Effects of cortical and striatal dopamine D1 receptor blockade on cued versus noncued behavioral responses.

Various lines of evidence suggest that disruptions in brain dopamine (DA) transmission produce behavioral impairments that can be overcome by salient response-eliciting environmental stimuli. We examined here whether D1 receptor blockade within striatal or frontal cortical DA target regions would differentially affect head entry responses elicited by an auditory cue compared with those occurring during noncued intertrial intervals. Rats received 2 drug-free 28-trial daily sessions in which an auditory cue was immediately followed by food delivery. On the following day, separate groups of rats received bilateral infusions of D1 antagonist SCH23390 to the dorsomedial striatum (DMS), nucleus accumbens (NAcc) core, or the medial prefrontal cortex (mPFC). SCH23390 infused into the DMS and NAcc core suppressed noncued head entries but had no effect on head entries in response to the auditory cue. SCH23390 infused to the mPFC did not reduce either cued or noncued approach responses. Systemic administration of the drug, in contrast, reduced the frequency of both cued and noncued approaches. The results are consistent with the notion that has emerged from the Parkinson's literature that reduced DA transmission produces behavioral suppression that can be overcome by salient environmental response elicitors, and extends this notion by showing that D1 receptor transmission within the striatum strongly suppresses noncued responses while leaving the identical behavior intact when cued by an environmental stimulus.

Dopamine D1 and D2 antagonist effects on response likelihood and duration.

Experimentally induced and parkinsonian disruptions in dopamine (DA) transmission are associated with motor abnormalities that include a reduced likelihood of behavioral response initiation and an increased duration of executed responses. Here we investigated the dopamine receptor subtypes involved in regulating these two aspects of behavior. We examined the effects of D1 family (D1/D5) antagonist R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SCH23390; 0, 0.04, 0.08, or 0.16 mg/kg) and D2/D3 antagonist 3,5-dichloro-N-(1-ethylpyrrolidin-2-ylmethyl)-2-hydroxy-6-methoxybenzamide (+)-tartrate salt (raclopride; 0, 0.2, or 0.4 mg/kg) on the likelihood and duration of a cued Pavlovian approach and a cued operant lever-press response. While the high doses of the D1 and D2 antagonists produced similar levels of overall locomotor suppression, only the D2 antagonist increased the duration of time that animals' heads remained in the food compartment during both Pavlovian and operant task performance. In contrast, D1 antagonist SCH23390 decreased the proportion of trials in which animals executed both the Pavlovian approach and operant lever-press, while raclopride did not. The results suggest that D2 receptor blockade preferentially increases response duration, and, under the simple discrete-trial procedures employed here, D1 receptor blockade preferential reduces Pavlovian and operant response likelihood.

A "good parent" function of dopamine: transient modulation of learning and performance during early stages of training.

While extracellular dopamine (DA) concentrations are increased by a wide category of salient stimuli, there is evidence to suggest that DA responses to primary and conditioned rewards may be distinct from those elicited by other types of salient events. A reward-specific mode of neuronal responding would be necessary if DA acts to strengthen behavioral response tendencies under particular environmental conditions or to set current environmental inputs as goals that direct approach responses. As described in this review, DA critically mediates both the acquisition and expression of learned behaviors during early stages of training, however, during later stages, at least some forms of learned behavior become independent of (or less dependent upon) DA transmission for their expression.

Visual search deficits in Parkinson's disease are attenuated by bottom-up target salience and top-down information.

Patients with Parkinson's disease (PD), a degenerative disorder primarily affecting the nigrostriatal dopamine system, exhibit deficits in selecting task-relevant stimuli in the presence of irrelevant stimuli, such as in visual search tasks. However, results from previous studies suggest that these deficits may vary as a function of whether selection must rely primarily on the "bottom-up" salience of the target relative to background stimuli, or whether "top-down" information about the identity of the target is available to bias selection. In the present study, moderate-to-severe medicated PD patients and age-matched controls were tested on six visual search tasks that systematically varied the relationship between bottom-up target salience (feature search, noisy feature search, conjunction search) and top-down target knowledge (Target Known versus Target Unknown). Comparison of slope and intercepts of the RT x set size function provided information about the efficiency of search and non-search (e.g., decision, response) components, respectively. Patients exhibited higher intercepts than controls as bottom-up target salience decreased, however these deficits were disproportionately larger under Target Unknown compared to Target Known conditions. Slope differences between PD and controls were limited to the Target Unknown Conjunction condition, where patients exhibited a shallower slope in the target absent condition, indicating that they terminated search earlier. These results suggest that under conditions of high background noise, medicated PD patients were primarily impaired in decision and/or response processes downstream from the target search itself, and that the deficit was attenuated when top-down information was available to guide selection of the target signal.

Extended habit training reduces dopamine mediation of appetitive response expression.

A wide range of behaviors is impaired after disruption of dopamine (DA) transmission, yet behaviors that are reflexive, automatic, or elicited by salient cues often remain intact. Responses triggered by strong external cues appear to be DA independent. Here, we examined the possibility that a single behavior may become DA independent as a result of extended training. Rats were trained to execute a head-entry response to a cue signaling food delivery. Vulnerability of the response to D1 or D2 receptor blockade was assessed on day 3, 7, or 17 of 28-trial-per-day training. During the early stages of training, the D1 receptor antagonist R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SCH 23390) increased response latencies; however, the same behavior was unaffected by SCH 23390 in animals tested during the later stages of training. Other aspects of behavior such as locomotion and head-entry responses during the uncued intertrial interval remained vulnerable to SCH 23390 throughout the experiment. This D1-mediated response was unaffected by the D2 antagonist raclopride, even at a dose that strongly suppressed locomotion. The results provide strong evidence that a D1-dependent behavior becomes less dependent on DA with extended training. A number of fundamental neurobiological changes occur as behaviors become learned habits; at least for some responses, this change involves a shift from D1-mediated to D1-independent responding.