Scott-Railton J, Arnold G, Vezina P. , Jan 1, 2006
Previous exposure to amphetamine attenuates its ability to induce conditioned taste aversion (CTA... more Previous exposure to amphetamine attenuates its ability to induce conditioned taste aversion (CTA). Because amphetamine, unlike emetic agents like LiCl, possesses appetitive properties that sensitize when it is administered repeatedly, the present study assessed the contribution of sensitization to this US pre-exposure effect (US-PEE). It was found that not all sensitizing regimens of systemic amphetamine injections produce a US-PEE. In addition, previous exposure to amphetamine in the VTA, where it acts to induce sensitization but not CTA, did not produce a US-PEE. It is concluded that amphetamine sensitization alone does not modulate this drug’s ability to produce CTA. Implications of these findings for anatomically based associative and non-associative models of CTA and the US-PEE are discussed.
The present experiments assessed the effect of the Group II-specific metabotropic glutamate recep... more The present experiments assessed the effect of the Group II-specific metabotropic glutamate receptor (mGluR) agonist, LY379268, on the expression of the locomotor sensitization observed following repeated exposure to amphetamine (AMPH). Rats in different groups were administered five injections of AMPH (1 mg/kg ip), one injection every 2-3 days. Two weeks after the last injection, rats were challenged with either AMPH (1 mg/kg ip) or AMPH coinjected with LY379268 (1 mg/kg ip). As expected, AMPH produced levels of locomotion that increased progressively from the first to the fifth injection. This locomotor sensitization was still evident 2 weeks later in rats challenged with AMPH. Rats challenged on this test with AMPH+LY379268, however, showed levels of locomotion similar to those observed following the first AMPH injection. These results indicate that Group II mGluRs can play an important role in the expression of locomotor sensitization by AMPH. The ability of Group II mGluR activ...
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 2015
Prenatal ethanol exposure (PE) is one of the developmental factors leading to increased addiction... more Prenatal ethanol exposure (PE) is one of the developmental factors leading to increased addiction propensity (risk). However, the neuronal mechanisms underlying this effect remain unknown. We examined whether increased excitatory synaptic transmission in ventral tegmental area (VTA) dopamine (DA) neurons, which is associated with drug addiction, was impacted by PE. Pregnant rats were exposed to ethanol (0 or 6 g/kg/day) via intragastric intubation from gestational day 8-20. Amphetamine self-administration, whole-cell recordings, and electron microscopy were performed in male offspring between 2 and 12-week-old. The results showed enhanced amphetamine self-administration in PE animals. In PE animals, we observed a persistent augmentation in calcium-permeable AMPA receptor (CP-AMPAR) expression, indicated by increased rectification and reduced decay time of AMPAR-mediated excitatory postsynaptic currents (AMPAR-EPSCs), enhanced depression of AMPAR-EPSCs by NASPM (a selective CP-AMPAR ...
A novel version of the conditioned place preference (CPP) technique was used in an attempt to det... more A novel version of the conditioned place preference (CPP) technique was used in an attempt to determine whether tactile stimuli previously associated with morphine elicit approach and sustained contact. Empirical support for this view has been equivocal, prompting some to question the validity of the CPP technique. In the present study, rats received, during conditioning, morphine (10 mg/kg, IP) paired exclusively with an open field floor made of four quadrants of one texture (CS+) and saline with another floor made of four quadrants of a different texture (CS-). On the test for CPP, rats were given saline and placed in an open field containing either 1, 2, or 4 quadrants of the CS+ (with 3, 2, 0 quadrants of the CS-, respectively). These animals showed high absolute CPP scores on the test, spending, on average, as much as 83% and 75% of their time on the CS+ when two and one CS+ quadrants, respectively, were present. Concurrent measures of activity indicated that animals were most ...
While the ventral striatum has long been implicated in the rewarding properties of psychomotor st... more While the ventral striatum has long been implicated in the rewarding properties of psychomotor stimulants and opiates, little attention has been paid to the possible contribution of more dorsal regions of the striatum. We have thus examined the effects of lesions in three different striatal subregions on cocaine and morphine self-administration. Different groups of rats were trained to self-administer intravenous cocaine (1.0mg/kg/infusion) or morphine (0.5mg/kg/infusion) first under fixed ratio (FR) and then under progressive ratio (PR) schedules of reinforcement. Upon completion of the training, independent groups received bilateral electrolytic or sham lesions of the dorsal portion of the caudate-putamen (dCPu), the ventral portion of the caudate-putamen (vCPu) or the more ventral nucleus accumbens (NAS). Following recovery, they were tested for self-administration of cocaine (0.25, 0.5, 1.0 and 1.5mg/kg/infusion) or morphine (0.125, 0.25, 0.5 and 0.75mg/kg/infusion) under the PR schedule. The PR responding for each drug was significantly reduced in a dose-dependent manner following lesions of dCPu, vCPu and NAS. While the relative effectiveness of these lesions is likely to be specific to the conditions of this experiment, NAS lesions reduced self-administration of each drug to a greater extent than did dCPu or vCPu lesions.
In animals and humans, vulnerability to drug abuse varies among individuals. Animals that display... more In animals and humans, vulnerability to drug abuse varies among individuals. Animals that display high activity levels in a novel environment are more likely to self-administer psychostimulant drugs, including nicotine, cocaine, amphetamine, and morphine. Recent reports from behavioral studies indicate that nicotinic acetylcholine receptor (nAChR) activity contributes to the rewarding effects of several different addictive drugs. Thus, we hypothesized that differences in nAChR activity may contribute to the predisposition to drug self-administration. After screening of adult rats (>60 d postnatal) for the behavioral response to a novel environment, electrophysiological measures of nAChR function were conducted in brain slices that included the mesoaccumbens dopamine neurons of the ventral tegmental area (VTA). We found a positive correlation between the response to novelty and nAChR function in each assay conducted, including nAChR modulation of glutamatergic and GABAergic synaptic inputs to VTA dopamine neurons, as well as somatic nAChR responses of VTA neurons. The response to novelty and sensitivity to addictive drugs are positively correlated with the hormonal response to stress. Consistent with this observation, we found enhanced nAChR responses in vitro after a 48 h corticosterone treatment and in vivo after 48 h of repeated stress. Each of these effects was inhibited by RU486 (11beta-[p-(dimethylamino)phenyl]-17beta-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one) pretreatment, suggesting a steroid hormone receptor-dependent process. These findings suggest that differences in nAChR function within the mesoaccumbens dopamine system may contribute to individual differences in drug abuse vulnerability and that these are likely attributable to differences in stress hormone levels.
Amphetamine exposure transiently increases Ca(2+)/calmodulin-dependent protein kinase II (CaMKII)... more Amphetamine exposure transiently increases Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) α expression in the nucleus accumbens (NAcc) shell and this persistently increases local GluA1 S831 phosphorylation and enhances behavioral responding to the drug. Here we assessed whether transiently interfering with CaMKII signaling using a dominant-negative CaMKIIα mutant delivered to the NAcc shell with herpes simplex viral vectors could reverse these long-lasting biochemical and behavioral effects observed following exposure to amphetamine. As expected, transient expression of CaMKIIα K42M in the NAcc shell produced a corresponding transient increase in CaMKIIα and decrease in pCaMKIIα (T286) protein levels in this site. Remarkably, this transient inhibition of CaMKII activity produced a long-lasting reversal of the increased GluA1 S831 phosphorylation levels in NAcc shell and persistently blocked the enhanced locomotor response to and self-administration of amphetamine normally observed in rats previously exposed to the drug. Together, these results indicate that even transient interference with CaMKII signaling may confer long-lasting benefits in drug-sensitized individuals and point to CaMKII and its downstream pathways as attractive therapeutic targets for the treatment of stimulant addiction.
Neuroadaptations of the mesoaccumbens dopamine (DA) system likely underlie the emergence of locom... more Neuroadaptations of the mesoaccumbens dopamine (DA) system likely underlie the emergence of locomotor sensitization following the repeated intermittent systemic administration of amphetamine (AMPH). In the nucleus accumbens (NAc), such neuroadaptations include enhanced DA overflow in response to a subsequent AMPH challenge as well as increased sensitivity to the inhibitory effects of D1 DA receptor (D1R) activation and an altered profile of D1R-dependent induction of immediate early genes (IEGs). Previous results indicate that AMPH acts in the ventral tegmental area (VTA) to initiate those changes leading to sensitization of the locomotor activity and NAc DA overflow produced by systemic administration of this drug. These observations are intriguing, given that acute infusion of AMPH into the VTA does not stimulate locomotor activity or, as we report presently, increase extracellular NAc DA concentrations. Two experiments, therefore, assessed the ability of repeated VTA AMPH to produce adaptations in D1R signaling in the NAc. Rats were administered three bilateral VTA infusions of saline or AMPH (2.5 microg/0.5 microl/side, one every third day). In the first experiment, in vivo extracellular electrophysiological recordings revealed that previous exposure to VTA AMPH enhanced the sensitivity of NAc neurons to the inhibitory effects of iontophoretic application of the D1R agonist SKF 38393. This effect was observed early (2-3 days) and at 1 month of withdrawal, but not after 2 months. Similarly, in the second experiment it was found that the D1R-dependent induction by AMPH of Fos, FosB, and JunB, but not NGFI-A, in the NAc was enhanced in rats exposed 1 week earlier to repeated VTA AMPH. These findings indicate that repeated VTA AMPH administration initiates relatively long-lasting adaptations in D1R signaling in the NAc that may, together with presynaptic adaptations affecting DA overflow, contribute to the expression of locomotor sensitization by this drug.
Interactions between excitatory amino acid (EAA) and dopamine (DA) pathways in the basal ganglia ... more Interactions between excitatory amino acid (EAA) and dopamine (DA) pathways in the basal ganglia have been known for some time to contribute importantly to the generation of motor behaviors. In particular, the role played by ionotropic glutamate receptors (iGluRs) in such interactions and in the production of locomotion has received considerable attention, particularly in brain areas such as the ventral tegmental area (VTA) where EAA afferants are known to modulate the activity of DA neurons and the nucleus accumbens (NAcc) where descending EAA projections and ascending DA mesencephalic projections come in close apposition to each other and co-innervate intrinsic neurons projecting to motor output regions. Recently, the growing importance of the metabotropic glutamate receptor (mGluR) in the generation of motor behaviors and various forms of plasticity has begun to emerge. The known coupling of the mGluR to second messenger systems and its demonstrated role in the long-term modulation of synaptic transmission make it a logical candidate not only for the generation of locomotion involving EAA-DA interactions, but also for the induction and expression of locomotor plasticity involving these neurotransmitters. In this review, we examine the evidence supporting a role for mGluRs in the generation of DA-dependent locomotion as well as in one form of locomotor plasticity: the sensitization of locomotor activity by psychomotor stimulant drugs.
Scott-Railton J, Arnold G, Vezina P. , Jan 1, 2006
Previous exposure to amphetamine attenuates its ability to induce conditioned taste aversion (CTA... more Previous exposure to amphetamine attenuates its ability to induce conditioned taste aversion (CTA). Because amphetamine, unlike emetic agents like LiCl, possesses appetitive properties that sensitize when it is administered repeatedly, the present study assessed the contribution of sensitization to this US pre-exposure effect (US-PEE). It was found that not all sensitizing regimens of systemic amphetamine injections produce a US-PEE. In addition, previous exposure to amphetamine in the VTA, where it acts to induce sensitization but not CTA, did not produce a US-PEE. It is concluded that amphetamine sensitization alone does not modulate this drug’s ability to produce CTA. Implications of these findings for anatomically based associative and non-associative models of CTA and the US-PEE are discussed.
The present experiments assessed the effect of the Group II-specific metabotropic glutamate recep... more The present experiments assessed the effect of the Group II-specific metabotropic glutamate receptor (mGluR) agonist, LY379268, on the expression of the locomotor sensitization observed following repeated exposure to amphetamine (AMPH). Rats in different groups were administered five injections of AMPH (1 mg/kg ip), one injection every 2-3 days. Two weeks after the last injection, rats were challenged with either AMPH (1 mg/kg ip) or AMPH coinjected with LY379268 (1 mg/kg ip). As expected, AMPH produced levels of locomotion that increased progressively from the first to the fifth injection. This locomotor sensitization was still evident 2 weeks later in rats challenged with AMPH. Rats challenged on this test with AMPH+LY379268, however, showed levels of locomotion similar to those observed following the first AMPH injection. These results indicate that Group II mGluRs can play an important role in the expression of locomotor sensitization by AMPH. The ability of Group II mGluR activ...
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 2015
Prenatal ethanol exposure (PE) is one of the developmental factors leading to increased addiction... more Prenatal ethanol exposure (PE) is one of the developmental factors leading to increased addiction propensity (risk). However, the neuronal mechanisms underlying this effect remain unknown. We examined whether increased excitatory synaptic transmission in ventral tegmental area (VTA) dopamine (DA) neurons, which is associated with drug addiction, was impacted by PE. Pregnant rats were exposed to ethanol (0 or 6 g/kg/day) via intragastric intubation from gestational day 8-20. Amphetamine self-administration, whole-cell recordings, and electron microscopy were performed in male offspring between 2 and 12-week-old. The results showed enhanced amphetamine self-administration in PE animals. In PE animals, we observed a persistent augmentation in calcium-permeable AMPA receptor (CP-AMPAR) expression, indicated by increased rectification and reduced decay time of AMPAR-mediated excitatory postsynaptic currents (AMPAR-EPSCs), enhanced depression of AMPAR-EPSCs by NASPM (a selective CP-AMPAR ...
A novel version of the conditioned place preference (CPP) technique was used in an attempt to det... more A novel version of the conditioned place preference (CPP) technique was used in an attempt to determine whether tactile stimuli previously associated with morphine elicit approach and sustained contact. Empirical support for this view has been equivocal, prompting some to question the validity of the CPP technique. In the present study, rats received, during conditioning, morphine (10 mg/kg, IP) paired exclusively with an open field floor made of four quadrants of one texture (CS+) and saline with another floor made of four quadrants of a different texture (CS-). On the test for CPP, rats were given saline and placed in an open field containing either 1, 2, or 4 quadrants of the CS+ (with 3, 2, 0 quadrants of the CS-, respectively). These animals showed high absolute CPP scores on the test, spending, on average, as much as 83% and 75% of their time on the CS+ when two and one CS+ quadrants, respectively, were present. Concurrent measures of activity indicated that animals were most ...
While the ventral striatum has long been implicated in the rewarding properties of psychomotor st... more While the ventral striatum has long been implicated in the rewarding properties of psychomotor stimulants and opiates, little attention has been paid to the possible contribution of more dorsal regions of the striatum. We have thus examined the effects of lesions in three different striatal subregions on cocaine and morphine self-administration. Different groups of rats were trained to self-administer intravenous cocaine (1.0mg/kg/infusion) or morphine (0.5mg/kg/infusion) first under fixed ratio (FR) and then under progressive ratio (PR) schedules of reinforcement. Upon completion of the training, independent groups received bilateral electrolytic or sham lesions of the dorsal portion of the caudate-putamen (dCPu), the ventral portion of the caudate-putamen (vCPu) or the more ventral nucleus accumbens (NAS). Following recovery, they were tested for self-administration of cocaine (0.25, 0.5, 1.0 and 1.5mg/kg/infusion) or morphine (0.125, 0.25, 0.5 and 0.75mg/kg/infusion) under the PR schedule. The PR responding for each drug was significantly reduced in a dose-dependent manner following lesions of dCPu, vCPu and NAS. While the relative effectiveness of these lesions is likely to be specific to the conditions of this experiment, NAS lesions reduced self-administration of each drug to a greater extent than did dCPu or vCPu lesions.
In animals and humans, vulnerability to drug abuse varies among individuals. Animals that display... more In animals and humans, vulnerability to drug abuse varies among individuals. Animals that display high activity levels in a novel environment are more likely to self-administer psychostimulant drugs, including nicotine, cocaine, amphetamine, and morphine. Recent reports from behavioral studies indicate that nicotinic acetylcholine receptor (nAChR) activity contributes to the rewarding effects of several different addictive drugs. Thus, we hypothesized that differences in nAChR activity may contribute to the predisposition to drug self-administration. After screening of adult rats (>60 d postnatal) for the behavioral response to a novel environment, electrophysiological measures of nAChR function were conducted in brain slices that included the mesoaccumbens dopamine neurons of the ventral tegmental area (VTA). We found a positive correlation between the response to novelty and nAChR function in each assay conducted, including nAChR modulation of glutamatergic and GABAergic synaptic inputs to VTA dopamine neurons, as well as somatic nAChR responses of VTA neurons. The response to novelty and sensitivity to addictive drugs are positively correlated with the hormonal response to stress. Consistent with this observation, we found enhanced nAChR responses in vitro after a 48 h corticosterone treatment and in vivo after 48 h of repeated stress. Each of these effects was inhibited by RU486 (11beta-[p-(dimethylamino)phenyl]-17beta-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one) pretreatment, suggesting a steroid hormone receptor-dependent process. These findings suggest that differences in nAChR function within the mesoaccumbens dopamine system may contribute to individual differences in drug abuse vulnerability and that these are likely attributable to differences in stress hormone levels.
Amphetamine exposure transiently increases Ca(2+)/calmodulin-dependent protein kinase II (CaMKII)... more Amphetamine exposure transiently increases Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) α expression in the nucleus accumbens (NAcc) shell and this persistently increases local GluA1 S831 phosphorylation and enhances behavioral responding to the drug. Here we assessed whether transiently interfering with CaMKII signaling using a dominant-negative CaMKIIα mutant delivered to the NAcc shell with herpes simplex viral vectors could reverse these long-lasting biochemical and behavioral effects observed following exposure to amphetamine. As expected, transient expression of CaMKIIα K42M in the NAcc shell produced a corresponding transient increase in CaMKIIα and decrease in pCaMKIIα (T286) protein levels in this site. Remarkably, this transient inhibition of CaMKII activity produced a long-lasting reversal of the increased GluA1 S831 phosphorylation levels in NAcc shell and persistently blocked the enhanced locomotor response to and self-administration of amphetamine normally observed in rats previously exposed to the drug. Together, these results indicate that even transient interference with CaMKII signaling may confer long-lasting benefits in drug-sensitized individuals and point to CaMKII and its downstream pathways as attractive therapeutic targets for the treatment of stimulant addiction.
Neuroadaptations of the mesoaccumbens dopamine (DA) system likely underlie the emergence of locom... more Neuroadaptations of the mesoaccumbens dopamine (DA) system likely underlie the emergence of locomotor sensitization following the repeated intermittent systemic administration of amphetamine (AMPH). In the nucleus accumbens (NAc), such neuroadaptations include enhanced DA overflow in response to a subsequent AMPH challenge as well as increased sensitivity to the inhibitory effects of D1 DA receptor (D1R) activation and an altered profile of D1R-dependent induction of immediate early genes (IEGs). Previous results indicate that AMPH acts in the ventral tegmental area (VTA) to initiate those changes leading to sensitization of the locomotor activity and NAc DA overflow produced by systemic administration of this drug. These observations are intriguing, given that acute infusion of AMPH into the VTA does not stimulate locomotor activity or, as we report presently, increase extracellular NAc DA concentrations. Two experiments, therefore, assessed the ability of repeated VTA AMPH to produce adaptations in D1R signaling in the NAc. Rats were administered three bilateral VTA infusions of saline or AMPH (2.5 microg/0.5 microl/side, one every third day). In the first experiment, in vivo extracellular electrophysiological recordings revealed that previous exposure to VTA AMPH enhanced the sensitivity of NAc neurons to the inhibitory effects of iontophoretic application of the D1R agonist SKF 38393. This effect was observed early (2-3 days) and at 1 month of withdrawal, but not after 2 months. Similarly, in the second experiment it was found that the D1R-dependent induction by AMPH of Fos, FosB, and JunB, but not NGFI-A, in the NAc was enhanced in rats exposed 1 week earlier to repeated VTA AMPH. These findings indicate that repeated VTA AMPH administration initiates relatively long-lasting adaptations in D1R signaling in the NAc that may, together with presynaptic adaptations affecting DA overflow, contribute to the expression of locomotor sensitization by this drug.
Interactions between excitatory amino acid (EAA) and dopamine (DA) pathways in the basal ganglia ... more Interactions between excitatory amino acid (EAA) and dopamine (DA) pathways in the basal ganglia have been known for some time to contribute importantly to the generation of motor behaviors. In particular, the role played by ionotropic glutamate receptors (iGluRs) in such interactions and in the production of locomotion has received considerable attention, particularly in brain areas such as the ventral tegmental area (VTA) where EAA afferants are known to modulate the activity of DA neurons and the nucleus accumbens (NAcc) where descending EAA projections and ascending DA mesencephalic projections come in close apposition to each other and co-innervate intrinsic neurons projecting to motor output regions. Recently, the growing importance of the metabotropic glutamate receptor (mGluR) in the generation of motor behaviors and various forms of plasticity has begun to emerge. The known coupling of the mGluR to second messenger systems and its demonstrated role in the long-term modulation of synaptic transmission make it a logical candidate not only for the generation of locomotion involving EAA-DA interactions, but also for the induction and expression of locomotor plasticity involving these neurotransmitters. In this review, we examine the evidence supporting a role for mGluRs in the generation of DA-dependent locomotion as well as in one form of locomotor plasticity: the sensitization of locomotor activity by psychomotor stimulant drugs.
Uploads
Papers by Paul Vezina