Marijuana is currently the most commonly abused illicit drug. According to recent studies, cannab... more Marijuana is currently the most commonly abused illicit drug. According to recent studies, cannabinoid use occurring prior to pregnancy can impact brain plasticity and behavior in future generations. The purpose of the present study was to determine whether adolescent exposure of female rats to 9-tetrahydrocannabinol (9-THC) induces transgenerational effects on the reward-facilitating effects of 9-THC and d-amphetamine in their adult male offspring. Female Sprague-Dawley rats received 9-THC (0.1 or 1 mg/kg, i.p.) or vehicle during postnatal days 28-50. As adults, females were mated with drug-naïve males. We then assessed potential alterations of the 9-THC's (0, 0.1, 0.5, and 1 mg/kg, i.p.) and d-amphetamine's (0, 0.1, 0.5, and 1 mg/kg, i.p.) reward-modifying effects using the curve-shift variant of the intracranial self-stimulation (ICSS) procedure in their adult male F1 offspring. The reward-facilitating effect of the 0.1 mg dose of 9-THC was abolished in the F1 offspring of females that were exposed to 9-THC (0.1 or 1 mg/kg), whereas the reward-attenuating effect of the 1 mg dose of 9-THC remained unaltered. The reward-facilitating effects of 0.5 and 1 mg of d-amphetamine were significantly decreased in the F1 offspring of females that were exposed to 9-THC (1 mg/kg and 0.1 or 1 mg, respectively). The present results reveal that female 9-THC exposure during adolescence can diminish the rewardfacilitating effects of 9-THC and d-amphetamine in the adult male offspring. These transgenerational effects occur in the absence of in utero exposure. It is speculated that 9-THC exposure during female adolescence may affect neural mechanisms that are shaping reward-related behavioral responses in a subsequent generation, as indicated by the shifts in the reward-facilitating effects of commonly used and abused drugs.
In the present study the role of the ventral pallidum (VP)in self-stimulation behavior was examin... more In the present study the role of the ventral pallidum (VP)in self-stimulation behavior was examined in ratw. The distribution of electrical self-stimulation foci within the ventral pallidum was mapped using moveable electrodes. Our results show that 98% of VP sites supported self-stimulation behavior. A comparable high rate of positive sites was not obtained from adjacent brain areas. The estimation of poststimulation excitability of ventral pallidum neurons point to the suggestion that the self-stimulation substrate in the VP involves heterogeneous neurons.These excitability properties are different from those characterising catecholaminergic neurons. Studies using the psychophysical technique of collision show that the VP and the ipsilateral lateral hypothalamus and the ipsilateral or contralateral ventral tegmental area share no common reward fibres. Immunohistochemical studies show that rewarding electrical stimulation of the VP increased c-fos expression in several structures k...
The endocannabinoid system has been implicated in the regulation of a variety of physiological pr... more The endocannabinoid system has been implicated in the regulation of a variety of physiological processes, including a crucial involvement in brain reward systems and the regulation of motivational processes. Behavioral studies have shown that cannabinoid reward may involve the same brain circuits and similar brain mechanisms with other drugs of abuse, such as nicotine, cocaine, alcohol and heroin, as well as natural rewards, such as food, water and sucrose, although the conditions under which cannabinoids exert their rewarding effects may be more limited. The purpose of the present review is to briefly describe and evaluate the behavioral and pharmacological research concerning the major components of the endocannabinoid system and reward processes. Special emphasis is placed on data received from four procedures used to test the effects of the endocannabinoid system on brain reward in animals; namely, the intracranial self-stimulation paradigm, the self-administration procedure, the conditioned place preference procedure and the drug-discrimination procedure. The effects of cannabinoid 1 (CB1) and cannabinoid 2 (CB2) receptor agonists, antagonists and endocannabinoid modulators in these procedures are examined. Further, the involvement of CB1 and CB2 receptors, as well the fatty acid amid hydrolase (FAAH) enzyme in reward processes is investigated through presentation of respective genetic ablation studies in mice. We suggest that the endocannabinoid system plays a major role in modulating motivation and reward processes. Further research will provide us with a better understanding of these processes and, thus, could lead to the development of potential therapeutic compounds for the treatment of rewardrelated disorders.
Introduction Methadone and buprenorphine are among the most widely employed pharmacological treat... more Introduction Methadone and buprenorphine are among the most widely employed pharmacological treatments currently available for opioid addiction. Cognitive effects of buprenorphine in abstinent heroin abusers are nevertheless far from being understood. Methods Neuropsychological performance of 18 buprenorphine-maintained patients (BMP) was evaluated relative to that of 32 currently abstinent heroin abusers on naltrexone hydrochloride therapy (FHAN), and 34 non-drug dependent controls. The three groups were demographically balanced. Clinical groups reported histories of similar patterns of drug use and had increased periods of abstinence from any illicit substance use including heroin. Results The BMP group performed poorer than controls on the RAVLT (encoding and delayed recall of verbal information), CTT (conceptual flexibility, executive functions) and the RBANS figure copy (visual perception) and delayed recall of visual information. There were no significant differences in any of the cognitive measures between the BMP and FHAN groups or between the FHAN group and controls. Furthermore, there were no differences in the percentage of abnormal cases between the two patient groups. Conclusion Overall, results suggest that treatment with naltrexone in abstinent heroin abusers may result in less impairment of cognitive functions compared to treatment with buprenorphine. These findings are relevant for improved prognosis and treatment strategies in opioid dependence.
The international journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale Neuropsychopharmacologicum (CINP), Jan 7, 2014
The endocannabinoid system interacts extensively with other neurotransmitter systems and has been... more The endocannabinoid system interacts extensively with other neurotransmitter systems and has been implicated in a variety of functions, including regulation of basal ganglia circuits and motor behavior. The present study examined the effects of repeated administration of the nonselective cannabinoid receptor 1 agonist WIN55,212-2 on locomotor activity and on binding and mRNA levels of dopamine receptors and transporters and GABAA receptors in mesostriatal dopaminergic regions of the rat. Rats received systemic injections of WIN55,212-2 (0, 0.1, 0.3, or 1mg/kg, intraperitoneally) for 20 consecutive days. Locomotor activity was measured on days 1, 10, and 20. Following the last measurement, rats were euthanized and prepared for in vitro binding and in situ hybridization experiments. Acutely, 0.3 and 1mg/kg of WIN55,212-2 produced hypolocomotion, which was sustained for the next 2 measurements, compared to vehicle. Repeated administration of WIN55,212-2 decreased the mRNA levels of the...
Although cannabis derivatives produce clear subjective motivational responses in humans leading t... more Although cannabis derivatives produce clear subjective motivational responses in humans leading to drug-seeking behaviour, the reinforcing attributes of these subjective effects are difficult to define in experimental animals. The aim of this study was to examine how exposure to chronic unpredictable stress (CUS) will affect reward function and anxiety after acute administration of Δ9-tetrahydrocannabinol (Δ9-THC) in rats. Male rats were
International Journal of Neuropsychopharmacology, 2014
Restless legs syndrome (RLS) and Parkinson's disease (PD) are movement disorders usually accompan... more Restless legs syndrome (RLS) and Parkinson's disease (PD) are movement disorders usually accompanied by emotional and cognitive deficits. Although D 3 /D 2 receptor agonists are effective against motor and non-motor deficits in RLS and PD, the exact behavioral and neurochemical effects of these drugs are not clearly defined. This study aimed to evaluate the effects of acute ropinirole (0, 0.1, 1 or 10 mg/kg, i.p.), a preferential D 3 /D 2 receptor agonist, on intracranial self-stimulation (ICSS), spontaneous motor activity, anxiety-and depression-like behaviors, spatial reference and working memory in rats as well as on certain markers of neuronal activity, i.e. induction of immediate early genes, such as c-fos and arc, and crucial phosphorylations on GluA1 subunit of α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors and NA1, NA2A and NA2B subunits of N-methyl-D-aspartate (NMDA) receptors. Ropinirole decreased ICSS thresholds and induced anxiolytic-and antidepressive-like effects without affecting motor activity or spatial memory. The effects on emotionality were associated with a decrease in p-Ser897-NA1 and an increase in p-Tyr1472-NA2B in the ventral striatum as well as an increased induction of c-fos messenger RNA (mRNA) in the prefrontal cortex (PFC) and decreased expression of arc mRNA in the striatum and the shell of the nucleus accumbens. Our data indicate that ropinirole significantly affects emotionality at doses (1–10 mg/kg, i.p.) that exert no robust effects on locomotion or cognition. The data reinforce the use of D 3 /D 2 receptor agonists in the treatment of RLS and PD patients characterized by emotional deficits and suggest that altered NMDA-mediated neurotransmission in the limbic forebrain may underlie some of ropinirole's therapeutic actions.
The serotonergic system is implicated in the pathophysiology of obsessive–compulsive disorder (OC... more The serotonergic system is implicated in the pathophysiology of obsessive–compulsive disorder (OCD). However, the distinct role of serotonin (5-HT) receptor subtypes remains unclear. This study investigates the contribution of 5-HT2A and 5-HT2C receptors in the modulation of persistence in the reinforced spatial alternation model of OCD.Male Wistar rats were assessed for spontaneous and pharmacologically induced (by m-chlorophenylpiperazine: mCPP) directional persistence in the reinforced alternation OCD model. Systemic administration of mCPP (non-specific 5-HT agonist, 2.5 mg/kg), M100907 (selective 5-HT2A receptor antagonist, 0.08 mg/kg), SB242084 (selective 5-HT2C receptor antagonist, 0.5 mg/kg) and vehicle was used. Experiment 1 investigated M100907 and SB242084 effects in animals spontaneously exhibiting high and low persistence during the early stages of alternation training. Experiment 2 investigated M100900 and SB242084 effects on mCPP-induced persistence.Under the regime used in Experiment 1, 5-HT2A or 5-HT2C receptor antagonism did not affect spontaneous directional persistence in either high or low persistence groups. In Experiment 2, 5-HT2C but not 5-HT2A receptor antagonism significantly reduced, but did not abolish, mCPP-induced directional persistence.These findings suggest that 5-HT2C but not 5-HT2A receptors contribute to the modulation of mCPP-induced persistent behaviour, raising the possibility that the use of 5-HT2C antagonists may have a therapeutic value in OCD.► We examined spontaneous and mCPP-induced persistence in an OCD model. ► Acute 5-HT2A or 2C antagonism did not affect spontaneous persistence. ► mCPP-induced persistence was reduced by 5-HT2C but not 5-HT2A antagonism. ► Use of 5-HT2C antagonists may have therapeutic value in OCD.
We examined spontaneous and mCPP-induced persistence in an OCD model. Acute 5-HT2A or 2C antagoni... more We examined spontaneous and mCPP-induced persistence in an OCD model. Acute 5-HT2A or 2C antagonism did not affect spontaneous persistence. mCPP-induced persistence was reduced by 5-HT2C but not 5-HT2A antagonism. Use of 5-HT2C antagonists may have therapeutic value in OCD.
Marijuana is currently the most commonly abused illicit drug. According to recent studies, cannab... more Marijuana is currently the most commonly abused illicit drug. According to recent studies, cannabinoid use occurring prior to pregnancy can impact brain plasticity and behavior in future generations. The purpose of the present study was to determine whether adolescent exposure of female rats to 9-tetrahydrocannabinol (9-THC) induces transgenerational effects on the reward-facilitating effects of 9-THC and d-amphetamine in their adult male offspring. Female Sprague-Dawley rats received 9-THC (0.1 or 1 mg/kg, i.p.) or vehicle during postnatal days 28-50. As adults, females were mated with drug-naïve males. We then assessed potential alterations of the 9-THC's (0, 0.1, 0.5, and 1 mg/kg, i.p.) and d-amphetamine's (0, 0.1, 0.5, and 1 mg/kg, i.p.) reward-modifying effects using the curve-shift variant of the intracranial self-stimulation (ICSS) procedure in their adult male F1 offspring. The reward-facilitating effect of the 0.1 mg dose of 9-THC was abolished in the F1 offspring of females that were exposed to 9-THC (0.1 or 1 mg/kg), whereas the reward-attenuating effect of the 1 mg dose of 9-THC remained unaltered. The reward-facilitating effects of 0.5 and 1 mg of d-amphetamine were significantly decreased in the F1 offspring of females that were exposed to 9-THC (1 mg/kg and 0.1 or 1 mg, respectively). The present results reveal that female 9-THC exposure during adolescence can diminish the rewardfacilitating effects of 9-THC and d-amphetamine in the adult male offspring. These transgenerational effects occur in the absence of in utero exposure. It is speculated that 9-THC exposure during female adolescence may affect neural mechanisms that are shaping reward-related behavioral responses in a subsequent generation, as indicated by the shifts in the reward-facilitating effects of commonly used and abused drugs.
In the present study the role of the ventral pallidum (VP)in self-stimulation behavior was examin... more In the present study the role of the ventral pallidum (VP)in self-stimulation behavior was examined in ratw. The distribution of electrical self-stimulation foci within the ventral pallidum was mapped using moveable electrodes. Our results show that 98% of VP sites supported self-stimulation behavior. A comparable high rate of positive sites was not obtained from adjacent brain areas. The estimation of poststimulation excitability of ventral pallidum neurons point to the suggestion that the self-stimulation substrate in the VP involves heterogeneous neurons.These excitability properties are different from those characterising catecholaminergic neurons. Studies using the psychophysical technique of collision show that the VP and the ipsilateral lateral hypothalamus and the ipsilateral or contralateral ventral tegmental area share no common reward fibres. Immunohistochemical studies show that rewarding electrical stimulation of the VP increased c-fos expression in several structures k...
The endocannabinoid system has been implicated in the regulation of a variety of physiological pr... more The endocannabinoid system has been implicated in the regulation of a variety of physiological processes, including a crucial involvement in brain reward systems and the regulation of motivational processes. Behavioral studies have shown that cannabinoid reward may involve the same brain circuits and similar brain mechanisms with other drugs of abuse, such as nicotine, cocaine, alcohol and heroin, as well as natural rewards, such as food, water and sucrose, although the conditions under which cannabinoids exert their rewarding effects may be more limited. The purpose of the present review is to briefly describe and evaluate the behavioral and pharmacological research concerning the major components of the endocannabinoid system and reward processes. Special emphasis is placed on data received from four procedures used to test the effects of the endocannabinoid system on brain reward in animals; namely, the intracranial self-stimulation paradigm, the self-administration procedure, the conditioned place preference procedure and the drug-discrimination procedure. The effects of cannabinoid 1 (CB1) and cannabinoid 2 (CB2) receptor agonists, antagonists and endocannabinoid modulators in these procedures are examined. Further, the involvement of CB1 and CB2 receptors, as well the fatty acid amid hydrolase (FAAH) enzyme in reward processes is investigated through presentation of respective genetic ablation studies in mice. We suggest that the endocannabinoid system plays a major role in modulating motivation and reward processes. Further research will provide us with a better understanding of these processes and, thus, could lead to the development of potential therapeutic compounds for the treatment of rewardrelated disorders.
Introduction Methadone and buprenorphine are among the most widely employed pharmacological treat... more Introduction Methadone and buprenorphine are among the most widely employed pharmacological treatments currently available for opioid addiction. Cognitive effects of buprenorphine in abstinent heroin abusers are nevertheless far from being understood. Methods Neuropsychological performance of 18 buprenorphine-maintained patients (BMP) was evaluated relative to that of 32 currently abstinent heroin abusers on naltrexone hydrochloride therapy (FHAN), and 34 non-drug dependent controls. The three groups were demographically balanced. Clinical groups reported histories of similar patterns of drug use and had increased periods of abstinence from any illicit substance use including heroin. Results The BMP group performed poorer than controls on the RAVLT (encoding and delayed recall of verbal information), CTT (conceptual flexibility, executive functions) and the RBANS figure copy (visual perception) and delayed recall of visual information. There were no significant differences in any of the cognitive measures between the BMP and FHAN groups or between the FHAN group and controls. Furthermore, there were no differences in the percentage of abnormal cases between the two patient groups. Conclusion Overall, results suggest that treatment with naltrexone in abstinent heroin abusers may result in less impairment of cognitive functions compared to treatment with buprenorphine. These findings are relevant for improved prognosis and treatment strategies in opioid dependence.
The international journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale Neuropsychopharmacologicum (CINP), Jan 7, 2014
The endocannabinoid system interacts extensively with other neurotransmitter systems and has been... more The endocannabinoid system interacts extensively with other neurotransmitter systems and has been implicated in a variety of functions, including regulation of basal ganglia circuits and motor behavior. The present study examined the effects of repeated administration of the nonselective cannabinoid receptor 1 agonist WIN55,212-2 on locomotor activity and on binding and mRNA levels of dopamine receptors and transporters and GABAA receptors in mesostriatal dopaminergic regions of the rat. Rats received systemic injections of WIN55,212-2 (0, 0.1, 0.3, or 1mg/kg, intraperitoneally) for 20 consecutive days. Locomotor activity was measured on days 1, 10, and 20. Following the last measurement, rats were euthanized and prepared for in vitro binding and in situ hybridization experiments. Acutely, 0.3 and 1mg/kg of WIN55,212-2 produced hypolocomotion, which was sustained for the next 2 measurements, compared to vehicle. Repeated administration of WIN55,212-2 decreased the mRNA levels of the...
Although cannabis derivatives produce clear subjective motivational responses in humans leading t... more Although cannabis derivatives produce clear subjective motivational responses in humans leading to drug-seeking behaviour, the reinforcing attributes of these subjective effects are difficult to define in experimental animals. The aim of this study was to examine how exposure to chronic unpredictable stress (CUS) will affect reward function and anxiety after acute administration of Δ9-tetrahydrocannabinol (Δ9-THC) in rats. Male rats were
International Journal of Neuropsychopharmacology, 2014
Restless legs syndrome (RLS) and Parkinson's disease (PD) are movement disorders usually accompan... more Restless legs syndrome (RLS) and Parkinson's disease (PD) are movement disorders usually accompanied by emotional and cognitive deficits. Although D 3 /D 2 receptor agonists are effective against motor and non-motor deficits in RLS and PD, the exact behavioral and neurochemical effects of these drugs are not clearly defined. This study aimed to evaluate the effects of acute ropinirole (0, 0.1, 1 or 10 mg/kg, i.p.), a preferential D 3 /D 2 receptor agonist, on intracranial self-stimulation (ICSS), spontaneous motor activity, anxiety-and depression-like behaviors, spatial reference and working memory in rats as well as on certain markers of neuronal activity, i.e. induction of immediate early genes, such as c-fos and arc, and crucial phosphorylations on GluA1 subunit of α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors and NA1, NA2A and NA2B subunits of N-methyl-D-aspartate (NMDA) receptors. Ropinirole decreased ICSS thresholds and induced anxiolytic-and antidepressive-like effects without affecting motor activity or spatial memory. The effects on emotionality were associated with a decrease in p-Ser897-NA1 and an increase in p-Tyr1472-NA2B in the ventral striatum as well as an increased induction of c-fos messenger RNA (mRNA) in the prefrontal cortex (PFC) and decreased expression of arc mRNA in the striatum and the shell of the nucleus accumbens. Our data indicate that ropinirole significantly affects emotionality at doses (1–10 mg/kg, i.p.) that exert no robust effects on locomotion or cognition. The data reinforce the use of D 3 /D 2 receptor agonists in the treatment of RLS and PD patients characterized by emotional deficits and suggest that altered NMDA-mediated neurotransmission in the limbic forebrain may underlie some of ropinirole's therapeutic actions.
The serotonergic system is implicated in the pathophysiology of obsessive–compulsive disorder (OC... more The serotonergic system is implicated in the pathophysiology of obsessive–compulsive disorder (OCD). However, the distinct role of serotonin (5-HT) receptor subtypes remains unclear. This study investigates the contribution of 5-HT2A and 5-HT2C receptors in the modulation of persistence in the reinforced spatial alternation model of OCD.Male Wistar rats were assessed for spontaneous and pharmacologically induced (by m-chlorophenylpiperazine: mCPP) directional persistence in the reinforced alternation OCD model. Systemic administration of mCPP (non-specific 5-HT agonist, 2.5 mg/kg), M100907 (selective 5-HT2A receptor antagonist, 0.08 mg/kg), SB242084 (selective 5-HT2C receptor antagonist, 0.5 mg/kg) and vehicle was used. Experiment 1 investigated M100907 and SB242084 effects in animals spontaneously exhibiting high and low persistence during the early stages of alternation training. Experiment 2 investigated M100900 and SB242084 effects on mCPP-induced persistence.Under the regime used in Experiment 1, 5-HT2A or 5-HT2C receptor antagonism did not affect spontaneous directional persistence in either high or low persistence groups. In Experiment 2, 5-HT2C but not 5-HT2A receptor antagonism significantly reduced, but did not abolish, mCPP-induced directional persistence.These findings suggest that 5-HT2C but not 5-HT2A receptors contribute to the modulation of mCPP-induced persistent behaviour, raising the possibility that the use of 5-HT2C antagonists may have a therapeutic value in OCD.► We examined spontaneous and mCPP-induced persistence in an OCD model. ► Acute 5-HT2A or 2C antagonism did not affect spontaneous persistence. ► mCPP-induced persistence was reduced by 5-HT2C but not 5-HT2A antagonism. ► Use of 5-HT2C antagonists may have therapeutic value in OCD.
We examined spontaneous and mCPP-induced persistence in an OCD model. Acute 5-HT2A or 2C antagoni... more We examined spontaneous and mCPP-induced persistence in an OCD model. Acute 5-HT2A or 2C antagonism did not affect spontaneous persistence. mCPP-induced persistence was reduced by 5-HT2C but not 5-HT2A antagonism. Use of 5-HT2C antagonists may have therapeutic value in OCD.
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Papers by George Panagis