Effects of dopamine partial-agonist aminoergolines on dopamine metabolism in limbic and extrapyramidal regions of rat brain.

The aminoergolines SDZ-208-911, -208-912, and -212-327, weak partial D2 agonists with agonist/antagonist properties, are proposed as potential atypical antipsychotic agents with limited risk of extrapyramidal effects or hyperprolactinemia. The in vivo effects on dopamine (DA) metabolism in limbic (accumbens) and extrapyramidal (striatum) regions of rat brain were evaluated by measuring the accumulation of L-dihydroxyphenylalanine (DOPA) after inhibiting decarboxylation alone ("open-loop" model) or with added gamma-butyrolactone (GBL, autoreceptor model). All three aminoergolines markedly increased DOPA in both regions, dose-dependently, with only minor decreases when GBL was included, and so evidently lack appreciable agonist activity at D2-like autoreceptors and resemble typical neuroleptics in stimulating DA synthesis, without regional selectivity.

Nicotine and brain-stimulation reward: interactions with morphine, amphetamine and pimozide.

Using a rate-independent discrete trial method of determining thresholds for rewarding electrical intracranial stimulation in rats, we evaluated the pharmacological interaction of nicotine plus morphine, d-amphetamine, or the D2 receptor antagonist, pimozide. Both morphine and amphetamine shifted the dose-response curve for nicotine down and to the left, indicating increased efficacy and potency, respectively. Pimozide at doses that have no effect on performance and only minimal effect on brain-stimulation reward blocked the effect of nicotine. These data suggest that the same dopaminergic substrate that supports the positive reinforcing effects of other drugs of abuse also supports nicotine reward.

Tissue concentrations of clozapine and its metabolites in the rat.

Clozapine (CLZ) and its metabolites norclozapine (NOR) and clozapine-N-oxide (NOX) were assayed in rat serum and brain tissue after intraperitoneal injection of CLZ. Clozapine levels rose with dose, averaging 28 ng/ml (87 nmol/L) serum per milligram/kilogram dose. Brain- and serum-CLZ levels correlated closely, averaging 24-fold higher in brain. Norclozapine and NOX averaged approximately 58% and 13% of CLZ in serum, respectively, whereas in brain, NOR was detected only at doses greater than or equal to 10 mg/kg (approximately 5.6% of CLZ) and NOX was undetectable. Levels peaked within 30 minutes, and elimination of CLZ from brain and CLZ or NOR from blood was very rapid (half-life = 1.5 to 1.6 hours). A week of daily dosing with CLZ led to no accumulation of drug in brain; a week of fluoxetine pretreatment increased analyte concentrations (serum, 86%; brain, 61%), but valproate had little effect.

Do central antiadrenergic actions contribute to the atypical properties of clozapine?

Full neuropharmacological understanding of the atypical antipsychotic agent clozapine remains elusive. Antidopaminergic actions of most neuroleptics probably contribute to their antipsychotic benefits, but also to neurological side-effects. Clinical evidence of abnormalities of dopamine (DA) and serotonin (5-HT) in psychotic disorders is inconsistent, but there is substantial metabolic and post-mortem evidence for hyperactivity of noradrenaline (NA). Clozapine is only weakly antidopaminergic but is a potent antagonist at brain alpha 1-adrenergic, 5-HT2-serotonergic, and muscarinic receptors. Its apparent limbic-over-extrapyramidal neurophysiological selectivity can be mimicked by combining a typical neuroleptic with a central alpha 1 antagonist. Clozapine strongly upregulates alpha 1, but not DA, receptor abundance, and may supersensitise alpha 1 but not DA receptors in rat brain. Clozapine also selectively increases activity of NA neurons and metabolic turnover in NA more than DA areas of rat brain, and also increases NA, but not DA or 5-HT, metabolites in human CSF. Potential psychotropic effects of selective central antiadrenergic agents may deserve reconsideration.

Effects of nicotine on the threshold for rewarding brain stimulation in rats.

The rewarding effects of nicotine alone and nicotine challenged with mecamylamine, a nicotine receptor blocker, or naloxone were determined using a rate-independent discrete-trial threshold measure of brain-stimulation reward in rats. If nicotine acts as other drugs of abuse, it would be expected to lower the reward threshold, that is, increase an animal's sensitivity to rewarding brain stimulation, and naloxone would be expected to block this effect, as it does other stimulants in this paradigm. Nicotine was found to significantly lower the reward threshold and mecamylamine blocked this effect. However, although naloxone increased the variability of nicotine's effect on the reward threshold, it failed to dose dependently block nicotine's threshold-lowering effect.

The role of the olfactory tubercle in the effects of cocaine, morphine and brain-stimulation reward.

Using the quantitative 2-[14C]deoxyglucose autoradiographic method, local rates of glucose utilization were measured in rats after the administration of morphine or cocaine in the presence or absence of rewarding brain stimulation to the medial forebrain bundle. In animals that did not receive brain stimulation, cocaine significantly increased glucose utilization in the olfactory tubercle, medial prefrontal cortex and substantia nigra pars reticulata, whereas morphine significantly increased glucose metabolism in the olfactory tubercle only. Stimulation itself increased metabolic rates in a number of sites, such as the olfactory tubercle, nucleus accumbens, medial prefrontal cortex, ventral tegmental area and others. However, in self-stimulating animals both morphine and cocaine caused further increases in activity in the olfactory tubercle. Since the olfactory tubercle was the only structure to cause a significant increase in metabolic rate following each treatment, the results implicate this limbic structure in the rewarding effects of morphine, cocaine and brain-stimulation reward.

The distribution of changes in local cerebral energy metabolism associated with brain stimulation reward to the medial forebrain bundle of the rat.

Using the quantitative 2-[14C]deoxyglucose autoradiographic method, local rates of glucose utilization were measured in rats during brain stimulation reward to the medial forebrain bundle. Metabolic activation was observed both rostral and caudal to the site of stimulation. These sites included the nucleus accumbens, olfactory tubercle, lateral septum, and ventral tegmental area. In many cases, increases in glucose utilization occurred bilaterally. These data suggest the involvement of both ascending and descending systems in brain stimulation reward. Furthermore, despite the unilateral nature of the electrical stimulation, increases in glucose utilization were observed both ipsilateral and contralateral to the site of stimulation.

Opiate dependence alters central reward of nalbuphine or pentazocine plus tripelennamine.

The threshold lowering effects of the coadministration of tripelennamine plus nalbuphine or tripelennamine plus pentazocine on the threshold for rewarding electrical intracranial stimulation, a model of drug-induced euphoria, was determined in rats physically dependent to morphine. Although tripelennamine plus nalbuphine had threshold-lowering effects similar to tripelennamine plus pentazocine in non-opiate-dependent subjects, tripelennamine plus nalbuphine failed to lower the threshold for rewarding stimulation in morphine-dependent animals. To the extent that these data may be applied to human addicts, it suggests that opiate-dependent addicts are unlikely to use the combination of tripelennamine plus nalbuphine but are likely to use tripelennamine plus pentazocine.