Depression is a psychiatric disorder characterized by a marked decrease in reward sensitivity. By using the olfactory bulbectomy (OBX) model of depression, it was shown that OBX rats display enhanced drug-taking and seeking behaviors in a self-administration paradigm than sham-operated (SHAM) controls, and sex is an important regulating factor. To reveal potential strain effects, we compared the operant behavior of male and female Sprague-Dawley and Wistar OBX and SHAM rats trained to self-administer palatable food pellets. Results showed that Sprague-Dawley OBX rats of both sexes exhibited lower operant responding rates and food intake than SHAM controls. Food restriction increased responding in both OBX and SHAM groups. Female rats responded more than males, but the OBX lesion abolished this effect. In Wistar rats, bulbectomy lowered food self-administration only during the last training days. Food self-administration was not significantly affected in Wistar rats by sex. In summary, this study showed that bulbectomy significantly reduces operant responding and food intake in male and female Sprague-Dawley rats while inducing a mild reducing effect only in the Wistar strain. Strain-dependent effects were also observed in the modulating role of sex and food restriction on operant responding and palatable food intake.

• Keywords
• depression, olfactory bulbectomy, reward, self-administration, sex, strain,
• Publication type
• Journal Article MeSH

OBJECTIVE: Addiction is a chronic disease with limited pharmacological options for intervention. Focusing on reducing glutamate levels in the brain seems to be a promising strategy in addiction treatment research. Our research aimed to evaluate the effects of CNQX, an antagonist that targets AMPA and kainate glutamatergic receptors while also exhibiting affinity for the NMDA receptor, especially by modulating its glycine site. We conducted this assessment on the self-administration of nicotine and methamphetamine via intravenous (IV) administration in rats. METHODS: An operant IV self-administration model was used in male Wistar rats. When animals maintained a stable intake of nicotine or methamphetamine, we administered a single injection of CNQX (in the dose of 3 or 6 mg/kg IV) to evaluate its effect on drug intake. Subsequently, the rats were forced to abstain by staying in their home cages for 2 weeks. The period of abstinence was followed by a context-induced relapse-like session before which animals were pretreated with the injection of CNQX (3 or 6 mg/kg IV) to evaluate its effect on drug seeking. RESULTS: CNQX significantly reduced nicotine intake during the maintenance phase, but no effect was revealed on nicotine seeking after forced abstinence. CNQX did not affect methamphetamine taking or seeking. CONCLUSION: The effect of reducing nicotine taking but not seeking could be explained by different involvement of glutamatergic receptors in various stages of nicotine dependence.

• Keywords
• AMPA/kainate receptor, CNQX, methamphetamine, nicotine, relapse, self-administration,
• Publication type
• Journal Article MeSH

Cannabis/cannabinoids are widely used for recreational and therapy purposes, but their risks are largely disregarded. However, cannabinoid-associated use disorders and dependence are alarmingly increasing and an effective treatment is lacking. Recently, the growth hormone secretagogue receptor (GHSR1A) antagonism was proposed as a promising mechanism for drug addiction therapy. However, the role of GHS-R1A and its endogenous ligand ghrelin in cannabinoid abuse remains unclear. Therefore, the aim of our study was to investigate whether the GHS-R1A antagonist JMV2959 could reduce the tetrahydrocannabinol (THC)-induced conditioned place preference (CPP) and behavioral stimulation, the WIN55,212-2 intravenous self-administration (IVSA), and the tendency to relapse. Following an ongoing WIN55,212-2 self-administration, JMV2959 3 mg/kg was administered intraperitoneally 20 min before three consequent daily 120-min IVSA sessions under a fixed ratio FR1, which significantly reduced the number of the active lever-pressing, the number of infusions, and the cannabinoid intake. Pretreatment with JMV2959 suggested reduction of the WIN55,212-2-seeking/relapse-like behavior tested in rats on the twelfth day of the forced abstinence period. On the contrary, pretreatment with ghrelin significantly increased the cannabinoid IVSA as well as enhanced the relapse-like behavior. Co-administration of ghrelin with JMV2959 abolished/reduced the significant efficacy of the GHS-R1A antagonist in the cannabinoid IVSA. Pretreatment with JMV2959 significantly and dose-dependently reduced the manifestation of THC-induced CPP. The THC-CPP development was reduced after the simultaneous administration of JMV2959 with THC during conditioning. JMV2959 also significantly reduced the THC-induced behavioral stimulation in the LABORAS cage. Our findings suggest that GHS-R1A importantly participates in the rewarding/reinforcing effects of cannabinoids.

• Keywords
• WIN55,212-2, addiction, behavioral stimulation, conditioned place preference, ghrelin antagonism, intravenous self-administration, synthetic cannabinoid, tetrahydrocannabinol (THC),
• MeSH
• Self Administration MeSH
• Behavior, Animal drug effects   MeSH
• Glycine analogs & derivatives   pharmacology   MeSH
• Administration, Intravenous MeSH
• Cannabinoids administration & dosage   pharmacology   MeSH
• Rats MeSH
• Conditioning, Operant drug effects   MeSH
• Conditioning, Psychological drug effects   MeSH
• Reinforcement, Psychology MeSH
• Rats, Wistar MeSH
• Receptors, Ghrelin antagonists & inhibitors   MeSH
• Triazoles pharmacology   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Ghsr1a protein, rat MeSH Browser
• Glycine MeSH
• Cannabinoids MeSH
• N-(1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-aminoacetamide MeSH Browser
• Receptors, Ghrelin MeSH
• Triazoles MeSH

Substance abuse and depression are common psychiatric disorders with a high rate of comorbidity. Both conditions affect differently men and women and preclinical research has showed many sex differences in drug addiction and depression. The most common approach for modeling depression-addiction comorbidity is the combination of the intravenous drug self-administration and the olfactory bulbectomy (OBX) models in rats. Such a combination has revealed enhanced drug-taking and drug-seeking behaviors in OBX rats, but no study has investigated so far potential sex differences in operant responding and motivation for natural reinforcers in OBX rats. This study investigated for the first time operant self-administration of palatable food pellets in male and female OBX rats under different feeding status, i.e., ad libitum vs. restricted food, and schedules of reinforcement, i.e., a continuous ratio schedule fixed ratio 1 (FR1) vs. a complex (FR5(x)) second order schedule of reinforcement. In the FR1 experiment, OBX rats of both sexes exhibited lower operant responding and intake of palatable food pellets than sham-operated controls, with food restriction leading to increased operant responding in both OBX and SHAM groups. Female rats showed higher responding than males but this effect was abolished by the OBX lesion. Similarly, in the (FR5(x)) second order schedule of reinforcement both male and female OBX rats showed lower responding and food intake, with SHAM and OBX females showing higher operant responding than corresponding male groups. Overall, our findings showed that: (i) responding for food was lower in OBX than in SHAM rats under both FR1 and (FR5(x)) schedules of reinforcement; (ii) sex and food restriction affect operant responding for palatable food; and (iii) the suppressing effect of OBX lesion on food intake was consistently present in both sexes and represents the most robust factor in the analysis. This may represent anhedonia which is associated with depressive-like phenotype and palatable food self-administration may serve as a robust behavioral index of anhedonia in the OBX model.

• Keywords
• depression, food intake, olfactory bulbectomy, reward, self-administration, sex difference,
• Publication type
• Journal Article MeSH

The devastating consequences of alcohol-use disorder (AUD) on the individual and the society are well established. Current treatments of AUD encompass various strategies, all of which have only modest effectiveness. Hence, there is a critical need to develop more efficacious therapies. Recently, specific glutamatergic receptors have been identified as potential novel targets for intervention in AUD. Thus, the current study was designed to evaluate the effects of acute administration of sub-anesthetic doses of ketamine, an NMDA receptor antagonist, as well as NBQX, an AMPA/kainate receptor antagonist on alcohol intake and its possible behavioural consequences. Adult male Wistar rats were trained in drinking in dark paradigm (3 weeks), and following stable alcohol intake, ketamine, NBQX as well as their combination were injected prior to a 90 min drinking session. In addition to alcohol intake, sucrose preference (overnight), and locomotor activity and forced swim test (FST) were also evaluated before and following alcohol intake. Both doses of ketamine (5 and 10 mg/kg) and NBQX (5 and 10 mg/kg) significantly attenuated percent alcohol intake. The combination of the higher dose of ketamine and NBQX, however, did not significantly affect percent alcohol intake. Moreover, animals exposed to alcohol showed decreased sucrose intake (reflective of anhedonia), decreased locomotor activity and swimming in the FST (reflective of helplessness), that were not affected by ketamine and/or NBQX. These results suggest that selective antagonism of the NMDA or AMPA/kainate receptors may be of therapeutic potential in AUD.

• Keywords
• AMPA receptor, Alcohol use disorder, Alcoholism, Glutamatergic receptors, Kainate receptor, NMDA receptor,
• MeSH
• Receptors, AMPA antagonists & inhibitors   MeSH
• Quinoxalines pharmacology   MeSH
• Depression drug therapy   MeSH
• Ketamine pharmacology   MeSH
• Kainic Acid pharmacology   MeSH
• Alcohol Drinking adverse effects   MeSH
• Rats, Wistar MeSH
• Receptors, N-Methyl-D-Aspartate antagonists & inhibitors   MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• 2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline MeSH Browser
• Receptors, AMPA MeSH
• Quinoxalines MeSH
• Ketamine MeSH
• Kainic Acid MeSH
• Receptors, N-Methyl-D-Aspartate MeSH

Ketamine may prove to be a potential candidate in treating the widespread drug addiction/substance abuse epidemic among patients with schizophrenia. Clinical studies have shown ketamine to reduce cocaine and heroin cravings. However, the use of ketamine remains controversial as it may exacerbate the symptoms of schizophrenia. Therefore, the aim of this study is to characterize the effects of ketamine on drug addiction in schizophrenia using the methylazoxymethanol (MAM) acetate rat model on operant IV methamphetamine (METH) self-administration. MAM was administered intraperitoneally (22 mg/kg) on gestational day 17. Locomotor activity test and later IV self-administration (IVSA) were then performed in the male offspring followed by a period of forced abstinence and relapse of METH taking. After reaching stable intakes in the relapse phase, ketamine (5 mg/kg) was administered intraperitoneally 30 min prior to the self-administration session. As documented previously, the MAM rats showed a lack of habituation in the locomotor activity test but developed stable maintenance of METH self-administration with no difference in operant behaviour to control animals. Results show that ketamine treatment significantly reduced the METH intake in the control animals but not in MAM animals. Ketamine effect on METH self-administration may be explained by increased glutamatergic signalling in the prefrontal cortex caused by the N-methyl-D-aspartate antagonism and disinhibition of GABA interneurons which was shown to be impaired in the MAM rats. This mechanism may at least partly explain the clinically proven anti-craving potential of ketamine and allow development of more specific anti-craving medications with fewer risks.

• Keywords
• Ketamine, MAM model, Methamphetamine, Self-administration, Sprague-Dawley rats,
• MeSH
• Analysis of Variance MeSH
• Self Administration MeSH
• Ketamine pharmacology   toxicity   MeSH
• Rats MeSH
• Locomotion drug effects   MeSH
• Methamphetamine administration & dosage   MeSH
• Methylazoxymethanol Acetate analogs & derivatives   toxicity   MeSH
• Disease Models, Animal MeSH
• Conditioning, Operant drug effects   MeSH
• Rats, Sprague-Dawley MeSH
• Schizophrenia chemically induced   drug therapy   MeSH
• Central Nervous System Stimulants administration & dosage   MeSH
• Dose-Response Relationship, Drug MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Ketamine MeSH
• Methamphetamine MeSH
• methylazoxymethanol MeSH Browser
• Methylazoxymethanol Acetate MeSH
• Central Nervous System Stimulants MeSH

Preventing relapse to drug abuse is one of the struggles faced by clinicians in order to treat patients with substance use disorders (DSM-5). There is a large body of clinical evidence suggesting differential characteristics of the disorder in men and women, which is in line with preclinical findings as well. The aim of this study was to assess differences in relapse-like behavior in methamphetamine (METH) seeking after a period of forced abstinence, which simulates the real clinical situation very well. Findings from such study might add new insights in gender differences in relapse mechanisms to previous studies, which employ a classical drug or cue-induced reinstatement procedure following the extinction training. Adult male and female Sprague-Dawley rats were used in IV self-administration procedure conducted in operant boxes using nose-poke operandi (Coulborn Instruments, USA). Active nose-poke resulted in activation of the infusion pump to deliver one intravenous infusion of METH (0.08 mg/kg). After baseline drug intake was established (maintenance phase), a period of forced abstinence was initiated and rats were kept singly in their home cages for 14 days. Finally, one reinstatement session in operant boxes was conducted. Females were found to self-administer significantly lower dose of METH. The relapse rate was assessed as a number of active nose-pokes during the reinstatement session, expressed as a percentage of active nose-poking during the maintenance phase. Females displayed approximately 300% of active nose-pokes compared to 50% in males. This indicates higher vulnerability to relapse of METH seeking behavior in female rats. This effect was detected in all females, independently of current phase of their estrous cycle. Therefore, this paradigm using operant drug self-administration and reinstatement of drug-seeking after forced abstinence model can be used for preclinical screening for potential new anti-relapse medications specific for women.

• Keywords
• Sprague-Dawley rats, forced abstinence, methamphetamine, reinstatement of drug-seeking behavior, sex/gender differences,
• Publication type
• Journal Article MeSH