Rex Y. Wang

Morphine-induced activation of A10 dopamine neurons in the rat

The effects of intravenous administration of morphine (MOR) on the spontaneous discharge rate of dopamine (DA) neurons in the ventral tegmental area (VTA or A10) and the substantia nigra pars compacta (SNC or A9) were compared. MOR (0.5-3.5 mg/kg) produced a marked increase in the spontaneous firing of both A10 and A9 DA neurons. Naloxone (NAL) reversed the MOR effects. Acute transection of the medial forebrain bundle (MFB) did not interfere with the observed MOR effects on either A10 or A9 DA neurons. However, following chronic lesions of the MFB (6 days), A9 DA neurons were no longer responsive to MOR whereas A10 DA cells were still activated by MOR. Neither radiofrequency lesions of the dorsal raphe nucleus (DRN) nor administration of the 5-HT2 antagonist ketanserin affected the stimulatory effect of MOR on either A10 or A9 DA cells. Thus, it is confirmed that the effects of MOR on A9 DA cells depend on striatonigral feedback pathways. In contrast, it appears that the MOR-induced activation of A10 DA cells does not depend on afferents from the forebrain or on projections from the DRN, suggesting a more direct action of MOR on A10 DA cells. Microiontophoretic application of MOR or enkephalin analogues significantly increased the spontaneous activity of both A9 and A10 DA cells. However, these effects were not reversed by either iontophoretic or intravenous NAL. On the other hand, both intravenously (0.5-1.5 mg/kg) and iontophoretically administered MOR markedly suppressed the electrical activity of non-DA cells found in the vicinity of A10 DA neurons, and this effect was completely reversed by NAL. It is proposed that the MOR-induced activation of A10 DA cells could be mediated indirectly by non-DA cells.

Dopaminergic neurons in the rat ventral tegmental area. I. Identification and characterization

By use of various histochemical techniques, it was shown that both DA and non-DA cells in the VTA project to the NAc. Of these VTA-NAc output cells, the great majority were DA-containing cells. A small number of non-DA cells were encountered most frequently in the lateral part of the VTA. Correspondingly, two distinct groups of neurons, types I and II, could be identified by antidromic stimulation of the NAc. Several lines of evidence suggest that type I cells are DA-containing neurons. The evidence may be summarized as follows: 1. (1) type I cells had a slow-bursting or regular firing pattern, slow discharge rate and wide spike duration which appears to be identical to the characteristics of DA neurons originally described by Bunney et al.16; 2. (2) the great majority of these cells could be activated antidromically by stimulation of the NAc; 3. (3) the conduction velocity and absolute refractory period of type I cells are consistent with unmyelinated fine DA fibers; 4. (4) injection of 6-OHDA, but not 5,7-DHT directly in the MFB blocked antidromic responses of these cells; 5. (5) they were extremely sensitive to intravenously administered DA agonist apomorphine (ID50 = 7 μg/kg); and 6. (6) direct fluorescence histochemical examination of serial sections from brains of animals in which type I cells have been identified by antidromic stimulation of the NAc showed that type I cells are most likely catecholamine-containi ng neurons. By contrast, type II cells possessed an entirely different spectrum of physiological characteristics; in addition, they showed no consistent response to apomorphine and their antidromic responses to stimulation of the NAc were not affected by 6-OHDA. It is concluded that (1) VTA output neurons consist of both DA and nonDA neurons, and (2) identified types I and II neurons in the VTA by antidromic stimulation of the NAc are DA and non-DA cells, respectively.

Comparison of the effects of chronic haloperidol treatment on A9 and A10 dopamine neurons in the rat

The effects of chronic haloperidol (CHAL) treatment on A9 and A10 dopamine (DA) neurons were compared using extracellular single cell recording techniques. CHAL caused a time-dependent reduction in the number of spontaneously active A9 and A10 DA cells and induced an irregular firing pattern in many of the DA cells that remained active. Both of these effects occurred earlier and to a greater extent in A10 than in A9. Intravenous injection of the DA agonist apomorphine reversed both the reduction of active DA neurons and the irregular discharge pattern, suggesting that both effects were due to the process of depolarization inactivation. Lesions of the nucleus accumbens (NAc) produced by ibotenic acid prevented the development of depolarization inactivation of A10 DA neurons, indicating that this process is mediated primarily by NAc-A10 feedback pathways. The results suggest that the slow development of depolarization inactivation of DA cells produced by CHAL may contribute to the delayed onset of the clinical effects of long-term treatment with antipsychotic drugs.

A10 dopamine neurons: Role of autoreceptors in determining firing rate and sensitivity to dopamine agonists

The present experiments investigated the relationship between the spontaneous basal firing rate of A10 dopamine (DA) neurons and their sensitivity to the rate-suppressant effects of intravenously administered apomorphine (APO) and d-amphetamine (AMP) as well as microiontophoretically ejected DA. The results indicated highly significant inverse relationships between basal neuronal activity and sensitivity to DA and DA agonists, i.e. the faster the spontaneous rate of an A10 DA neuron, the less sensitive that cell was to agonist-induced suppression. This relationship was not found for the rate suppressant effects of iontophoretic gamma-aminobutyric acid. There were no significant differences between the effects of iontophoretic DA on pre-glutamate and glutamate-driven activity of the same A10 DA neurons indicating that faster firing rates, per se, did not determine the sensitivity of these cells to DA agonists. Rather, these results suggest that both spontaneous activity and sensitivity to DA agonists may be determined by the density (or sensitivity) of DA autoreceptors on A10 DA neurons. This hypothesis was supported by the finding that antidromically identified mesocortical DA neurons, which were significantly less responsive to DA, APO and AMP exhibited significantly faster firing rates than other A10 DA neurons. Thus, this subpopulation of A10 DA neurons is primarily made up of cells with low autoreceptor density (or sensitivity).

Electrophysiological evidence for A10 dopamine autoreceptor subsensitivity following chronicd-amphetamine treatment

Extracellular single unit recording techniques were used to determine whether chronic treatment with D-amphetamine (AMP) causes a subsensitivity of dopamine (DA) autoreceptors on A10 DA neurons in the rat ventral tegmental area. Either once daily or twice daily intraperitoneal (i.p.) administration of 5.0 mg/kg AMP for 1 week significantly reduced the ability of intravenous (i.v.) AMP and apomorphine (APO) to suppress the firing of A10 DA neurons when tested 24-32 h after the final administration of i.p. AMP. For both of these treatment regimens, the dose-response curves for AMP and APO induced suppression were shifted approximately 4-fold to the right of control. Following an 8 day abstinence period, only the rats that received twice daily AMP injections exhibited subsensitivity to i.v. AMP and APO; the degree of subsensitivity was reduced by 50% as compared to that observed 24-32 h post-treatment. These results were not due to acute tolerance phenomena since a single i.p. injection of AMP 24-32 h before testing failed to alter sensitivity to i.v. AMP and APO. Rather, the results indicate that chronic AMP treatment reduces the sensitivity of A10 DA neurons to DA agonists. DA autoreceptor subsensitivity was demonstrated further by the finding that the ability of microiontophoretically applied DA to suppress A10 DA neuronal activity was markedly reduced (5.8-fold shift of the dose-response curve) by chronic AMP treatment (2 X 5 mg/kg/day). In contrast, there was no alteration in the ability of iontophoretic gamma-amino butyric acid (GABA) to suppress A10 DA activity in chronic AMP rats. Chronic AMP-treatment also increased the number of spontaneously active A10 DA neurons as well as their basal firing rate. It is suggested that the ability of chronic AMP treatment to decrease the auto-regulatory ability of A10 DA neurons may be related to the phenomena of behavioral sensitization and AMP psychosis.

Interactions of cholecystokinin octapeptide and dopamine on nucleus accumbens neurons.

Local microiontophoretic administration of cholecystokinin octapeptide (CCK) increased the firing rates of neurons in the dorsomedial nucleus accumbens (NAc), but exerted little to no effect on lateral NAc neurons. This regionally defined CCK-effect corresponds to the topographical distribution of CCK-like immunoreactive nerve terminal fiber networks and CCK receptors within the NAc. The excitatory effects of CCK were selectively antagonized by the CCK antagonist proglumide. Dopamine (DA) decreased the firing of NAc cells and reversed CCK-induced excitation. These results suggest that CCK and DA may interact to influence the activity of neurons within the dorsomedial NAc.

Dopaminergic neurons in the rat ventral tegmental area. II. Evidence for autoregulation

Abstract Previous studies have shown that the firing activity of A10 DA neurons are depressed following antidromic stimulation of the NAc. This study present data showing that the N Ac-induced effect might be mediated by a direct DA dendrodendritic and/ or axon collateral inhibitory system. The evidence may be summarized as follows: 1. (1) the response of A10 DA neurons to stimulation of the Nac depended upon antidromic invasion of DA fibers; either destruction of DA projections or acutely blocked DA transmission by 6-OHDA prevented the depressant response of the great majority of A10 cells to NAc-stimulation, 2. (2) DA antagonists either blocked or markedly reduced NAc-induced depressant effect on identified A10 DA neurons, and 3. (3) iontophoresis of DA consistently inhibited firing of identified A10 DA neurons. However, destruction of neuronal perikarya in the NAc by ibotenic acid also caused a reduction of NAc-induced effect. The latter finding suggests that in addition to the DA autoregulatory system in the VTA, afferent inputs from the NAc may also contribute to the NAc-induced depressant effect on A10 DA cells.

In vivo release of dopamine in the nucleus accumbens of the rat: modulation by cholecystokinin

We observed that the release of endogenous dopamine (DA), induced by perfusion of a 55 mM K+-containing buffer in the nucleus accumbens, was Ca2+-dependent and confined to a local region. We also demonstrated that the sulphated form of cholecystokinin octapeptide, but not the unsulphated form, suppressed this stimulated release of dopamine in a concentration-dependent manner. This suggests that cholecystokinin may act as a functional antagonist to dopamine within this structure.

Dopaminergic neurons in the rat ventral tegmental area. III. Effects of d-and l-amphetamine

Abstract The effect of d - and l -isomers of amphetamine on the activity of mesolimbic and mesocortical dopamine (DA) neurons in the ventral tegmental area (VTA or A10) was studied in chloral hydrate anesthetized rats. Mesolimbic and mesocortical DA neurons were identified by their antidromic responses to stimulation of the nucleus accumbens (NAc) and the frontal-cingulate cortices, respectively. Similar to their effects on A9 DA cells, d -A was found to be 9.2-fold more potent than l -A in producing 50% inhibition of discharge rate of A10 DA neurons. In addition, pre-treatment with αMT caused approximately a 5-fold increase in the ID 50 of d -A. The depressant effect of d -A could be completely prevented by pre-treatment with both reserpine and αMT; the blockade of d -A effect by reserpine and αMT could be reversed by injections of low doses of l -DOPA. However, unlike its effect on A9 DA cells, the depressant action of d -A on A10 DA neurons was not mediated by forebrain feedback pathways; in rats with either destruction of neuronal perikarya in the NAc by ibotenic acid or acute dience-phalic transection, the IDso of d -A on A10 DA cells remained unchanged. It is concluded that 1. (1) d -A is much more potent than l -A in depressing firing activity of identified A10 DA neurons, and 2. (2) the depressant effect of amphetamine on A10 DA cells is not mediated via a forebrain feedback loop; it may be mediated by a DA dendro-dendritic and/or axon collateral autoregulatory system.

The identification of some sources of afferent input to the rat nucleus basalis magnocellularis by retrograde transport of horseradish peroxidase

Neurons of the nucleus basalis magnocellularis (NBm) of the rat are contained within the ventromedial globus pallidus and adjacent internal capsule. Horseradish peroxidase injection limited to the ventromedial globus pallidus result in sparse neuronal labeling in a variety of brainstem, thalamic and hypothalamic nuclei, and the basal nuclei identified after NBm injections. Thus, these contiguous regions have comparable subcortical inputs. By contrast, only NBm injections yielded a large number of labeled neurons in layer V of NBm cholinergic neurons. in addition to the reciprocity observed between NBm and frontal cortex, the ventral tegmental area and NBm likewise appear to be reciprocally connected.