Angela Cavallaro

Acetaldehyde, Motivation and Stress: Behavioral Evidence of an Addictive ménage à trois

Acetaldehyde (ACD) contributes to alcohol’s psychoactive effects through its own rewarding properties. Recent studies shed light on the behavioral correlates of ACD administration and the possible interactions with key neurotransmitters for motivation, reward and stress-related response, such as dopamine and endocannabinoids. This mini review article critically examines ACD psychoactive properties, focusing on behavioral investigations able to unveil ACD motivational effects and their pharmacological modulation in vivo. Similarly to alcohol, rats spontaneously drink ACD, whose presence is detected in the brain following chronic self-administration paradigm. ACD motivational properties are demonstrated by operant paradigms tailored to model several drug-related behaviors, such as induction and maintenance of operant self-administration, extinction, relapse and punishment resistance. ACD-related addictive-like behaviors are sensitive to pharmacological manipulations of dopamine and endocannabinoid signaling. Interestingly, the ACD-dopamine-endocannabinoids relationship also contributes to neuroplastic alterations of the NPYergic system, a stress-related peptide critically involved in alcohol abuse. The understanding of the ménage-a-trois among ACD, reward- and stress-related circuits holds promising potential for the development of novel pharmacological approaches aimed at reducing alcohol abuse.

Homer2 and Alcohol: A Mutual Interaction

The past two decades of data derived from addicted individuals and preclinical animal models of addiction implicate a role for the excitatory glutamatergic transmission within the mesolimbic structures in alcoholism. The cellular localization of the glutamatergic receptor subtypes, as well as their signaling efficiency and function, are highly dependent upon discrete functional constituents of the postsynaptic density, including the Homer family of scaffolding proteins. The consequences of repeated alcohol administration on the expression of the Homer family proteins demonstrate a crucial and active role, particularly for the expression of Homer2 isoform, in regulating alcohol-induced behavioral and cellular neuroplasticity. The interaction between Homer2 and alcohol can be defined as a mutual relation: alcohol consumption enhances the expression of Homer2 protein isoform within the nucleus accumbens and the extended amygdala, cerebral areas where, in turn, Homer2 is able to mediate the development of the “pro-alcoholic” behavioral phenotype, as a consequence of the morpho-functional synaptic adaptations. Such findings are relevant for the detection of the strategic molecular components that prompt alcohol-induced functional and behavioral disarrangement as targets for future innovative treatment options.

The role of (E)-6-chloro-3-(3-methyl-1-phenyl-1H-pyrazol-5-yl)-2-styrylquinazolin-4(3H)-one in the modulation of cannabinoidergic system. A pilot study

BACKGROUND Compounds acting on endocannabinoid system regulate different neuronal processes through the cannabinoid receptors activation. The main aim of this study was determining whether the 2-styrylquinazolin-4(3H)-one 5, a structural analogue of rimonabant, was able to counteract the behavioural signs of the activation of the endocannabinoidergic system induced by CP 55.940. METHODS Behavioural assessment was carried out using the tetrad task and the novel object recognition test. The endocannabinoidergic system activation was possible by the administration of CP 55.940 and 30min after rats were tested in the tetrad task for the evaluation of the antinociceptive-, cataleptic-, hypothermic- and locomotor- effects. The evaluation of the declarative memory was carried out through the novel object recognition test. The administration of the new compound was made at three different doses, 30min before CP 55.940 administration on a separate group of animals. RESULTS Our results demonstrated that compound 5, at the highest dose, was able to counteract the effects exerted by CP 55.940, shown by an increase in body temperature, total distance travelled, latency to fall and decrease in tail flick latency, interfering conjointly in memory impairment. CONCLUSION This study shows that compound 5 is able to counteract the cannabinoid activation induced by the agonist CP 55.940. Further investigations on its pharmacological profile are mandatory before considering it as a potential candidate for clinical studies and its possible employment as pharmacological agent for the management of different pathological conditions such as motor incoordination, obesity and brain related disorders.

Reward-related limbic memory and stimulation of the cannabinoid system: An upgrade in value attribution?

While a lot is known about the mechanisms promoting aversive learning, the impact of rewarding factors on memory has received comparatively less attention. This research investigates reward-related explicit memory in male rats, by taking advantage of the emotional-object recognition test. This is based on the prior association, during conditioned learning, between a rewarding experience (the encounter with a receptive female rat) and an object; afterwards rat discrimination and recognition of the ‘emotional object’ is recorded in the presence of a novel object, as a measure of positive limbic memory formation. Since endocannabinoids are critical for processing reward and motivation, the consequences of the stimulation of cannabinoid signalling are also assessed by the administration of WIN 55,212-2 at pre- and post-conditioning time. Our results show that rats encode the association between object and rewarding experience, form positive limbic memory of the emotional object, and retrieve this information in the face of novelty. Stimulation of the cannabinoid system at pre-conditioning time is able to strengthen reward-related explicit memory in the presence of novelty, whereas post-conditioning activation increases approach behaviour to novel stimuli. The assessment of limbic memory by the emotional-object recognition test can help unveiling the addictive and confounding properties of psychotropic drugs.

Pre-conceptional and Peri-Gestational Maternal Binge Alcohol Drinking Produces Inheritance of Mood Disturbances and Alcohol Vulnerability in the Adolescent Offspring

Although binge drinking is on the rise in women of reproductive age and during pregnancy, the consequences in the offspring, in particular the inheritance of alcohol-related mood disturbances and alcohol abuse vulnerability, are still poorly investigated. In this study, we modeled both Habitual- and Binge Alcohol Drinking (HAD and BAD) in female rats by employing a two-bottle choice paradigm, with 20% alcohol and water. The exposure started 12 weeks before pregnancy and continued during gestation and lactation. The consequences induced by the two alcohol drinking patterns in female rats were assessed before conception in terms of behavioral reactivity, anxiety- and depressive-like behavior. Afterwards, from adolescence to young-adulthood, male offspring was assessed for behavioral phenotype and alcohol abuse vulnerability. At pre-conceptional time BAD female rats showed higher mean alcohol intake and preference than HAD group; differences in drinking trajectories were attenuated during pregnancy and lactation. Pre-conceptional BAD induced a prevalent depressive/anhedonic-like behavior in female rats, rather than an increase in anxiety-like behavior, as observed in HAD rats. In the adolescent offspring, peri-gestational BAD did not affect behavioral reactivity in the open field and anxiety-like behavior in the elevated plus maze. Rather, BAD dams offspring displayed higher despair-behavior and lower social interaction with respect to control- and HAD dams progeny. Notably, only binge drinking exposure increased offspring vulnerability to alcohol abuse and relapse following forced abstinence. This is the first report showing that binge-like alcohol consumption from pre-conceptional until weaning induces relevant consequences in the affective phenotype of both the mothers and the offspring, and that such effects include heightened alcohol abuse vulnerability in the offspring. These findings highlight the need for more incisive public education campaigns about detrimental consequences of peri-gestational alcohol exposure.