Evidence for involvement of ventral tegmental area cyclic AMP systems in behavioral sensitization to psychostimulants

The present study investigated the role of ventral tegmental area (VTA) cyclic AMP (cAMP) systems in the behavioral sensitivity to psychostimulants in male Sprague-Dawley rats. Bilateral microinjections of cholera toxin (CTX) into the VTA (50-500 ng/500 nl/side) dose-dependently sensitized animals to the locomotor stimulant effects of systemic d-amphetamine, cocaine and apomorphine, but were without effects on morphine-induced locomotion 24 hr after microinjection. The CTX-induced behavioral sensitization to amphetamine was even greater 72 hr after microinjection, but was no longer present 14 days after intra-VTA CTX pretreatment. Coadministration of the cAMP-dependent protein kinase inhibitor H8 into the VTA blocked CTX-induced sensitization to amphetamine, suggesting that the sensitization is dependent on phosphorylation events in the VTA mediated by cAMP-dependent protein kinase. Pretreatment with CTX did not enhance amphetamine-induced dopamine release in the nucleus accumbens relative to saline controls 24 hr after microinjection. A single bilateral injection of d-amphetamine into the VTA (5 micrograms/side) produced a significant sensitization to systemic amphetamine challenge 72 hr later, and this effect was also blocked by coadministration of H8 into the VTA. These results extend previous studies which have established the importance of the VTA in the development of behavioral sensitization and suggest that cAMP systems may play a crucial role in this neuroadaptive process.     

Evidence for the involvement of phospholipase A2 mechanisms in the development of stimulant sensitization

Evidence suggests that phospholipase A2 (PLA2) activation is involved in numerous neuroplastic phenomena, including long-term potentiation. Considering the pharmacological similarities between long-term potentiation and stimulant sensitization, it seems possible that PLA2 inhibition activity also might have a role in the induction of stimulant sensitization. In this study, we have investigated whether PLA2 inhibition, by quinacrine, has any effects on stimulant-induced behavioral sensitization. Both locomotor and stereotypic behavioral sensitization were dose-dependently blocked in rats pretreated with quinacrine (8-25 mg/kg i.p.) 15 min before cocaine (30 mg/kg i.p.), when tested with cocaine (15 mg/kg i.p) 72 hr later. Similar results also were found with d-amphetamine (2 mg/kg i.p.) sensitization using a 10-day treatment regimen with testing on day 11. The ability of PLA2 activation, by melittin, to produce cocaine sensitization also was tested. Local injections of melittin (0.1 microgram/0.4 microliter) into the ventral tegmental area sensitized the subsequent stimulation of locomotor activity, stereotypy and nucleus accumbens dopamine release by cocaine, when tested 72 hr later. Local injections of melittin (0.1-1.0 microgram/0.8 microliter) into the nucleus accumbens had a moderate sensitizing effect on locomotion. Quinacrine (16 mg/kg) pretreatment 45 min before intraventral tegmental area melittin injection significantly decreased melittin-induced sensitization of the locomotor and stereotypy response to cocaine. These results indicate that PLA2 activation may play a role in the induction of stimulant sensitization. It is proposed that PLA2 activity in mesolimbic dopamine neurons, at the level of the cell bodies and perhaps the nerve terminals, is involved in the biochemical mechanisms mediating the development of stimulant sensitization.     

Dopamine receptor antagonists in the nucleus accumbens attenuate analgesia induced by ventral tegmental area substance P or morphine and by nucleus accumbens amphetamine

In the present study, we examined the effects of dopamine (DA) receptor antagonists infused into the nucleus accumbens septi (NAS) on analgesia induced by intra-ventral tegmental area (VTA) infusions of the substance P (SP) analog, DiMe-C7 or morphine and intra-NAS infusions of amphetamine. Rats received intra-NAS infusions of either the mixed DA receptor antagonist flupenthixol (1.5 or 3.0 microg/0.5 microl/side; DiMe-C7 only), the DA D1/D5 receptor antagonist SCH 23390 (0.1 microg/0.5 microl/side; DiMe-C7 only) or the DA D2-type receptor antagonist raclopride (1.0, 3.0 or 5.0 microg/0.5 microl/side). Ten minutes later, rats received intra-VTA infusions of DiMe-C7 (3.0 microg/0.5 microl/side) or morphine (3.0 microg/0.5 microl/side) or intra-NAS infusions of amphetamine (2.5 microg/0.5 microl/side). Animals were then administered the formalin test for tonic pain. Intra-NAS raclopride prevented analgesia induced by intra-VTA DiMe-C7, intra-VTA morphine and intra-NAS amphetamine. Similarly, intra-NAS flupenthixol or SCH 23390 attenuated the analgesia induced by intra-VTA DiMe-C7. These findings suggest that tonic pain is inhibited, at least in part, by enhanced DA released from terminals of mesolimbic neurons. Furthermore, the evidence that SP and opioids in the VTA mediate stress-induced analgesia suggests that the pain-suppression system involving the activation of mesolimbic DA neurons is naturally triggered by exposure to stress, pain or both.     

Differential development of autoreceptor subsensitivity and enhanced dopamine release during amphetamine sensitization

Various changes in the function of dopamine neurons have been proposed to underly the development of behavioral sensitization to the locomotor stimulant effects of d-amphetamine. The present study examined the relative importance of two such mechanisms after both short (3-4 days off) and longer (10-14 days off) withdrawals from repeated amphetamine or saline injection (1 mg/kg/day, days 1-5 and 8-12). First, single-unit recording was used to examine the sensitivity of impulse-regulating somatodendritic autoreceptors located on mesoaccumbens dopamine neurons in the rat ventral tegmental area. Second, in vivo microdialysis was used to examine the ability of amphetamine challenge to increase extracellular dopamine levels in the rat nucleus accumbens. Amphetamine-treated rats exhibited robust behavioral sensitization at both time points as compared to saline-treated rats. At 3 to 4 days off, autoreceptor subsensitivity was observed in the ventral tegmental area of amphetamine-treated rats, but there was no significant change in the ability of amphetamine to increase extracellular dopamine levels in nucleus accumbens. However, after 10 to 14 days off, autoreceptor subsensitivity was no longer observed, but amphetamine challenge resulted in a significantly greater increase in extracellular dopamine levels in amphetamine-treated as compared to saline-treated rats. These findings suggest that autoreceptor subsensitivity is a transient effect which may be related to the development of sensitization, whereas enhancement of amphetamine-stimulated dopamine release does not accompany early stages of behavioral sensitization, but may be involved in the persistence of the phenomenon after longer withdrawal periods.     

The effects of cocaine, amphetamine, and the dopamine D1 receptor agonist SKF 38393 on fear extinction as measured with potentiated startle: implications for psychomotor stimulant psychosis

Using Pavlovian conditioned increases in the amplitude of the acoustic startle reflex as a behavioral indicator of fear motivation, the authors previously showed a resistance to extinction after repeated associations of cocaine with the fear-evoking conditioned stimulus (CS). In Experiment 1, acute administration of cocaine, amphetamine, and the dopamine (DA) D1 receptor agonist SKF 38393 produced a similar fear enhancement. In Experiment 2, a noncontingent injection of cocaine and SKF 38393 provoked a CS potentiation of acoustic startle in fear-extinguished laboratory rats. Potential behavioral, neurochemical, and neuroendocrine explanations for the effects of psychomotor stimulants on conditional fear were discussed. It was suggested that DA agonist drugs increase fear expression possibly by activating mesoamygdaloid associative neurocircuitry involved in excitatory conditioned fear reactions.     

Cocaine sensitization can accelerate the onset of peak cocaine behavioral effects

The development of sensitization to the behavioral effects of cocaine occurs with repeated intermittent usage. In the present study rats were given five daily i.p. injections of cocaine (10 mg/kg) immediately prior to placement in an open-field environment for 20 min to induce cocaine sensitization. Control groups received saline injections or cocaine injections (10 mg/kg) 30 min after testing in the home cage. One week later the animals were given a challenge test with 10 mg/kg cocaine. The animals that had received cocaine in the test environment exhibited a more rapid onset of cocaine-induced behavioral effects than either animals previously treated with saline or animals that had received cocaine in the home cage. In a second experiment, the same sensitization protocol was followed except that during the interval between the end of the cocaine/saline treatments and the challenge test, the animals were given six daily 20-min saline tests to assess the contribution of differential habituation and/or Pavlovian conditioning to the sensitization effect. Neither habituation or Pavlovian conditioning altered the more rapid onset of cocaine stimulant effects induced by repeated cocaine treatments. It is suggested that the faster onset of cocaine effects is another way in which cocaine sensitization contributes to cocaine abuse liability.     

Activation of CTP:phosphocholine cytidylyltransferase by hypochlorite-oxidized phosphatidylcholines

The acute psychomotor response and development of sensitization to amphetamine is attenuated if i.p. injections are given in the cage where a rat lives relative to when injections are given in a novel but physically identical test environment. Furthermore, when the environmental cues predicting i.p. injections are completely eliminated by using remotely activated i.v. injections in the home cage, 1.0 mg/kg amphetamine produces a very small acute response and no sensitization. The same treatments do produce sensitization if i.v. injections are signaled by placement of the rat in a novel test cage. The present experiment was designed to determine if there is a similar effect of environmental condition on the response to i.v. cocaine, and to what extent the effect may be dose-dependent. This was accomplished by comparing the psychomotor activating effects (rotational behavior) of repeated i.v. administrations of one of eight doses of cocaine (0.0, 0.3, 0.6, 1.2, 2.4, 3.6, 4.8, or 7.2 mg/kg) given in the home cage, with infusions of the same doses given in a novel test cage. There was no effect of environment on the acute psychomotor response to cocaine. There was, however, a significant effect of environment on the induction of sensitization. A higher dose of cocaine was required to induce sensitization when i.v. administrations were given in the home cage than when they were given in a physically identical but novel test environment. At high doses, however, cocaine induced sensitization regardless of environmental condition. The results suggest that the effect of this environmental manipulation is to shift the dose-effect curve for the induction of sensitization, and support the notion that the ability of psychostimulant drugs to induce sensitization can be modulated by the circumstances surrounding drug administration.     

Repeated cocaine augments excitatory amino acid transmission in the nucleus accumbens only in rats having developed behavioral sensitization

Rats were pretreated with daily cocaine or saline injections for 1 week. The rats treated with daily cocaine were separated into two groups: a sensitized group of animals demonstrating > 20% increase in motor activity on the last injection compared with the first injection of daily cocaine, and a nonsensitized group showing < 20% elevation. At 2-3 weeks after the last daily injection, four experiments were performed to assess changes in excitatory amino acid (EAA) transmission in the nucleus accumbens produced by repeated cocaine administration. (1) Rats were challenged with a microinjection of AMPA into the shell or core of the nucleus accumbens. The sensitized rats demonstrated greater motor activity than did the saline-pretreated or nonsensitized animals after AMPA injection into either subnucleus. (2) It was shown that the behavioral distinction between sensitized, nonsensitized, and control rats in behavioral responsiveness to AMPA was not mediated by differences in AMPA-induced dopamine release. (3) The extracellular content of glutamate was measured after a cocaine challenge given at 21 d of withdrawal. Cocaine elevated the levels of glutamate in the core of sensitized rats, but not of nonsensitized or control rats. (4) Microinjection of the non-NMDA antagonist 6-cyano-7-nitroquinoxaline-2,3-dione into the core abolished the augmented motor response to a cocaine challenge in sensitized rats, but was without effect on cocaine-induced motor activity in nonsensitized animals. These results indicate that repeated cocaine administration increases EAA transmission in the nucleus accumbens only in rats that develop behavioral sensitization to cocaine.     

The effects of cocaine, amphetamine, and the dopamine D? receptor agonist SKF 38393 on fear extinction as measured with potentiated startle: Implications for psychomotor stimulant psychosis.

Using Pavlovian conditioned increases in the amplitude of the acoustic startle reflex as a behavioral indicator of fear motivation, the authors previously showed a resistance to extinction after repeated associations of cocaine with the fear-evoking conditioned stimulus (CS). In Experiment 1, acute administration of cocaine, amphetamine, and the dopamine (DA) D? receptor agonist SKF 38393 produced a similar fear enhancement. In Experiment 2, a noncontingent injection of cocaine and SKF 38393 provoked a CS potentiation of acoustic startle in fear-extinguished laboratory rats. Potential behavioral, neurochemical, and neuroendocrine explanations for the effects of psychomotor stimulants on conditional fear were discussed. It was suggested that DA agonist drugs increase fear expression possibly by activating mesoamygdaloid associative neurocircuitry involved in excitatory conditioned fear reactions. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Sensitization of amphetamine-induced stereotyped behaviors during the acute response

The quantitative and qualitative features of the behavioral response to amphetamine-like stimulants in rats can be dissociated from the dopamine response. This dissociation is particularly evident in the temporal profiles of the extracellular dopamine and stereotypy responses to higher doses of amphetamine. One possible mechanism contributing to this temporal dissociation is that during the acute response to amphetamine, dopamine receptor mechanisms are enhanced such that stereotyped behaviors can be supported by synaptic concentrations of dopamine which are not sufficient to initiate these behaviors. To further explore the dynamics of stimulant sensitivity during the acute response, we examined the behavioral and extracellular dopamine responses to a low, nonstereotypy-producing dose of amphetamine (0.5 mg/kg) at various times after an acute, priming injection of 4.0 mg/kg when stereotypies had subsided and extracellular dopamine was approaching predrug baseline levels. The low-dose challenge produced intense stereotypies although the regional dopamine responses were not significantly different from control animals. Blockade of the expression of stereotypies during the priming response by the D2 antagonist haloperidol or the D1 antagonist SCH 23390 prevented the expression of an enhanced stereotypy response to the challenge injection. Our results suggest that an exposure to amphetamine results in a rapid sensitization of the stereotypy response which does not involve changes in the extracellular dopamine response but requires activation of dopamine receptors. Such a mechanism may be significantly implicated during binge patterns of stimulant abuse and may also play a role in the sensitization associated with repeated amphetamine administration.     

Behavioral sensitization to cocaine, but not cocaine-conditioned behavior, is associated with increased dopamine occupation of its receptors in the nucleus accumbens.

Rats had repeated treatments with cocaine associated with a specific context (paired group). Evidence for classical conditioning of cocaine's motor-activity effects and context-specific behavioral sensitization to cocaine was obtained, relative to vehicle-treated (control) and pseudoconditioned (unpaired) groups. Only the paired group exhibiting context-specific behavioral sensitization had more dopamine bound to both D?-like and D?-like receptors in the nucleus accumbens than did rats in the control group receiving cocaine on the test day. No effects on receptor occupation were found in rats showing a classical conditioned response to a context previously paired with cocaine. Thus, sensitization to cocaine, but not classical conditioning of cocaine's behavioral effects, was associated with greater dopaminergic neurotransmission selectively in the nucleus accumbens. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Neuropeptide FF in the VTA blocks the analgesic effects of both intra-VTA morphine and exposure to stress

Experiments were designed to examine the analgesic effects induced by selective tachykinin receptor agonists microinfused into either the ventral tegmental area (VTA) or nucleus accumbens septi (NAS). Rats were tested in the formalin test for tonic pain following an injection of 0.05 ml of 2.5% formalin into one hind paw immediately after bilateral intra-VTA infusions of either the NK-1 agonist, GR-73632 (0.005, 0.05 or 0.5 nmol/side), the NK-3 agonist, senktide (0.005, 0.5 or 1.5 nmol/side), or saline. Two weeks later, the saline-treated rats were assessed in the tail-flick test for phasic pain after infusions of the tachykinin agonists. Tail-flick latencies were recorded following immersion of the tail in 55 degrees C hot water at 10 min intervals for 1 h immediately after intra-VTA infusions of either GR-73632 (0.5 nmol/side), senktide (1.5 nmol/side) or saline. In a second group of rats, the same effects were studied after infusions into the nucleus accumbens (NAS) of GR-73632 (0.005, 0.5 or 1.5 nmol/side), senktide (0.005, 0.5 or 1.5 nmol/side), or saline. In both the VTA and NAS, the NK-1 and the NK-3 agonists caused significant analgesia in the formalin test, although the NK-1 agonist appeared to be more effective. Naltrexone (2.0 mg/kg) pretreatment failed to reverse the analgesic effects in the formalin test induced by intra-VTA infusions of the substance P (SP) analog, DiMe-C7 (3.0 microg/side), GR-73632 (0.5 nmol/side), or senktide (1.5 nmol/side). Neither compound given at either site was effective in the tail-flick test. These findings suggest that SP-dopamine (DA) interactions within the mesolimbic DA system play an important role in the inhibition of tonic pain. Furthermore, they support our earlier ideas that activation of midbrain DA systems by SP might play a role in stress- and/or pain-induced analgesia.     

Cumulative pregnancy rates and selective drop-out of patients in in-vitro fertilization treatment

Rats were given repeated infusions of i.v. amphetamine in association with placement in a novel test environment, a protocol that produces behavioral sensitization, or in the home cage, a protocol that fails to induce sensitization. In several brain areas amphetamine altered calmodulin content, but only in the group treated in a novel environment, suggesting that amphetamine-induced alterations in calmodulin may occur only when drug treatments induce behavioral sensitization.     

Clozapine and haloperidol block the induction of behavioral sensitization to amphetamine and associated genomic responses in rats

Behavioral sensitization resulting from repeated, intermittent exposure to psychostimulants such as amphetamine (Amp) is hypothesized to model pathophysiology of psychotic disorders. The present study was designed to characterize the effects of a typical and an atypical antipsychotic drug, haloperidol and clozapine, respectively, on the induction of context-independent sensitization to Amp. Peripheral Amp treatment for five days (2 mg/kg/day, s.c.) produced an augmented stimulant response to an acute Amp challenge (2 mg/kg, s.c.) given seven days after the last pretreatment injection. Interestingly, preexposure to high doses of either clozapine (20 mg/kg) or haloperidol (0.5 mg/kg) alone also led to a sensitized behavioral response to an acute Amp challenge. The cross-sensitization between Amp and high doses of the haloperidol and clozapine may have occluded any blockade of Amp behavioral sensitization by the antipsychotics. Indeed, administration of a lower dose of clozapine (4 mg/kg) or haloperidol (0.1 mg/kg) with Amp during the preexposure phase clearly blocked the induction of behavioral sensitization. In addition to the behavioral sensitization, Amp-pretreated rats showed a reduction in the ability of the acute Amp challenge to induce c-fos mRNA in the medial prefrontal cortex and neurotensin/neuromedin N (NT/N) mRNA in the nucleus accumbens-shell. At doses that blocked the initiation of behavioral sensitization to Amp, clozapine fully and haloperidol partially restored the capacity of acute Amp to induce c-fos and NT/N gene expression. These data lend support to the psychostimulant-sensitization model of psychosis and a role of dopamine D2-like receptors in the phenomenon.     

Laryngeal tuberculosis and laryngeal cancer

The primary objective of this study was to determine whether the development of behavioral sensitization to the putative dopamine D3 receptor agonist 7-OH-DPAT could be prevented by either selective D1-type or D2-type dopamine receptor antagonists. In three experiments, male Wistar rats (250-350 g) were given seven to nine injections (at 48-h intervals) of 7-OH-DPAT (1.0 mg/kg, SC) or vehicle in combination with the D2-type dopamine antagonist eticlopride (0.3 mg/kg, SC), the D1-type dopamine antagonist SCH 23390 (0.1 or 0.2 mg/kg, SC), or vehicle. After the injections, the rats were tested for locomotor activity in photocell arenas for 2 h. In the first two experiments, after seven injections, all rats were tested for activity following vehicle injections to test for possible conditioning effects. In each experiment, after the last pre-exposure session, all rats were given a challenge injection of 7-OH-DPAT (1.0 mg/kg, SC) and tested for activity. Major findings were as follows: a) 7-OH-DPAT treatments produced a progressively greater increase in locomotor activity with repeated treatment; b) concurrent treatment with eticlopride or SCH 23390 (0.1 and 0.2 mg/kg) blocked the acute locomotor-activating effects of 7-OH-DPAT across days; c) eticlopride, but not SCH 23390, completely blocked the development of behavioral sensitization to 7-OH-DPAT. Although the low dose of SCH 23390 (0.1 mg/kg) produced a partial attenuation of sensitization, the higher dose (0.2 mg/kg) of SCH 23390 appeared to augment, rather than block, sensitization to 7-OH-DPAT; d) rats previously treated with SCH 23390 (0.2 mg/kg, but not 0.1 mg/kg) without 7-OH-DPAT displayed a hyperactive response to the 7-OH-DPAT challenge injection; and e) after vehicle injections, rats previously given 7-OH-DPAT, SCH 23390, or eticlopride either alone or in combination were more active than vehicle control rats. These findings suggest that the neurochemical mechanisms mediating the development of behavioral sensitization to 7-OH-DPAT may differ from those of other dopamine D2-type agonists such as quinpirole or bromocriptine. Moreover, these results demonstrate that hyperactivity responses following vehicle injections in drug-pretreated animals do not necessarily reflect conditioning mechanisms.     

Involvement of the fimbria fornix in the initiation but not in the expression of methamphetamine-induced sensitization

To put forward our previous finding that the lesion of the fimbria fornix, a hippocampo-accumbal pathway, blocked the development of behavioral sensitization induced by repeated methamphetamine (MAP) administrations, we examined the role of the fimbria fornix in the expression of sensitization in this study. After rats had shown locomotor augmentation following repeated drug injections, they received either the fimbria fornix lesion or a sham operation. Both groups of rats still exhibited a similar sensitized locomotor response to MAP as before the surgeries. In addition, we evaluated dopamine metabolism in the nucleus accumbens of these rats following a challenge injection of MAP after the behavioral study. The data obtained correspond to the results of behavioral experiments in that 3-methoxytyramine, one of the dopamine metabolites, increased significantly after MAP challenge only in the groups of sensitized animals. These findings further support the recent concept that there may exist different neural mechanisms in the initiation and expression of sensitization phenomenon.     

The role of excitatory amino acids in behavioral sensitization to psychomotor stimulants

Behavioral sensitization refers to the progressive augmentation of behavioral responses to psychomotor stimulants that develops during their repeated administration and persists even after long periods of withdrawal. It provides an animal model for the intensification of drug craving believed to underlie addiction in humans. Mechanistic similarities between sensitization and other forms of neuronal plasticity were first suggested on the basis of the ability of N-methyl-D-aspartate (NMDA) receptor antagonists to prevent the development of sensitization [Karler, R., Calder, L. D., Chaudhry, I. A. and Turkanis, S. A. (1989) Blockade of "reverse tolerance" to cocaine and amphetamine by MK-801. Life Sci., 45, 599-606]. This article will review the large number of subsequent studies addressing: (1) the roles of NMDA, alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) and metabotropic glutamate receptors in the development and expression of behavioral sensitization, (2) excitatory amino acids (EAAs) and the role of conditioning in sensitization, (3) controversies regarding EAA involvement in behavioral sensitization based on studies with MK-801, (4) the effects of acute and repeated stimulant administration on EAA neurochemistry and EAA receptor expression, and (5) the neuroanatomy of EAA involvement in sensitization. To summarize, NMDA, AMPA metabotropic glutamate receptors all participate in the development of sensitization, while maintenance of the sensitized state involves alterations in neurochemical measures of EAA transmission as well as in the expression and sensitivity of AMPA and NMDA receptors. While behavioral sensitization likely involves complex neuronal circuits, with EAAs participating at several points within this circuitry, EAA projections originating in prefrontal cortex may play a particularly important role in the development of sensitization, perhaps via their regulatory effects on midbrain dopamine neurons. The review concludes by critically evaluating various hypotheses to account for EAA involvement in the development of behavioral sensitization, and considering the question of whether EAA receptors are involved in mediating the rewarding effects of psychomotor stimulants and sensitization of such rewarding effects.     

Ibotenic acid lesions of the dorsal prefrontal cortex disrupt the expression of behavioral sensitization to cocaine

The present study determined the effect of bilateral lesions of specific cortical or thalamic nuclei that provide excitatory amino acid afferents to the nucleus accumbens (i.e. the dorsal prefrontal cortex, ventral prefrontal cortex, amygdala, hippocampus and periventricular thalamus) on the expression of cocaine-induced behavioral sensitization. Lesions of these nuclei were made during a three-week withdrawal period following repeated daily injections of cocaine or saline. The results indicate that dorsal prefrontal cortex lesions block the expression of behavioral sensitization to cocaine, while ventral prefrontal cortex, fimbria fornix, amygdala and thalamic lesions have no effect. A subsequent microdialysis experiment was performed in order to evaluate the effect of dorsal prefrontal cortex lesions on glutamate transmission in the nucleus accumbens core of cocaine- and saline-pretreated rats. The systemic injection of cocaine produced a significant increase in extracellular glutamate in the nucleus accumbens core among animals with a sham surgery; this effect was blocked by a bilateral lesion of the dorsal prefrontal cortex. Taken together, these results indicate that the dorsal prefrontal cortex, which provides excitatory amino acid input selectively to the core region of the nucleus accumbens, enhances the expression of behavioral sensitization to cocaine by increasing glutamate transmission in this subnucleus.     

The propensity for nonregulatory ingestive behavior is related to differences in dopamine systems: Behavioral and biochemical evidence.

Investigated the relation between properties of dopaminergic neural systems and the predisposition to exhibit nonregulatory ingestive behavior in 54 male Long-Evans rats. It was found that Ss that ate and drank during electrical stimulation of the lateral hypothalamus (ESLH) showed greater behavioral sensitization to a series of amphetamine injections (3 mg/kg) than those that did not exhibit ingestive behavior during ESLH. In addition, footshock stress produced a greater increase in forebrain dopamine utilization in Ss that engaged in nonregulatory ingestive behavior. This evidence is consistent with the hypothesis that there are individual differences in the responsiveness of forebrain dopamine systems that are related to the behavioral predisposition to exhibit nonregulatory ingestive behavior. (51 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Depletion of striatal dopamine transporter does not affect psychostimulant-induced locomotor activity

The effect of neurotoxin-induced depletion of striatal dopamine transporter (DAT) binding sites on animals' responses to psychostimulants was investigated. Multiple 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or methamphetamine (METH) injections but not a single METH injection to Swiss Webster mice resulted in > 60% depletion of striatal DAT. MPTP-induced depletion of DAT did not affect METH- and cocaine-stimulated locomotor activity compared with the response of control mice. Pre-exposure to either the neurotoxic or the single non-neurotoxic dose of METH resulted in a marked locomotor sensitization in response to METH or cocaine challenge injections. The present results indicate that > 60% loss in striatal DAT binding sites has no effect on animals' responses to psychostimulants, and suggest that neural systems other than striatal DAT may contribute to the induction of locomotor sensitization to METH and cocaine.