The effect of long-term diethylstilbestrol treatment or hyperprolactinemia on the response of the tuberoinfundibular dopamine neurons to elevated prolactin

Adult male rats were rendered hyperprolactinemic by two different methods. Some animals received subcutaneous implants of diethylstilbestrol (DES) or empty capsules. After 2 months the capsules were removed. Other rats received 3 anterior pituitary homografts under the kidney capsule or had sham surgery. The DES-treated rats were killed 8 months after capsule removal, while pituitary-grafted rats were killed 4 or 12 months after surgery. The DES-treated rats had hyperplastic anterior pituitaries, and both the DES-treated rats and the rats with anterior pituitary homografts were hyperprolactinemic. The activity of the TIDA neurons, as evidenced by dopamine (DA) synthesis in the median eminence (ME), was markedly and comparably elevated in both of these experimental groups of rats when compared to their respective controls. These data: show that the maintenance of hyperplastic pituitaries 8 months after DES withdrawal is not due to impaired function of the TIDA neurons; and provide no evidence for a neurotoxic effect of prolonged hyperprolactinemia on the response of the TIDA neurons to elevated PRL.     

Tubero-infundibular dopamine neurons and the secretion of luteinizing hormone and prolactin: extrahypothalamic influences, interaction with cholinergic systems and the effect of urethane anesthesia

In ovariectomized, estrogen-progesterone-pretreated rats, the fluorescence intensity of the cell bodies of tubero-infundibular dopamine (DA) neurons — as detected by histochemical microfluorimetry — increased rapidly after unilateral stimulation (10 min) of arcuate nucleus, medial preoptic area, medial amygdaloid nucleus, nucleus of diagonal tract, bed nucleus of stria terminalis or ventromedial midbrain tegmentum. After catecholamine synthesis inhibition, ventral hippocampal stimulation (30 min) retarded the depletion of DA neurons and thus differed in its effect from preoptic stimulation.Atropine reduced the intensity response to stimulation in all the areas where its action was studied, except for the arcuate nucleus where the DA neurons are mainly localized. Its effect was dose-dependent (0.4–10 mg/kg). Methylatropine, which crosses the blood-brain barrier in much lower amounts, remained ineffective. An increase in the variance of the DA neuron population was noted after atropine, suggesting a certain functional heterogeneity.The changes in fluorescence intensity were correlated with the serum levels of luteinizing hormone (LH) and prolactin. Response patterns depended upon site of stimulation and treatment. With preoptic stimulation, the intensity response was accompanied by a rise in LH and no change in prolactin; atropine caused a reduction of intensity change and LH rise together with an increase in prolactin. With stimulation sites outside the preoptico-tuberal axis, such as medial amygdala, stimulation and atropine affected the intensity in a similar way, yet LH increased only after atropine while prolactin levels were elevated with or without atropine. Urethane anesthesia probably contributed to the differentiation of neuroendocrine responses, its effect being partly counteracted by atropine. Thus, short-term influences depending in part on cholinergic activity reach the tubero-infundibular DA neurons from various extrahypothalamic areas. The accompanying patterns of hormone secretion probably result from an interaction of these neurons with other systems projecting to the median eminence.     

Depletion of dopamine in the prefrontal cortex decreases the basal electrophysiological activity of mesolimbic dopamine neurons

One hypothesis regarding the etiology of schizophrenia proposes that disruption of the dopaminergic innervation of the prefrontal cortex leads to an increase in dopamine (DA) transmission in subcortical regions. In the present study, we examined the effect of 6-hydroxydopamine lesions of the medial prefrontal cortex (mPFC) dopamine innervation on the spontaneous electrophysiological activity of ventral tegmental DA neurons recorded in vivo. DA cell activity was assessed along three dimensions: (1) the relative proportion of DA neurons exhibiting spontaneous activity, (2) their basal firing rate, and (3) the mean percentage of spikes fired in bursts. In lesioned rats, DA neurons in the ventral tegmental area (VTA) exhibited a significantly slower mean firing rate, as well as a significant reduction in the percentage of spikes fired in bursts relative to controls. In contrast, depletion of DA in the mPFC did not have a significant effect on the relative proportion of VTA DA neurons exhibiting spontaneous activity. We suggest that by reducing the basal electrophysiological activity of VTA DA neurons, mPFC DA depletion may lead to an increase in the level of responsivity of the system to excitatory stimuli. Thus, the magnitude of increase in action potential-dependent DA release that occurs in response to a challenge may be augmented in lesioned rats.     

Action of neurotropin on rat hypothalamic neurons in tissue slices

To clarify some of the actions of Neurotropin (NSP), intra- and extracellular measurements were made of 140 paraventricular (PVN) and 48 ventromedial nucleus (VMH) neurons in rat hypothalamic tissue slices in vitro while perfusing NSP, an extract from the inflamed skin of rabbits inoculated with vaccinia virus, through the recording chamber. NSP mostly decreased activity in PVN neurons (inhibition, 46; excitation, 27; excitation-inhibition, 5; no response, 62), and mostly increased it in VMH neurons (excitation, 12; inhibition, 3; no response, 33). Inhibition of PVN neurons by NSP was due to hyperpolarization with no change in membrane conductance. Since ouabain antagonized the NSP-induced inhibition of PVN neurons, the effect was probably due to activation of the sodium pump. Activity of some NSP-responsive PVN neurons was increased by increase of extracellular osmolarity, and activity of some NSP-responsive VMH neurons was increased by glucose application. The results suggest central modulation of autonomic or neuroendocrinological function by distinct NSP influence on PVN and VMH neural activity.     

Inhibitory inputs from rostromedial tegmental neurons regulate spontaneous activity of midbrain dopamine cells and their responses to drugs of abuse

The rostromedial tegmental nucleus (RMTg), a structure located just posterior to the ventral tegmental area (VTA), is an important site involved in aversion processes. The RMTg contains γ-aminobutyric acid neurons responding to noxious stimuli, densely innervated by the lateral habenula and providing a major inhibitory projection to reward-encoding dopamine (DA) neurons in the VTA. Here, we studied how RMTg neurons regulate both spontaneous firing of DA cells and their response to the cannabinoid agonist WIN55212-2 (WIN), morphine, cocaine, and nicotine. We utilized single-unit extracellular recordings in anesthetized rats and whole-cell patch clamp recordings in brain slices to study RMTg-induced inhibition of DA cells and inhibitory postsynaptic currents (IPSCs) evoked by stimulation of caudal afferents, respectively. The electrical stimulation of the RMTg elicited a complete suppression of spontaneous activity in approximately half of the DA neurons examined. RMTg-induced inhibition correlated with firing rate and pattern of DA neurons and with their response to a noxious stimulus, highlighting that inhibitory inputs from the RMTg strongly control spontaneous activity of DA cells. Both morphine and WIN depressed RMTg-induced inhibition of DA neurons in vivo and IPSCs evoked by RMTg stimulation in brain slices with presynaptic mechanisms. Conversely, neither cocaine nor nicotine modulated DA neuron responses to RMTg stimulation. Our results further support the role of the RMTg as one of the main inhibitory afferents to DA cells and suggest that cannabinoids and opioids might disinhibit DA neurons by profoundly influencing synaptic responses evoked by RMTg activation.     

KCNQ Channels in the Mesolimbic Reward Circuit Regulate Nociception in Chronic Pain in Mice

Mesocorticolimbic dopaminergic (DA) neurons have been implicated in regulating nociception in chronic pain, yet the mechanisms are barely understood. Here, we found that chronic constructive injury (CCI) in mice increased the firing activity and decreased the KCNQ channel-mediated M-currents in ventral tegmental area (VTA) DA neurons projecting to the nucleus accumbens (NAc). Chemogenetic inhibition of the VTA-to-NAc DA neurons alleviated CCI-induced thermal nociception. Opposite changes in the firing activity and M-currents were recorded in VTA DA neurons projecting to the medial prefrontal cortex (mPFC) but did not affect nociception. In addition, intra-VTA injection of retigabine, a KCNQ opener, while reversing the changes of the VTA-to-NAc DA neurons, alleviated CCI-induced nociception, and this was abolished by injecting exogenous BDNF into the NAc. Taken together, these findings highlight a vital role of KCNQ channel-mediated modulation of mesolimbic DA activity in regulating thermal nociception in the chronic pain state.     

Long-term effects of dopamine-depleting brain lesions on spontaneous activity of type II striatal neurons: Relation to behavioral recovery

The long-term effects of dopamine (DA)-depleting brain lesions on behavior and spontaneous activity of Type II striatal neurons were measured in rats after intraventricular injection of the neurotoxin 6-hydroxydopamine (6-OHDA). Spontaneous firing rates were increased relative to control values when recorded 4-8 days or 4-6 weeks postlesion in animals displaying aphagia, adipsia and akinesia. In contrast, spontaneous activity was not increased when recorded 4-6 weeks after the lesion in animals that had recovered from behavioral deficits. Other animals that had recovered from the effects of an earlier 6-OHDA treatment were given either a second injection of 6-OHDA or a systemic injection of haloperidol, a DA receptor antagonist. In both groups, discharge rates were elevated relative to control levels in association with a reinstatement of behavioral deficits. These results demonstrate that behavioral recovery after large DA-depleting brain lesions is associated with a return of spontaneous activity of striatal neurons to normal levels, and suggest that both behavioral and electrophysiological measures are dependent on the functioning of residual elements of the DA system.     

Modifications of mesolimbic and nigrostriatal dopaminergic activities after intracerebroventricular administration of prolactin

Summary In the present study we examined the effects of intracerebroventricular (i.c.v.) injections of prolactin (PRL) on the presynaptic activity and postsynaptic sensitivity of mesolimbic and nigrostriatal dopaminergic neurons. In addition, the effects of PRL onin vitro release of dopamine (DA) from perifused striatal fragments were examined. Tyrosine hydroxylase (TH) activity and D2 receptor density in the striatum decreased after i.c.v. PRL administration; this was accompanied by an increase in D2 receptor affinity. These effects occurred after i.c.v. administration of PRL to normoprolactinemic rats, although normally they did not appear after administration to animals with pituitary grafting-induced hyperprolactinemia. Thus, in these animals, i.c.v. PRL failed to decrease TH activity and D1 and D2 receptor densities to a significant extent. In the case of D2 receptors, this was probably due to the fact that pituitary grafting-induced hyperprolactinemia itself was able to reduce the density of this receptor. No changes were observed in DA or L-3, 4-dihydroxyphenylacetic acid (DO-PAC) contents after i.c.v. administration of PRL to both normo- and hyperprolactinemic animals. Basal and K⁺-evoked DA releasein vitro from perifused striatal fragments of normoprolactinemic rats were not affected by the addition of PRL, whereas this hormone enhanced K⁺-evoked DA release when added to perifused striatal fragments from hyperprolactinemic animals. In the limbic forebrain, i.c.v. administration of PRL to normoprolactinemic animals produced a decrease in DA and DOPAC contents and D1 receptor density. Interestingly, none of these effects appeared when PRL was injected to hyperprolactinemic animals. In summary, our results suggest a possible inhibitory role of PRL on the activity of both the nigrostriatal and mesolimbic dopaminergic neuronal systems. These inhibitory effects were reflected in the decreases elicited in a set of neurochemical parameters, indicating either presynaptic activity or postsynaptic sensitivity, after i.c.v.-administered PRL. This observation supports the hypothesis of a possible neuromodulatory role for an extrapituitary PRL on the activity of these neurons, although the fact that most of these effects did not appear when i.c.v. administration was performed in hyperprolactinemic rats also suggests that they are influenced by peripheral PRL levels.     

SKF 38393 alters the rate-dependent D2-mediated inhibition of nigrostriatal but not mesoaccumbens dopamine neurons

Previous electrophysiological studies have failed to identify significant effects of the D1 dopamine (DA) agonist SKF 38393, either alone or in combination with the D2 agonist quinpirole (LY 171555), on the spontaneous firing rate of midbrain DA neurons. We have utilized extracellular single-unit recording techniques to examine whether SKF 38393 can alter D2-mediated inhibition of DA cell activity. Quinpirole-induced inhibition of the spontaneous activity of midbrain DA neurons was observed to be positively correlated with the basal firing rate of the neuron being examined (i.e., faster cells required higher doses to achieve 50% and maximal inhibition). Pretreatment with SKF 38393 (1.0 mg/kg, i.v.; 4 minutes) eliminated the rate dependency of quinpirole-induced inhibition of nigrostriatal but not mesoaccumbens DA neurons. This effect of SKF 38393 was blocked both by the D1 antagonist SCH 23390 and by hemitransections of the forebrain. In summary, SKF 38393 appears to exert Dl-specific, feedback pathway-dependent effects on the profile of responsiveness of nigrostriatal DA neurons to D2-mediated inhibition of cell firing rate.     

Independent glucose effects on rat hypothalamic neurons: an in vitro study

The effects of changes in glucose concentration were studied on 256 ventromedial (VMH), 212 dorsomedial (DMH) and 59 lateral (LHA) neurons recorded from coronally-oriented rat hypothalamic slices. When glucose concentration of the medium was increased (5.5-20 mM), these neurons exhibited 3 response patterns: excitation, excitation followed by inhibition, and inhibition. Twenty percent of neurons in VMH, 33% in DMH, and 41% in LHA responded to increases in glucose concentration. The majority in VMH and DMH were excited, and in LHA, inhibited. Only minor modifications of these ratios were obtained by isolating VMH from the other areas. In isolated DMH, equal numbers were excited and inhibited. Both glucose-responsive and non-glucose-responsive neurons in VMH and DMH were identified by intracellular horseradish peroxidase staining. The dendritic arborizations of glucose-responsive neurons were richer than in non-glucose-responsive neurons. These results suggest that the different populations of glucose-responsive neurons in the VMH, DMH and LHA might have different functions in the regulation of glucose.