Abnormal error processing in depressive states: a translational examination in humans and rats.

Depression has been associated with poor performance following errors, but the clinical implications, response to treatment and neurobiological mechanisms of this post-error behavioral adjustment abnormality remain unclear. To fill this gap in knowledge, we tested depressed patients in a partial hospital setting before and after treatment (cognitive behavior therapy combined with medication) using a flanker task. To evaluate the translational relevance of this metric in rodents, we performed a secondary analysis on existing data from rats tested in the 5-choice serial reaction time task after treatment with corticotropin-releasing factor (CRF), a stress peptide that produces depressive-like signs in rodent models relevant to depression. In addition, to examine the effect of treatment on post-error behavior in rodents, we examined a second cohort of rodents treated with JDTic, a kappa-opioid receptor antagonist that produces antidepressant-like effects in laboratory animals. In depressed patients, baseline post-error accuracy was lower than post-correct accuracy, and, as expected, post-error accuracy improved with treatment. Moreover, baseline post-error accuracy predicted attentional control and rumination (but not depressive symptoms) after treatment. In rats, CRF significantly degraded post-error accuracy, but not post-correct accuracy, and this effect was attenuated by JDTic. Our findings demonstrate deficits in post-error accuracy in depressed patients, as well as a rodent model relevant to depression. These deficits respond to intervention in both species. Although post-error behavior predicted treatment-related changes in attentional control and rumination, a relationship to depressive symptoms remains to be demonstrated.

Pitx3-deficient aphakia mice display unique behavioral responses to psychostimulant and antipsychotic drugs.

The dorsal (A9) and ventral striatum (A10) of the midbrain mediate many of the effects of psychoactive drugs that alter emotion, cognition, and motor activity within the contexts of therapy or abuse. Although transgenic and knockout technologies have enabled development of genetic models to dissect contributions of specific dopamine (DA) receptor subtypes to psychoactive drug effects, few models exist that can distinguish contributions of A9 versus A10 circuits. Pitx3 is a transcription factor enriched in DA neurons. Aphakia (ak) mice deficient in Pitx3 show selective loss of nigrostriatal DA, while other DA pathways are relatively spared, and therefore could be a useful tool for investigating the role of this subclass of DA projections. We investigated the effects of stimulants amphetamine, apomorphine, and MK-801 and the antipsychotic drug haloperidol on behavior in ak mice. Whereas wild-type mice showed the characteristic locomotor hyperactivity in response to amphetamine (5 mg/kg) and apomorphine (4 mg/kg), these drugs caused a paradoxical suppression of locomotor hyperactivity in ak mice. MK-801 (0.2 mg/kg) induced hyperactivity was maintained in both wt and ak mice. Additionally, mutant but not wild-type mice were insensitive to the cataleptic effects of haloperidol (1 mg/kg). These studies indicate that the nigrostriatal DA circuit plays a critical role in maintaining normal responsiveness to psychotropic drugs that either stimulate or block DA neurotransmission. We propose that ak mice may represent a valuable genetic model not only to study Parkinson's disease, but also to dissect the pathophysiologic and pharmacotherapuetic mechanisms of other DA-mediated disorders such as attention-deficit hyperactivity disorder, drug abuse and schizophrenia.

Altered responsiveness to cocaine and increased immobility in the forced swim test associated with elevated cAMP response element-binding protein expression in nucleus accumbens.

Drugs of abuse regulate the transcription factor cAMP response element-binding protein (CREB) in striatal regions, including the nucleus accumbens (NAc). To explore how regulation of CREB in the NAc affects behavior, we used herpes simplex virus (HSV) vectors to elevate CREB expression in this region or to overexpress a dominant-negative mutant CREB (mCREB) that blocks CREB function. Rats treated with HSV-mCREB in place conditioning studies spent more time in environments associated with cocaine, indicating increased cocaine reward. Conversely, rats treated with HSV-CREB spent less time in cocaine-associated environments, indicating increased cocaine aversion. Studies in which drug-environment pairings were varied to coincide with either the early or late effects of cocaine suggest that CREB-associated place aversions reflect increased cocaine withdrawal. Because cocaine withdrawal can be accompanied by symptoms of depression, we examined how altered CREB function in the NAc affects behavior in the forced swim test (FST). Elevated CREB expression increased immobility in the FST, an effect that is opposite to that caused by standard antidepressants and is consistent with a link between CREB and dysphoria. Conversely, overexpression of mCREB decreased immobility, an effect similar to that caused by antidepressants. Moreover, the kappa opioid receptor antagonist nor-Binaltorphimine decreased immobility in HSV-CREB- and HSV-mCREB-treated rats, suggesting that CREB-mediated induction of dynorphin (an endogenous kappa receptor ligand) contributes to immobility behavior in the FST. Exposure to the FST itself dramatically increased CREB function in the NAc. These findings raise the possibility that CREB-mediated transcription within the NAc regulates dysphoric states.

A high-efficiency synthetic promoter that drives transgene expression selectively in noradrenergic neurons.

Gene promoter systems that drive high-level, long-term, and cell-specific transgene expression are of great interest because of their potential utility for gene therapy. To generate an efficient promoter system specific for noradrenergic (NA) neurons, we multimerized an NA-specific cis-regulatory element (PRS2) identified in the human dopamine beta-hydroxylase (hDBH) promoter, and combined it with a minimal promoter (containing a TATA box and transcription start site). Forms of this synthetic promoter that contain 8 or more copies of PRS2 were >50 times more effective than the 1.15-kb hDBH promoter at driving reporter gene expression in cell lines originated from NA neurons. Neither the synthetic promoter nor the 1.15-kb hDBH promoter drove reporter gene expression in nonneuronal cells. Microinjections of an adenoviral vector containing the synthetic promoter directly into rat brain caused more strict NA-specific reporter gene expression than that caused by a vector containing the 1.15-kb hDBH promoter when the targeted region contained large numbers of NA neurons (locus coeruleus). Furthermore, the vector containing the synthetic promoter caused less nonspecific ("leaky") reporter gene expression than that caused by the vector containing the 1.15-kb hDBH promoter when the targeted region was devoid of NA neurons (cerebellum, dentate gyrus). Together, these studies provide in vitro and in vivo evidence that this novel synthetic promoter can target transgene expression to NA neurons even more efficiently and selectively than the naturally occurring, 1.15-kb hDBH promoter.

Repeated exposure to rewarding brain stimulation downregulates GluR1 expression in the ventral tegmental area.

There is considerable evidence that drug reward and brain stimulation reward (BSR) share common neural substrates. Although it is known that exposure to drugs of abuse causes a variety of molecular changes in brain reward systems, little is known about the molecular consequences of BSR. We report that repeated exposure to rewarding stimulation of the medial forebrain bundle (MFB) selectively decreases expression of GluR1 (an AMPA receptor subunit) in the VTA, without effect on expression of several other proteins (GluR2, NMDAR1, tyrosine hydroxylase). This effect of BSR on GluR1 expression is opposite of that caused by intermittent exposure to cocaine and morphine, which are known to elevate GluR1 expression in the VTA. Considering that elevated GluR1 expression in the VTA has been associated with increased sensitivity to drug reward, the finding that BSR and drugs of abuse have opposite effects on GluR1 expression in this region may provide an explanation for why the reward-related effects of many drugs (cocaine, morphine, amphetamine, PCP, nicotine) do not sensitize with repeated testing in BSR procedures that quantify reward strength.

Long-term memory is facilitated by cAMP response element-binding protein overexpression in the amygdala.

At least two temporally and mechanistically distinct forms of memory are conserved across many species: short-term memory that persists minutes to hours after training and long-term memory (LTM) that persists days or longer. In general, repeated training trials presented with intervening rest intervals (spaced training) is more effective than massed training (the same number of training trials presented with no or short intervening rest intervals) in producing LTM. LTM requires de novo protein synthesis, and cAMP response element-binding protein (CREB) may be one of the transcription factors regulating the synthesis of new proteins necessary for the formation of LTM. Here we show that rats given massed fear conditioning training show no or weak LTM, as measured by fear-potentiated startle, compared with rats given the same amount of training but presented in a spaced manner. Increasing CREB levels specifically in the basolateral amygdala via viral vector-mediated gene transfer significantly increases LTM after massed fear training. The enhancing effect of CREB overexpression on LTM formation is shown to be specific in terms of biochemistry, anatomy, time course, and the training procedure used. These results suggest that CREB activity in the amygdala serves as a molecular switch for the formation of LTM in fear conditioning.

Behavioral interactions caused by combined administration of morphine and MK-801 in rats.

RATIONALE: The NMDA antagonist MK-801 reportedly blocks experience-dependent changes in sensitivity to morphine, including tolerance to its analgesic actions and sensitization to its locomotor-stimulating effects. However, evidence in the existing literature suggests that some of MK-801's effects are additive (or synergistic) with those of morphine. OBJECTIVES: Experiments were conducted to characterize the effects of acute and repeated administration of the combination of MK-801 and morphine on analgesia, locomotor activity, and drug discrimination in rats. METHODS: In each experiment, rats were first tested repeatedly after treatment with the combination of MK-801 and morphine, and then after treatment with either drug alone. RESULTS: The analgesic effects of MK-801 combined with morphine were greater than those of morphine alone, but tolerance to the combination of drugs developed at a similar rate as to morphine alone. The locomotor-stimulating effects of MK-801 combined with morphine were also greater than those of either drug alone, and locomotor sensitization developed to the combination of drugs but not to either drug alone at the low doses used. Rats learned to discriminate a combination of MK-801 and morphine from vehicle as quickly as they learned to discriminate morphine alone from vehicle, but those trained with the combination of MK-801 and morphine responded primarily at the vehicle-appropriate lever when given either drug alone. CONCLUSIONS: Since behavioral adaptations readily occur in the presence of MK-801, it appears that NMDA antagonists fail to invariably block the cellular plasticity that underlies such adaptations. Rather, the expression of adaptations in drug sensitivity appears related, at least in part, to the continued presence of the discriminative stimulus cues that are present during conditioning. Although NMDA receptors are important for some forms of cellular plasticity, the present studies illustrate the difficulty in interpreting behavioral studies in which MK-801 is given with morphine.

Role for GDNF in biochemical and behavioral adaptations to drugs of abuse.

The present study examined a role for GDNF in adaptations to drugs of abuse. Infusion of GDNF into the ventral tegmental area (VTA), a dopaminergic brain region important for addiction, blocks certain biochemical adaptations to chronic cocaine or morphine as well as the rewarding effects of cocaine. Conversely, responses to cocaine are enhanced in rats by intra-VTA infusion of an anti-GDNF antibody and in mice heterozygous for a null mutation in the GDNF gene. Chronic morphine or cocaine exposure decreases levels of phosphoRet, the protein kinase that mediates GDNF signaling, in the VTA. Together, these results suggest a feedback loop, whereby drugs of abuse decrease signaling through endogenous GDNF pathways in the VTA, which then increases the behavioral sensitivity to subsequent drug exposure.

Distinct sites of opiate reward and aversion within the midbrain identified using a herpes simplex virus vector expressing GluR1.

Repeated administration of morphine increases expression of GluR1 (an AMPA glutamate receptor subunit) in the ventral tegmental area (VTA) of the midbrain, an important neural substrate for the rewarding actions of morphine. Microinjections of a herpes simplex virus (HSV) vector that causes local overexpression of GluR1 (HSV-GluR1) into the VTA can enhance the ability of morphine to establish conditioned place preferences, suggesting that altered GluR1 expression in this region is directly associated with changes in the rewarding efficacy of morphine. We now report that in rats given HSV-GluR1 directly into the VTA, morphine is most rewarding when maximal transgene expression is in the rostral VTA, whereas morphine is aversive when maximal transgene expression is in the caudal VTA. Dual-labeling immunohistochemistry shows that this difference cannot be explained by a different fraction of dopaminergic neurons infected in the rostral versus caudal VTA. No such anatomical specificity is seen in rats given VTA microinjections of HSV-LacZ, a vector expressing a control protein (-galactosidase). These results suggest that distinct substrates within the VTA itself differentially contribute to the rewarding and aversive properties of opiates.

Herpes simplex virus-mediated gene transfer as a tool for neuropsychiatric research.

There is an enormous initiative to establish causal relationships between brain biology (including patterns of gene expression) and behavior. Unfortunately, genetic intervention is not accomplished easily in the brain. One strategy is to engineer and deliver to the brain specialized viral vectors that carry a gene (or genes) of interest, thereby exploiting the natural ability of viruses to insert genetic information into cells. When delivered to the brain, these vectors cause infected cells to increase expression of the genes of interest. Viral vectors are particularly useful when the goal is to manipulate expression of a single gene in a specific brain region, at a specific time, and in animals that developed normally. There are several types of virus that can be adapted for use as viral vectors, including those based on herpes simplex virus (HSV-1), adenovirus (AV), adeno-associated virus (AAV), and lentivirus. Although each vector has its own unique advantages and disadvantages, this rapidly evolving technology has the potential to revolutionize neuropsychiatric research by offering the opportunity to establish, with anatomical and temporal specificity, causal relations between altered expression of individual gene products and alterations in complex behavior.

Expression of the transcription factor deltaFosB in the brain controls sensitivity to cocaine.

Acute exposure to cocaine transiently induces several Fos family transcription factors in the nucleus accumbens, a region of the brain that is important for addiction. In contrast, chronic exposure to cocaine does not induce these proteins, but instead causes the persistent expression of highly stable isoforms of deltaFosB. deltaFosB is also induced in the nucleus accumbens by repeated exposure to other drugs of abuse, including amphetamine, morphine, nicotine and phencyclidine. The sustained accumulation of deltaFosB in the nucleus accumbens indicates that this transcription factor may mediate some of the persistent neural and behavioural plasticity that accompanies chronic drug exposure. Using transgenic mice in which deltaFosB can be induced in adults in the subset of nucleus accumbens neurons in which cocaine induces the protein, we show that deltaFosB expression increases the responsiveness of an animal to the rewarding and locomotor-activating effects of cocaine. These effects of deltaFosB appear to be mediated partly by induction of the AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole) glutamate receptor subunit GluR2 in the nucleus accumbens. These results support a model in which deltaFosB, by altering gene expression, enhances sensitivity to cocaine and may thereby contribute to cocaine addiction.

Region-specific induction of deltaFosB by repeated administration of typical versus atypical antipsychotic drugs.

Whereas acute administration of many types of stimuli induces c-Fos and related proteins in brain, recent work has shown that chronic perturbations cause the region-specific accumulation of novel Fos-like proteins of 35-37 kD. These proteins, termed chronic FRAs (Fos-related antigens), have recently been shown to be isoforms of DeltaFosB, which accumulate in brain due to their enhanced stability. In the present study, we sought to extend earlier findings that documented the effects of acute administration of antipsychotic drugs (APDs) on induction of Fos-like proteins by investigating the ability of typical and aytpical APDs, after chronic administration, to induce these DeltaFosB isoforms in several brain regions implicated in the clinical actions of these agents. By Western blotting we found that chronic administration of the typical APD, haloperidol, dramatically induces DeltaFosB in caudate-putamen (CP), a brain region associated with the extrapyramidal side effects of this drug. A smaller induction was seen in the nucleus accumbens (NAc) and prefrontal cortex (PFC), brain regions associated with the antipsychotic effects of the drug. In contrast, chronic administration of the prototype atypical APD clozapine failed to significantly increase levels of DeltaFosB in any of the three brain regions, and even tended to reduce DeltaFosB levels in the NAc. Two putative atypical APDs, risperidone and olanzapine, produced small but still significant increases in the levels of DeltaFosB in CP, but not NAc or PFC. Studies with selective receptor antagonists suggested that induction of DeltaFosB in CP and NAc is most dependent on antagonism of D2-D3 dopamine receptors, with antagonism of D1-like receptors most involved in the PFC. Immunohistochemical analysis confirmed the greater induction of DeltaFosB in CP by typical versus atypical APDs, with no significant induction seen in PFC with either class of APD. Together, these findings demonstrate that repeated administration of APDs results in the induction of long-lasting Fos-like transcription factors that could mediate some of the persistent and region-specific changes in brain function associated with chronic drug exposure. Synapse 33:118-128, 1999.

Dark Agouti and Fischer 344 rats: differential behavioral responses to morphine and biochemical differences in the ventral tegmental area.

We sought to identify behavioral and biochemical differences between Dark Agouti and Fischer 344 inbred rat strains to assess whether they could serve as a model of genetically determined differences in sensitivity to drugs of abuse. We compared the strains for the following traits: morphine-induced locomotor activity and sensitization; circadian variation in plasma levels of corticosterone, a hormone reported to affect sensitivity to drugs of abuse; and several biochemical parameters in the ventral tegmental area and nucleus accumbens, brain regions implicated in the locomotor activating and reinforcing actions of drugs of abuse. Fischer 344 rats exhibited greater initial locomotor responses to morphine but, unlike Dark Agouti rats, did not develop sensitization to a second morphine exposure. Fischer 344 rats displayed a marked rise in basal plasma corticosterone levels in the late light phase and early dark phase, whereas Dark Agouti rats showed no significant circadian variation in corticosterone levels. Relative to drug-naive Fischer 344 rats, drug-naive Dark Agouti rats showed higher levels of tyrosine hydroxylase and glial fibrillary acidic protein, and lower levels of neurofilament proteins, in the ventral tegmental area. In contrast, no strain differences were found in levels of tyrosine hydroxylase, specific G protein subunits or protein kinase A in the nucleus accumbens. Together, these results demonstrate that Dark Agouti rats and Fischer 344 rats exhibit differences in specific behavioral, endocrine and biochemical parameters related to sensitivity to drugs of abuse.

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.

Regulation of cocaine reward by CREB.

Cocaine regulates the transcription factor CREB (adenosine 3', 5'-monophosphate response element binding protein) in rat nucleus accumbens, a brain region that is important for addiction. Overexpression of CREB in this region decreases the rewarding effects of cocaine and makes low doses of the drug aversive. Conversely, overexpression of a dominant-negative mutant CREB increases the rewarding effects of cocaine. Altered transcription of dynorphin likely contributes to these effects: Its expression is increased by overexpression of CREB and decreased by overexpression of mutant CREB. Moreover, blockade of kappa opioid receptors (on which dynorphin acts) antagonizes the negative effect of CREB on cocaine reward. These results identify an intracellular cascade-culminating in gene expression-through which exposure to cocaine modifies subsequent responsiveness to the drug.

Genetic analysis of behavioral, neuroendocrine, and biochemical parameters in inbred rodents: initial studies in Lewis and Fischer 344 rats and in A/J and C57BL/6J mice.

Previous work has identified inherent behavioral, neuroendocrine, and biochemical differences among inbred rodent strains that have been related to the animals' differential responsiveness to drugs of abuse or stress. In the present study, we sought to determine (1) whether there are genetic correlations among particular phenotypic traits that differ between a pair of inbred rat strains (Lewis and Fischer 344) or a pair of inbred mouse strains (A/J and C57BL/6J); (2) which of these traits might be amenable to quantitative trait locus analysis; and (3) whether additional behavioral or biochemical differences relevant to drug- or stress-responsiveness could be identified in these strains. Specifically, we measured several behavioral, neuroendocrine, and biochemical traits in parental Lewis and Fischer 344 rats and in 298 members of an F2 intercross population, as well as in parental A/J and C57BL/6J mice and in 11 of the AXB/BXA recombinant inbred mouse strains. Traits measured included exploratory locomotor activity in a novel environment; amphetamine-induced locomotor activity; several specific protein levels in striatal regions, including inhibitory G protein subunits, the dopamine transporter, the Fos family member transcription factor DeltaFosB, and the protein phosphatase inhibitor DARPP-32; and late-afternoon plasma corticosterone concentrations. Each of the traits measured in F2 rats or recombinant inbred mice appears to be influenced by multiple genes, as well as by environmental factors. There were statistically significant, albeit relatively weak, correlations among several traits in an F2 intercross population bred from Lewis and Fischer rats. Among the traits studied in Lewis and Fischer rats, one seemed most amenable to quantitative trait locus analysis: the level of the inhibitory G-protein subunit, Galphai, in the nucleus accumbens. We also found a robust genetic correlation between levels of DeltaFosB and levels of the dopamine transporter in striatal regions in AXB/BXA recombinant inbred mouse strains. While these studies demonstrate the likely complexity of the genetic factors that influence the numerous phenotypes associated with altered responsiveness to drugs of abuse and stress, they represent an initial and necessary step toward identifying specific genetic factors involved.

Sensitization to morphine induced by viral-mediated gene transfer.

Repeated administration of morphine sensitizes animals to the stimulant and rewarding properties of the drug. It also selectively increases expression of GluR1 (an AMPA glutamate receptor subunit) in the ventral tegmental area, a midbrain region implicated in morphine action. By viral-mediated gene transfer, a causal relation is shown between these behavioral and biochemical adaptations: Morphine's stimulant and rewarding properties are intensified after microinjections of a viral vector expressing GluR1 into the ventral tegmental area. These results confirm the importance of AMPA receptors in morphine action and demonstrate specific locomotor and motivational adaptations resulting from altered expression of a single localized gene product.

Microinjections of phencyclidine (PCP) and related drugs into nucleus accumbens shell potentiate medial forebrain bundle brain stimulation reward.

Microinjections of phencyclidine (PCP) into the ventro-medial portion of nucleus accumbens in rats potentiated the rewarding impact of lateral hypothalamic brain stimulation. Similar effects were found with nomifensine, which shares with PCP the ability to block dopamine uptake and thus elevate synaptic dopamine levels but does not share with PCP the ability to block NMDA receptors. Similar effects were also seen with dizocilpine (MK-801) and [3-((+/-)2-carboxypiperazin-4-yl)propyl-1-phosphonate] (CPP), which share with PCP the ability to block NMDA receptors but not to block dopamine uptake. Thus PCP's properties as a dopamine uptake inhibitor and as an NMDA receptor antagonist each appear capable of producing reward-related actions in this brain region. The common denominator of these two PCP actions is decreased output of medium spiny neurons; these neurons are tonically activated by a glutamate projection from prefrontal cortex (PCP blocks this source of activation) and are tonically inhibited by a dopaminergic projection from the ventral tegmental area (PCP augments this inhibition).

Rewarding actions of phencyclidine and related drugs in nucleus accumbens shell and frontal cortex.

Rats learned to lever-press when such behavior was reinforced by microinjections of phencyclidine (PCP) directly into the ventromedial (shell) region of nucleus accumbens, indicating that the drug has direct rewarding actions in that region. Separate groups of rats learned to lever-press when reinforced with microinjections of dizoclipine (MK-801) or 3-((+/-)2-carboxypiperazin-4yl)propyl-1-phosphate (CPP), drugs known to block NMDA receptor function but not dopamine uptake, into the same region. Each drug was ineffective or markedly less effective when injected at a slightly more dorsal and lateral site in the core of nucleus accumbens. Self-administration of PCP, MK-801, or CPP directly into nucleus accumbens was not altered by co-infusion of a dose of the dopamine antagonist sulpiride that effectively blocked intracranial self-administration of the dopamine uptake inhibitor nomifensine, suggesting that the rewarding actions of the NMDA receptor antagonists are not dopamine-dependent. Rats also developed lever-pressing habits when PCP, MK-801, and CPP were each microinjected directly into frontal cortex, a region previously associated with the rewarding actions of cocaine but not nomifensine. Thus nucleus accumbens and frontal cortex are each potential substrates for the rewarding properties of PCP and related drugs, and the ability of these drugs to disrupt NMDA receptor function seems sufficient to account for their rewarding actions. When considered with independent evidence, the present results suggest a model of drug reward within which the critical event is inhibition of medium spiny neurons in nucleus accumbens.

MK-801 (dizocilpine): synergist and conditioned stimulus in bromocriptine-induced psychomotor sensitization.

Intraperitoneal injections of the D2/D3 dopamine agonist bromocriptine (5.0 mg/kg, IP) induced locomotion that became progressively stronger on successive days of testing. The sensitized response developed twice as rapidly when the non-competitive NMDA antagonist MK-801 (0.25 mg/kg, IP) was given 30 min after bromocriptine (so that the peak effects of the two drugs overlapped). In a second group of animals, MK-801 was given 30 min prior to bromocriptine (the pretreatment regimen typical of studies where MK-801 is reported to block cocaine, amphetamine or morphine sensitization) and locomotion was monitored during the pretreatment period; in this case sensitization to the locomotor-stimulating effects of MK-801 alone (in the pretreatment period) as well as sensitization to the locomotor-stimulating effects of the drug combination (following the second injection) were observed. No sensitization to the effects of MK-801 alone (pretreatment) were seen in animals that received saline rather than bromocriptine as their second injection in this experiment. Thus MK-801 does not block but rather enhances bromocriptine sensitization; it appears to do so by a synergism with the locomotor effects of bromocriptine and by becoming a conditioned stimulus for the sensitized response. These findings confirm the earlier report that NMDA receptor activation is not critical to bromocriptine-induced sensitization, and they illustrate the importance of controls for conditioning and state-dependency phenomena in studies of drug interactions in psychomotor sensitization.