Alessandro Orrù

The cannabinoid CB1 receptor antagonist, rimonabant, as a promising pharmacotherapy for alcohol dependence: preclinical evidence.

Several lines of preclinical evidence indicate the ability of the prototypic cannabinoid CB1 receptor antagonist, rimonabant, to suppress various alcohol-related behaviors, including alcohol drinking and seeking behavior and alcohol self-administration in rats and mice. Together, these data—synthetically reviewed in the present paper—suggest (a) the involvement of the cannabinoid CB1 receptor in the neural substrate controlling alcohol intake, alcohol reinforcement, and the motivational properties of alcohol and (b) that rimonabant may constitute a new and potentially effective medication for the treatment of alcohol dependence.

Hydroxytyrosol attenuates peripheral neuropathy in streptozotocin-induced diabetes in rats

Peripheral neuropathy is one of the most frequent and severe complications of diabetes. Hydroxytyrosol (HT), the major antioxidant polyphenolic compound of olive oil, has been investigated as a new potential treatment to counteract the progression of peripheral diabetic neuropathy in rats. An established model of streptozotocin-induced diabetes has been used. After confirmation of hyperglycemia, diabetic and nondiabetic animals were randomized to receive either a low dose or a high dose of HT, or the corresponding vehicle, for 6 weeks. At the end of the 6-week period of treatment, HT blunted plasma thiobarbituric acid-reactive substances increase (p < 0.05) and significantly reduced nerve conduction velocity (p < 0.05) and thermal nociception impairment in diabetic rats (p < 0.05). Sciatic nerve Na(+), K(+)-ATPase activity reduction was also abolished by HT (p < 0.05). The present study provides evidence of the therapeutic potential of the natural substance hydroxytyrosol in the early stage of diabetic neuropathy.

Six-Month ischemic mice show sensorimotor and cognitive deficits associated with brain atrophy and axonal disorganization

To identify long‐term sensorimotor and cognitive deficits and to evaluate structural alterations in brain ischemic mice.

Bifeprunox: a partial agonist at dopamine D2 and serotonin1A receptors, influences nicotine‐seeking behaviour in response to drug‐associated stimuli in rats

Environmental stimuli repeatedly associated with the self‐administered drugs may acquire motivational importance. Because dopamine (DA) D2/D3 partial agonists and D3 antagonists interfere with the ability of drug‐associated cues to induce drug‐seeking behaviour, the present study investigated whether bifeprunox, 7‐[4‐([1,1′biphenyl]‐3‐ylmethyl)‐1‐piperazinyl]‐2(3H)‐benzoxazolone mesylate), a high‐affinity partial agonist of the D2 subfamily of DA receptors and of serotonin1A receptors, influences reinstatement of drug‐associated cue‐induced nicotine‐seeking behaviour. The study also explored whether bifeprunox reduced motivated behaviour by evaluating its effects on reinstatement induced by stimuli conditioned to sucrose. To verify whether bifeprunox interferes with the primary reinforcing properties of either drug or sucrose, we compared its effects on nicotine self‐administration and on sucrose‐reinforced behaviour. Different groups of experimentally naïve, food‐restricted Wistar rats were trained to associate a discriminative stimulus with response‐contingent availability of nicotine or sucrose and tested for reinstatement after extinction of nicotine or sucrose‐reinforced behaviour. Bifeprunox (4–16 µg/kg, s.c.) dose‐dependently attenuated the response‐reinstating effects of nicotine‐associated cues. Higher doses (64–250 µg/kg, s.c.) reduced spontaneous locomotor activity and suppressed operant responding induced by sucrose‐associated cues and by the primary reinforcing properties of nicotine or sucrose. Provided they can be extrapolated to abstinent human addicts, these results suggest the potential therapeutic use of partial DA D2 receptor agonist to prevent cue‐controlled nicotine‐seeking and relapse. The profile of action of high doses of bifeprunox remains to be examined for potential sedation or anhedonia effects.

Short-term abstinence from cocaine self-administration, but not passive cocaine infusion, elevates αCaMKII autophosphorylation in the rat nucleus accumbens and medial prefrontal cortex

Increases in alpha calcium/calmodulin-dependent protein kinase type II (αCaMKII) activity in the nucleus accumbens shell has been proposed as a core component in the motivation to self-administer cocaine and in priming-induced drug-seeking. Since cocaine withdrawal promotes drug-seeking, we hypothesized that abstinence from cocaine self-administration should enhance αCaMKII as well. We found that short-term abstinence from contingent, but not non-contingent, cocaine i.v. self-administration (2 h/d for 14 d; 0.25 mg/0.1 ml, 6 s infusion) elevates αCaMKII autophosphorylation, but not the kinase expression, in a dynamic, time- and brain region-dependent manner. Increased αCaMKII autophosphorylation in the nucleus accumbens (NAc) and medial prefrontal cortex (mPFC), but not dorsolateral striatum (dlS), was found 24 h, but not immediately, after the last cocaine self-administration session. Notably, in the mPFC, but not NAc and dlS, αCaMKII autophosphorylation was still enhanced 7 d later. The persistent enhancement in the mPFC of abstinent rats may represent a previously unappreciated contribution to initial incubation of cocaine-seeking.

Evaluation for the withdrawal syndrome from γ-hydroxybutyric acid (GHB), γ-butyrolactone (GBL), and 1,4-butanediol (1,4-BD) in different rat lines

Abstract:  A severe and life‐threatening γ‐hydroxybutyric acid (GHB) withdrawal syndrome, clinically similar to the alcohol withdrawal syndrome, is increasingly being reported in GHB addicts. We investigated for the occurrence of withdrawal in Wistar and Sprague‐Dawley rats, and in the selectively bred lines of GHB‐sensitive (GHB‐S) and Sardinian alcohol‐preferring (sP) rats, following chronic administration of GHB, γ‐butyrolactone (GBL), and/or 1,4‐butanediol (1,4‐BD). Using validated rodent alcohol withdrawal scoring scales, little to no spontaneous or pharmacologically precipitated withdrawal effects were observed in Wistar, Sprague‐Dawley, or GHB‐S rats. Conversely, sP rats displayed both spontaneous and precipitated audiogenic seizures following abrupt cessation of chronic GHB or 1,4‐BD administration and following pharmacological challenge with the GABAB receptor‐selective antagonist, SCH 50911, respectively.

mGluR2/3 mediates short-term control of nicotine-seeking by acute systemic N-acetylcysteine

Chronic self‐administration of nicotine induces maladaptive changes in the cortico‐accumbal glutamate (Glu) network. Consequently, re‐exposure to nicotine‐associated cues raises extracellular Glu in the nucleus accumbens reinstating drug‐seeking. Restoring basal concentrations of extracellular Glu, thereby increasing tonic activation of the presynaptic group II metabotropic Glu receptors (mGluR2/3) with N‐acetylcysteine (N‐AC), might offer a valid therapeutic approach for maintaining smoking abstinence. Although N‐AC modulates nicotine‐seeking behavior by drug‐associated stimuli in abstinent rats, it is still unclear whether it occurs through activation of mGluR2/3. Male Wistar rats were trained to associate discriminative stimuli (SDs) with the availability of intravenous nicotine (0.03 mg/kg/65 µl/2‐second/infusion) or oral saccharin (100 µl of 50 mg/l) self‐administration versus non‐reward. Reinforced response was followed by a cue signaling 20‐second time‐out (CSs). Once the training criterion was met, rats underwent lever press extinction, without reinforcers, SDs and CSs. Re‐exposure to nicotine or saccharin SD+/CS+, but not non‐reward SD−/CS−, revived responding on the previously reinforced lever. Acute N‐AC, 100 but not 60 or 30 mg/kg i.p., reduced cue‐induced nicotine‐seeking. N‐AC 100 mg/kg did not modify cue‐induced saccharin‐seeking behavior or influenced locomotor activity. Blocking mGluR2/3 with the selective antagonist LY341495, 1 mg/kg i.p., completely prevented the antirelapse activity of N‐AC. The finding that N‐AC prevents cue‐induced nicotine‐seeking by stimulating mGluR2/3 might indicate a therapeutic opportunity for acute cue‐controlled nicotine‐seeking. Future studies could evaluate the persistent effects of chronic N‐AC in promoting enduring suppression of nicotine‐cue conditioned responding.

Suppression of maintenance of alcohol-drinking behavior by the concurrent availability of saccharin in Sardinian alcohol-preferring (sP) rats.

In the current study, we investigated the effect of the concurrent presentation of saccharin on the maintenance of alcohol-drinking behavior in selectively bred Sardinian alcohol-preferring (sP) rats. Rats were initially given access to alcohol [10% (volume/volume) in water] and water under the home cage, two-bottle, free-choice regimen, with unlimited access for 24 h/day for eight consecutive weeks. Next, a third bottle, containing saccharin [0%, 0.01%, 0.1%, 1%, or 3% (weight/volume) in water], was concomitantly offered for an additional 10 consecutive days. Intake of saccharin solution resulted as an inverted-U function of saccharin concentration, with the 0.1% saccharin solution being the highest accepted. Alcohol intake was a U function of saccharin concentration, being reduced by 65%-95% in the group of rats exposed to the 0.1% saccharin solution. These results indicate that (1) the concurrent presentation of highly palatable solutions of saccharin markedly reduced alcohol intake in alcohol-experienced sP rats and (2) the reducing effect of saccharin solutions on the alcohol intake in sP rats was positively related to their degree of acceptability. We hypothesized that saccharin solutions may have functioned as a reinforcer, partially substituting for alcohol reinforcement and rendering alcohol drinking less urgent.