H.C. Fibiger

ehavioural evidence for supersensitivtiy of postsynaptic dopamine receptors in the mesolimbic system after chronic administration of desipramine

The effects of acute and chronic administration of desipramine (DMI) on a number of behaviors thought to be dependent on central dopaminergic (DA) systems were examined in the rat. Chronic but not acute administration of DMI potentiated the locomotor response to d-amphetamine within a narrow dosage range. The potentiation of the amphetamine response was observed up to 5 days after cessation of chronic DMI but had nearly returned to baseline by 10 days. Neither amphetamine- nor apomorphine-induced stereotypy was affected by chronic DMI. Chronic administration of iprindole but not fluoxetine potentiated amphetamine-induced locomotor activity. Chronic DMI administration did not affect the concentration or distribution of [3H]d-amphetamine in the brain. Furthermore, residual anticholinergic effects of DMI did not appear to be responsible for the potentiated amphetamine response. Chronic administration of DMI did not significantly influence the hypomotility induced by low doses of apomorphine. The increased locomotor activity and rearing produced by moderate doses of apomorphine were significantly increased by chronic DMI administration. The results suggest that chronic DMI may produce supersensitivity of postsynaptic receptors in the mesolimbic DA projection, a system that has been associated with the mediation of amphetamine- and apomorphine-induced increases in locomotor activity. There was no evidence for subsensitivity of presynaptic DA receptors after DMI. The findings are discussed with reference to the possible role of central DA neurons in the antidepressant mechanism of action of the tricyclic compounds.

Cholinergic activity in the rat hippocampus, cortex and striatum correlates with locomotor activity: An in vivo microdialysis study

The possible relationship between behavioral arousal and acetylcholine release in the striatum, hippocampus and frontal cortex was investigated in rats. In vivo microdialysate concentrations of acetylcholine and choline from these brain structures, and photocell beam interruptions (as a measure of behavioral arousal), were measured simultaneously under three conditions: after injections of 1) vehicle or 2) scopolamine (0.4 mg/kg), and 3) before and after the beginning of the rats night cycle. Dialysate concentrations of ACh in all 3 brain structures and locomotor activity were increased after scopolamine and the onset of the lights out condition. Vehicle injections transiently increased ACh in the hippocampus and cortex and caused short-lasting increases in locomotor activity. Under all conditions, the release of ACh from each of the 3 brain structures correlated with the level of locomotor activity.

Effect of acute and chronic methamphetamine treatment on tyrosine hydroxylase activity in brain and adrenal medulla.

Abstract The effect of methamphetamine on tyrosine hydroxylase in brain and adrenal medulla of rats was investigated. Chronic administration of methamphetamine (10 mg/kg) resulted in increased activity of this enzyme in the adrenal medulla, no effect in the brain stem or hypothalamus, and inhibition in the corpus striatum. Under the same conditions, a lower dosage of methamphetamine (5 mg/kg) did not significantly influence tyrosine hydroxylase activity in any of these structures. Acute methamphetamine treatment at either dosage failed to modify tyrosine hydrocylase activity. The diverse effects preclude a direct pharmacological action of methamphetamine on this system. The increased tyrosine hydroxylase activity in the adrenal medulla was interpreted as a non-specific stress reaction to high doses of methamphetamine. The results support the presence of a previously postulated interneuronal feedback mechanism in brain which can regulate dopamine synthesis (Carlsson and Lindqvist, 1963) and this may function at least in part through an effect on tyrosine hydroxylase activity.

Dopaminergic regulation of striatal cholinergic interneurons: an in vivo microdialysis study

SummaryIn vivo microdialysis was used to study the putative inhibitory effects of dopamine on cholinergic interneurons in the striatum of conscious rats. The dopamine receptor agonists apomorphine (0.3 and 3 mg/kg, s.c.) and (±)N-0437 (1.4 mg/kg, s.c.) decreased interstitial concentrations of acetylcholine while increasing those of choline. In contrast, the dopamine receptor antagonists haloperidol (0.1 and 1 mg/kg, i.p.) and (±)sulpiride (20 mg/kg, i.p.) enhanced striatal acetylcholine output but had little effect on choline. Previously, a lack of effect of these drugs on striatal acetylcholine was reported. The main methodological difference between these studies was that the calcium concentration of the microdialysis perfusion solution was 3.4 mM in the former study versus 1.2 mM in the present experiments. The results of this study reemphasize the importance of the calcium concentration in determining the effects of drugs on central neurotransmitter release, and confirm a role of dopamine in the regulation of striatal cholinergic interneurons.

Dopaminergic-cholinergic interactions in the striatum : the critical significance of calcium concentrations in brain microdialysis

SummaryBrain microdialysis experiments were performed to assess the effects of calcium (1.2 mmol/l and 3.4 mmol/l) in the perfusio solution on a variety of pharmacological treatments known to affect the release of dopamine (DA) and/or acetylcholine (ACh). Intrastriatal infusion of the muscarinic receptor agonist oxotremorine (100 μM), the selective dopamine D-2 receptor agonist (−)-N-0437 (1 μM), and the indirect DA agonists (+)amphetamine (10 μM) and nomifensine (1 μM) via the dialysis probe did not affect the overflow of ACh when the perfusion fluid contained 3.4 mmol/l calcium. In contrast, these compounds produced pronounced decreases in the overflow of ACh at 1.2 mmol/l calcium. Intrastriatal infusion of the muscarinic receptor antagonist atropine (1 μM) increased the output of ACh both at 1.2 mmol/l and 3.4 mmol/1 calcium. The selective DA D-2 receptor antagonist (−)-sulpiride (1 μM) did not affect the overflow of ACh at either calcium concentration. Infusion of oxotremorine and atropine had no effect on the overflow of DA at either 1.2 mmol/l or 3.4 mmol/l calcium. (−)-N-0437 decreased and (−)-sulpirde increased DA overflow, both effects being independent of the calcium concentration in the perfusion fluid. Nomifensine and (−)amphetamine caused relatively (but not absolutely) larger increases in the overflow of DA at 1.2 mmol/1 calcium. These findings emphasize the critical importance of the calcium concentration of the perfusion fluid in determining the nature of pharmacological responses in microdialysis experiments, and demonstrate that locally applied dopaminergic drugs can modulate striatal cholinergic function.

Clonidine-induced sedation in rats: Evidence for mediation by postsynapticα2-adrenoreceptors

The effect of low doses of clonidine on exploration and motility was investigated in rats after destruction of central noradrenergic systems by 6-hydroxydopamine (6-OHDA) or DSP-4. In accordance with previous results, clonidine decreased exploration and motility in control animals. This sedative effect of clonidine was potentiated in animals that suffered selective and extensive depletions of brain NA as a result of neonatal treatment with 6-OHDA. Depletion of NA by administration of DSP-4 to adult animals did not influence clonidines sedative effects. Yohimbine, but not phentolamine, antagonized clonidine-induced hypomotility both in control and in neonatal 6-OHDA treated groups. The results suggest that clonidineinduced sedation is mediated by postsynapticα 2-adrenoreceptors.

PHARMACOLOGY OF SENSORY STIMULATION-EVOKED INCREASES IN FRONTAL CORTICAL ACETYLCHOLINE RELEASE

Recent research has demonstrated that a variety of sensory stimuli can increase acetylcholine release in the frontal cortex of rats. The aim of the present experiments was to investigate the pharmacological regulation of sensory stimulation-induced increases in the activity of basal forebrain cholinergic neurons. To this end, the effects of agonists and antagonists at a variety of neurotransmitter receptors on basal and tactile stimulation-evoked increases in frontal cortical acetylcholine release were studied using in vivo brain microdialysis. Tactile stimulation, produced by gently stroking the rats neck with a nylon brush for 20 min, significantly increased frontal cortical acetylcholine release by more than 100% above baseline. The noradrenergic alpha2 agonist clonidine (0.1 or 0.2 mg/kg) and alpha1 antagonist prazosin (1 mg/kg) failed to affect basal cortical acetylcholine release; however, both compounds significantly reduced the increases evoked by sensory stimulation. In contrast, the alpha2 antagonist yohimbine (3 mg/kg) increased basal cortical acetylcholine release, thereby preventing meaningful investigation of its effects on tactile stimulation-evoked increases. The benzodiazepine agonist diazepam (5 mg/kg) reduced, and the GABA(A) receptor antagonist picrotoxin (2 mg/kg) increased basal cortical acetylcholine release; in addition, diazepam attenuated the increases in cortical acetylcholine release evoked by tactile stimulation. While dopaminergic D1 (SCH 23390, 0.15 mg/kg) and D2 (raclopride, 1 mg/kg) receptor antagonists did not by themselves significantly influence the increases evoked by tactile stimulation, their co-administration produced a significant reduction. The opioid receptor antagonist naltrexone (1.5 mg/kg) failed to affect either basal or tactile stimulation-evoked increases in acetylcholine overflow. Finally, the non-competitive N-methyl-D-aspartate receptor antagonist, dizocilpine maleate (MK-801; 0.025 and 0.05 mg/kg) increased basal cortical acetylcholine release. These results confirm that cortically projecting cholinergic neurons are activated by sensory stimuli, and indicate that the increases in cortical acetylcholine release produced by tactile stimulation are inhibited by stimulation of alpha2 or blockade of alpha1 noradrenergic receptors, and by enhanced GABAergic transmission. In addition, simultaneous blockade of dopamine D1 and D2 receptors appears necessary to achieve a significant reduction of sensory stimulation-evoked acetylcholine release in the frontal cortex. The results are consistent with the hypothesis that cortical acetylcholine release is a component of the neurochemistry of arousal and/or attention and indicate that this is modulated by GABAergic, noradrenergic and dopaminergic systems. In contrast, endogenous opioid actions do not appear to be involved.

The potent and selective dopamine D1 receptor agonist A-77636 increases cortical and hippocampal acetylcholine release in the rat

The effects of systemic administration of the full dopamine D1 receptor agonist A-77636 on acetylcholine release in rat frontal cortex and hippocampus were studied using in vivo microdialysis. Administration of A-77636 (4 mumol/kg s.c.) greatly (> 230%) increased both cortical and hippocampal acetylcholine release for more than 3 h; at a lower dose (1 mumol/kg s.c.) A-77636 significantly stimulated cortical but not hippocampal acetylcholine release. The effect of the higher dose of A-77636 on cortical acetylcholine release was blocked by the dopamine D1 receptor antagonist SCH 23390 (300 micrograms/kg s.c.). These results confirm that stimulation of dopamine D1 receptors facilitates cortical and hippocampal acetylcholine release in vivo, and indicate that these two structures are differentially sensitive to this effect. They also raise the possibility that dopamine D1 receptor agonists may be useful in the treatment of cortical and hippocampal acetylcholine deficit-related syndromes.

The effects of dose and duration of chronic pimozide adminstration on dopamine receptor supersensitivity

SummaryThe neuroleptic drug pimozide was administered chronically to rats at different doses (0.75, 1.5 or 3.0 mg/kg, twice daily for 10 days) or for different durations (1.5 mg/kg twice daily for 5, 10, 20 or 40 days). At various intervals (4–40 days) after withdrawal dopamine (DA) receptor density in the striatum was assessed directly using specific [3H]-spiroperidol binding and indirectly by means of apomorphine-induced stereotypy and amphetamine-induced locomotor activity. The incease in the density of DA receptors was shown to be dependent upon the dose but not upon the duration of chronic pimozide. In contrast, the enhanced apomorphine-induced stereotypy was influenced by the duration but not by the dose of chronic pimozide. The potentiation of d-amphetamine-induced locomotor activity was found to vary as a function of both dose and duration of chronic pimozide administration. The results indicate that the augmentation of these apomorphine- and amphetamine-induced behaviors cannot be attributed solely to striatal DA receptor supersensitivity and that other, presently unspecified factors must contribute. It is also argued that in the absence of pharmacologically-induced DA receptor stimulation, the functional consequences of neuroleptic-induced increases in the density of striatal DA receptors are not apparent and remain unknown. In addition, these findings support the view that neuroleptic-induced proliferation of DA receptors cannot be the sole mechanism underlying tardive dyskinesia in man.

Force requirements in lever-pressing and responding after haloperidol

One hypothesis regarding the actions of neuroleptic drugs on operant responding is that they interfere in some manner with the motoric capability of the animal. To further explore this possibility, we investigated the effects of haloperidol on a bar press response after animals were trained on levers with different force requirements. In the first experiment, two groups of rats were trained to press levers having either low (30 g) or high (100 g) force requirements. The effects of haloperidol on bar pressing when both groups were responding on the light lever were then examined. Under these conditions, the groups showed similar declines in response rates, indicating little transfer between previous experience on the heavy lever and responding in the presence of haloperidol. In the second experiment, the same groups of rats received further training exclusively on either the heavy or the light lever; the rate of responding was similar for the two groups. The effects of haloperidol on pressing either the heavy or the light lever were then examined. It was found that the rate-decreasing effects of haloperidol were similar in both groups. However, when the lever-pressing response was subsequently extinguished, rats working on the heavy lever were significantly more resistant to extinction than the light lever groups. The results of these experiments fail to indicate that the putative motoric effects of haloperidol interact significantly with response force demands. Furthermore, the data provide yet further evidence that blockade of dopamine receptors and removal of reinforcement are not equivalent.