Transient viral-mediated overexpression of alpha-calcium/calmodulin-dependent protein kinase II in the nucleus accumbens shell leads to long-lasting functional upregulation of alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptors: dopamine type-1 receptor and protein kinase A dependence.

Calcium/calmodulin-dependent protein kinase II (CaMKII) activity is necessary for the long-lasting expression of locomotor sensitization and enhanced drug-taking observed in rats previously exposed to psychostimulants. Exposure to these drugs also transiently increases alphaCaMKII levels in the nucleus accumbens (NAcc), an effect that, when mimicked by transient viral-mediated overexpression of alphaCaMKII in NAcc shell neurons, leads to long-lasting enhancement in locomotor responding to amphetamine and NAcc alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA). The present experiments characterized the dopamine (DA) dependence of the functional AMPA receptor upregulation observed long after transient overexpression of alphaCaMKII. Rats infected with herpes simplex virus-alphaCaMKII in the NAcc shell showed a transient increase in alphaCaMKII levels that peaked at 4 days post-infection and returned to baseline 8 days later. When challenged with AMPA (0.8 nmol/side) in the NAcc shell at 20 days post-infection, these rats showed enhanced locomotion compared with controls. This sensitized locomotor response was blocked when AMPA was coinfused with either the DA type-1 receptor antagonist SCH23390 (0.8 nmol/side) or the protein kinase A inhibitor Rp-cAMPS (80 nmol/side). Neither SCH23390 nor Rp-cAMPS produced locomotor effects when infused by itself into the NAcc shell. Furthermore, these antagonists did not block the acute non-sensitized locomotor response to AMPA observed in control rats. These findings show that transient viral-mediated overexpression of alphaCaMKII in neurons of the NAcc shell leads to long-lasting functional upregulation of AMPA receptors that is DA type-1 receptor and protein kinase A dependent. Thus, transient increases in levels of alphaCaMKII in the NAcc shell produce long-lasting changes in the way that DA and glutamate interact in this site to generate locomotor behavior.

Exposure to nicotine and sensitization of nicotine-induced behaviors.

Evidence for an important link between sensitization of midbrain dopamine (DA) neuron reactivity and enhanced self-administration of amphetamine and cocaine has been reported. To the extent that exposure to nicotine also sensitizes nucleus accumbens DA reactivity, it is likely that it will also impact subsequent drug taking. It is thus necessary to gain an understanding of the long-term effects of exposure to nicotine on nicotinic acetylcholine receptors (nAChRs), neuronal excitability and behavior. A review of the literature is presented in which different regimens of nicotine exposure are assessed for their effects on upregulation of nAChRs, induction of LTP in interconnected midbrain nuclei and development of long-lasting locomotor and DA sensitization. Exposure to nicotine upregulates nAChRs and nAChR currents and produces LTP of excitatory inputs to midbrain DA neurons. These effects appear in the hours to days following exposure. Exposure to nicotine also leads to long-lasting sensitization of nicotine's nucleus accumbens DA and locomotor activating effects. These effects appear days to weeks after drug exposure. A model is proposed in which nicotine exposure regimens that produce transient nAChR upregulation and LTP consequently produce long-lasting sensitization of midbrain DA neuron reactivity and nicotine-induced behaviors. These neuroadaptations are proposed to constitute critical components of the mechanisms underlying the initiation, maintenance and escalation of drug use.

Previous exposure to amphetamine enhances the subsequent locomotor response to a D1 dopamine receptor agonist when glutamate reuptake is inhibited.

The role of nucleus accumbens (NAcc) glutamate (GLU) and D(1) dopamine (DA) receptor activation in the expression of locomotor sensitization to amphetamine (AMPH) was investigated in rats. Rats were preexposed to either AMPH or saline, and 2 weeks later their locomotion was assessed after a microinjection into the NAcc of the selective glutamate reuptake blocker l-trans-pyrrolidine-2,4-dicarboxylic acid (PDC) (10 nmol per side), the D(1)-like DA receptor agonists SKF82958 (2.4 nmol per side) and SKF38393 (3.1 nmol per side), the D(2)-like DA receptor agonist quinelorane (3.1 nmol per side), or AMPH (6.8 nmol per side). All compounds other than quinelorane increased locomotion when infused into the NAcc. Only AMPH, however, produced enhanced locomotion in AMPH relative to saline-preexposed rats. When additional rats were tested after NAcc infusions of PDC together with either SKF82958 or quinelorane, enhanced locomotion was observed in AMPH relative to saline-preexposed rats after NAcc PDC + SKF82958. These results suggest that in the NAcc, increased GLU neurotransmission and activation of D(1) DA receptors, neither of which is by itself sufficient, together contribute to the expression of locomotor sensitization by AMPH. They stress, with other findings, the importance of GLU-DA interactions in the NAcc not only in the generation of acute stimulant drug effects but in sensitized responding to these drugs as well.

Metabotropic glutamate receptors and the generation of locomotor activity: interactions with midbrain dopamine.

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.

Opposed Behavioural Outputs of Increased Dopamine Transmission in Prefrontocortical and Subcortical Areas: A Role for the Cortical D-1 Dopamine Receptor.

The possibility that the dopaminergic neurons innervating the medial prefrontal cortex (mPFC) can inhibit locomotor behaviour has been suggested in several studies. The evidence remains indirect, however, because the manipulations tested aimed exclusively at permanently depleting mPFC dopamine. Here we demonstrate in rats that acute increases in dopamine transmission in this site by local injections of amphetamine inhibit the known locomotor-activating effects of amphetamine in the nucleus accumbens (N.Acc.). Further, intra-mPFC injections of the D-1 dopamine receptor antagonist SCH-23390, but not other dopamine antagonists with greater affinities for noradrenergic, serotonergic and D-2 dopamine receptors, enhanced the locomotion induced by intra-N.Acc. amphetamine. These findings provide direct evidence for the inhibition of locomotor activity by mPFC dopamine and suggest that it is acting at D-1 dopamine receptors in this site.

Previous exposure to VTA amphetamine enhances cocaine self-administration under a progressive ratio schedule in a D1 dopamine receptor dependent manner.

The effect of previous exposure to amphetamine (AMPH) in the ventral tegmental area (VTA) on the subsequent self-administration of cocaine was assessed. Rats in different groups were pre-exposed to three injections into the VTA of either saline (0.5 microl/side) or AMPH (2.5 microg/0.5 microl/side). Injections were given once every third day. Starting 7-10 days after the last pre-exposure injection, rats were trained to self-administer cocaine (0.3 mg/kg/infusion) under fixed ratio 1 and 2 (FR1 and FR2) schedules and then tested under a progressive ratio (PR) schedule of reinforcement for six consecutive days. No differences between groups were observed during self-administration training under the FR schedules of reinforcement. However, when tested under the PR schedule, VTA AMPH pre-exposed rats worked more and, as a result, obtained more infusions of cocaine than saline pre-exposed rats. Rats in a separate group pre-exposed to VTA AMPH but co-infused with the D(1)-like dopamine (DA) receptor antagonist SCH23390 (0.25 microg/0.5 microl/side) did not show enhanced cocaine self-administration. These rats, as well as others pre-exposed to VTA SCH23390 alone showed levels of cocaine self-administration similar to saline pre-exposed rats. Thus, in a manner paralleling the sensitization of AMPH-induced locomotion and nucleus accumbens DA overflow, previous exposure to AMPH in the VTA leads to enhanced intravenous self-administration of cocaine and activation of D(1) DA receptors in this site during pre-exposure is necessary for the production of this effect.

The metabotropic glutamate receptor antagonist (RS)-MCPG produces hyperlocomotion in amphetamine pre-exposed rats.

It is known that, over a wide range of doses, the selective metabotropic glutamate receptor (mGluR) agonist, 1-aminocyclopentane-trans-1,3-dicarboxylic acid [(1S,3R)-ACPD], increases locomotion whereas the selective mGluR antagonist, (RS)-alpha-methyl-4-carboxyphenylglycine (MCPG) [(RS)-MCPG], is without effect when microinjected into the nucleus accumbens (NAcc) of drug-naive rats. The present experiments determined whether these responses are altered by pre-exposing rats to a regimen of systemic amphetamine (AMPH) injections known to produce locomotor sensitization. Rats in different groups were administered four injections of saline or AMPH (1.0 mg/kg, i.p.), one injection every third day. Two weeks after the last injection, rats were challenged with microinjections of either saline, (RS)-MCPG (2.5 nmole/side) or (1S,3R)-ACPD (0.5 nmole/side) into the NAcc. While (1S,3R)-ACPD increased locomotor activity when injected into the NAcc, no significant difference between saline and AMPH pre-exposed rats was observed. However, and interestingly, (RS)-MCPG which had no effect on locomotor activity when given to saline pre-exposed rats induced significantly higher locomotor activity in AMPH compared to saline pre-exposed rats. These results indicate that glutamatergic neurotransmission mediated by mGluRs in the NAcc is altered by repeated systemic injections of AMPH. Such changes may ultimately position the mGluR to contribute to the expression of sensitization by AMPH as well as other psychomotor stimulant drugs.

Group II, but not group I, metabotropic glutamate receptors in the rat nucleus accumbens contribute to amphetamine-induced locomotion.

Recently, it was reported that blocking metabotropic glutamate receptors (mGluRs) in the rat nucleus accumbens (NAcc) prevents the generation of locomotion by amphetamine (AMPH) in this site. In these studies, the non-selective group I/group II mGluR antagonist (R,S)-alpha-methyl-4-carboxyphenylglycine [(R,S)-MCPG] was used. The present study used more selective receptor antagonists to examine the specific contribution of group I and group II mGluRs to this effect. When co-injected bilaterally with AMPH into the NAcc, the group II selective mGluR antagonist (2S)-alpha-ethylglutamic acid [EGLU; 0.5-5.0 nmole/side] dose-dependently blocked the locomotion and rearing produced by AMPH. Equimolar concentrations of the group I selective antagonist (R,S)-1-aminoindan-1,5-dicarboxylic acid [AIDA; 0.5-5.0 nmole/side] were without effect. As previously reported for (R,S)-MCPG, neither of these receptor antagonists produced locomotor effects when injected alone in these concentrations into the NAcc. These results suggest that group II, but not group I, mGluRs in the rat NAcc contribute importantly to the ability of AMPH to produce locomotor activation.

Contribution of an alpha 1-adrenergic receptor subtype to the expression of the "ventral tegmental area syndrome".

Bilateral electrolytic lesions of the rat ventral tegmental area, a mesencephalic structure containing the cell bodies of ascending dopaminergic neurons, induce a behavioural syndrome characterized by a permanent locomotor hyperactivity. Acute intraperitoneal injections of prazosin, an alpha 1-adrenergic receptor antagonist, at a dose (0.5 mg/kg) which does not affect locomotor activities of control animals, abolished locomotor hyperactivities of lesioned rats. Antagonists of other monoaminergic receptors (propranolol, ritanserin, yohimbine), and also another antagonist of alpha 1-adrenergic receptors, 2-(2',6'-dimenthoxyphenoxyethyl)-aminomethyl-1,4-benzodioxan (WB4101) were ineffective. Comparisons of autoradiograms of brain slices incubated in the presence of 1 nM [3H]prazosin or 10 nM [3H]WB4101 indicated clear topographical differences. [3H]Prazosin labelling is present in the septum and in layer III of the cerebral cortex but absent in the striatum. [3H]WB 4101 labelling is diffuse in the superficial layers of the cerebral cortex and present in the striatum. In addition, intraperitoneal injection of WB4101 displaces, only weakly, [3H]prazosin binding in layer III of the cerebral cortex (-18%) while it decreases by 50% [3H]prazosin binding in the more superficial cortical layers. These observations strongly suggest that the binding site labelled by [3H]prazosin is different from alpha 1A- and alpha 1B-adrenergic receptor subtypes labelled by [3H]WB4101. Finally, it is proposed that the prazosin-induced blockade of the locomotor hyperactivity exhibited by ventral tegmental area lesioned animals is linked to the previously demonstrated regulatory role of noradrenergic neurons on cortical dopamine transmission.

Morphine conditioned place preference and locomotion: the effect of confinement during training.

The effect of confinement during conditioning on subsequent test levels of locomotor activity and conditioned place preference (CPP) was investigated by giving rats discrimination training with morphine and saline in the presence of different tactile floor cues in an open field. Groups of rats were trained under one of three levels of confinement (not confined, confined to 1/4, or confined to 1/16 of the open field) and tested for locomotor activity and CPP in the entire open field after receiving a saline injection. Confined rats subsequently spent less time on the morphine-paired floor cues (CS+) and were more active throughout the open field during the test than rats not confined during conditioning. Rats confined to the smallest area spent the least time on the CS+ and were the most active. It is suggested that confinement may preserve the novelty of the testing environment, which in turn may interfere with rats' usual responses to incentive drug-paired stimuli. These findings may have important implications for versions of the CPP technique in which training and testing environments differ considerably.

Conditioned locomotion and place preference elicited by tactile cues paired exclusively with morphine in an open field.

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 active when all four quadrants were CS+ and least active when zero or one CS+ quadrant was present. Thus, once an animal approached and made contact with the CS+ it tended to maintain contact with this stimulus and to reduce its approach to and contact with other stimuli. The differentiating features of this version of the CPP technique, as well as the relationship between morphine-induced conditioned locomotion and CPP, are discussed.

Effects of naltrexone on amphetamine-induced locomotion and rearing: acute and repeated injections.

The present experiment investigated the ability of the opiate receptor antagonist naltrexone to block the increased locomotion and rearing produced acutely by amphetamine as well as the sensitization of these responses produced when this drug is administered repeatedly. Rats in different groups received an injection of amphetamine (1.5 mg/kg, i.p.) or saline preceded 30 min earlier by an injection of naltrexone (0, 0.5, 1.0, 5.0 or 10.0 mg/kg, i.p.). Naltrexone dose-dependently reduced the rearing but had no effect on the locomotion produced by this dose of amphetamine. The locomotion and rearing observed following saline were not affected. This pattern of results was observed following each of six additional pairs of injections, one pair of injections given every third day. Once, soon (2-4 days) and once, long (9-12 days) after the last injection, all animals were injected with amphetamine (0.75 mg/kg, i.p.) in the absence of naltrexone (tests for sensitization). Animals having been pre-exposed to amphetamine preceded by naltrexone showed no evidence of sensitized rearing on either test, indicating that naltrexone blocked sensitization of this response to amphetamine. These animals, however, exhibited sensitized locomotion on both tests. These results suggest an important but complex role for dopamine-opioid interactions not only in the production of acute locomotor responding to amphetamine but also in the sensitization of locomotor responding when this drug is administered repeatedly. The present findings also suggest that amphetamine-induced rearing is more dependent than locomotion on neuronal mechanisms involving dopamine-opioid interactions.

Predisposition to self-administer amphetamine: the contribution of response to novelty and prior exposure to the drug.

The present experiment examined the contribution of locomotor response to novelty and prior exposure to amphetamine to rats' predisposition to self-administer a low dose of the drug. Rats were screened for their locomotor response to a novel environment and divided into high (HR) or low (LR) responders based on whether their locomotor scores were above or below the median activity level of the subject sample. Animals were then pre-exposed to nine daily injections of either saline (1 ml/kg, i.p.) or amphetamine (1.5 mg/kg, i.p.). Starting 1 week after pre-exposure, animals in the four different groups (HR pre-exposed to saline or amphetamine; LR pre-exposed to saline or amphetamine) were given the opportunity, in each of ten daily sessions, to lever press for a low dose of amphetamine (10 micrograms/kg per infusion) in a two lever (active versus inactive) continuous reinforcement operant task. Initial lever press performance revealed no difference in active versus inactive lever pressing between amphetamine and saline pre-exposed animals. However, in agreement with previous reports, with successive test sessions amphetamine pre-exposed rats maintained higher levels of active versus inactive lever pressing for drug while saline pre-exposed rats showed a progressive decrease in the pressing of either lever. Interestingly, this enhanced active lever pressing was observed in HR but not LR rats pre-exposed to amphetamine. In addition, HR saline pre-exposed animals showed initial active versus inactive lever pressing equivalent to that of HR amphetamine pretreated rats but this enhanced responding for drug diminished over days and by the last day of self-administration was indistinguishable from that of LR animals having been pre-exposed either to amphetamine or saline. These findings confirm that prior exposure to amphetamine promotes the subsequent self-administration of the drug and suggest that response to novelty may be a predictor more closely linked to an animal's propensity to become sensitized to the facilitatory effects of the drug rather than to an animal's current sensitization state and predisposition to self-administer the drug.

D1 dopamine receptor blockade prevents the facilitation of amphetamine self-administration induced by prior exposure to the drug.

Prior exposure to amphetamine leads to sensitized locomotor responding to subsequent injections and an enhanced predisposition to self-administer low doses of the drug. Because D1 dopamine (DA) receptors have been shown to play an important role in the development of sensitized locomotor responding to amphetamine, the present experiment assessed their contribution to the development of facilitated amphetamine self-administration produced by prior exposure to the drug. During a pre-exposure phase, rats were administered two injections on each of 10 consecutive days. The first injection (saline, 1 ml/kg, i.p., or the D1 DA receptor antagonist SCH23390, 0.04 mg/kg, s.c.) preceded the second (saline or amphetamine, 1.5 mg/kg, i.p.) by 30 min. Starting 10 days after the last injection, animals were given the opportunity to lever press for a low dose of amphetamine (10 microg/kg per infusion) in a two-lever (active versus inactive) continuous reinforcement operant task, in each of seven daily sessions. Consistent with previous reports, prior exposure to amphetamine resulted in an increase in active versus inactive lever pressing. Blocking D1 DA receptors with SCH23390 prior to each of the amphetamine pre-exposure injections prevented the development of this enhanced self-administration of amphetamine. When animals were grouped according to their locomotor response to a novel environment (assessed prior to the experiment), it was found, again in agreement with previous reports, that enhanced drug self-administration (as indicated by increased active versus inactive lever pressing as well as shorter latencies to emit the first active lever press, shorter inter-response times and more time-out responses on this lever) was observed only in amphetamine pre-exposed rats that had shown a locomotor response to novelty above the median of the subject sample (high responders). Preceding the amphetamine pre-exposure injections with SCH23390 blocked the development of enhanced drug self-administration observed in these animals. These findings, indicating that manipulations known to block the induction of locomotor and dopaminergic sensitization by amphetamine also block the facilitation of drug self-administration, suggest an important and common role for D1 DA receptor activation in the development of enhanced responding to and for drug.

Induction of locomotor sensitization by amphetamine requires the activation of NMDA receptors in the rat ventral tegmental area.

RATIONALE: The activation of NMDA receptors in the rat ventral tegmental area has been proposed to be necessary for the induction of locomotor sensitization by amphetamine, yet there has been no direct assessment of this view. OBJECTIVE: The present study examined the ability of the competitive NMDA receptor antagonist D(-)-2-amino-5-phosphonopentanoic acid (AP-5) to block this effect when infused either into the ventral tegmental area or, for comparison, into the nucleus accumbens. These sites are known to be important for the induction and expression, respectively, of locomotor sensitization by amphetamine. METHODS: Rats in different groups received four pairs of injections (one IC and one IP), one pair given every third day. The IC injection (0, 1 or 5 nmol/side AP-5) was administered immediately before the IP injection (saline or amphetamine, 1 mg/kg). Locomotor activity was measured following each pair of injections and again 2 weeks later when all rats were tested for sensitization following a challenge injection of amphetamine (1 mg/kg, IP). AP-5 was not administered on this test. RESULTS: As expected, rats previously exposed to amphetamine alone showed higher levels of horizontal locomotion and rearing on the test for sensitization when compared to saline pre-exposed rats. Preceding the amphetamine pre-exposure injections with infusions of AP-5 into the ventral tegmental area, but not the nucleus accumbens, dose-dependently blocked the induction of this effect. Rats previously exposed to AP-5 alone in either site did not differ significantly from saline preexposed rats on the test for sensitization. CONCLUSION: The results indicate that NMDA receptor activation in the ventral tegmental area, but not the nucleus accumbens, is necessary for the induction of locomotor sensitization by amphetamine.

Locomotor response to novelty predicts a rat's propensity to self-administer nicotine.

RATIONALE: A positive correlation between responding to novelty and propensity to subsequently self-administer a drug has been reported for opioids and psychomotor stimulants but remains to be investigated for nicotine. OBJECTIVE: The possibility that locomotor responding to novelty can predict a rat's propensity to self-administer nicotine was therefore assessed. METHODS: Rats' locomotor response to a novel environment was assessed, and animals were subsequently tested for their self-administration of nicotine. RESULTS: Significant positive correlations were obtained between responding to novelty and acquisition of nicotine self-administration over 12 days of testing under fixed-ratio schedules as well as subsequent responding for the drug under a progressive-ratio (PR) schedule of reinforcement. When designated as high (HR) or low (LR) responders based on whether their locomotor responses on the novelty screen were above or below the median activity level of the subject sample, HR animals, compared with LR rats, acquired nicotine self-administration more readily and worked more to obtain the drug when tested under the PR schedule. CONCLUSION: These findings are consistent with those obtained with other drugs and suggest that locomotor responding to a novel environment can be used to predict a rat's propensity to self-administer nicotine.

The effect of previous exposure to amphetamine on drug-induced locomotion and self-administration of a low dose of the drug.

RATIONALE AND OBJECTIVES: In order to assess directly the relationship between locomotor activity and drug self-administration, the present experiment simultaneously measured these two behaviors in rats with different histories of pre-exposure to amphetamine either following or in the absence of priming injections of the drug. METHODS: Different groups of rats were exposed to ten daily injections of either saline (1.0 ml/kg, i.p.) or amphetamine (1.5 mg/kg, i.p.) and, in each of 13 daily sessions starting 10 days later, were given the opportunity to lever press for a low dose of amphetamine (10 microg/kg per i.v. infusion) in a two-lever (active versus inactive) continuous reinforcement task. Animals were administered a priming injection of amphetamine (1.0 mg/kg, i.p.) immediately before testing on the first 8 days, a saline injection (1.0 ml/kg, i.p.) on the next 3 days and amphetamine on the final 2 days of testing. RESULTS: Consistent with previous reports, prior exposure to amphetamine led to an enhanced locomotor response to the priming injection of amphetamine on the first day of testing. Little pressing for drug was observed on this day. Following priming injections on the subsequent test days, evidence for enhanced locomotion by amphetamine-pre-exposed rats diminished and both groups showed comparable and progressive increases in active versus inactive lever pressing. When priming injections were not made, however, only animals previously exposed to amphetamine maintained lever pressing for the drug. Under these conditions, these animals emitted more active lever presses and time-out responses and exhibited higher levels of locomotor activation in proximity to the active drug administering lever than did saline-pre-exposed rats. CONCLUSIONS: These results are consistent with the view that previous exposure to amphetamine produces a long-lasting enhancement in the behavioral activation animals will direct toward stimuli associated with the drug. This enhancement was displayed initially as a sensitized locomotor response to amphetamine on the first day of testing and was subsequently observed on those test days when no priming injections were given when animals continued to self-administer a low dose of amphetamine under a simple schedule of reinforcement. The implications of these findings for our understanding of the excessive expression of drug-directed behaviors are discussed.

Metabotropic glutamate receptors are necessary for sensitization by amphetamine.

The contribution of metabotropic glutamate receptors (mGluRs) in the ventral tegmental area (VTA) to the induction of locomotor sensitization by amphetamine (AMPH) was investigated. Rats pre-exposed to AMPH in the VTA showed significantly higher locomotor activity when subsequently tested with a systemic AMPH challenge than rats preexposed to VTA saline. Rats pre-exposed to AMPH but co-injected with the selective mGluR antagonist (RS)-alpha-methyl-4-carboxyphenylglycine [(RS)-MCPG] did not show this effect. These findings indicate that activation of mGluRs in the VTA is necessary for the induction of locomotor sensitization by AMPH and provide further support for the important role played by excitatory amino acids in this site in the development of sensitization to AMPH.

Microinjection of CART peptide 55-102 into the nucleus accumbens blocks amphetamine-induced locomotion.

The role played by the biologically active CART 55-102 peptide in NAcc AMPH induced locomotion was investigated. When microinjected alone into this site, none of the doses of CART 55-102 tested (0.1, 0.4, 1.0 or 2.5 microg/0.5 microl/side) produced effects on locomotion during a two-h test. However, when co-injected with AMPH (2.5 microg/0.5 microl/side) into the NAcc, moderately high (2.5 microg/side) and middle to high (0.4-2.5 microg/side) doses of CART 55-102 significantly attenuated the effects of AMPH on locomotion and rearing, respectively. These results indicate that CART peptides can exert an antagonistic effect on the generation of locomotion by AMPH in the NAcc.

In vivo microdialysis in the rat: low cost and low labor construction of a small diameter, removable, concentric-style microdialysis probe system.

A method for construction of a serviceable and low cost intracerebral microdialysis system is presented. The system includes a probe and its supporting components. The probe is of the concentric design. The supporting components are an implantable guide cannula, a tether, and a swivel. After minimal training, workers can make many probes of consistent performance characteristics in a short time. Because all of the parts are commercially produced, users may obtain custom-made components which are finished with factory precision and accuracy. The user may readily vary probe characteristics such as depth of implant and size of active portion, so that different types of dialysis may be performed in different brain regions. The available choices in tether and swivel configurations make this microdialysis system readily adaptable to diverse testing environments. Excluding labor and startup costs, the costs, the cost per probe is approximately $11.00 (US). Taken together, the system provides a flexible, low cost means for performing in vivo microdialysis in freely moving rats.