Richard J. Beninger

The Role of Dopamine in Locomotor Activity and Learning

The discovery that the brain contains neurons utilizing dopamine (DA) as their transmitter has led to studies of the behavioral function of these neurons. Changes in overall level of activity of DA neurons appear to produce parallel changes in locomotor activity. Additionally, DA neurons seem to mediate in part the effects of biologically significant (reinforcing) stimuli on learning. One way in which reinforcing stimuli produce learning is to increase the incentive motivational (response-eliciting) properties of neutral stimuli associated with them; also, reinforcing stimuli maintain the incentive motivational properties of previously conditioned incentive stimuli. Normal DA functioning appears to be required for the establishment and maintenance of incentive learning in naive animals. Previous incentive learning in trained animals can influence behavior for a time even when the function of DA neurons is disrupted; however, with continued testing in the absence of normal DA functioning, previously established conditioned incentive stimuli cease to influence behavior. From these observations and recent physiological, anatomical and biochemical studies of DA systems it is suggested that the biological substrate of DA-mediated incentive learning is a heterosynaptic facilitation of muscarinic cholinergic synapses. This model has important clinical implications since it has been suggested that DA hyperfunctioning underlies the development of schizophrenia.

Dopamine D1-like receptors and reward-related incentive learning.

There now is general agreement that dopaminergic neurons projecting from ventral mesencephalic nuclei to forebrain targets play a critical role in reward-related incentive learning. Many recent experiments evaluate the role of dopamine (DA) receptor subtypes in various paradigms involving this type of learning. The first part of this paper reviews evidence from these studies that use antagonists or agonists relatively specific for D1- or D2-like receptors in operant paradigms with food, brain stimulation, self-administered stimulant or conditioned rewards or place conditioning. The focus is on studies that directly compare agents acting at the two DA receptor families, especially those studies where the agents produce differential actions. Results support the conclusion that D1-like receptors play a more critical role in reward-related learning than D2-like receptors. D1-like receptors initiate a cascade of intracellular events including cyclic adenosine monophosphate (cAMP) formation and activation of cAMP-dependent protein kinase (PKA). The final section of this paper reviews evidence from a wide range of neuroscience experiments that implicates the cAMP/PKA pathway in learning in general and in reward-related incentive learning in particular. We conclude that the molecular mechanism underlying DA-mediated incentive learning may involve DA release in association with reward, stimulation of D1-like receptors, activation of the cAMP/PKA cascade and additional intracellular events leading to modification of cortico-striatal glutamatergic synapses activated by stimuli encountered in close temporal contiguity with reward. Thus, when reward-related incentive learning takes place, it may be the action of DA acting at D1-like receptors that leads to plastic changes in the striatum that form the substrate of that learning.

The cannabinoid CB1 receptor antagonist SR141716A attenuates the memory impairment produced by Δ9-tetrahydrocannabinol or anandamide

Abstract The administration of Δ9-tetrahydrocannabinol (THC), the principle psychoactive ingredient in marijuana, or the endogenous cannabinoid anandamide, has been shown to impair recent memory. The purpose of the present investigation was to determine if the cannabinoid CB1 receptor antagonist SR141716A could attenuate THC- or anandamide-induced memory impairment, and to assess the effects on memory of SR141716A alone. Memory was assessed in rats well-trained in a two-component instrumental discrimination task, consisting of a conditional discrimination, and a non-match-to-position to assess recent or working memory. SR141716A (0.0–2.0 mg/kg) had no effect on either the conditional discrimination or the non-match-to-position. However, SR141716A (0.0–2.0 mg/kg) attenuated the memory impairment produced by THC (2.0 or 4.0 mg/kg) as indexed by an enhancement of performance in the non-match-to-position. When administered to rats pretreated with anandamide (2.0 mg/kg), SR141716A (0.0–2.5 mg/kg) impaired performance in the conditional discrimination at the highest dose. This was interpreted as a deficit in some capacity unrelated to memory (e.g., motor impairment). However, lower doses of SR141716A (0.1 and 0.5 mg/kg) attenuated the anandamide-induced impairment of performance in the non-match-to-position without affecting the conditional discrimination. This is the first report that the memory impairment produced by anandamide can be attenuated by a cannabinoid antagonist; results suggest that anandamide-induced memory disruption is mediated by CB1 receptors.

Pimozide blocks establishment but not expression of cocaine-produced environment-specific conditioning

Two experiments were conducted to examine the effects of pimozide on cocaine-produced conditioning to a specific environmental context. On 8 treatment days, 12 rats were injected with cocaine (10 mg/kg i.p.) and 12 with saline prior to placement for 60 min into a test chamber outfitted with infrared emitters and detectors. Following each treatment session the saline group received cocaine in their home-cages and the cocaine group received saline. Cocaine produced a significant increase in vertical activity on treatment days. On test days all rats received saline. Significantly greater vertical activity was observed in the group previously receiving cocaine in the test environment. All rats then received 8 more treatment sessions. On saline test days, pimozide (0.4 mg/kg i.p.) pretreatment failed to antagonize expression of the conditioned effect. In experiment 2, pimozide was given prior to treatment and no evidence of conditioning was seen on saline test days. Thus, pimozide blocked the establishment but not the expression of cocaine-produced environment-specific conditioning. These results suggest that during conditioning, the effects of cocaine on dopaminergic neurons may have produced a change that subsequently influenced behaviour even when dopaminergic systems were blocked.

Differential Effects of Scopolamine on Working and Reference Memory of Rats in the Radial Maze

Anticholinergics have often been found to impair choice accuracy in the radial maze. Some researchers have suggested that this indicates involvement of cholinergically innervated structures in cognitive mapping while others argue that these structures mediate working memory. However, most results are open to either interpretation since the baiting method did not allow a distinction between reference and working memory errors. To further test these hypotheses this study examined the effects of systemic scopolamine on radial maze performance, using a 4-out-of-8 baiting procedure. Food-deprived Wistar rats were pretrained until working memory choice accuracy stabilized to a criterion of 87% or better. Scopolamine (0.1, 0.4 and 0.8 mg/kg, IP, 30 min before a session) significantly increased the number of working memory errors (re-entries into baited arms) whereas reference memory errors (entries into never baited arms) did not change significantly. Observed deficits appeared not to be attributable to a drug-induced disruption of motivational systems. Results confirm the behavioural similarities between the memorial effects of hippocampectomy and anticholinergics, and implicate cholinergically innervated structures in working memory.

Depressive Symptoms in Parkinson's Disease: A Comparison With Disabled Control Subjects

A high incidence of depressive symptoms has been observed in patients with Parkinsons disease (PD). PD involves a loss of central monoamines, and a decrease of monoamines has been implicated in depression; therefore, it is possible that depressive symptoms in PD result from the loss of endogenous neurotransmitters. However, it is equally possible that depressive symptoms represent a reaction to the chronic disabling course of PD. By comparing depressive symptoms in PD patients to those in matched patients with other chronic disabling diseases not involving a loss of central monoamines, it may be possible to decide between these alternatives. Thus, depressive symptoms were assessed in 45 patients with PD and 24 disabled controls that did not differ from the PD subjects on a measure of functional disability. Results showed that PD subjects obtained significantly higher total scores on the Beck Depression Inventory (BDI) than controls. PD subjects scored significantly higher than controls on BDI items grouped to reflect cognitive-affective and somatic depressive symptoms. The BDI scores of PD subjects were not reliably related to age, sex, duration of PD, or clinical ratings of PD symptom severity or functional disability. Self-rated disability and the number of recent medical problems were the greatest predictors of depressive symptoms. These findings supported the hypothesis that depressive symptoms in PD may not represent solely a reaction to disability. (J Geriatr Psychiatry Neurol 1989; 2:3-9).

The effect of pimozide on the establishment of conditioned reinforcement

The effect of pimozide on conditioned reinforcement was determined by comparing rate of lever pressing for a tone in groups previously treated with or without the drug when the tone was paired with food. Eight groups of six to eight rats each received three phases of training in a two-lever box. The pre-exposure phase measured the operant rate of pressing the two levers, one of which produced a 3 s tone. In the conditioning phase, with the levers absent, the tone was paired with food over four sessions. The test phase again measured the rate of pressing the two levers. In an undrugged experimental group (i.e., Paradigm group), the number of presses on the tone lever significantly increased from the pre-exposure to the test phase, thereby confirming that the procedure could establish conditioned reinforcement. A control group receiving tones and pellets randomly during the conditioning phase also showed conditioned reinforcement but a group receiving negatively correlated tones and pellets did not. Groups receiving the dopamine-receptor blocker pimozide (1.0 mg/kg) prior to each conditioning session failed to show conditioned reinforcement in the test session. Control groups ruled out state dependent learning and drug-induced performance impairments as explanations of this pimozide-related effect. These data may indicate a possible role for dopamine neurons in mediating the control of behavior by certain positive reinforcing stimuli.

Pimozide-induced suppression of responding: evidence against a block of food reward.

Male albino rats injected with 0.5 or 1.0 mg/kg pimozide showed a decline in the rate of lever pressing on a continuously reinforced schedule for food reward. A similar decline was seen when responding was no longer reinforced (extinction). On this basis, Wise et al. [15] have previously hypothesized that pimozide blocks the reinforceing effects of the food pellets. However, in the present experiments the effects of pimozide were found to be additive with those of extinction so that animals treated with pimozide and placed into extinction ceased responding more quickly than animals subjected to either manipulation on its own. In addition, the effects of one condition failed to transfer to the other condition so that animals exposed to three days of pimozide failed to show a further decline when exposed to a day of extinction under vehicle and vice versa. Similar additivity and failure of transfer were seen on a DRL schedule for food reward; however, using this schedule pimozide failed to produce a decline in reinforced responding. In a further experiment pimozide failed to mimic extinction by blocking the reinforcing effects of food so as to cause a partial reinforcement extinction effect in a runway. It is concluded that these effects of pimozide on operant behavior are not mediated by block of reward.

Dopaminergic substrates of cocaine-induced place conditioning

Recently, Spyraki et al. (Brain Research, 253 (1982) 195-203) reported that cocaine-induced place preference conditioning was unaffected by blockade of central dopamine (DA) or norepinephrine function. In addition, systemic injections of the local anesthetic procaine produced place preference conditioning. The present study was undertaken to further evaluate the possible role of DA in cocaine-induced place conditioning. In Expt. 1, a partial replication of Spyraki et al., systemic cocaine (5.0 mg/kg, i.p.) produced significant place conditioning that was not disrupted with the DA antagonist pimozide (1.0 mg/kg, i.p.). In Expt. 2, cocaine was microinjected unilaterally into the lateral ventricles to eliminate peripheral local anesthesia. Cocaine (50.0 micrograms, i.c.v.) produced place conditioning and pretreatment with pimozide (1.0 mg/kg, i.p.) disrupted the effect. In Expt. 3, place conditioning was not observed when cocaine presentations (50.0 micrograms, i.c.v.) were paired with both compartments. The substrates of cocaine-induced place conditioning were further investigated in Expt 4: Procaine (250 micrograms, i.c.v.) did not produce place conditioning whereas the DA agonist bromocriptine (50.0 micrograms, i.c.v.) did. Results suggest the involvement of central DA in cocaine-induced place conditioning.

Typical and atypical antipsychotic medications differentially affect two nondeclarative memory tasks in schizophrenic patients: a double dissociation

Nondeclarative memory (NDM) has subtypes associated with different brain regions; learning of a probabilistic classification task is impaired by striatal damage and learning of a gambling task is impaired by ventromedial prefrontocortical damage. Typical and atypical antipsychotic medications differentially affect immediate early gene expression in the striatum and frontal cortex in normal rats. This suggested the hypothesis that schizophrenic patients treated with typical antipsychotics will have impaired probabilistic classification learning (PCL) and that similar patients treated with atypical antipsychotics will have impaired learning of the gambling task. Groups of schizophrenia patients treated with typical or atypical antipsychotics did not differ from each other on the Brief Psychiatric Rating Scale (BPRS), Mini Mental State Exam (MMSE) or a number of indexes of the Wisconsin Card Sorting Task (WCST) but performed worse than normal controls on these instruments. In the first study, patients treated with typicals (n=20) but not atypicals (n=20) or normal controls (n=32) were impaired in probabilistic classification. In the second study, those treated with atypicals (n=18) but not typicals (n=18) or normal controls (n=18) were impaired in the gambling task. Results suggest that typical and atypical antipsychotics differentially affect nondeclarative memory mediated by different brain regions.