Search

Rich evidence has highlighted that stimulation of gamma-amino-butyric acid (GABA)(B) receptors increases the occurrence of spike-and-wave discharges (SWDs), the electroencephalographic (EEG) landmark of absence epilepsy (AE). Recent findings suggest that the outcomes of GABA(B) activation in vivo are contingent on the chemical characteristics of the agonist. In particular, the endogenous ligand gamma-hydroxybutyrate (GHB) and its precursor gamma-butyro-lactone (GBL) have been shown to elicit different effects than the prototypical GABA(B) agonist baclofen. In view of these premises, the present study was aimed at the characterization of the effects of baclofen (0.5-10 mg/kg, i.p.) and GBL (5-100 mg/kg, i.p.) on the spontaneous SWDs and locomotor activity of DBA/2J mice. While both baclofen and GBL dose-dependently increased SWDs episodes, high doses of the latter (100 mg/kg, i.p.) reduced the occurrence of these phenomena and increased the number of isolated spikes. Interestingly, both compounds elicited a dose-dependent reduction of locomotor activity, in comparison with their vehicle-treated controls. The GABA(B) selective antagonist, SCH50911 (50 mg/kg, i.p.), reversed the changes in SWD occurrence and locomotion induced by baclofen and GBL, but failed to elicit intrinsic effects on either paradigm. These results indicate that GABA(B) receptor signaling might exert differential effects on SWDs in DBA/2J mice.

The anticonvulsant topiramate (TPM) has been recently proposed as a novel adjuvant therapy for bipolar disorder and schizophrenia, yet its efficacy remains controversial. As both disorders are characterized by gating deficits, we tested the effects of TPM on the behavioral paradigm of prepulse inhibition (PPI) of the acoustic startle response, a validated animal model of sensorimotor gating. TPM (10, 18, 32, 58, 100 mg/kg, intraperitoneal, i.p.) enhanced PPI in rats in a dose-dependent fashion, prevented the PPI reduction mediated by the dopaminergic agonist apomorphine (0.25 mg/kg, subcutaneous, s.c.) and potentiated the effects of the antipsychotic drugs haloperidol (0.05, 0.1 mg/kg, i.p.) and clozapine (2.5, 5 mg/kg, i.p.). Conversely, TPM elicited no significant effect on the PPI disruption mediated by the NMDA receptor antagonist dizocilpine (0.05, 0.1 mg/kg, s.c.) and surprisingly antagonized the attenuation of dizocilpine-induced PPI disruption mediated by clozapine (5 mg/kg, i.p.). Our results suggest that TPM may exert diverse actions on the neural substrates of sensorimotor gating. While the pharmacological mechanisms of such effects are still elusive, our findings might contribute to shed light on some controversies on the therapeutic action of TPM, and point to this drug as a putative novel adjuvant therapy for some clusters of gating disturbances.

Background Compelling evidence indicates that kappa opioid receptor (KOR) agonists produce perceptual distortions in animals and humans, yet the mechanism of action and clinical relevance of such effects remain unclear. Since abnormalities in preattentional functions and informational processing are hypothesized to underlie psychotic disorders, the present study has been designed to assess the role of KOR on sensorimotor gating. Methods The effects of the selective KOR agonist U50488 were evaluated on the behavioral paradigm of prepulse inhibition (PPI) of the acoustic startle reflex (ASR). Results U50488 (1.25, 2.5, and 5 mg/kg, subcutaneous [SC]) induced a dose-dependent reduction of PPI, which was efficiently prevented by the selective KOR antagonist norbinaltorphimine (nor-BNI, 10 mg/kg, SC), as well as by the atypical antipsychotic clozapine (5, 8 mg/kg, intraperitoneal [IP]) but not by the typical antipsychotic haloperidol (.1, .5 mg/kg, IP). Conversely, nor-BNI (10 mg/kg, SC) failed to reverse the PPI disruption mediated by both apomorphine (.25 mg/kg, SC) and dizocilpine (.1 mg/kg, SC). Conclusions Our results support a pivotal role of KOR in the regulation of preattentional functions and sensorimotor gating, pointing to these receptors as a possible neurobiological substrate especially relevant to the clusters of psychosis unresponsive to typical antipsychotics.

Our previous studies have suggested that dopamine and noradrenaline may be coreleased from noradrenergic nerve terminals in the cerebral cortex. To further clarify this issue, the effect of electrical stimulation of the locus coeruleus on extracellular noradrenaline, dopamine and DOPAC in the medial prefrontal cortex, parietal cortex and caudate nucleus was analysed by microdialysis in freely moving rats. Stimulation of the locus coeruleus for 20 min with evenly spaced pulses at 1 Hz failed to modify cortical catecholamines and DOPAC levels. Stimulation with bursts of pulses at 12 and 24 Hz increased, in a frequency-related manner, not only noradrenaline but also dopamine and DOPAC in the two cortices. In both cortices noradrenaline returned to baseline within 20 min of stimulation, irrespective of the stimulation frequency, whereas dopamine returned to normal within 20 and 60 min in the medial prefrontal cortex and within 60 and 80 min in the parietal cortex after 12 and 24 Hz stimulation, respectively. DOPAC remained elevated throughout the experimental period. Phasic stimulation of the locus coeruleus at 12 Hz increased noradrenaline in the caudate nucleus as in the cerebral cortices but was totally ineffective on dopamine and DOPAC. Tetrodotoxin perfusion into the medial prefrontal cortex dramatically reduced noradrenaline and dopamine levels and suppressed the effect of electrical stimulation. These results indicate that electrical stimulation-induced increase of dopamine is a nerve impulse exocytotic process and suggest that cortical dopamine and noradrenaline may be coreleased from noradrenergic terminals.

The present study was aimed at determining whether the concurrent availability of highly palatable fluids (i.e., a chocolate-flavored drink and a sucrose solution) would alter voluntary ethanol drinking in selectively bred, alcohol-preferring sP and -nonpreferring sNP rats. Ethanol intake occurred under the three-bottle, free choice regimen between 10% ( v v ) ethanol solution, tap water, and the palatable fluids for 24 h per day. When rats were given ethanol and water, but no alternative fluids, mean ethanol intake in sP rats ranged between 6 and 7 g/kg per day and mean preference ratio was steadily higher than 80%, whereas mean ethanol intake and preference ratio in sNP rats were constantly lower than 0.3 g/kg and 5%, respectively. In the presence of either the chocolate-flavored drink or sucrose solution, both prepared as isocaloric to the ethanol solution, absolute ethanol intake in sP rats declined by 60–70%; similarly, the preference ratio was reduced by 80–90%. Ethanol intake in sNP rats was unaffected by the simultaneous presentation of either palatable fluids. The results of the present study closely replicate those previously reported in genetically selected, ethanol-preferring HAD rats; however, they differ from those of ethanol-preferring P rats, which were reported to maintain high levels of ethanol intake and preference in the presence of highly palatable fluids. These results are discussed in terms of a) an alternative reinforcement partially substituting for the reinforcing properties of ethanol in sP rats, resulting in a less urgent need of ethanol, and b) genetic animal models of alcoholism diverging in some neurochemical and behavioral traits (e.g., response to the presentation of palatable fluids), which might parallel the different types of alcoholism observed in humans.

The variations of Acetylcholine (ACh) release in the cerebral cortex and dorsal hippocampus were monitored by microdialysis during the electroencephalographically recorded sleep-waking cycle in freely moving cats. The results show a state-dependent variation in ACh output in both the cortex and the hippocampus. ACh release increased by approximately 100% during quiet waking (QW) and by 175% during active waking (AW) as referred to slow wave sleep (SWS) baseline. In contrast, a clear difference between the two areas was observed during REM sleep. During this stage ACh release in the cortex reached approximately the same values observed during QW, while in the hippocampus ACh release rose to about 4-fold the level obtained during SWS or twice that of QW. The results support the idea that the increase in ACh release in the cortex reflects the desynchronized EEG of wakefulness and REM sleep, while the marked increase of ACh during REM in the hippocampus may be related to the sustained theta activity in this area.

Summary Recent evidence highlights levetiracetam (LEV) as an advantageous treatment of absence epilepsy (AE). Thus, we investigated the effects of this drug in DBA/2J mice, a murine model of AE. Similarly to ethosuximide (200 mg/kg, intraperitoneal, i.p.) and sodium valproate (250 mg/kg, i.p.), two classic antiabsence agents, LEV (50–200 mg/kg, i.p.) reduced the occurrence of spike-and-wave discharges, AE's typical electroencephalographic patterns. Our results confirm LEV's efficacy in AE treatment.

Although substantial evidence has shown interactions between glutamatergic and dopaminergic systems play a cardinal role in the regulation of attentional processes, their involvement in informational filtering has been poorly investigated. Chiefly, little research has focused on functional correlations between the dopaminergic system and the mechanism of action of N-methyl-D-aspartate (NMDA) receptor antagonists on sensorimotor gating. The present study was targeted at evaluating whether the activation of D1 and D2 receptors is able to interact with the disruption of prepulse inhibition (PPI) of startle mediated by dizocilpine, a selective, noncompetitive NMDA receptor antagonist. We tested the effects of SKF 38393 ((+/-)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol) (10 mg/kg, s.c.), a selective D1 agonist, and quinpirole (0.3, 0.6 mg/kg, s.c.), a D2 agonist, in rats, per se and in cotreatment with different doses of dizocilpine, ranging from 0.0015 to 0.15 mg/kg (s.c.). Subsequently, the effect of the D1 antagonist SCH 23390 ((R)-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine) (0.05, 0.1 mg/kg, s.c.) on PPI disruptions mediated by dizocilpine and by combination of dizocilpine and SKF 38393 was tested. Two further experiments were performed to verify whether the synergic effect of the D1 agonist with dizocilpine was counteracted by effective doses of haloperidol (0.1, 0.5 mg/kg, i.p.) and clozapine (5, 10 mg/kg, i.p.). All experiments were carried out using standard procedures for the assessment of PPI of the acoustic startle reflex. SKF 38393, while unable to impair sensorimotor gating alone, induced PPI disruption in cotreatment with 0.05 and 0.15 mg/kg of dizocilpine, both ineffective per se. Furthermore, this effect was reversed by SCH 23390, but not by haloperidol or clozapine. Conversely, no synergistic effect was exhibited between quinpirole and dizocilpine, at any given dose. These findings suggest that D1, but not D2 receptors, enhance the disruptive effect of dizocilpine on PPI.

Extracellular single-unit recordings of nigral dopamine (DA) neurons were obtained from conscious rats habituated to having their body suspended in a cloth jacket and their head immobilized in the stereotaxic frame by means of a "restraining platform" permanently fixed to the skull. The electrophysiological characteristics of DA neurons from head-restrained rats and their responses to apomorphine and haloperidol were compared with single-unit recordings obtained from rats lightly and deeply anesthetized with chloral hydrate and from mesencephalic slices. Head-restrained rats showed a higher number of spontaneously active DA neurons and a higher percentage of bursting neurons than lightly and deeply anesthetized rats. Indeed, bursting activity was rare in deeply anesthetized rats and was totally absent in slices. Haloperidol was more potent and effective in stimulating the firing rate and bursting activity in head-restrained than in lightly anesthetized rats, while it was virtually ineffective in deeply anesthetized rats and totally ineffective in slices. On the other hand, DA neurons in head-restrained rats showed the same average firing rate as DA neurons in lightly and deeply anesthetized rats and in slices. The potency of apomorphine in inhibiting the firing rate, and that of haloperidol in reversing apomorphine effect, did not vary among the different in vivo preparations. The results suggest that chloral hydrate anesthesia blunts or suppresses not only the excitatory inputs which normally sustain the number of spontaneously active DA neurons and their bursting activity, but also the feedback excitation of DA neurons following haloperidol-induced D(2) receptor blockade. On the other hand, chloral hydrate anesthesia modifies neither D(2) autoreceptor sensitivity to apomorphine and haloperidol nor the automatic genesis of action potentials. The head-restrained rat appears to be an important model for studies into the pharmacology and physiology of DA neurons.

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.

COLOMBO, G., R. AGABIO, G. DIAZ, M. FA, C. LOBINA, R. REALI AND G. L. GESSA. γ-Hydroxybutyric acid intake in ethanol-preferring sP and -nonpreferring sNP rats. Physiol Behav 64(2) 197–202, 1998. γ-hydroxybutyric acid (GHB) and ethanol share several pharmacological similarities, suggesting that GHB may exert ethanol-like effects in the central nervous system. The present study was designed to test whether selectively bred ethanol-preferring rats would, unlike ethanol-nonpreferring ones, self-administer GHB, consistent with their higher preference for ethanol. Male ethanol-naive Sardinian alcohol-preferring (sP) and Sardinian alcohol-nonpreferring (sNP) rats were used. In Experiment 1, GHB solution (1% (w/v) in water) was initially offered as the sole fluid available for 14 consecutive days and then presented under the two-bottle, free-choice regimen, one bottle containing water and the other the GHB solution, for an additional 14 consecutive days. During the free-choice phase, high preference for GHB and intake of pharmacologically relevant daily doses of GHB developed in both rat lines, presumably because the 14-day no-choice period would unmask the reinforcing properties of GHB and lead to acquisition of GHB preference also in the supposedly less susceptible sNP rats. In Experiment 2, the forced GHB drinking phase was reduced to 3 days. Under the subsequent free-choice regimen, daily GHB preference and intake were initially low in both sP and sNP rats; however, after approximately 10 days, GHB preference and intake in sP rats rose progressively and then stabilized to significantly higher levels than in sNP rats throughout the entire free-choice phase. It is likely that episodic binges of GHB intake occurring during the first 10 days resulted in experiencing the reinforcing properties of GHB by sP but not sNP rats. The results of the present study suggest that a) sP rats are genetically more sensitive to the reinforcing effects of both ethanol and GHB than sNP rats; and b) disclosure of the higher sensitivity of sP rats to the reinforcing effects of GHB is a function of the length of the induction procedure. The results are also discussed in terms of differences in GHB receptors contributing to the predisposition to ethanol preference and avoidance, respectively.

The present study was designed to evaluate ethanol drinking behaviour in Sardinian alcohol-preferring (sP) and Sardinian alcohol-non-preferring (sNP) rats in the presence of different ethanol concentrations. Ethanol intake was tested under the two-bottle, free-choice regimen and continuous access schedule. Ethanol-naive sP and sNP rats were initially given ethanol solution at the standard, constant concentration of 10% (v/v) for 8 consecutive days (Phase 1). As expected, daily ethanol intake in sP rats rose from 4 to approximately 6 g/kg; in contrast sNP rats consumed10 g/kg/day ethanol. Subsequently, an ascending series of ethanol concentrations, ranging from 3 to 60% (v/v), was presented to sP and sNP rats over a 28-day period (Phase 2). At concentrations varying from 7 to 30%, sP rats consumed constant amounts of absolute ethanol per kg of body weight (approximately 6.0 g/kg/day). Daily ethanol intake in sNP rats remained constantly lower than 1.0 g/kg, irrespective of the ethanol concentration. Data from Phase 2 demonstrate the ability of sP rats to precisely adjust daily ethanol intake and support the hypothesis that voluntary ethanol drinking in sP rats is sustained by specific pharmacological effects of ethanol.

The aim of the present study was to investigate whether functional changes at CA3-CA1 synapses in the hippocampus could underlie learning and memory deficits produced in rat offspring by a prenatal exposure model simulating the carbon monoxide (CO) exposure observed in human cigarette smokers. Electrophysiological endpoints, including long-term potentiation, were examined in 15- to 30-day-old male rats whose mothers were exposed, from day 0 to day 20 of gestation, to 150 ppm of CO resulting in blood levels of carboxyhemoglobin comparable to those found in human cigarette smokers. Evoked field excitatory postsynaptic potentials were measured in the stratum radiatum in hippocampal slices. Results show that before tetanus, input/output functions, presynaptic volley, and paired-pulse facilitation were not affected in CO-exposed offspring, indicating that basal synaptic excitability and terminal Ca(2+) influx were not influenced by prenatal exposure to this gas. Conversely, evoked field excitatory postsynaptic potentials potentiation in response to tetanization was reduced by about 23% and decayed rapidly to baseline values in slices from CO-exposed animals. No changes between and within groups were observed in paired-pulse facilitation after tetanus. The selective impairment of long-term potentiation expression exhibited by CO-exposed rats was paralleled by a significant decrease in heme-oxygenase 2 and neuronal nitric-oxide synthase in the hippocampus. No changes in either enzymatic activity were found in frontal cortex and cerebellum. These electrophysiological and biochemical alterations might account for cognitive deficits previously observed in rats exposed prenatally to CO. Our findings could have clinical implications for the offspring of mothers who smoke during pregnancy.

The present study assessed the efficacy of the cannabinoid CBi receptor antagonist, SR- 141716, in reducing voluntary ethanol intake in selectively bred Sardinian alcohol-preferring (sP) rats. Ethanol (10%, v/v) and food were available in daily 4h scheduled access periods; water was present 24 h/day. The acute administration of a 2.5 and a 5 mg/kg dose of SR-141716 selectively reduced ethanol intake, whereas a 10 mg/kg dose of SR-141716 reduced to a similar extent both ethanol and food intake. These results suggest that the cannabinoid CBi receptor is involved in the mediation of the ethanol- reinforcing effects in sP rats.