN. Administration of tertatolol induced a 15-fold increase in the ED 50 for fluvoxamine. The antagonistic effect of tertatolol was much less evident in blocking the inhibitory action exerted by paroxetine and sertraline on the activity of serotonergic neurons. Pretreatment with tertatolol (1 mg/kg, i.v.) potentiated the inhibitory effect of fluvoxamine on the basal activity of VTA dopaminergic neurons. Tertatolol did not affect the inhibitory action exerted by paroxetine and sertraline on these neurons. It is concluded that inhibition of the basal firing rate of dopaminergic neurons in the VTA is a common characteristic of selective serotonin reuptake inhibitors (SSRIs). The effects of SSRIs on VTA dopaminergic cell activity might be relevant for their therapeutic action and may explain the origin of the reported cases of akathisia.

Differential effects of neurotensin on dopamine release in the caudal and rostral nucleus accumbens: A combined in vivo electrochemical and electrophysiological study

The time-course of variations in extracellular dopamine concentration following local pressure ejection of 10 −7 to 10 −3 M neurotensin into the ventral tegmental area of the rat was determined in the minute range in the nucleus accumbens by means of differential normal pulse voltammetry associated with carbon fibre electrodes. The effects of neurotensin ejection into the ventral tegmental area were further investigated on the firing activity of the corresponding dopaminergic neurons. The lowest concentration of neurotensin (10 −7 M) enhanced the extracellular dopamine concentration throughout the nucleus accumbens and stimulated the discharge activity of ventral tegmental area dopaminergic neurons. The two highest concentrations of neurotensin (10 −5 M and 10 −3 M) evoked two patterns of responses on the extracellular dopamine concentration and on the discharge activity of dopaminergic neurons. The extracellular dopamine concentration was increased above basal levels in the caudal part of the nucleus accumbens. In the rostral part, the evoked changes exhibited a multiphasic time-course characterized by a decreasing phase below baseline. The firing rate of dopaminergic neurons was either increased or decreased, depending on the neuron being tested. In fact, neurotensin ejection was always followed by an exacerbation of bursting activity, the resulting effect on the mean firing rate being related to the duration of the interburst intervals. Indeed, short interburst intervals permitted an increase in mean firing rate whereas long interburst intervals, indicative of excessive depolarization, led to a decrease in mean firing rate. These results suggest that variations in extracellular dopamine concentration evoked by neurotensin administration into the ventral tegmental area are the result of neurotensin-evoked changes in dopaminergic activity. Moreover, the differential effects evoked by high concentrations of neurotensin could be attributable to two subpopulations of ventral tegmental area dopaminergic neurons which could project differentially to the caudal and the rostral parts of the nucleus accumbens.

Postsynaptic nicotinic receptors on dopaminergic neurons in the substantia nigra pars compacta of the rat

Previous studies have shown that application of nicotinic agonists in the substantia nigra pars compacta increases the firing rate of dopaminergic neurons. We have used intracellular recordings to show that the response of these neurons to nicotine is postsynaptic, since it persists in the presence of low-calcium buffer containing tetrodotoxin. Burst firing in the presence of nicotine was not observed. The presence of postsynaptic nicotinic receptors was confirmed by immunohistochemical localization of the α4 nicotinic receptor subunit on dendrites in the substantia nigra pars compacta. The majority of tyrosine hydroxylase-immunopositive neurons in the substantia nigra pars compacta were also immunopositive for the α4 subunit. Immunohistochemical localization of the α4 and β2 subunits in adjacent brain sections produced similar patterns of staining. Electron micrographs clearly indicated the presence of α4 subunit at postsynaptic densities. The predominant role of nicotinic receptors in the central nervous system has been suggested to be the presynaptic modulation of neurotransmitter release [McGehee D. S. and Role L. W. (1995) A. Rev. Physiol. 57, 521–546]. Although several postsynaptic nicotinic responses have also been reported in the literature, it is unclear as to whether the postsynaptic nicotinic receptors mediating responses to exogenously applied agonists are involved in synaptic transmission. From our electrophysiological and immunohistochemical results, we conclude that α4-containing nicotinic receptors are found at synapses on dopaminergic neurons. These synapses are similar to the cholinergic synapses described at these neurons, suggesting that nicotinic receptors are important in modulating the excitability of dopaminergic neurons by direct synaptic transmission.

Nicotine modifies the activity of ventral tegmental area dopaminergic neurons and hippocampal GABAergic neurons

While trying to mimic the dose and time course of nicotine as it is obtained by a smoker, we found the following results. The initial arrival of even a low concentration of nicotine increased the firing rate of dopaminergic neurons from the ventral tegmental area (VTA) and increased the spontaneous vesicular release of GABA from hippocampal neurons. Longer exposure to nicotine caused variable, but dramatic, desensitization of nicotine receptors and diminished the effects of nicotine. The addictive properties of nicotine as well as its diverse effects on cognitive function could be mediated through differences in activation and desensitization of nicotinic receptors in various areas of the brain.

The Effects of Ethanol on Dopaminergic Neurons of the Ventral Tegmental Area Studied with Intracellular Recording in Brain Slices

Dopaminergic neurons in the ventral tegmental area of Tsai (VTA) have been implicated in the mediation of the rewarding effects of ethanol and many other drugs of abuse. Our previous extracellular studies in brain slices have demonstrated that ethanol increases the firing rate of dopaminergic neurons in the VTA. In the present intracellular study, ethanol (40-160 mM) increased the spontaneous firing rate of most (77%) VTA neurons. In addition, most (75%) VTA neurons were depolarized by ethanol. Ethanol also changed the shape of the spontaneous action potential in VTA neurons, reducing the amplitude of the spike after-hyperpolarization (in 74% of neurons) and also reducing the amplitude of the depolarizing phase of the action potential (in 86% of neurons tested). Furthermore, analysis of Voltage/Current curves in the presence and absence of ethanol showed that ethanol had little effect on the resistance of the cell membrane at membrane potentials near rest, but enhanced the time-dependent inward rectification activated at more hyperpolarized membrane potentials (Ih). This intracellular study identifies several electrophysiological effects of ethanol that may underlie the ethanol-induced excitation of VTA neurons and, therefore, may be important for the rewarding effects of ethanol.

Effects of electrical stimulation of the central nucleus of the amygdala on the in vivo electrophysiological activity of rat nigral dopaminergic neurons.

The central nucleus of the amygdala (CeA) receives a dopaminergic (DA) innervation from the midbrain. Among its many efferent projections, the CeA innervates the substantia nigra. The possibility that the CeA influences the activity of nigral DA neurons was evaluated. The effects of electrical stimulation of the CeA on the firing rate and pattern of nigral DA neurons were investigated in anesthetized rats. Poststimulus time histograms revealed that nigral DA cells were either inhibited (N = 15), excited (N = 13), or unresponsive (N = 17) to CeA stimulation (250 stimuli at 0.5 Hz). The mean (+/- SEM) latency to inhibition (24 +/- 9 msec) was significantly shorter than that for excitation (65 +/- 10 msec); the duration of inhibition (200 +/- 29 msec) was also significantly greater than the duration of excitation (86 +/- 11 msec) (P < 0.01 for both). DA cells that were excited had basal firing rates significantly lower than those of the inhibited or unresponsive cells (P < 0.05). Preliminary data suggest that DA cell burst-firing increases or decreases, respectively, in association with stimulation-evoked increases or decreases in firing rate. The relatively long latencies for stimulation-evoked responses suggest that CeA projection neurons indirectly affect nigral DA neurons via polysynaptic pathways. These results demonstrate that the CeA has the ability to influence the activity of nigral DA neurons, consistent with the putative role of the CeA as an interface between the limbic and extrapyramidal systems. Given the crucial role of the amygdala in anxiety states, these findings suggest that DA cell function may also be affected in such disorders.

Differential effects of acute and chronic fluoxetine administration on the spontaneous activity of dopaminergic neurones in the ventral tegmental area.

1. Electrophysiological techniques were used to study the effects of fluoxetine and citalopram on the basal activity of dopaminergic neurones in the ventral tegmental area (VTA) and substantia nigra, pars compacta (SNc) of rats. 2. Acute i.v. injection of fluoxetine (20-1280 micrograms kg-1) caused a dose-dependent inhibition of the firing rate of VTA dopaminergic neurones, but did not affect the activity of dopaminergic cells in the SNc. Citalopram (20-1280 micrograms kg-1, i.v.) inhibited the firing rate of dopaminergic neurones in the VTA, but its effect (maximal inhibition: 14 +/- 7%) was less pronounced than that of fluoxetine (maximal inhibition: 34 +/- 7%). 3. Pretreatment with mesulergine (80 micrograms kg-1, i.v.), a 5-hydroxytryptamine2C/2B (5-HT2C/2B) receptor antagonist, blocked the inhibitory effect of fluoxetine on VTA dopaminergic cells. Selective lesions of 5-hydroxytryptaminergic neurones by the neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT), abolished the fluoxetine-induced reduction of VTA dopaminergic activity. 4. In a series of experiments, fluoxetine (10 mg kg-1, i.p.) was administered once daily for 21 consecutive days. Acute i.v. administration of fluoxetine (20-1280 micrograms kg-1, 72 h after the last i.p. injection) did not cause any change in the basal firing rate of VTA dopaminergic neurones in treated rats, whereas it induced the typical inhibitory effect in control animals. A group of rats chronically treated with fluoxetine, received i.v. m-chlorophenylpiperazine (mCPP; 10-320 micrograms kg-1), a 5-HT2C/2B receptor agonist. This drug significantly inhibited VTA dopaminergic function in control rats, but did not modify the basal activity of dopaminergic cells in animals given chronic fluoxetine. 5 It is concluded that fluoxetine inhibits dopaminergic function in the VTA by enhancing the synaptic levels of 5-HT, which possibly acts through the 5-HT2C/2B receptor subtype. Repeated treatment with fluoxetine induces tolerance to its inhibitory effect on dopaminergic activity, possibly as a consequence of down-regulation of 5-HT2C/2B receptors. The effects of fluoxetine on VTA dopaminergic cell activity might be relevant for its therapeutic actions and may explain the origin of the reported cases of akathisia.

Activation of dopamine D 3 autoreceptors inhibits firing of ventral tegmental dopaminergic neurones in vivo

The firing rate of dopaminergic neurones in the ventral tegmental area of anaesthetised rats was dose-dependently (0.31–5.0 μg/kg i.v.) inhibited by the dopamine D 3 receptor agonist, (+)-7-OH-DPAT (7-hydroxy-2-(di- n-propylamino)tetralin). The selective dopamine D 3 receptor antagonist, (+)-S 14297 ((+)-[7-( N,N-dipropylamino)-5,6,7,8-tetrahydro-naphtho(2,3 b)dihydro,2,3-furane]), dose-dependently (16–125 μg/kg i.v.) inhibited the action of (+)-7-OH-DPAT (5 μg/kg i.v.); its inactive distomer, (−)-S 17777 (125 μg/kg i.v.), was ineffective. Alone, (+)-S 14297 (125 μg/kg i.v.) did not modify the firing rate. Haloperidol (16 μg/kg i.v.) fully reversed the action of (+)-7-OH-DPAT and, alone, significantly increased firing rate. These data suggest that inhibitory (dendritic) dopamine D 3 (auto)receptors control the electrical activity of ventral tegmental area-localised dopaminergic neurones.

Dopamine agonists in schizophrenia: a review

Although it is unlikely that the different types of course and severity of schizophrenia are caused by one neurochemical abnormality alone, indirect pharmacological evidence still suggests a relative excess of dopaminergic activity being implicated in the pathogenesis of most of the schizophrenic symptoms, e.g. positive symptomatology. Synthesis and release of dopamine as well as firing rates of dopaminergic neurons are controlled by stimulation of autoreceptors via a negative feedback regulation. Investigations on therapeutic effects of autoreceptor-nonselective dopamine agonists in schizophrenia have yielded inconsistent results. Dopamine autoreceptor agonists like pramipexole, roxindole, talipexole and OPC-4392 as well as partial agonists like terguride and SDZ HDC 912 have been tested in positive schizophrenic symptomatology in order to reduce the postulated excess of central dopaminergic activity. However, administration of autoreceptor-`selective' agonists did not result in a significant improvement of positive symptoms. In predominantly negative schizophrenic symptomatology, a dopamine deficit rather than an excess has been hypothesized. Consequently, a nonselective dopamine agonistic action could be effective in some negative symptoms. Current evidence from several open and one placebo-controlled clinical trial suggests that some dopamine autoreceptor agonists like pramipexole, roxindole and talipexole may produce a mild improvement of symptoms like affective flattening, depressed mood, alogia and avolition. Nevertheless, these findings do not yet allow a reliable judgement and remain to be clarified by further double-blind placebo-controlled studies over a sufficient treatment duration.