Dopaminergic Neural Activity Research Articles

Dopamine signaling from ganglion cells directs layer-specific angiogenesis in the retina

During central nervous system (CNS) development, a precisely patterned vasculature emerges to support CNS function. How neurons control angiogenesis is not well understood. Here, we show that the neuromodulator dopamine restricts vascular development in the retina via temporally limited production by an unexpected neuron subset. Our genetic and pharmacological experiments demonstrate that elevating dopamine levels inhibits tip-cell sprouting and vessel growth, whereas reducing dopamine production by all retina neurons increases growth. Dopamine production by canonical dopaminergic amacrine interneurons is dispensable for these events. Instead, we found that temporally restricted dopamine production by retinal ganglion cells (RGCs) modulates vascular development. RGCs produce dopamine precisely during angiogenic periods. Genetically limiting dopamine production by ganglion cells, but not amacrines, decreases angiogenesis. Conversely, elevating ganglion-cell-derived dopamine production inhibits early vessel growth. These vasculature outcomes occur downstream of vascular endothelial growth factor receptor (VEGFR) activation and Notch-Jagged1 signaling. Jagged1 is increased and subsequently inhibits Notch signaling when ganglion cell dopamine production is reduced. Our findings demonstrate that dopaminergic neural activity from a small neuron subset functions upstream of VEGFR to serve as developmental timing cue that regulates vessel growth.

Ethanol metabolism: The good, the bad, and the ugly

Throughout the world, ethanol is both an important commercial commodity and a source of major medical and social problems. Ethanol readily passes through biological membranes and distributes throughout the body. It is oxidized, first to acetaldehyde and then to acetate, and finally by the citric acid cycle in virtually all tissues. The oxidation of ethanol is irreversible and unregulated, making the rate dependent only on local concentration and enzyme activity. This unregulated input of reducing equivalents increases reduction of both cytoplasmic and intramitochondrial NAD and, through the latter, cellular energy state {[ATP]/([ADP][Pi])}. In brain, this increase in energy state stimulates dopaminergic neural activity signalling reward and a sense of well being, while suppressing glutamatergic neural activity signalling anxiety and unease. These positive responses to ethanol ingestion are important to social alcohol consumption. Importantly, decreased free [AMP] decreases AMP-dependent protein kinase (AMPK) activity, an important regulator of cellular energy metabolism. Oxidation of substrates used for energy metabolism in the absence of ethanol is down regulated to accommodate the input from ethanol. In liver, chronic ethanol metabolism results in fatty liver and general metabolic dysfunction. In brain, transport of other oxidizable metabolites through the blood-brain barrier and the enzymes for their oxidation are both down regulated. For exposures of short duration, ethanol induced regulatory changes are rapid and reversible, recovering completely when the concentrations of ethanol and acetate fall again. Longer periods of ethanol exposure and associated chronic suppression of AMPK activity activates regulatory mechanisms, including gene expression, that operate over longer time scales, both in onset and reversal. If chronic alcohol consumption is abruptly ended, metabolism is no longer able to respond rapidly enough to compensate. Glutamatergic neural activity adapts to chronic dysregulation of glutamate metabolism and suppression of glutamatergic neural activity by increasing excitatory and decreasing inhibitory amino acid receptors. A point is reached (ethanol dependence) where withdrawal of ethanol results in significant metabolic energy depletion in neurons and other brain cells as well as hyperexcitation of the glutamatergic system. The extent and regional specificity of energy depletion in the brain, combined with hyperactivity of the glutamatergic neuronal system, largely determines the severity of withdrawal symptoms.

Arousal State-Dependent Alterations in VTA-GABAergic Neuronal Activity.

Decades of research have implicated the ventral tegmental area (VTA) in motivation, learning and reward processing. We and others recently demonstrated that it also serves as an important node in sleep/wake regulation. Specifically, VTA-dopaminergic neuron activation is sufficient to drive wakefulness and necessary for the maintenance of wakefulness. However, the role of VTA-GABAergic neurons in arousal regulation is not fully understood. It is still unclear whether VTA-GABAergic neurons predictably alter their activity across arousal states, what is the nature of interactions between VTA-GABAergic activity and cortical oscillations, and how activity in VTA-GABAergic neurons relates to VTA-dopaminergic neurons in the context of sleep/wake regulation. To address these, we simultaneously recorded population activity from VTA subpopulations and electroencephalography/electromyography (EEG/EMG) signals during spontaneous sleep/wake states and in the presence of salient stimuli in freely-behaving mice. We found that VTA-GABAergic neurons exhibit robust arousal-state-dependent alterations in population activity, with high activity and transients during wakefulness and REM sleep. During wakefulness, population activity of VTA-GABAergic neurons, but not VTA-dopaminergic neurons, was positively correlated with EEG γ power and negatively correlated with θ power. During NREM sleep, population activity in both VTA-GABAergic and VTA-dopaminergic neurons negatively correlated with δ, θ, and σ power bands. Salient stimuli, with both positive and negative valence, activated VTA-GABAergic neurons. Together, our data indicate that VTA-GABAergic neurons, like their dopaminergic counterparts, drastically alter their activity across sleep-wake states. Changes in their activity predicts cortical oscillatory patterns reflected in the EEG, which are distinct from EEG spectra associated with dopaminergic neural activity.

Local administration of the orexin receptor antagonist MK-4305, but not orexin-A, into the nucleus accumbens increases accumbal dopamine efflux in freely moving rats

The nucleus accumbens (NAc), a major terminal area of mesolimbic dopaminergic projections, receives inputs from orexin neurons. Behavioural studies suggest that accumbal orexin receptors (-Rs) play modulatory roles in the regulation of accumbal dopaminergic activity-dependent locomotion in rats (Kotani et al., 2008). We studied the effects of intra-accumbal application of orexin-R ligands on accumbal dopamine (DA) efflux in freely moving rats, using in vivo microdialysis, to analyse the roles of orexin-Rs in regulating accumbal dopaminergic neural activity. Orexin-R ligands were applied into NAc though a microinjection needle attached with a dialysis probe. The OX1- and OX2-R agonist orexin-A failed to alter DA levels in NAc. However, the OX1- and OX2-R antagonist MK-4305 induced a dose-related increase in DA levels. This MK-4305-induced increase in accumbal DA levels was suppressed by infusion of TTX through the probe and was inhibited by local co-administration of orexin-A. These results suggest that intra-accumbal application of MK-4305 could enhance accumbal DA efflux by antagonism of OX1- and/or OX2-Rs. The present study also indicates that accumbal OX1- and/or OX2-Rs could play inhibitory roles in the regulation of accumbal dopaminergic neural activity.

Lorcaserin bidirectionally regulates dopaminergic function site-dependently and disrupts dopamine brain area correlations in rats

Lorcaserin, which is a selective agonist of serotonin2C receptors (5-HT2CRs), is a new FDA-approved anti-obesity drug that has also shown therapeutic promise in other brain disorders, such as addiction and epilepsy. The modulation of dopaminergic function might be critical in the therapeutic effect of lorcaserin, but its exact effect is unknown. Here, we studied the effect of the peripheral administration of lorcaserin on the ventral tegmental area (VTA), the substantia nigra pars compacta (SNc) dopaminergic neural activity, dopamine (DA) dialysis levels in the nucleus accumbens and striatum and on DA tissue levels in 29 different rat brain regions. Lorcaserin (5–640 μg/kg, i.v.) moderately inhibited only a subpopulation of VTA DA neurons, but had no effect on the SNc neurons. Lorcaserin (0.3, 3 mg/kg, i.p.) did not change VTA and SNc DA population neural activity but slightly decreased the firing rate and burst firing of the spontaneously active VTA neurons, without altering DA extracellular dialysate levels in both the nucleus accumbens and the striatum. Quantitative analysis of DA and metabolites tissue contents of the 29 areas studied revealed that lorcaserin (0.3 or 3 mg/kg, i.p.) only affected a few brain regions, i.e., increased DA in the central amygdala, ventral hypothalamus and nucleus accumbens core and decreased it in the ventromedial striatum. On the other hand, lorcaserin dramatically changed the direction and reduced the number of correlations of DA tissue content among several brain areas. These effects on DA terminal networks might be significant in the therapeutic mechanism of lorcaserin.This article is part of the special issue entitled ‘Serotonin Research: Crossing Scales and Boundaries’.

13. ENDOCANNABINOID MODULATION OF DOPAMINE NEUROTRANSMISSION

Overall : There are converging lines of evidence that the endocannabinoid system is involved in the pathophysiology of schizophrenia and that understanding these mechanisms may lead to novel treatment targets. In this symposium, we will present a series of experiments that link cannabinoid pharmacology to major fields of schizophrenia research including the dopaminergic, glutamatergic and serotonergic systems, glial cell function and the genetics of cognition.Dopamine is a major neurotransmitter implicated in the pathophysiology of schizophrenia. Thus, understanding processes that modulate dopaminergic signalling may lead to new insights into the biology and treatment of this disorder. The endocannabinoids anandamide and 2-arachidonoylglicerol (2-AG) modulate dopaminergic neural activity through interactions with CB1 and CB2 receptors. CB1 antagonists inhibit the effects of drugs that potentiate dopaminergic activity, such as cocaine. There is also evidence of interactions between CB1 and CB2 receptors in terms of cannabinoid-mediated changes in dopaminergic function. We will present new evidence that CB2 receptor antagonism opposes the inhibitory effects of rimonabant on cocaine-induced hyperlocomotion. Thus, highlighting the co-modulatory role of CB1 and CB2 receptors on dopaminergic function.We will then present a new study investigating the antipsychotic mode of action of cannabidiol (CBD). CBD attenuates the psychotomimetic effects of delta-9-tetrahydrocannabinol (THC) and there is evidence that CBD has antipsychotic effects in patients with psychosis. CBD prevents a range of behavioural impairments associated with the NMDA hypofunction model of psychosis measured in the pre-pulse inhibition, social interaction and novel object recognition tests following a two week exposure to the NMDA antagonist MK801. In addition, CBD, prevented neural (measured by delta-FosB) and microglia activation, and the decreased decrease in the number of medial prefrontal parvalbumin-positive neurons. The effects of CBD were blocked by pre-treatment with the 5-HT1A receptor antagonist WAY100635. This indicates that the antipsychotic effects of CBD may be mediated via 5HT1A-mediated mechanisms.Next, we will describe the effects of CBD on glial cells. Glial cells, which express CB1 and CB2 receptors and synthesise endocannabinoid transmitters, have been implicated in schizophrenia whereby oligodendrocyte dysfunction has been associated with white matter deficits in the illness. In an investigation of the effects of CBD on a human oligodendrocyte culture (MO3.13), CBD administration resulted in diverse changes in the expression of proteins implicated in the pathophysiology of schizophrenia.Finally, we provide further evidence that polymorphisms in cannabinoid receptor genes are associated with cognitive impairments in humans. In particular, the rs12720071 polymorphism T/T allele is associated with impaired working memory in patients with psychosis.

Mechanisms underlying δ- and μ-opioid receptor agonist-induced increases in extracellular dopamine level in the nucleus accumbens of freely moving rats.

The nucleus accumbens is a terminal area of the mesolimbic dopaminergic system that arises in the ventral tegmental area. Opioids are thought to enhance dopaminergic activity in the nucleus accumbens by activating δ- and μ-opioid receptors in the ventral tegmental area. However, δ- and μ-opioid receptor agonists increase extracellular levels of accumbal dopamine when infused directly into the nucleus accumbens of rats. Therefore, the roles of δ- and μ-opioid receptors in regulation of accumbal dopaminergic neural activity have been analyzed by using δ- and μ-opioid receptor ligands. This review describes the mechanisms underlying the stimulatory effects on accumbal dopamine efflux, which are induced by local administration of δ- and μ-opioid receptor agonists into the nucleus accumbens of freely moving rats. The focus of this article is neurochemical studies that use in vivo microdialysis techniques. Taken together, the in vivo neurochemical evidence from these studies indicates that δ- and μ-opioid receptor agonists increase accumbal dopamine efflux by activating naloxone-sensitive opioid receptors, and by mechanisms independent of naloxone-sensitive opioid receptors, in the nucleus accumbens.

Noradrenaline and dopamine: sharing the Workload

Varazzani and colleagues explored how noradrenergic and dopaminergic neural activity relates to cost/benefit decisions involving effort. They show these systems may play complementary roles in resolving these decisions; dopamine encodes cost-discounted values of rewards, whereas noradrenergic cells modify activity in relation to the amount of effort required to obtain them.

Caffeine, dopamine and thermoregulation

We wish to comment on the recent publication by Ganio et al. (2011) relating to the effects of caffeine on performance in the heat. Based on their demonstration of caffeine’s ergogenicity and lack of effects on core temperature during exercise in high ambient temperature, these authors concluded that caffeine counteracts the negative consequences of elevated core temperature on performance. It is yet not clear through which mechanism this happens, but one possibility is that changes in neurotransmitter concentrations are responsible (influence antagonism adenosine on brain dopamine concentration; Ganio et al. 2011). The effects of caffeine on performance and thermoregulation in hot environments appear not as unanimous as they are for normal ambient temperature. Some studies found an ergogenic effect of caffeine administration, with (Del Coso et al. 2008) or without (Ganio et al. 2011) addition of carbohydrates, while others found no effects of caffeine on performance in the heat (Cheuvront et al. 2009; Roelands et al. 2011). The thermogenic properties of caffeine during exercise in the heat are also not conclusive. Cheuvront et al. (2009) showed thermogenic properties of caffeine during exercise in 40 C, while Ganio et al. (2011) found no effect on thermoregulation during exercise in 33 C. Ganio et al. (2011) observed a 0.2 C increase in core temperature after 90 min of alternating between 60 and 70% _ VO2max and a 0.4 C increase in rectal temperature after a 15-min time trial in the caffeine condition compared to the placebo (derived from Ganio et al. 2011). Although in our experiment (Roelands et al. 2011), the increase in core temperature is slightly higher, our results reached statistical significance. We acknowledge that studies performed on 10–15 subjects may lack statistical power: a power analysis shows that a very large number of subjects (100) are needed to obtain a power of 80%. The mechanism of action of caffeine in the human brain is not clearly understood at this point. Several animal studies have already provided us with information on the role of ascending neurotransmitter systems in the psychostimulant effects of caffeine. The actions of caffeine appear to be mediated by the antagonism of adenosine receptors, leading to increases in neurotransmitter release, with most importantly an increase in dopaminergic neurotransmission (Glaister et al. 2008). In animals, there is evidence for an important role of dopamine in thermoregulation (Hasegawa et al. 2005, 2008), and Balthazar et al. (2010) recently showed that the blockade of dopamine D1 and D2 receptors impairs running performance in rats by decreasing the tolerance to heat storage. Of course, we acknowledge that animal and human models are not entirely the same, but Bridge et al. (2003) reported that in humans, a higher dopaminergic neural activity may demonstrate a higher tolerance to exercise in the heat. Our study design is relevant for describing different exercise situations and other disturbances of homeostasis. Disturbance of brain homeostasis is difficult to accomplish and previously we clearly indicated that specific physiological reactions can occur, i.e., a marked difference in core temperature. Our previous human studies have shown Communicated by Susan A. Ward.

Movement and extrapyramidal disorders associated with interferon use in HIV/hepatitis C coinfection

Movement and extrapyramidal disorders associated with interferon use in HIV/hepatitis C coinfection

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.

Pentobarbital inhibits l-DOPA-induced dopamine increases in the rat striatum: An in vivo microdialysis study

Pentobarbital is reported to inhibit ketamine-induced dopamine (DA) release in the rat nucleus accumbens. The accumbens is a part of the limbic dopaminergic system in the brain, and the dopaminergic neural activity of other components may also be sensitive to pentobarbital. We investigated the effect of pentobarbital administration on DA release in the striatum known as DA-rich basal ganglia, and the interaction between pentobarbital and l-DOPA, using in vivo microdialysis techniques. Male SD rats were implanted microdialysis probe into the right striatum. The probe was perfused with modified Ringer's solution and dialysate was directly injected to an HPLC. Every group of rats was consisted of six to seven animals. In the first experiment, rats were given saline, 25 and 50 mg kg −1 pentobarbital. The second, each rat was given a local administration of 2 and 5 μg ml −1 of l-DOPA with perfusate. Finally, other sets of rats were given 5 μg ml −1 of l-DOPA and 25, 50, or 100 mg kg −1 pentobarbital. Pentobarbital anaesthesia decreased the extracellular concentration of DA, and local administration of l-DOPA significantly increased DA concentration. Pretreatment with pentobarbital diminished the l-DOPA-induced DA increase. The results of the present investigation demonstrate that administration of pentobarbital might inhibit dopaminergic neural activity not only in the nucleus accumbens but also in the rat striatum. Pentobarbital anaesthesia antagonizes DA increase induced by l-DOPA and suggests the inhibition of metabolism of l-DOPA. The results of some animal experiments on dopaminergic activity under pentobarbital anaesthesia should be reconsidered.

Ovulation delay induced by blockade of the cholinergic system on dioestrus-1, is related to changes in dopaminergic activity of the preoptic anterior-hypothalamic area of the rat

One hour after the injection of 100 mg/kg of atropine-sulphate at 1300 h of dioestrus-1, there was an abrupt increase of 17β-oestradiol plasma level and a significant increase in dopaminergic neural activity in preoptic anterior-hypothalamic area, without changes in luteinizing hormone serum level, in comparison with the saline injected group. Animals injected with atropine-sulphate showed a second increase in dopaminergic neural activity in the preoptic anterior-hypothalamic at 1100 of dioestrus-2 (atropine-sulphate 0.471 ± 0.7 vs. saline 0.241 ± 0.03, p < 0.01). In this group of animals, the preovulatory surges of 17β-oestradiol and luteinizing hormone occurred simultaneously at 1700 h of the expected day of oestrus; spontaneous ovulation was delayed until the expected day of dioestrus-1. Present results suggest that during dioestrus-1 there is a functional relationship between the cholinergic and dopaminergic systems in preoptic anterior-hypothalamic area, regulating the release of luteinizing hormone resulting in ovulation.

Effects of selective dopamine D 4 receptor blockers, NRA0160 and L-745,870, on A9 and A10 dopamine neurons in rats

Extracellular single-unit activities of dopamine neurons were recorded using chloral hydrate anaesthetized rats. We examined the reversal effects of the selective dopamine D 4 receptor blockers, NRA0160 (2-Carbamoyl-4-(4-fluorophenyl)-5-[2-[4-(3-fluorobenzylidene) piperidin-1-yl] ethyl] thiazole) and L-745,870 (3-[[4-(4-chlorophenyl) piperazin-1-yl] methyl]-1H-pyrrolo [2,3-b] pyridine), on dopamine agonists induced inhibition of dopamine neural activity. The firing rates of the substantia nigra pars compacta (A9) and the ventral tegmental area (A10) dopamine neurons were inhibited by methamphetamine (MAP: 1 mg kg , i.v.) and apomorphine (APO: 40 μg kg , i.v). NRA0160 dosedependently reversed the inhibitory effects of MAP and APO on both A9 and A10 dopamine neurons. NRA0160 was more potent in reversing the inhibitory effects of both MAP and APO on A10 than A9 dopamine neurons. L-745,870 failed to reverse the inhibition produced by MAP on A9 and A10 dopamine neurons, whereas L-745,870, at the highest dose used, significantly reversed APO-induced inhibition of A10 but not A9 dopamine neurons. These results suggest that NRA0160 has different electrophysiological profiles on dopaminergic neural activity compared to L-745,870 and may have atypical antipsychotic effects.

Repeated interferon-α administration inhibits dopaminergic neural activity in the mouse brain

In vivo effects of single and repeated interferon-α administrations on the dynamics of noradrenaline, dopamine and 5-hydroxytryptamine were investigated in the mouse brain. Single interferon-α administration (15.30 and 60 × 10 6 U/kg i.p.) had no significant effect on the levels of monoamines and their metabolites or monoamine turnover. When interferon-α (15 × 10 6 U/kg i.p.) was administered once a day for 5 days, however, both dopamine and 3,4-dihydroxyphenylacetic acid levels were significantly decreased and α-methyl- p-tyrosine-induced dopamine depletion was significantly suppressed. These results suggest that repeated interferon-α administration inhibits dopaminergic neural activity. This inhibitory action of interferon-α in dopamine neurons may be involved in adverse central effects, such as parkinsonism and depression with suicidal potential.

Inhibition of tuberoinfundibular dopaminergic neural activity during suckling: involvement of mu and kappa opiate receptor subtypes.

Previous studies have shown that mu (mu) and kappa (kappa) opioid antagonists inhibit suckling-induced prolactin release. Prolactin responses elicited by pup suckling or opioid administration are mediated, at least in part, by suppression of dopamine (DA) release from tuberoinfundibular dopaminergic (TIDA) neurons in the hypothalamus. We examined the effects of the mu opiate receptor antagonist, beta-funaltrexamine (beta-FNA), and the kappa opiate receptor antagonist, nor-binaltorphimine (nor-BNI) on the activity of TIDA neurons in lactating rats. TIDA neuronal activity was determined by measuring DOPA accumulation in the caudate putamen (CP) and median eminence (ME). The effects of opioid antagonist treatment were determined in pup-deprived (low circulating prolactin levels) or pup-suckled rats (high circulating prolactin levels). The accumulation of 5-hydroxytryptophan (5-HTP) in the medial preoptic area (MPOA), the anterior hypothalamus (AH) and the median eminence (ME) was quantified as an index of serotonergic activity in the same animals for comparative purposes. In vehicle treated rats, suckling caused a significant and selective decrease in DOPA accumulation in the ME. beta-FNA (5 micrograms, i.c.v.) pretreatment significantly increased DOPA accumulation in the ME of pup-deprived and pup-suckled rats. beta-FNA pretreatment also prevented the suckling-induced suppression of DOPA accumulation in the ME. In contrast to the actions of beta-FNA, pretreatment with nor-BNI (8 micrograms, i.c.v.) did not significantly affect the activity of the TIDA neurons in pup-deprived or pup-suckled rats. Suckling alone did not alter 5-HTP accumulation in any of the brain regions examined, and neither opioid antagonist had appreciable effects on 5-HTP accumulation. These results demonstrate that the EOP tonically inhibit the TIDA neurons in both pup-deprived and pup-suckled, post-partum female rats by acting through the mu, but not the kappa, opiate receptor subtype. Furthermore, the suckling-induced inhibition of TIDA neurons is also mediated through the EOP acting at mu, but not kappa opioid receptors.

Intranigral application of substance P antagonists prevents the haloperidol-induced activation of striatal tyrosine hydroxylase.

The effect of intranigral injections of stable substance P analogs with antagonist properties, namely [D-Pro2, D-Trp7,9]-substance P and [D-Pro2, D-Phe7, D-Trp9]-substance P, on the activity of the nigrostriatal dopaminergic pathway was studied. Dopaminergic neural activity was evaluated by measuring changes in striatal tyrosine hydroxylase activity in response to systemic treatment with haloperidol. When injected into the substantia nigra of normal rats, neither of the two substance P analogs influenced the Vmax of striatal tyrosine hydroxylase or the affinity of the enzyme for its pteridine cofactor. However, when applied into the substantia nigra 10 min before systemic haloperidol, 20 micrograms of either substance P analog was able to prevent the haloperidol-induced activation of striatal tyrosine hydroxylase. The effect was not altered by concurrent microinjection of the GABA-antagonist bicuculline. These results suggests that nigral substance P plays an important role in the activation of nigrostriatal dopamine neurons produced by haloperidol. Thus, both substance P and GABA may reciprocally and independently regulate the activity of nigrostriatal dopamine neurons in response to changes in dopamine receptor activity.

Inhibition by lithium of dopamine receptors in rat prolactin release

We investigated the effect of lithium on prolactin (PRL) secretion in both urethane-anesthetized rats and right atrial catheter-bearing conscious rats. Basal plasma PRL levels were not significantly altered for 4 h after lithium administration. However, lithium treatment apparently potentiated PRL release by haloperidol in both conscious and urethane-anesthetized rats. In addition, the inhibition by apomorphine of PRL secretion was significantly antagonized by lithium in conscious rats. Lithium had no effect on the enhancement of PRL secretion by either 5-hydroxytryptophan or β-endorphin in conscious rats. These observations indicate that lithium affects PRL secretion when dopaminergic neural activity is altered. Therefore, it is possible to postulate that the decrease of dopamine receptor sensitivity by lithium may be related to the therapeutic action of the drug on affective disorders.