Systemic Administration Of Haloperidol Research Articles

Locomotor activity and accumbens Fos expression driven by ventral hippocampal stimulation require D 1 and D 2 receptors

Numerous studies have suggested that excitatory projections from the ventral hippocampus to the nucleus accumbens modulate locomotor activity in rats. Furthermore, the ability of ventral hippocampal neurons to alter locomotor activity may involve the dense dopaminergic innervation found in the nucleus accumbens. The purpose of this study was to: (i) more fully characterize the locomotor effects of acute alterations in ventral hippocampal activity; (ii) ascertain the influence of dopamine agonists and antagonists on locomotor changes produced by altered ventral hippocampal activity; and (iii) use immediate early gene induction to determine whether dopamine antagonists alter the response of nucleus accumbens neurons to ventral hippocampal stimulation. By comparing a variety of excitatory amino acid agonists, it was found that ventral hippocampal infusion of N-methyl- d-aspartate elevated locomotor activity in a subconvulsive manner, while other excitatory amino acid receptor agonists did not. Inactivation of the ventral hippocampus achieved by lidocaine infusion did not suppress ongoing locomotor activity, nor did it affect amphetamine-induced increases in locomotor activity. Increases in locomotor activity induced by ventral hippocampal N-methyl- d-aspartate infusion were blocked by systemic administration of haloperidol (a D 2 receptor antagonist), SCH-23390 (a D 1 receptor antagonist) or reserpine. Cellular expression of the protein product of the immediate early gene, c-fos, was dramatically increased in the nucleus accumbens shell after ventral hippocampal N-methyl- d-aspartate infusion, and haloperidol, SCH-23390 and reserpine attenuated this effect. These results suggest that the increases, but not decreases, in ventral hippocampal activity have a measurable effect on ongoing rates of locomotion, and that this effect requires both D 1 and D 2 receptors. Moreover, the studies of Fos expression suggest that dopamine receptor antagonists attenuate neuronal responses to ventral hippocampal stimulation within the nucleus accumbens, a brain region important in the generation and maintenance of locomotor activity.

Effects of calcium channel ligands on hypnotic activity of ethanol in mice: G. Biała. Department of Pharmacodynamics, Medical University School, Staszica 4, PL-20-081 Lublin, Poland

The globus pallidus plays a critical role in movement regulation. Morphological studies have shown that group I mGluRs including mGluR1 and mGluR5 are expressed in the globus pallidus. Up to now, little is known about the in vivo electrophysiological effects of group I mGluRs on the pallidal neurons. The present study investigated the electrophysiological effects of group I mGluRs on the firing rate of pallidal neurons in anesthetized rats. Single unit in vivo extracellular recordings showed that micropressure ejection of group I mGluRs agonist, 3,5-dihydroxyphenylglycine (DHPG), increased the spontaneous firing rate of pallidal neurons. DHPG-induced excitation could be blocked by mGluR1 antagonist, (S)-(+)-α-amino-4-carboxy-2-methylb-enzeneacetic acid (LY367385), but not mGluR5 antagonist, 2-methyl-6-(phenylethynyl)-pyridine (MPEP). LY367385 alone had no effect but MPEP alone increased the excitability of pallidal neurons. Unilateral microinjection of DHPG into the globus pallidus induced a contralateral dystonic posturing in the presence of systemic haloperidol administration and this effect could be blocked by LY367385 but not MPEP. The present in vivo electrophysiological and behavioral studies indicate that group I mGluRs could produce excitatory effect on pallidal neurons via mGluR1, and blockade of mGluR5 also has an excitatory effect on pallidal neurons. Our findings suggest that the effects of globus pallidus in movement regulation is partly mediated by group I mGluRs.

α1‐adrenergic, D1, and D2 receptors interactions in the prefrontal cortex: Implications for the modality of action of different types of neuroleptics

The activation of rat mesocortical dopaminergic (DA) neurons evoked by the electrical stimulation of the ventral tegmental area (VTA) induces a marked inhibition of the spontaneous activity of prefrontocortical cells. In the present study, it was first shown that systemic administration of either clozapine (a mixed antagonist of D1, D2, and α1-adrenergic receptors) (3–5 mg/ kg, i.v.), prazosin (an α1-adrenergic antagonist) (0.2 mg/ kg, i.v.), or sulpiride (a D2 antagonist) (30 mg/ kg, i.v.), but not SCH 23390 (a D1 antagonist) (0.2 mg/ kg, i.v.), reversed this cortical inhibition. Second, it was found that following the systemic administration of prazosin, the VTA-induced cortical inhibition reappeared when either SCH 23390 or sulpiride was applied by iontophoresis into the prefrontal cortex. Third, it was seen that, whereas haloperidol (0.2 mg/ kg, i.v.), a D2 antagonist which also blocks α1-adrenergic receptors, failed to reverse the VTA-induced inhibition, the systemic administration of haloperidol plus SCH 23390 (0.2 mg/ kg, i.v.) blocked this inhibition. Finally, it was verified that the cortical inhibitions obtained following treatments with either “prazosin plus sulpiride” or “prazosin plus SCH 23390” were blocked by a superimposed administration of either SCH 23390 or sulpiride, respectively. These data indicate that complex interactions between cortical D2, D1, and α1-adrenergic receptors are involved in the regulation of the activity of prefrontocortical cells innervated by the VTA neurons. They confirm that the physiological stimulation of cortical α1-adrenergic receptors hampers the functional activity of cortical D1 receptors and suggest that the stimulations of cortical D1 and D2 receptors exert mutual inhibition on each other's transmission. Synapse 30:362–370, 1998. © 1998 Wiley-Liss, Inc.

Alpha1-adrenergic, D1, and D2 receptors interactions in the prefrontal cortex: implications for the modality of action of different types of neuroleptics.

The activation of rat mesocortical dopaminergic (DA) neurons evoked by the electrical stimulation of the ventral tegmental area (VTA) induces a marked inhibition of the spontaneous activity of prefrontocortical cells. In the present study, it was first shown that systemic administration of either clozapine (a mixed antagonist of D1, D2, and alpha1-adrenergic receptors) (3-5 mg/kg, i.v.), prazosin (an alpha1-adrenergic antagonist) (0.2 mg/kg, i.v.), or sulpiride (a D2 antagonist) (30 mg/kg, i.v.), but not SCH 23390 (a D1 antagonist) (0.2 mg/kg, i.v.), reversed this cortical inhibition. Second, it was found that following the systemic administration of prazosin, the VTA-induced cortical inhibition reappeared when either SCH 23390 or sulpiride was applied by iontophoresis into the prefrontal cortex. Third, it was seen that, whereas haloperidol (0.2 mg/kg, i.v.), a D2 antagonist which also blocks alpha1-adrenergic receptors, failed to reverse the VTA-induced inhibition, the systemic administration of haloperidol plus SCH 23390 (0.2 mg/kg, i.v.) blocked this inhibition. Finally, it was verified that the cortical inhibitions obtained following treatments with either "prazosin plus sulpiride" or "prazosin plus SCH 23390" were blocked by a superimposed administration of either SCH 23390 or sulpiride, respectively. These data indicate that complex interactions between cortical D2, D1, and alpha1-adrenergic receptors are involved in the regulation of the activity of prefrontocortical cells innervated by the VTA neurons. They confirm that the physiological stimulation of cortical alpha1-adrenergic receptors hampers the functional activity of cortical D1 receptors and suggest that the stimulations of cortical D1 and D2 receptors exert mutual inhibition on each other's transmission.

Regulation of extracellular dopamine by the norepinephrine transporter.

There is growing evidence of an interaction between dopamine and norepinephrine. To test the hypothesis that norepinephrine terminals are involved in the uptake and removal of dopamine from the extracellular space, the norepinephrine uptake blocker desmethylimipramine (DMI) was infused locally while the extracellular concentrations of dopamine were simultaneously monitored. DMI increased the extracellular concentrations of dopamine in the medial prefrontal cortex and nucleus accumbens shell but had no effect in the striatum. The combined systemic administration of haloperidol and the local infusion of DMI produced an augmented increase in extracellular dopamine in the cortex compared with the increase produced by either drug alone. This synergistic increase in dopamine overflow is likely due to the combination of impulse-mediated dopamine release produced by haloperidol and blockade of the norepinephrine transporter. No such synergistic effects were observed in the nucleus accumbens and striatum. Local perfusion of the alpha2-antagonist idazoxan also increased the extracellular concentrations of dopamine in the cortex. Although the stimulation of extracellular dopamine by idazoxan and DMI could be due to the increased extracellular concentrations of norepinephrine produced by these drugs, an increase in dopamine also was observed in lesioned rats that were depleted of norepinephrine and challenged with haloperidol. This contrasted with the lack of an effect of haloperidol on cortical dopamine in unlesioned controls. These results suggest that norepinephrine terminals regulate extracellular dopamine concentrations in the medial prefrontal cortex and to a lesser extent in the nucleus accumbens shell through the uptake of dopamine by the norepinephrine transporter.

Dystonic posturing and circling behaviors induced by dopaminergic agents in rats with unilateral globus pallidus lesions

The present study examined the behavioral effects of dopamine receptor agonists, antagonists, or N-methyl- d-aspartate (NMDA) glutamate receptor antagonist in rats with a unilateral excitotoxic lesion of the globus pallidus (GP). After the unilateral GP lesions were made by injections of the ibotenic acid, drugs were systemically given and the elicited behaviors were quantitatively assessed. Systemic administration of haloperidol, but not SCH23390, dose-dependently induced contraversive dystonic posturing in unilateral GP-lesioned rats. On the other hand, systemic administration of quinpirole, but not SKF38393, induced ipsiversive circling. MK-801, only when given at a high dose, caused ipsiversive circling with dystonic posturing. The present results showed that, in unilateral GP-lesioned rat, the D2 receptor agonist and antagonist caused ipsiversive and contraversive posturing or circling, respectively. Since the rotational behavior is induced on the basis of asymmetry of the basal ganglia output activity, there must be a marked difference between the GP ablation and the administration of D2 receptor blockade on the basal ganglia output activity, supporting a speculation that overactivity of the basal ganglia under dopamine depletion is not solely a result of the disinhibition from the inhibitory GP efferents. The present unilateral GP-lesion model appears to be a useful one for the pharmacobehavioral investigation of D2-mediated mechanisms.

Activation of tyrosine hydroxylase by haloperidol in fetal nigral transplants.

Release of dopamine (DA) from the terminals of solid fetal mesencephalic grafts has been shown to be modulated by DA receptor activity. In order to determine whether DA synthesis in the terminals of these grafts is regulated by the host, we examined the activity of tyrosine hydroxylase (TH), the rate limiting enzyme in the synthesis of dopamine, after blockade of DA receptors with haloperidol (HAL). Solid fetal mesencephalic tissue was grafted over the dorsal surface of the striatum, ipsilateral to a 6-hydroxydopamine lesion in the medial forebrain bundle. Systemic administration of HAL caused an activation of TH in the transplant terminals, reflected by an increased affinity of TH for the pteridine cofactor. Our results indicate that a transneuronal feedback mechanism similar to that operating in the intact nigrostriatal system is regulating DA synthesis and utilization in the terminals of the transplant.

Vacuous jaw movements and feeding deficits in rats with ventrolateral striatal dopamine depletion: possible relation to parkinsonian symptoms

A series of experiments examined the effects of regional dopamine depletions produced by intrastriatal injections of 6-hydroxydopamine on voluntary and involuntary movements in rats. Depletion of dopamine in the ventrolateral striatum produced a substantial decrease in food intake, from which the animals recovered. Rats with dopamine depletions in anteroventromedial or dorsolateral striatum did not have significant feeding deficits. Rats with ventrolateral dopamine depletions showed no deficits in locomotor activity or rearing behavior; however, depletions of dopamine in dorsolateral striatum significantly reduced rearing. Vacuous jaw movements that resemble chewing were produced by dopamine depletion in the ventrolateral striatum, but not the anteroventromedial or dorsolateral striatum. Systemic administration of haloperidol (0.4 mg/kg) increased vacuous chewing responses in dopamine-depleted and control rats. Thus, vacuous chewing responses can result from reduced functional activity of striatal dopamine, and these responses share some characteristics with human parkinsonian symptoms. In addition, these data support the notion that the neostriatum is functionally heterogeneous and that the ventrolateral region is particularly important for oral motor control.

Role of dopamine in anticipatory and consummatory aspects of sexual behavior in the male rat.

The ability of dopamine (DA) receptor antagonists to disrupt anticipatory and consummatory measures of sexual behavior displayed by male rats in bilevel chambers was investigated. In Experiment 1, systemic administration of haloperidol, pimozide, and the D1 antagonist SCH 23390 reduced the number of anticipatory level changes (LC) displayed during a 5-min period before the introduction of a sexually receptive female, increased the mount and intromission latencies (ML and IL), and decreased the number of intromissions before ejaculation (NI) and the total number of ejaculations (NE). The dosages of these drugs required to reduce the LC were lower than those required to increase the ML or IL. Clozapine and the D2 antagonist sulpiride reduced the LC and increased the IL at comparable dosages, although neither drug affected the NI or NE. High dosages of haloperidol, pimozide, and clozapine delayed or abolished level changing and the initiation of copulation. In Experiment 2, bilateral infusions of haloperidol into the nucleus accumbens reduced the LC but did not affect consummatory measures of copulation, whereas bilateral infusions into the dorsal striatum increased the NE. Midline infusions of haloperidol to the medial preoptic area (MPOA) produced nearly all the effects of systemic administration, including a reduced LC, increased ML and IL, a decreased NI, and a decreased NE. These results indicate that both anticipatory and consummatory measures of sexual behavior were disrupted by DA receptor antagonists; however, the measure of anticipatory sexual behavior was more sensitive to disruption than consummatory measures of copulation. DA in the nucleus accumbens and MPOA may be involved in the control of anticipatory sexual behavior, whereas in the MPOA it may also be involved in the initiation of copulation and copulatory rate.

The NMDA antagonist dizocilpine (MK-801) reverses haloperidol-induced movement initiation deficits

The present study shows that systemic dopamine receptor blockade impaired movement initiation of rats, trained in a simple reaction time task for rapid initiation of locomotion in response to a combined optic/acoustic cue. Reaction time, movement time and the accelerative force were recorded for each initiation of locomotion. Results indicate a dose-related increase of reaction time following systemic administration of haloperidol (0.1, 0.15, 0.3 mg/kg i.p.). Measures derived from resulting force-time patterns showed a haloperidol-induced decrease (0.15 mg/kg i.p.) of the mean rate of force development, indicating a decreased initial acceleration. These effects were reversed by systemic co-administration of dizocilpine (MK-801) (0.08 mg/kg i.p.), a selective non-competitive N- methyl- d-aspartate (NMDA) antagonist. The haloperidol-induced movement initiation deficits in this task are in part comparable to akinesia seen in Parkinson's disease and their reversal by dizocilpine has implications for the treatment of this disease.

Striatal and nucleus accumbens D 1/D 2 dopamine receptors in neuroleptic catalepsy

Haloperidol (2.5–10 μg) injected bilaterally into the ventro-rostral striatum or into the nucleus accumbens induced dose-dependent catalepsy whereas its injection into the dorso-rostral striatum (2.5 μg) was ineffective. Similarly, the specific antagonist of D 1 receptors, SCH 23390 (1–5 μg), injected into the ventro-rostral striatum or nucleus accumbens, as well as the specific antagonist of D 2 receptors, sulpiride, injected into the ventro-rostral striatum (0.02–15 μg) or nucleus accumbens (1–15 μg), induced a dose-dependent catalepsy. Both drugs (SCH 23390 2 μg, sulpiride 0.5 μg) were ineffective when injected into the dorso-rostral striatum. Doses of sulpiride about 100 times lower than those injected into the nucleus accumbens were sufficient to evoke an equipotent catalepsy when injected into the ventro-rostral striatum. However, similar doses of haloperidol and SCH 23390, injected into the ventro-rostral striatum and nucleus accumbens, evoked a similar catalepsy. It is concluded that (1) the catalepsy induced by systemic administration of haloperidol seems to result from the action of this drug on both the ventro-rostral striatum and the nucleus accumbens, (2) both D 1 and D 2 dopamine receptors in the ventro-rostral striatum are involved in the cataleptogenic action of neuroleptics, and (3) in the nucleus accumbens, only D 1 dopamine receptors seem to play an important role in this phenomenon.

NMDA antagonists block restraint-induced increase in extracellular DOPAC in rat nucleus accumbens

The effects of the N-methyl-D-aspartate (NMDA) receptor antagonists CPP, TCP, PK 26124 and ifenprodil, and of the minor tranquillizer diazepam on stress-induced changes of dopamine metabolism in the nucleus accumbens were investigated in the rat. Dopamine metabolism was assessed by measuring the extracellular levels of 3,4-dihydroxyphenylacetic acid (DOPAC) by means of in vivo differential pulse voltammetry with electrochemically pretreated carbon fiber electrodes. Physical immobilization of the rats for 4 min caused a marked and long-lasting increase in extracellular DOPAC levels in the nucleus accumbens. A similar, though shorter-lasting, augmentation of extracellular DOPAC was observed in the nucleus accumbens after systemic administration of the anxiogenic agent methyl-β-carboline-3-carboxylate (β-CCM) (10 mg/kg s.c.). Pretreatment with CPP (1 mg/kg i.p.), TCP (3 mg/kg i.p.), PK 26124 (3 mg/kg i.p.), ifenprodil (3 mg/kg i.p.) or diazepam (2 mg/kg i.p.) totally antagonized the immobilization-induced increase in extracellular DOPAC in the nucleus accumbens. Diazepam and the benzodiazepine ( ω 1–2) receptor antagonist flumazenil (30 mg/kg i.p.), but not ifenprodil, also antagonized the β-CCM-induced activation of dopamine metabolism in the nucleus accumbens. Finally, systemic administration of haloperidol (25 μg/kg i.p.) increased the extracellular concentrations of DOPAC in the nucleus accumbens, but pretreatment with ifenprodil (3 mg/kg i.p.) did not modify this response. These data indicate that NMDA receptor antagonists prevent the activation of dopamine metabolism in the nucleus accumbens caused by immobilization stress but not by β-CCM-induced anxiogenic stimulation. These results suggest that NMDA receptor antagonists may possess an anxiolytic-like action in the rodent, which is exerted via neuroanatomical circuits distinct from those acted upon by diazepam.

Mesocortical dopaminergic neurons. 2. Electrophysiological consequences of terminal autoreceptor activation

Measurement of drug- and stimulation-induced changes in the electrical excitability of dopaminergic terminals was employed to assess the effects of stimulation of dopamine terminal autoreceptors in the prefrontal cortex in urethane-anesthetized rats. Systemic or local administration of amphetamine decreased, whereas systemic administration of haloperidol increased the excitability of prefrontal cortical dopaminergic terminals of ventral tegmental area dopaminergic neurons. Mesoprefrontal dopaminergic terminal excitability was also responsive to spontaneous and stimulation-induced alterations in the rate of impulses reaching the terminal fields. These results are comparable to those previously reported for nigrostriatal and mesoaccumbens dopaminergic neurons, and are discussed with regard to the operational characteristics of autoinhibition in the mesocortical dopaminergic system.

The anterior hypothalamus provides stimulatory input to tuberoinfundibular dopamine neurons which is not mediated by prolactin.

Complete or retrochiasmatic deafferentations of the mediobasal hypothalamus were made in female rats 7 days prior to experimentation in order to determine the role played by putative afferent neuronal connections (1) in maintaining the basal neuronal activity of tuberoinfundibular dopaminergic (TIDA) neurons, and (2) in the stimulatory actions of prolactin on these neurons. The neuronal activity of TIDA neurons was estimated by measuring the rates of synthesis, turnover or metabolism of dopamine (DA) in the terminals of these neurons in the median eminence. Complete deafferentation of the mediobasal hypothalamus reduced the basal rate of DA synthesis, and retrochiasmatic deafferentation decreased the rates of synthesis, turnover and metabolism of DA in the median eminence. A knife cut 1 mm rostral to the retrochiasmatic cut failed to alter basal TIDA neuronal activity. These results suggest that afferent neuronal inputs originating in or coursing through the caudal portion of the anterior hypothalamus mediate a tonic stimulatory influence on TIDA neurons in the female rat. Intracerebroventricular administration of rat prolactin or systemic administration of haloperidol (which increases circulating levels of prolactin) increased DA synthesis in the median eminence of both sham-operated rats and retrochiasmatic-deafferentated rats. Thus, the stimulatory action of prolactin was not blocked by retrochiasmatic deafferentation. In addition, elimination of the basal stimulatory action of endogenous prolactin by pretreating animals with bromocriptine reduced the rate of DA synthesis in the median eminence of both sham- and retrochiasmatic-deafferentated rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Dopaminergic modulation of bulbofugal projections in the rat olfactory tubercle

Neuronal activities following olfactory bulb electrical stimulation were examined before and after administration of dopamine and dopamine antagonist in the rat olfactory tubercle. The inhibitory response to olfactory bulb stimulation was attenuated by systemic haloperidol administration, but the excitatory response to olfactory bulb stimulation rarely was modulated. Topical application of dopamine by iontophoresis extended the duration of inhibition in 56% of the neurons sampled and diminished it in 25%; the excitatory response was modulated in 42% of neurons, most of which were attenuated. These findings suggest that dopamine in the olfactory tubercle could be involved in modulations of neuronal activities related to olfactory transduction.

Responsiveness of tuberoinfundibular dopamine neurons in the aged female rat to the stimulatory actions of prolactin.

The autoregulatory feedback control of prolactin, which is mediated by tuberoinfundibular dopamine (DA) neurons, is altered in the aged rat; this is evidenced by increased circulating concentrations of prolactin and decreased activity of these neurons. In the present study the action of prolactin on tuberoinfundibular DA neurons in young and aged female rats was estimated by measuring the rate of DA synthesis (dopa accumulation following the administration of a decarboxylase inhibitor) in the median eminence. The rate of dopa accumulation in the median eminence of the aged (26 months) rat was reduced to 50-60% of that in the young (3 months) rat. The acute systemic administration of haloperidol, a DA antagonist which increases serum concentrations of prolactin or intracerebroventricular infusions of prolactin increased the rate of dopa accumulation in the median eminence of both young and aged rats by the same relative amount. The administration of haloperidol and prolactin increased the rate of DA synthesis to a greater extent in young than in aged rats. The administration of bromocriptine, a DA agonist which reduces serum concentrations of prolactin, decreased the rate of dopa accumulation in the median eminence of both young and aged rats. In young animals the intracerebroventricular administration of prolactin reversed the bromocriptine-induced decrease in DA synthesis in the median eminence after 4 h and caused a further increase after 12 h. Qualitatively similar effects were seen in the aged rats; however, prolactin-treated young rats had much higher levels of DA synthesis than aged rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Unilateral, intranigral infusions of amphetamine produce differential, bilateral changes in unit activity and extracellular levels of ascorbate in the neostriatum of the rat

Simultaneous recordings of single-unit activity and oxidation current were obtained bilaterally from the neostriatum of rats in response to unilateral infusion of d-amphetamine (2.0 μl of 10 μg/μl) into the substantia nigra. Whereas neuronal activity increases ipsilaterally and decreases contralaterally, the electrochemical signals, which reflect extracellular ascorbate, increase bilaterally. In each case, changes in unit activity precede the change in ascorbate release. Systemic administration of haloperidol (0.2 mg/kg) blocks the increase in oxidation current bilaterally, but reverses the neuronal activity response only on the ipsilateral side. These results lend further support to the view that intranigral amphetamine facilitates neostriatal ascorbate release, but this effect is not correlated with changes in single-unit activity.

Effects of ventro-medial mesencephalic tegmentum (VMT) stimulation on the spontaneous activity of nucleus accumbens neurones: Influence of the dopamine system

The effects of VMT-stimulation (100–500 μA, 0.6 ms; 1 Hz) on the spontaneous activity of neurones in the nucleus accumbens were analyzed in ketamine-anaesthetized rats. On spontaneously active cells (firing > 0.5 spikes/s), 3 types of responses were observed: either inhibition (36%), excitation (5%) or a composite sequence of excitation followed by inhibition (12%). Moreover, 14% of silent nucleus accumbens neurones were excited by single pulse VMT-stimulation. Finally, 3% of nucleus accumbens neurones recorded were driven antidromically by VMT-stimulation. Destruction of dopamine (DA) projections by 6-hydroxydopamine prevented the inhibitory responses to VMT stimulation in the great majority of cells studied, without affecting the excitatory responses. After systemic administration of haloperidol or sulpiride, the inhibitory responses to VMT stimulation were attenuated markedly, whilst the excitatory responses were, however, maintained. These results suggest that the inhibitory, but not the excitatory, effects of VMT-stimulation on nucleus accumbens neurones may be mediated by an activation of the mesolimbic DA system.

Excitatory input from sensory motor cortex to neostriatum and its modification by conditioning stimulation of the substantia nigra

Extracellular single unit responses were recorded from 381 neurons in the neostriatum of urethane-anesthetized rats. Single pulse stimulation of the sensory motor cortex produced strong excitatory responses in neostriatal neurons with a mean onset latency of 7.9 ms. A train of 10 pulses (0.15 ms, 300–600 μA) at 10 Hz delivered to the substantia nigra 100 ms before cortical stimulation attenuated the original excitatory response of 22 of 53 striatal neurons tested and enhanced the excitatory response of 12 of these neurons. These attenuating and enhancing effects were reduced or abolished by the systemic administration of haloperidol, a dopamine antagonist. Single pulse nigral stimulation 100 ms before the cortical stimulation had little or no effect on the excitatory response of neostriatal neurons. The iontophoretic application of dopamine also had attenuation and enhancement effects on the excitatory response of striatal neurons to cortical stimulation. The results suggest that the attenuation and enhancement of the excitatory responses of striatal neurons to cortical stimulation which resulted from nigral conditioning stimulation is mediated by nigrostriatal dopaminergic neurons.

Effects of intranigral administration of dopamine agonists and antagonists and baclofen on concentrations of dopac and dopamine in the striatum and substantia nigra of the rat.

Systemic administration of haloperidol to rats failed to alter the concentration of dopamine but increased the concentration of 3,4-dihydroxy-phenylacetic acid (DOPAC), the major metabolite of dopamine, in both the striatum and substantia nigra. These haloperidol-induced changes in DOPAC were prevented by an intranigral microinjection of baclofen, a drug which reduces nigrostriatal dopaminergic neuronal activity. It has been proposed that nigrostriatal neurons are regulated, in part, by the activation of autoreceptors in substantia nigra. However, intranigral microinjections of high concentrations of several dopaminergic antagonists failed to mimic the biochemical effects resulting from systemic administration of these drugs; instead, they slightly increased the concentrations of both dopamine and DOPAC in the striatum and decreased dopamine in substantia nigra. Intranigral microinjections of the dopamine agonist, apomorphine, failed to alter the concentration of DOPAC in the striatum, but reduced both dopamine and DOPAC in the nigra. If DOPAC concentrations reflect nigrostriatal dopaminergic neuronal activity, the present results suggest that dopaminergic agonists and antagonists acting in substantia nigra do not exert a major influence on the activity of these neurons.