Alcohol binge drinking is common among adolescents and may challenge the signalling systems that process affective stimuli, including calcitonin gene-related peptide (CGRP) signalling. Here, we employed a rat model of adolescent binge drinking to evaluate reward-, social- and aversion-related behaviour, glucocorticoid output and CGRP levels in affect-related brain regions. As a potential rescue, the effect of the phytocannabinoid cannabidiol was explored. Adolescent male rats underwent the intermittent 20% alcohol two-bottle choice paradigm; at the binge day (BD) and the 24 h withdrawal day (WD), we assessed CGRP expression in medial prefrontal cortex (mPFC), nucleus accumbens (NAc), amygdala, hypothalamus and brainstem; in addition, we evaluated sucrose preference, social motivation and drive, nociceptive response, and serum corticosterone levels. Cannabidiol (40 mg/kg, i.p.) was administered before each drinking session, and its effect was measured on the above-mentioned readouts. At BD and WD, rats displayed decreased CGRP expression in mPFC, NAc and amygdala; increased CGRP levels in the brainstem; increased response to rewarding- and nociceptive stimuli and decreased social drive; reduced serum corticosterone levels. Cannabidiol reduced alcohol consumption and preference; normalised the abnormal corticolimbic CGRP expression, and the reward and aversion-related hyper-responsivity, as well as glucocorticoid levels in alcohol binge-like drinking rats. Overall, CGRP can represent both a mediator and a target of alcohol binge-like drinking and provides a further piece in the intricate puzzle of alcohol-induced behavioural and neuroendocrine sequelae. CBD shows promising effects in limiting adolescent alcohol binge drinking and rebalancing the bio-behavioural abnormalities.
- MeSH
- Ethanol MeSH
- Glucocorticoids MeSH
- Hypothalamus MeSH
- Cannabidiol * pharmacology MeSH
- Corticosterone MeSH
- Rats MeSH
- Binge Drinking * drug therapy metabolism psychology MeSH
- Calcitonin Gene-Related Peptide metabolism MeSH
- Alcohol Drinking adverse effects metabolism psychology MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
The negative affective state of opiate abstinence plays an important role in craving and relapse to compulsive drug use. The dopamine system participates in the reward effects of opiate use and the aversive effect of opiate abstinence. The amygdala is an essential neural substrate for associative learning of emotion. To establish a model of conditioned place aversion (CPA) in morphine-treated rats, we used different visual and tactual cues as conditioned stimuli (CS) within a conditioning apparatus. An injection of naloxone served as the unconditioned stimulus (US). The 6-hydroxydopamine (6-OHDA) lesion technique was used to investigate the effects of the dopaminergic system of the central nucleus of the amygdala (CeA) on naloxone-induced CPA. Rats were rendered physically dependent via administration of increasing doses of morphine delivered via intraperitoneal injection. Doses increased by 20 % each day for 14 days, starting from an initial dose of 6 mg/kg. All rats also received a low dose of naloxone (0.1 mg/kg) by injection 4 hours after morphine treatment on days 11 and 13 to induce CPA in a biased two-compartment conditioned place apparatus. Morphine-dependent rats with sham lesions were found to develop significant CPA after naloxone treatment. Bilateral 6-OHDA lesions of the CeA impaired the acquisition of CPA but had no effect on locomotor activity. These results suggest that the dopaminergic system of the CeA plays an important role in the negative affective state of opiate abstinence.
- MeSH
- Amygdala drug effects metabolism MeSH
- Cell Nucleus drug effects MeSH
- Dopamine metabolism MeSH
- Conditioning, Classical drug effects MeSH
- Rats MeSH
- Morphine administration & dosage pharmacology MeSH
- Narcotics administration & dosage pharmacology MeSH
- Oxidopamine administration & dosage pharmacology MeSH
- Rats, Sprague-Dawley MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Previous evidence suggests that prenatal exposure to THC (pTHC) derails the neurodevelopmental trajectories towards a vulnerable phenotype for impaired emotional regulation and limbic memory. Here we aimed to investigate pTHC effect on hippocampus-related cognitive functions and markers of neuroplasticity in adolescent male offspring. Wistar rats were exposed to THC (2 mg/kg) from gestational day 5 to 20 and tested for spatial memory, object recognition memory and reversal learning in the reinforce-motivated Can test and in the aversion-driven Barnes maze test; locomotor activity and exploration, anxiety-like behaviour, and response to natural reward were assessed in the open field, elevated plus maze, and sucrose preference tests, respectively. The gene expression levels of NMDA NR1-2A subunits, mGluR5, and their respective scaffold proteins PSD95 and Homer1, as well as CB1R and the neuromodulatory protein HINT1, were measured in the hippocampus. pTHC offspring exhibited deficits in spatial and object recognition memory and reversal learning, increased locomotor activity, increased NR1-, decreased NR2A- and PSD95-, increased mGluR5- and Homer1-, and augmented CB1R- and HINT1-hippocampal mRNA levels. Our data shows that pTHC is associated with specific impairment in spatial cognitive processing and effectors of hippocampal neuroplasticity and suggests novel targets for future pharmacological challenges.
- Publication type
- Journal Article MeSH
Přehledový článek shrnuje principy hédonické regulace příjmu potravy, která reprezentuje příjem potravy nezávislý na udržení homeostázy. Teorie popisující hédonickou regulaci, tzv. teorie senzitizace vůči podnětu, zahrnuje tři procesy: vytvoření pozitivního vztahu k potravnímu podnětu (liking), motivaci získat ho (wanting) a naučit se tyto podněty identifikovat a odlišit od jiných, jejichž konzumace naopak vyvolá averzní reakci (learning). Anatomickým a funkčním substrátem hédonické regulace jsou neuronální okruhy odměny (reward circuits), které reagují na chuťové, čichové (či zrakové) podněty spojené s příjmem potravy. Preference určité potravy nastane pouze v případě, že je její konzumace spojena s příjemným pocitem, který posiluje behaviorální odpověď, takže pravděpodobnost této odpovědi je při opakované expozici takovému podnětu zvýšená (naučená preference). Naopak naučená averze spočívá při opakované expozici ve vyhýbání se potravě, která byla spojena s negativním pocitem. Hlavními mediátory hédonické regulace jsou endokanabinoidy, opioidy a monoaminy (zvláště dopamin a méně serotonin). Dopamin prostřednictvím svých D2 receptorů generuje v dorzálním striatu motivaci k jídlu jako jednomu ze základních prostředků přežití, zatímco ve ventrálním striatu (nucleus accumbens) zodpovídá spíše za motivaci k jídlu přinášejícímu libé pocity. Serotonin přes své receptory 5-HT1A a 5-HT2C snižuje příjem zvláště chutné potravy. Hraje také významnou úlohu v patogenezi poruch příjmu potravy. U mentální anorexie představuje restrikce potravy určitou automedikaci patologicky zvýšených hladin serotoninu. Klíčem k novým farmakoterapeutickým intervencím poruch příjmu potravy je detailní pochopení procesů, jakými je příjem potravy regulován.
The review article summarizes the principles of hedonic regulation of food intake which represents the food intake independent on the maintenance of homeostasis. The theory describing hedonic regulation, so called Incentive Salience Theory, comprises three major processes: liking (positive attribution to food stimulus), wanting (motivation to gain it) and learning (identification of these stimuli and distinguishing them from those connected with aversive reaction). Neuronal reward circuits are the anatomical and functional substrates of hedonic regulation. They react to gustatory and olfactory (or visual) stimuli associated with food intake. A food item is preferred in case its consumption is connected with a pleasant feeling thus promoting the behavioural reaction. The probability of this reaction after repetitive exposure to such a stimulus is increased (learned preference). On the contrary, learned aversion after repetitive exposure is connected with avoidance of a food item associated with a negative feeling. Main mediators of hedonic regulation are endocannabinoids, opioids and monoamines (dopamine, serotonin). Dopamine in dorsal striatum via D2 receptors generates food motivation as a key means of survival, however in ventral striatum (nucleus accumbens) is responsible for motivation to food bringing pleasure. Serotonin via its receptors 5-HT1A a T-HT2C decreases intake of palatable food. It plays a significant role in the pathogenesis of eating disorders, particularly mental anorexia. There, a food restriction represents a kind of automedication to constitutionally pathologically increased serotonin levels. Detailed understanding of processes regulating food intake is a key to new pharmacological interventions in eating disorders.
- Keywords
- hédonická regulace, okruhy odměny,
- MeSH
- Appetite physiology MeSH
- Taste physiology MeSH
- Dopamine physiology MeSH
- Endocannabinoids physiology MeSH
- Humans MeSH
- Motivation physiology MeSH
- Brain Chemistry * MeSH
- Neural Pathways physiology MeSH
- Obesity physiopathology MeSH
- Feeding and Eating Disorders physiopathology MeSH
- Food Preferences * physiology MeSH
- Eating physiology MeSH
- Receptors, Opioid physiology MeSH
- Appetite Regulation * physiology MeSH
- Serotonin physiology MeSH
- Learning physiology MeSH
- Check Tag
- Humans MeSH
- Publication type
- Research Support, Non-U.S. Gov't MeSH
- Review MeSH
Binge alcohol consumption among adolescents affects the developing neural networks underpinning reward and stress processing in the nucleus accumbens (NAc). This study explores in rats the long-lasting effects of early intermittent exposure to intoxicating alcohol levels at adolescence, on: (1) the response to natural positive stimuli and inescapable stress; (2) stress-axis functionality; and (3) dopaminergic and glutamatergic neuroadaptation in the NAc. We also assess the potential effects of the non-intoxicating phytocannabinoid cannabidiol, to counteract (or reverse) the development of detrimental consequences of binge-like alcohol exposure. Our results show that adolescent binge-like alcohol exposure alters the sensitivity to positive stimuli, exerts social and novelty-triggered anxiety-like behaviour, and passive stress-coping during early and prolonged withdrawal. In addition, serum corticosterone and hypothalamic and NAc corticotropin-releasing hormone levels progressively increase during withdrawal. Besides, NAc tyrosine hydroxylase levels increase at late withdrawal, while the expression of dopamine transporter, D1 and D2 receptors is dynamically altered during binge and withdrawal. Furthermore, the expression of markers of excitatory postsynaptic signaling-PSD95; Homer-1 and -2 and the activity-regulated spine-morphing proteins Arc, LIM Kinase 1 and FOXP1-increase at late withdrawal. Notably, subchronic cannabidiol, during withdrawal, attenuates social- and novelty-induced aversion and passive stress-coping and rectifies the hyper-responsive stress axis and NAc dopamine and glutamate-related neuroplasticity. Overall, the exposure to binge-like alcohol levels in adolescent rats makes the NAc, during withdrawal, a locus minoris resistentiae as a result of perturbations in neuroplasticity and in stress-axis homeostasis. Cannabidiol holds a promising potential for increasing behavioural, neuroendocrine and molecular resilience against binge-like alcohol harmful effects.
- Publication type
- Journal Article MeSH
Deep brain stimulation (DBS) of the subthalamic nucleus (STN) can induce nonmotor side effects such as behavioral and mood disturbances or body weight gain in Parkinson's disease (PD) patients. We hypothesized that some of these problems could be related to an altered attribution of incentive salience (ie, emotional relevance) to rewarding and aversive stimuli. Twenty PD patients (all men; mean age ± SD, 58.3 ± 6 years) in bilateral STN DBS switched ON and OFF conditions and 18 matched controls rated pictures selected from the International Affective Picture System according to emotional valence (unpleasantness/pleasantness) and arousal on 2 independent visual scales ranging from 1 to 9. Eighty-four pictures depicting primary rewarding (erotica and food) and aversive fearful (victims and threat) and neutral stimuli were selected for this study. In the STN DBS ON condition, the PD patients attributed lower valence scores to the aversive pictures compared with the OFF condition (P < .01) and compared with controls (P < .01). The difference between the OFF condition and controls was less pronounced (P < .05). Furthermore, postoperative weight gain correlated with arousal ratings from the food pictures in the STN DBS ON condition (P < .05 compensated for OFF condition). Our results suggest that STN DBS increases activation of the aversive motivational system so that more relevance is attributed to aversive fearful stimuli. In addition, STN DBS-related sensitivity to food reward stimuli cues might drive DBS-treated patients to higher food intake and subsequent weight gain.
- MeSH
- Emotions physiology MeSH
- Deep Brain Stimulation adverse effects MeSH
- Middle Aged MeSH
- Humans MeSH
- Motivation physiology MeSH
- Statistics, Nonparametric MeSH
- Neuropsychological Tests MeSH
- Subthalamic Nucleus physiology MeSH
- Parkinson Disease psychology therapy MeSH
- Mood Disorders etiology MeSH
- Aged MeSH
- Statistics as Topic MeSH
- Case-Control Studies MeSH
- Photic Stimulation MeSH
- Body Weight MeSH
- Mental Status Schedule MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Clinical motor and non-motor effects of deep brain stimulation (DBS) of the subthalamic nucleus (STN) in Parkinson's disease (PD) seem to depend on the stimulation site within the STN. We analysed the effects of the position of the stimulation electrode within the motor STN on subjective emotional experience, expressed as emotional valence and arousal ratings to pictures representing primary rewards and aversive fearful stimuli in 20 PD patients. Patients' ratings from both aversive and erotic stimuli matched the mean ratings from a group of 20 control subjects at similar position within the STN. Patients with electrodes located more posteriorly reported both valence and arousal ratings from both the rewarding and aversive pictures as more extreme. Moreover, posterior electrode positions were associated with a higher occurrence of depression at a long-term follow-up. This brain-behavior relationship suggests a complex emotion topography in the motor part of the STN. Both valence and arousal representations overlapped and were uniformly arranged anterior-posteriorly in a gradient-like manner, suggesting a specific spatial organization needed for the coding of the motivational salience of the stimuli. This finding is relevant for our understanding of neuropsychiatric side effects in STN DBS and potentially for optimal electrode placement.
- MeSH
- Electrodes MeSH
- Emotions physiology MeSH
- Deep Brain Stimulation methods MeSH
- Middle Aged MeSH
- Humans MeSH
- Subthalamic Nucleus metabolism physiology MeSH
- Parkinson Disease metabolism physiopathology therapy MeSH
- Aged MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
BACKGROUND: Changes in motivational processing may play a role in weight gain and other non-motor side effects in Parkinson's disease (PD) patients treated with deep brain stimulation of the subthalamic nucleus. OBJECTIVE/HYPOTHESIS: We aimed to assess changes in aversive and appetitive motivational activation using modulation of the acoustic blink reflex (ABR) by rewarding and aversive stimuli. METHODS: ABR elicited during the viewing of erotic, food, aversive and neutral pictures was recorded in 11 off-medicated patients with the subthalamic stimulation switched ON and OFF, and in 11 control subjects. RESULTS: ABR to erotic stimuli was larger in patients in the ON compared to the OFF condition and controls (P < 0.01). Aversive stimuli caused a larger increase in the ABR in patients with the ON condition than in controls (P < 0.05). Additionally, we found a negative correlation of the ABR magnitude to food pictures in the ON condition with weight gain following subthalamic stimulation (P < 0.01, after adjustment to OFF condition). CONCLUSIONS: Our results suggest that subthalamic stimulation affects motivational processing. Subthalamic stimulation may disturb appetitive engagement by erotic cues and increase aversive activation in PD patients. Additionally, postoperative weight gain may be related to changes in the processing of food cues due to subthalamic stimulation.
- MeSH
- Deep Brain Stimulation * MeSH
- Middle Aged MeSH
- Humans MeSH
- Motivation physiology MeSH
- Blinking MeSH
- Subthalamic Nucleus physiology MeSH
- Parkinson Disease physiopathology therapy MeSH
- Sexual Behavior physiology MeSH
- Feeding Behavior physiology MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Reward based learning is broadly acknowledged to underpin the development and maintenance of addictive behaviour although the mechanism in sexual compulsivity is less understood. Using a Pavlovian-to-Instrumental Transfer (PIT) task we tested whether the motivational aspect of conditioned Pavlovian conditioned stimulus invigorated instrumental responding in relation to specific compatible monetary rewards. Performance on the task was analysed between two groups of males based on Low (N = 38) and High (N = 41) self-report online sexual behaviour (OSB). Psychometric tests including sexual compulsivity scale and behavioural activation/behavioural inhibition (BIS/BAS) were also administered to determine the relationship between OSB and general reward sensitivity. We show clear evidence of acquisition in the Pavlovian and instrumental conditioning phases. Specific transfer effect was greater in the High-OSB group although the difference compared to the Low-OSB group was non-significant. OSB negatively correlated with both BIS and BAS indicative of introversion and low reward sensitivity. OSB positively correlated with sexual compulsivity although it is unclear whether individuals in the High-OSB group considered their behaviour either excessive or problematic. These findings contribute to the ongoing debate regarding the nature of problematic OSB. Fundamental differences in motivational characteristics and mechanism contributing to compulsive behaviour in relation to high-OSB might indicate incompatibility with behavioural addiction models. PIT was not enhanced in high-OSB by appetitive conditioning, although problematic OSB could stem from failure to inhibit actions. Further research should investigate whether aversive conditioning differentially affects responding in high-OSB individuals, potentially explaining perseverant behaviour despite negative consequences.
- MeSH
- Conditioning, Classical physiology MeSH
- Humans MeSH
- Behavior, Addictive * MeSH
- Reward MeSH
- Conditioning, Operant physiology MeSH
- Transfer, Psychology * physiology MeSH
- Sexual Behavior MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
