Behavioral responses to cocaine and amphetamine administration in mice lacking the dopamine D1 receptor

Cocaine and amphetamine can induce both short-term and long-term behavioral changes in rodents. The major target for these psychostimulants is thought to be the brain dopamine system. To determine whether the dopamine D1 receptor plays a crucial role in the behavioral effects of psychostimulants, we tested both the locomotor and stereotyped behaviors in D1 receptor mutant and wild-type control mice after cocaine and amphetamine treatments. We found that the overall locomotor responses of D1 receptor mutant mice to repeated cocaine administration were significantly reduced compared to those of the wild-type mice and the responses of the D1 receptor mutant mice to cocaine injections were never significantly higher than their responses to saline injections. D1 receptor mutant mice were less sensitive than the wild-type mice to acute amphetamine stimulation over a dose range even though they exhibited apparently similar behavioral responses as those of the wild-type mice after repeated amphetamine administration at the 5 mg/kg dose. Immunostaining experiments indicated that there was no detectable neurotoxicity in the nucleus accumbens in both D1 receptor mutant and wild-type mice after repeated amphetamine administration. The data suggest that the D1 receptor plays an essential role in mediating cocaine-induced behavioral changes in mice. Moreover, the D1 receptor also participates in behavioral responses induced by amphetamine administration.     

Possible involvement of serotonergic neurons in the reduction of locomotor hyperactivity caused by amphetamine in neonatal rats depleted of brain dopamine

This experiment attempted to determine the mechanism by which amphetamine reduces locomotor hyperactivity in neonatal rats given brain dopamine (DA)-depleting 6-hydroxydopamine (6-OHDA) injections. Brain DA neurons were destroyed selectively in neonatal rats by intraventricular (i.v.t.) injections of 6-OHDA following desmethylimipramine (DMI) pretreatment. Control rats received DMI and i.v.t. injections of the 6-OHDA vehicle solution. Rats given the 6-OHDA treatment displayed 7-fold increases in locomotor activity compared to controls during days 16–55 of life. Throughout this period, amphetamine (1 mg/kg) reduced locomotor hyperactivity in 6-OHDA-treated rats but increased locomotor activity in control rats. The reduction of hyperactivity caused by amphetamine (0.5–4 mg/kg) was dose-related and was not accompanied by stereotyped behavior. Like amphetamine, methylphenidate (4 mg/kg) reduced locomotor hyperactivity in rats given 6-OHDA. The DA antagonist, spiroperidol (50–200 μg/kg) failed to attenuate the hyperactivity-reducing effect of amphetamine in 6-OHDA-treated rats at doses which abolished the stimulant effect of amphetamine in control rats. However, the serotonin antagonist methysergide (0.5–4 mg/kg) produced dose-dependent antagonism of the effect of amphetamine in 6-OHDA-treated rats. Pretreatment with propranolol (5 mg/kg), phentolamine (5 mg/kg), atropine (0.5 mg/kg) or naloxone (10 mg/kg) failed to alter the reduction in locomotor hyperactivity caused by amphetamine. The serotonin releasing agent, fenfluramine (3 mg/kg), and the serotonin agonist, quipazine (0.5–4 mg/kg), both reduced locomotor hyperactivity in 6-OHDA-treated rats while not altering locomotion in control rats. These results confirm previous observations that amphetamine reduces locomotor hyperactivity caused by neonatal 6-OHDA administration and suggest that this effect is mediated by increased serotonergic neurotransmission.     

D(3) dopamine receptors are down-regulated in amphetamine sensitized rats and their putative antagonists modulate the locomotor sensitization to amphetamine

D(3) dopamine receptor agonists inhibit locomotor activity in rodents and modulate the reinforcing effect of psychostimulants; however, their functional role during behavioral sensitization remains unclear. In the present study, we intend to investigate if D(3) dopamine receptors alter during the amphetamine sensitization and test if manipulation of D(3) receptors would affect the development of locomotor sensitization to amphetamine. We have found that D(3) dopamine receptors are down-regulated in the limbic forebrain in chronic amphetamine-treated (5 mg/kg x 7 days) animals. The levels of both D(3) receptor protein (B(max) value) and mRNA decreased significantly in the behaviorally sensitized rats compared to the saline-treated controls. When animals were co-administered a putative D(3) receptor antagonist (U99194A or GR103691; 20 microg x 7 days; intracerebroventricle) and amphetamine (5 mg/kg x 7 days, i.p.), the locomotor sensitization to amphetamine was significantly inhibited. However, when the putative D(3) receptor antagonist U99194A was administered during the amphetamine withdrawal period at day 10, it did not affect the development of locomotor sensitization. Furthermore, pretreatment with the preferential D(3) agonist 7-hydroxydipropylaminotetralin partially blocked the inhibitory effect of U99194A on locomotor sensitization. These data prove the participation of D(3) dopamine receptors in the development of amphetamine sensitization and, in addition, suggest a potential application for D(3) antagonists in the prevention of amphetamine addiction.     

Repeated administration of dopaminergic agents in the nucleus accumbens and morphine-induced place preference

In the present study, the effects of repeated intra nucleus accumbens (intra-NAc) injections of dopamine receptor agents on morphine-induced conditioned place preference (CPP) in rats were investigated by using an unbiased 3-days schedule of place conditioning design. The animals receiving once daily subcutaneous (s.c.) injections of morphine (0.5-7.5mg/kg) or saline (1.0 ml/kg, s.c.) showed a significant place preference in a dose-dependent manner. The maximum response was observed with 5mg/kg of the opioid. Three days intra-NAc injections of apomorphine (0.5 and 1 microg/rat) followed by 5 days free of the drug, increased or decreased, respectively CPP induced by the lower dose of morphine (0.5mg/kg, s.c.). Morphine-induced CPP was also significantly increased in the animals that had previously received the 3-days intra-NAc injections of SKF 38393 (4 and 8 microg/rat) or quinpirole (2 and 4 microg/rat, intra-NAc). The CPP induced by a higher dose of morphine (5mg/kg, s.c.) was significantly decreased in the animals that had previously received the 3-days SCH 23390 (0.005 and 0.01 microg/rat; intra-NAc). On the other hand, the CPP induced by morphine (5mg/kg, s.c.) was significantly increased in the animals that had previously received the 3-days sulpiride administration (5 microg/rat, intra-NAc). The 3-days administration of apomorphine, SKF 38393 or quinpirole, but not SCH 23390 and sulpiride reduced the locomotor activity in the test session. It is concluded that repeated injections of dopamine receptors agents followed by 5 days free of the drugs in the NAc can affect morphine reward.     

AMPA antagonist LY293558 blocks the development, without blocking the expression, of behavioral sensitization to morphine

Morphine (3.0 mg/kg, s.c.) stimulates locomotor activity in rats, and this effect sensitizes with repeated intermittent treatment. We examined the ability of the AMPA antagonist LY293558, administered systemically over a range of doses (0.1-3.0 mg/kg), to alter morphine sensitization. Pretreatment with 3.0 mg/kg LY293558 attenuated the acute (session 1) locomotor-stimulating actions of morphine, whereas 1.0, 0.3, and 0.1 mg/kg were without effect. No sensitization was observed after repeated morphine treatment (3.0 mg/kg, s.c., every other day for 9 days) when morphine injections were preceded by 0.3, 1.0, or 3.0 mg/kg LY293558, whereas significant sensitization was observed when morphine injections were preceded by vehicle or 0.1 mg/kg of the antagonist. When all rats were challenged with morphine (3.0 mg/kg, s.c.) alone on day 11, the locomotor activity of rats previously exposed to LY293558 at 3.0, 1.0, or 0.3 mg/kg--but not at 0.1 mg/kg--was significantly lower than that of rats previously given morphine preceded by vehicle. On day 13, pretreatment with 1.0 mg/kg LY293558 failed to alter preestablished morphine sensitization in rats previously pretreated with vehicle. These data indicate that LY293558 blocks the development but not the expression of morphine sensitization, confirming a role for AMPA receptors in the initiation of neurobiological adaptations that occur with chronic morphine treatment.     

The psychogenetically selected Roman rat lines differ in the susceptibility to develop amphetamine sensitization

The mesolimbic dopamine system is considered to play a pivotal role in the locomotor activation produced by psychostimulants and in the augmentation of this effect observed upon repeated drug administration, a process denominated behavioral sensitization. The selective breeding of Roman high- (RHA) and low-avoidance (RLA) rats, respectively, for rapid versus poor active avoidance acquisition has resulted in two phenotypes that differ in the functional properties of the mesolimbic dopamine system and in their behavioral and neurochemical responses to addictive drugs, including psychostimulants and opiates. Hence, the present study was designed to compare the ability of these lines to develop behavioral sensitization to psychostimulants. To this aim, the acute effects of amphetamine (0.125 or 0.25 mg/kg, s.c.) on locomotion were assessed in RHA and RLA rats prior to and subsequent to 10 daily doses of either amphetamine (1 mg/kg, s.c.) or saline (1 ml/kg, s.c.). In the RHA line, the locomotor activation produced by either challenge dose of amphetamine was more pronounced in rats that had been repeatedly treated with amphetamine versus the respective saline treated controls. In contrast, no significant change in locomotor activity was observed in RLA rats. Likewise, repeated amphetamine caused an increased frequency of sniffing, rearing, licking/gnawing, and grooming versus the control, repeated saline, group only in the RHA line. The results show that the repeated treatment regimen used in this study induced behavioral sensitization to amphetamine in RHA rats, but not in their RLA counterparts, and underscore the utility of these lines for studying the influence of neural substrates and genetic make up on the individual vulnerability to addiction.     

When injected into the fimbria-fornix/cingular bundle, not in the raphe, 5,7-dihydroxytryptamine prevents amphetamine-induced hyperlocomotion

The locomotor effects of acute amphetamine treatment (1 mg/kg, i.p.) were assessed in Long-Evans rats after 5,7-dihydroxytryptamine (5, 7-DHT) injections into the fimbria-fornix/cingular bundle (FiFx/CB; 4 microg/side), or the dorsal and median raphe (Raphe; 10 microg). In control rats, amphetamine induced a significant increase of home-cage activity for about 2 h. This effect was similar in Raphe rats, but was absent in FiFx/CB rats. The raphe lesions reduced serotonin concentrations by 50% in the dorsal hippocampus, 75% in the ventral hippocampus and 58% in the fronto-parietal cortex. After FiFx/CB lesions, the reduction amounted 50, 61 and only 25%, in each of these regions, respectively. In the fronto-partietal cortex, dopamine concentration was significantly decreased in Raphe (-27%) and FiFx/CB rats (-65%). The results suggest that a serotonergic denervation of the hippocampus by injections of 5,7-DHT into the FiFx/CB pathways hampers the stimulating effects of amphetamine on locomotor activity. This effect might be related to the reduced dopaminergic tone in the fronto-parietal cortex.     

Neonatal immune system activation with lipopolysaccharide enhances behavioural sensitization to the dopamine agonist, quinpirole, in adult female but not male rats

Administration of the bacterial cell wall component, lipopolysaccharide (LPS), stimulates the immune and endocrine systems inducing an acute phase of sickness and stress responses in adult and neonatal rats. Neonatal LPS exposure has been shown to alter a variety of behavioural and physiological processes in the adult animal. Early developmental stress, such as maternal separation, causes similar acute as well as long-term behavioural changes in adults, including altered sensitivity to drugs of abuse. Moreover, results of studies have shown evidence of a direct link between immune activation and sensitivity to dopamine-based drugs of abuse. The current study examined the effects of neonatal LPS treatment on subsequent locomotor sensitization to the dopamine (D(2)/D(3)) agonist, quinpirole, in adult rats as an index of drug sensitivity. Male and female Long-Evans rats were treated systemically with either LPS (50microg/kg) or saline (0.9%) on postnatal days 3 and 5. Locomotor sensitization was then examined in the adult rats (postnatal day 70). Animals were injected with quinpirole (0.5mg/kg, s.c.) or saline every other day for a total of 10 injections and locomotor activity was assessed for 60min immediately following injections 1, 2, 4, 6, and 10. Animals also received a 'challenge' injection of 0.5mg/kg quinpirole 28 days after injection 10, to assess persistence of behavioural sensitization. Locomotor activity progressively increased with repeated administration of quinpirole, indicating locomotor sensitization in all of the drug-treated groups. There was an overall sex difference, with females showing significantly greater sensitization than males. Moreover, neonatal LPS treatment potentiated both the level and the rate of development of locomotor sensitization to quinpirole administration in females, but not in males. Thus, the current study revealed that neonatal exposure to bacterial infection increases dopamine (D(2)/D(3)) agonist sensitivity in a sex-specific manner. These findings have important implications for the sexually dimorphic development of addictions to both natural and artificial rewards.     

Differential sensitivity to lithium's reversal of amphetamine-induced open-field activity in two inbred strains of mice

To determine whether genetic differences could contribute to the pharmacological sensitivity of lithium chloride (LiCl) to reverse amphetamine-associated changes in behavior C57BL/6nCrlBR and C3H/HenCrlBR male mice were tested for the ability of an acute dose of LiCl to reverse the locomotor enhancing effects of an acute dose of amphetamine. A series of experiments were conducted that compared dose response of LiCl, chamber lighting conditions, and chamber shape on amphetamine-induced activity in two strains of mice with different genetic backgrounds. Acute amphetamine (3 mg/kg) increased locomotor activity in C57BL/6nCrlBR mice and LiCl (1-4 mEq/kg) blocked this effect. LiCl-induced changes in baseline activity seen at high doses of LiCl were not seen for the low doses. The dark condition reduced time resting but chamber shape did not appear to alter results. In C3H/HenCrlBR mice, amphetamine did not significantly increase levels of activity but did decrease rearing behavior which suggests that genetic difference between C57BL/6nCrlBR and C3H/HenCrlBR mice may contribute to sensitivity to amphetamine. In sum, the ability of LiCl to reverse amphetamine-induced changes in locomotor activity in C57BL/6nCrlBR mice may provide a useful model to study genetic and pharmacological aspects of psychiatric illnesses such as bipolar disorder.     

Repeated ventral tegmental area amphetamine administration alters dopamine D1 receptor signaling in the nucleus accumbens

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.     

Argon blocks the expression of locomotor sensitization to amphetamine through antagonism at the vesicular monoamine transporter-2 and mu-opioid receptor in the nucleus accumbens

We investigated the effects of the noble gas argon on the expression of locomotor sensitization to amphetamine and amphetamine-induced changes in dopamine release and mu-opioid neurotransmission in the nucleus accumbens. We found (1) argon blocked the increase in carrier-mediated dopamine release induced by amphetamine in brain slices, but, in contrast, potentiated the decrease in KCl-evoked dopamine release induced by amphetamine, thereby suggesting that argon inhibited the vesicular monoamine transporter-2; (2) argon blocked the expression of locomotor and mu-opioid neurotransmission sensitization induced by repeated amphetamine administration in a short-term model of sensitization in rats; (3) argon decreased the maximal number of binding sites and increased the dissociation constant of mu-receptors in membrane preparations, thereby indicating that argon is a mu-receptor antagonist; (4) argon blocked the expression of locomotor sensitization and context-dependent locomotor activity induced by repeated administration of amphetamine in a long-term model of sensitization. Taken together, these data indicate that argon could be of potential interest for treating drug addiction and dependence.     

Amphetamine dose dependently disrupts prepulse inhibition of the acoustic startle response in rats within a narrow time window

Prepulse inhibition (PPI) of the acoustic startle response refers to the reduction in startle amplitude when a weak prepulse precedes a startle-inducing pulse. Prepulse inhibition has been shown to be disrupted by amphetamine at doses that also stimulate locomotor activity, and it has been suggested that the same neuroanatomical substrate, mesolimbic dopamine activation, mediates the effects of amphetamine on locomotor activity and PPI. Amphetamine stimulates locomotor activity and mesolimbic dopamine release over a 1- to 3-h period, whereas PPI is typically measured within the first 30 min following amphetamine treatment. The present study therefore determined whether delays in testing would alter the PPI-disruptive effect of amphetamine in male Wistar rats. Amphetamine dose dependently disrupted PPI when the test session occurred 10 min following amphetamine treatment and only when the prepulse intensity was 5-10 dB above background. Delays of 40 and 60 min post-amphetamine injection, however, resulted in a loss of the ability of amphetamine to disrupt PPI although locomotor activity was significantly stimulated by amphetamine at these time points. The data from the present study therefore do not readily fit with the notion that the effects of amphetamine on locomotion and PPI are mediated by the same substrate.     

Locomotor sensitization to cocaine in rats with olfactory bulbectomy

Olfactory bulbectomy in rats has been suggested as a comprehensive animal model of affective disorders associated with an array of behavioral changes, responsivity to chronic antidepressant treatment, and alterations in limbic structures thought to be critical in the pathophysiology of affective disorders. Recent work showing increased motivational responsivity to amphetamine suggests that olfactory bulbectomy could also be a useful animal model of dual diagnosis disorders. To further investigate this possibility, we studied locomotor activity in olfactory bulbectomized rats 14 days postsurgery in response to novelty and upon acute and repeated injections of cocaine (15/mg/kg) or saline. Consistent with prior studies, lesioned animals showed greater locomotor activity in response to a novel environment and significantly heightened locomotor activation upon initial cocaine exposure. Over 7 days of repeated cocaine injections, lesioned animals also showed a presensitized pattern of activity, with a loss of incremental increases in locomotion observed in control animals. Daily saline injections produced no group differences in pre- or postinjection activity, while cocaine-treated bulbectomized rats demonstrated a decline in their daily preinjection activity. These results suggest that neural alterations caused by olfactory bulbectomy produce altered behavioral response patterns to repeated doses of cocaine, and support the study of olfactory bulbectomy as a useful neurobehavioral model for understanding substance use disorder comorbidity in mental illness.     

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.     

Association of the mesencephalic locomotor region with locomotor activity induced by injections of amphetamine into the nucleus accumbens

Injections of amphetamine into the nucleus accumbens increased locomotor activity of rats. Subsequent injections of procaine into the midbrain, in the region of the pedunculopontine nucleus, significantly reduced the amphetamine-induced locomotor activity. Control experiments showed that procaine injections into the contralateral pedunculopontine nucleus had little or no effect, as well as ipsilateral injections dorsal and ventral to the pedunculopontine nucleus. These findings suggest that release of dopamine from amphetamine injections into the accumbens gives rise to ipsilateral descending influences on the region of the pedunculopontine nucleus, a major component of the mesencephalic locomotor region. Descending influences from the nucleus accumbens to mesencephalic locomotor region may serve as a link for limbic-motor integration in behavioral response initiation.     

Behavioral effects of neonatal and adult excitotoxic lesions of the mediodorsal thalamus in the adult rat

We examined in the rat, the effects of neonatal (postnatal Day 7) and adult excitotoxic lesions of the mediodorsal thalamus (MDT), a brain area innervating the prefrontal cortex and implicated as a site of neuropathology in schizophrenia. Previous studies showed that rats with neonatal excitotoxic damage of the ventral hippocampus (VH), used as an animal model of this disorder, display in young adulthood a variety of abnormalities reminiscent of schizophrenia, including hyperactivity to stressful stimuli and amphetamine. It has been speculated that behavioral abnormalities of the neonatally VH lesioned animals are mediated through MDT projections to the prefrontal cortex. We tested if rats with ibotenic acid (1.5 microg per hemisphere in neonates, 2 microg in adults) lesions of MDT exhibited motor hyperactivity in the same experimental conditions (i.e. in response to novelty, saline injections and amphetamine administration) as rats with the VH lesions. We found that, in contrast to rats with VH lesions, neonatally lesioned MDT rats showed reduced vertical activity in response to amphetamine and no changes in locomotor activity to novelty, saline or amphetamine injections 7 weeks postlesion. Adult lesioned MDT rats exhibited no changes in motor activity as compared to controls at 7 weeks postlesion. These results indicate that neonatal or adult excitotoxic lesions of MDT do not produce behavioral changes analogous to those seen after neonatal VH lesions and do not appear to reproduce animal model-like features of schizophrenia.     

CCK2 receptor-deficient mice have increased sensitivity of dopamine D2 receptors

The present study supports a role of CCK(2) receptors in the regulation of dopamine neurones. In pharmacological studies conducted on male CCK(2) receptor-deficient mice the changes in the activity of dopamine system were established. A low dose of dopamine agonist apomorphine (0.1 mg/kg), stimulating the pre-synaptic dopamine receptors, induced significantly stronger suppression of locomotor activity in mutant mice (-/-) compared to their wild-type littermates (+/+). The administration of amphetamine (3-6 mg/kg), a drug increasing dopamine release, caused a dose-dependent stimulation of locomotor activity in wild-type mice. In mice lacking CCK(2) receptors, a lower dose of amphetamine (3 mg/kg) tended to suppress the motor activity, whereas the higher dose (6 mg/kg) induced the significantly stronger motor stimulation in mutant mice. Moreover, in the CCK(2) receptor-deficient mice the affinity of dopamine D(2) receptors, but not 5-HT(2) receptors, was increased. Altogether, the targeted genetic suppression of CCK(2) receptors increased the sensitivity of pre- and post-synaptic dopamine D(2) receptors.     

Excitotoxic lesions of the prefrontal cortex attenuate the potentiation of amphetamine-induced locomotion by repeated neurotensin receptor activation

This study was aimed at determining the role of prefrontal cortex neurons in the development of the potentiation of amphetamine-induced locomotor activity by repeated central injections of D-Tyr[11]neurotensin. Excitotoxic lesions of the prefrontal cortex were made by injecting bilaterally at three anterior-posterior placements 2 microg/microl of ibotenic acid. Ten days after surgery, locomotor responses to an intracerebroventricular injection of 0.18 or 18 nmol/10 microl of D-Tyr[11]neurotensin, or vehicle-saline, were measured in different groups of lesioned and sham rats. Ambulatory, non-ambulatory and vertical movements were measured for 2 h in activity cages starting immediately after the injection. This training phase was repeated on four occasions, every second day. One week after the last day of the training phase (day 14), locomotor responses to a single injection of amphetamine (0.75 mg/kg, IP) were measured in all rats. Results show that D-Tyr[11]neurotensin produced in sham animals a dose-dependent initial suppression of locomotor activity followed by an augmentation. The latter behavioral effect tended to be smaller in the lesioned rats, but not statistically different than in sham, suggesting that prefrontal cortex neurons do not play a major role in the stimulant effect of neurotensin on locomotor activity. However, sham rats pre-exposed to the high dose of D-Tyr[11]neurotensin showed stronger non-ambulatory and vertical movements than saline pre-exposed rats when tested with amphetamine; this sensitization effect was not observed in lesioned rats. The present results show that prefrontal cortex neurons are part of the neural circuitry involved in the development of amphetamine sensitization by repeated activation of central neurotensin receptors.     

Intra-accumbens protein kinase C inhibitor NPC 15437 blocks amphetamine-produced conditioned place preference in rats

In a previous study, intracerebroventricular calcium-dependent protein kinase (PKC) inhibition attenuated cocaine place conditioning. This suggested the hypothesis that intra-nucleus accumbens (NAc) injections of the PKC inhibitor NPC 15437 may block place conditioning produced by NAc injections of amphetamine. An unbiased conditioned place preference paradigm was employed to evaluate the present hypothesis. Thus, during pre-conditioning rats had access to an apparatus consisting of two chambers connected by a tunnel for three 15-min sessions. During 8 conditioning days with the tunnel blocked, one chamber was paired with NAc injections of drug for four 30-min sessions alternating with pairing of the other chamber with NAc injections of saline. Time spent on the drug-paired side was assessed in a final drug-free test session and compared to the amount of time spent there in pre-conditioning; a significant increase was defined as a place preference. Intra-NAc amphetamine (20.0 microg/0.5 microl/side) produced a place preference. This effect was blocked dose dependently by NPC 15437 (0.1, 0.5 and 1.0 microg/0.5 microl/side). NPC 15437 (1.0 microg) alone did not produce a place preference or aversion. None of the doses of NPC 15437 affected the locomotor stimulant effect of intra-NAc amphetamine during conditioning revealing a dissociation between the locomotor stimulating and rewarding effects of intra-NAc amphetamine. Results implicate PKC in the NAc in reward-related learning. More work is needed to elucidate the signaling pathways involved in this type of learning.     

Differential effects of limbic versus striatal dopamine loss on motoric function

Bilateral 6-hydroxydopamine injections into either the ventral tegmental area, or the substantia nigra pars compacta in rats, produced severe losses of dopamine in the nucleus accumbens-olfactory tubercle and striatum respectively. After 1 and 3 months postoperation, the depletion of limbic dopamine was associated with reduced spontaneous locomotor activity, which was enhanced by apomorphine (0.125 mg/kg), but not amphetamine (1.0 mg/kg). The severe loss of striatal dopamine had no persistent effect on spontaneous or d-amphetamine-induced locomotor activity, but did produce a persistent augmentation of rigidity. Although there was considerable recovery, both lesions chronically increased catalepsy scores. The results of this study suggested that limbic dopamine deficits may be important in initiation of movement; whereas, striatal dopamine deficits may contribute more to the rigidity aspects of Parkinsonism.