Giampaolo Mereu

Low doses of ethanol activate dopaminergic neurons in the ventral tegmental area.

In unanesthetized rats the intravenous administration of low doses of ethanol (0.125-0.5 g/kg) produced a dose-dependent increase (30-80%) in the firing rate of dopaminergic (DA) neurons in the Ventral Tegmental Area (VTA). In agreement with previous observations, a dose range between 0.5 and 2 g/mg of ethanol was needed to produce comparable stimulant responses in DA neurons of the Substantia Nigra Pars Compacta. However, in anesthetized rats, doses of ethanol up to 1 g/kg failed to activate VTA-DA neurons. The high sensitivity of VTA-DA neurons to ethanol activation suggests that they might be involved in the reinforcing properties of the drug.

Ethanol stimulates the firing rate of nigral dopaminergic neurons in unanesthetized rats

In unanesthetized paralyzed rats, i.v. ethanol administration (0.5-2.0 g/kg) increased (by 30-120%) the firing rate of dopaminergic (DA) neurons in the substantia nigra, pars compacta. Doses of 4.0 g/kg or higher produced an initial stimulation followed by a long-lasting inhibition of firing. On the contrary, in rats anesthetized with halothane (2.5% v/v in air) or with chloral hydrate (400 mg/kg), doses of ethanol up to 2 g/kg failed to activate DA neurons, while a dose of 4 g/kg inhibited neuronal firing without the initial stimulant response. In unanesthetized-curarized rats, the i.v. administration of either chloral hydrate (100-400 mg/kg) or pentobarbital (10-40 mg/kg) or the inhalation of halothane (0.5-2.5% v/v in air) produced a dose-dependent increase in the firing rate of DA neurons. However, the maximum increase produced by these anesthetics was less pronounced and shorter lasting than that produced by ethanol.

Low doses of ethanol inhibit the firing of neurons in the substantia nigra, pars reticulata: a GABAergic effect?

The intravenous administration of relatively low doses of ethanol (0.25-2.00 g/kg) produced a dose-dependent inhibition of the firing rate of the neurons located in the substantia nigra, pars reticulata (PR neurons). This effect was eliminated both by picrotoxin and bicuculline, two blockers of gamma-aminobutyric acid (GABA) transmission, and potentiated by muscimol (a direct GABA agonist) and diazepam (a representative of the benzodiazepine class which facilitate GABA transmission). The specific benzodiazepine antagonist, Ro 15-1788, blocked the potentiating effect of diazepam on the ethanol effect but failed to antagonize ethanol-induced inhibition of the firing rate of the neurons. These results indicate that ethanol might inhibit the firing of PR neurons through a GABAergic mechanism. Moreover, since PR neurons are thought to exert an inhibitory control on nigral dopaminergic neurons, it is suggested that the depression of the activity of such inhibitory interneurons may be responsible for ethanol-induced stimulation of dopaminergic activity.

Prenatal exposure to a cannabinoid agonist produces memory deficits linked to dysfunction in hippocampal long-term potentiation and glutamate release

To investigate the possible long-term consequences of gestational exposure to cannabinoids on cognitive functions, pregnant rats were administered with the CB1 receptor agonist WIN 55,212-2 (WIN), at a dose (0.5 mg/kg) that causes neither malformations nor overt signs of toxicity. Prenatal WIN exposure induced a disruption of memory retention in 40- and 80-day-old offspring subjected to a passive avoidance task. A hyperactive behavior at the ages of 12 and 40 days was also found. The memory impairment caused by the gestational exposure to WIN was correlated with alterations of hippocampal long-term potentiation (LTP) and glutamate release. LTP induced in CA3–CA1 synapses decayed faster in brain slices of rats born from WIN-treated dams, whereas posttetanic and short-term potentiation were similar to the control group. In line with LTP shortening, in vivo microdialysis showed a significant decrease in basal and K+-evoked extracellular glutamate levels in the hippocampus of juvenile and adult rats born from WIN-treated dams. A similar reduction in glutamate outflow was also observed in primary cell cultures of hippocampus obtained from pups born from mothers exposed to WIN. The decrease in hippocampal glutamate outflow appears to be the cause of LTP disruption, which in turn might underlie, at least in part, the long-lasting impairment of cognitive functions caused by the gestational exposure to this cannabinoid agonist. These findings could provide an explanation of cognitive alterations observed in children born from women who use marijuana during pregnancy.

Sedation and sleep induced by high doses of apomorphine after blockade of D-1 receptors by SCH 23390

The effect of SCH 23390, a selective blocker of D-1 receptors, on apomorphine-induced behavioural and EEG changes was studied in rats. In control rats, a low dose of apomorphine (50 micrograms/kg s.c.) produced sedation associated with EEG synchronization. A high dose of apomorphine (1 mg/kg s.c.) produced stereotypy associated with EEG desynchronization. At the dose of 1 mg/kg i.p., SCH 23390 decreased motor activity but failed to alter the EEG pattern. The administration of either the low or high dose of apomorphine to SCH 23390-treated rats elicited a marked sedative response associated with EEG synchronization. The EEG synchronization produced by apomorphine (50 micrograms/kg) in SCH 23390-treated rats was prevented by (-)-sulpiride (25 mg/kg i.p.), a D-2 receptor blocker. It is concluded that by preventing the excitatory response to apomorphine SCH 23390 discloses the existence of a population of D-2 receptors mediating sedation and sleep.

Sulpiride activates the firing rate and tyrosine hydroxylase activity of dopaminergic neurons in unanesthetized rats

The effect of i.v. sulpiride on the firing rate of dopaminergic neurons in the substantia nigra, pars compacta (SN-DA cells) and tyrosine hydroxylase (TH) activity in the caudate nucleus was studied. In rats, paralyzed with succinylcholine and artificially respirated, (-)-sulpiride (10-50 mg/kg) produced a dose-related increase in the firing rate of SN-DA cells and in TH activity. On the contrary, in rats anesthetized with halothane, (-)-sulpiride (up to 50 mg/kg) activated neither dopaminergic firing nor TH activity. However, (-)-sulpiride (10-25 mg/kg) readily reversed the inhibitory effect of i.v. apomorphine (25 micrograms/kg) on dopaminergic firing in both anesthetized and unanesthetized rats. Since sulpiride fails to inhibit DA-sensitive adenylate cyclase, it may be concluded that DA receptors, whose blockade results in increased dopaminergic firing and TH activation, are not coupled with this enzyme. Moreover, the results indicate that the mechanism responsible for firing and TH stimulation is inhibited by halothane anesthesia. The latter significantly decreased also the stimulant effect of i.v. haloperidol on striatal TH activity.

SCH 23390, a selective dopamine D1 antagonist, activates dopamine neurons but fails to prevent their inhibition by apomorphine

SCH 23390, a rather selective D1 receptor blocker, activates the firing rate of dopamine (DA) neurons in the substantia nigra (SN-DA neurons) in rats, similarly to haloperidol (a D1-D2 receptor antagonist) and sulpiride (a selective D2 receptor blocker). These neuroleptics produce no additional increase over the maximal activation produced by SCH 23390. Unlike haloperidol or sulpiride, SCH 23390 fails to prevent the inhibition by apomorphine of SN-DA neurons, a DA autoreceptor-mediated effect. It is suggested that the doses of SCH 23390 that stimulate DA neurons block D2 in addition to D1 receptors, or that D1 blockade results in the functional inactivation of a specific population of D2 receptors as well. The failure of SCH 23390 to block the apomorphine effect indicates that DA autoreceptors can be pharmacologically differentiated form postsynaptic DA receptors.

Benzodiazepine-induced voraciousness in cats and inhibition of amphetamine-anorexia

Abstract The effect of different benzodiazepines on food intake was studied in cats which had been trained to eat their daily food within 3 hours, under conditions in which emotional factors were not present. When benzodiazepines were administered (at a dose ranging from 0.1 to 3 mg/Kg) before feeding, they increased both the total amount of food eaten and also the rate at which food was injested. When they were administered at the end of the feeding period, these compounds made the animals resume eating voraciously. The order of decreasing potency of the benzodiazepines tested was: oxazepam, N-methyl-lorazepam, diazepam, chlordiazepoxide, pinazepam, medazepam. Oxazepam (3 mg/Kg) stimulated maximally the food intake, even when administered up to 12 hours before feeding. Finally, oxazepam antagonized the anorexigenic effect of d-amphetamine, but did not influence amphetamine-induced hyperactivity and stereotyped behavior.

Depolarization inactivation of dopamine neurons: an artifact?

A widely accepted theory postulates that, in rats, chronic treatment with neuroleptics causes the depolarization inactivation of the majority of midbrain dopamine (DA) neurons. The present study was aimed to verify whether general anesthesia and/or other factors might contribute to the depolarization inactivation of A9 and A10 DA neurons. To investigate on the possible role played by DA receptor subtypes, three representatives DA antagonists were used: haloperidol (a mixed D1/D2), (-)-sulpiride (a selective D2) and SCH 23390 (a selective D1). In agreement with previous studies, where neuronal sampling was carried out in animals under chloral hydrate anesthesia, chronic treatment with haloperidol (0.5 mg/kg daily for 21–28 d) produced a profound reduction (about 80%) in the number of spontaneously active A9 DA neurons. However, when neuronal sampling was performed in unanesthetized rats, the single administration of haloperidol, (-)-sulpiride, or SCH 23390 (0.5, 25, and 0.3 mg/kg respectively 2–3 hr beforehand) increased the number of spontaneously active A9 and A10 DA neurons and their firing rate, whereas the chronic administration of these drugs (daily for 21– 28 d) failed to reduce the number of spontaneously active A9 and A10 DA neurons. The inhibitory effect of apomorphine on the firing rate of A9 and A10 DA neurons was prevented 3–4 hr after the acute or last injection of chronic haloperidol or (-)-sulpiride. However, the inhibitory effect was potentiated 24 hr after the last administration of the chronic regimen with these neuroleptics, but it was not influenced by either acute or chronic treatment with SCH 23390.(ABSTRACT TRUNCATED AT 250 WORDS)

Antipsychotic-Like Properties of 5-|[alpha]|-Reductase Inhibitors

Recent evidence indicates that neuroactive steroids may participate in the pathogenesis of schizophrenia spectrum disorders, yet the mechanisms of this involvement are elusive. As 5-α-reductase (5AR) is the rate-limiting enzyme of one of the two major metabolic pathways in brain steroidogenesis, we investigated the effects of its blockade in several rat models of psychotic-like behavior. The 5AR inhibitor finasteride (FIN, 60 or 100 mg/kg, intraperitoneal, i.p.) dose- and time-dependently antagonized prepulse inhibition (PPI) deficits induced by apomorphine (APO, 0.25 mg/kg, subcutaneous, s.c.) and d-amphetamine (AMPH, 5 mg/kg, s.c.), in a manner analogous to haloperidol (HAL, 0.1 mg/kg, i.p.) and clozapine (CLO, 5 mg/kg, i.p.). Similar results were observed with the other 5AR inhibitors dutasteride (DUT, 40 or 80 mg/kg, i.p.) and SKF 105111 (30 mg/kg, i.p.). FIN (60 or 100 mg/kg, i.p.) also reduced hyperlocomotion induced by AMPH (1 or 3 mg/kg, s.c.) and attenuated stereotyped behaviors induced by APO (0.25 mg/kg, s.c.). Nevertheless, FIN (100 mg/kg, i.p.) did not reverse the PPI disruption induced by the N-methyl-d-aspartate receptor antagonist dizocilpine (0.1 mg/kg, s.c.). FIN (60–300 mg/kg, i.p.) induced no catalepsy in either the bar test or the paw test. Our results suggest that 5AR inhibitors elicit antipsychotic-like effects in animals and may be proposed as a putative novel target in the management of psychotic disorders.