Antagonists of N-methyl-d-aspartate receptor partially prevent the development of cocaine sensitization

Behavioral sensitization to cocaine was tested for in rats pretreated with MK-801, a noncompetitive ^À/-methyl-D-aspartate (NMDA) receptor antagonist, or D-3-(2-carborypiperaan-4-yl)-l-propenyl-l-phosphonic acid (D-CPPene), a competitive NMDA antagonist. A 5-day regimen of once-daily ssç¡ine (15 mglkg) injections yielded sensitization to cocaine (15 mglkg)-induced behavioral activation. Cocaine sensitiz¿tion lilas partially prevented by MK-801 (0.25 m/kg) or D-CPPene (2A mdks) pretreatment. These rezults differ from previous reports that NMDA receptor antagonists completely prevented tåe development of stimulant sensitization. While raising questions about methodological differences among laboratories studying this iszue, our findings suggest that sensitization may involve mechanisms dependent on NMDA-receptor function as well as NMDA receptor-independent mechanisms

Amphetamine-Induced Excitations Predominate in Single Neostriatal Neurons Showing Motor-Related Activity

Neostriatal single-unit activity was recorded in freely moving rats. A majority (62%) of the 24 recorded neurons were activated during motor behavior such as locomotion (n = 11) or head movements (n = 4). The behavioral response to amphetamine (1.0 mg/kg) was associated with increases (n = 17) or decreases (n = 7) in firing rate. A significantly greater proportion of motor-related neurons were excited by the drug compared to nonmotor-related cells. These results, which confirm the heterogeneity of amphetamine-induced effects in the neostriatum, indicate that the baseline motor-response characteristics of neostriatal neurons may determine their response to amphetamine

Bilateral Cortical Ablations Attenuate Amphetamine-Induced Excitations of Neostriatal Motor-Related Neurons in Freely Moving Rats

Single-unit recordings from neostriatal neurons showing movement-related excitations were obtained in freely moving, cortically ablated rats and sham-lesioned controls. d-Amphetamine (AMPH, 1.0 mg/kg s.c.) increased neuronal activity relative to resting baseline firing rates in both groups of animals, but cortical ablation significantly attenuated this effect. A behavioral clamping analysis, which compared neuronal activity during identically rated pre- and post-AMPH behaviors, revealed that: (a) AMPH enhanced movement-related neuronal activity in sham-lesioned controls, but not in cortically ablated rats; and (b) the drug-induced neuronal activation in control rats was not simply secondary to the behavioral activation produced by AMPH. In contrast to its neuronal effects, cortical ablation did not affect ratings of AMPH-induced locomotion, rearing, or head movements, though sniffing scores showed a postive correlation with lesion size. Thus, corticostriatal projections are critically involved in AMPH-induced excitations of neostriatal motor-related neurons

Cortical Lesions Attenuate the Opposing Effects of Amphetamine and Haloperidol on Neostriatal Neurons in Freely Moving Rats

Neuronal activity was recorded from the neostriatum of freely moving rats at least 1 week following either sham or bilateral ablations of frontal and somatosensory cortex. In both groups of animals, the majority of neurons increased firing rat in close temporal association with spontaneous movement. No group differences emerged either with respect to baseline firing rates or open-field behavior. Following amphetamine administration, however, the excitatory response of motor-related neurons was suppressed in cortical-lesioned rats. A behavioral clamping procedure, which assessed neuronal activity during matched pre- and post-amphetamine behaviors, confirmed these results, suggesting that the amphetamine-induced changes in neuronal activity reflect a direct drug effect independent of behavioral feedback. In animals that received a subsequent injection of 1.0 mg/kg haloperidol, cortical lesions attenuated the ability of this neuroleptic to block both the behavioral and neuronal effects of amphetamine. Collectively, these results support mounting evidence for an important modulatory influence of cortical afferents on the amphetamine-induced excitation of neostriatal neurons and the reversal of this effect by haloperidol

Striatal single-unit responses to amphetamine and neuroleptics in freely moving rats

Single-unit recordings from 50 striatal neurons in freely moving rats revealed generally low activity (\u3c3 spikes\u3e/sec) during resting behavior and movement-related excitations in most (n = 36) neurons. While activating behavior, d-amphetamine (1.0 mg/kg, sc) usually excited and inhibited motor- and nonmotor-related neurons, respectively, relative to resting baseline firing rates. A behavioral clamping analysis, which controlled for neuronal effects secondary to behavior, yielded results suggesting a primary, amphetamine-induced excitation of striatal motor-related neurons. Haloperidol (0.1–1.0 mg/kg) strongly inhibited behavior and neuronal activity when injected 30 min after amphetamine. Clozapine (5.0–30.0 mg/kg) inhibited only selected behaviors, but reliably produced haloperidol-like reversals of amphetamine-induced neuronal excitations. A literature review revealed that the neuronal results in behaving animals differ markedly from the inhibitory striatal responses to amphetamine and the excitatory responses to dopamine antagonists often found in immobilized or anesthetized rat preparations. These contrasting, preparation-dependent results support a model based on drug interactions with a proposed neuromodulatory function of striatal dopamine, which is to facilitate or attenuate the activity of neurons receiving, respectively, substantial, or little excitatory afferent input

Amphetamine effects on striatal neurons: implications for models of dopamine function

HARACZ, J. L., J. T. TSCHANZ, Z. WANG, K. E. GRIFFITH AND G. V. REBEC. Amphetamine effects on striatal neurons: Implications for models of dopamine function. NEUROSCI BIOBEHAV REV 22(5) 613–622.—Models of dopamine function based on the bidirectional neuromodulation of afferents [40, 95] were tested by determining whether cortical ablation would affect the excitatory and inhibitory effects of amphetamine (AMPH) on striatal neurons in freely moving rats. By minimizing pre- and post-AMPH behavioral differences, behavioral clamping revealed that cortical ablation blocked the capacity of AMPH to produce a net excitation of striatal neurons that had shown AMPH-induced excitations under non-clamping conditions. Cortical ablation did not affect AMPH-induced neuronal inhibitions under behavioral clamping conditions. These results suggest that AMPH, possibly by enhancing dopaminergic neuromodulation, facilitates or inhibits the activity of neurons that respectively receive substantial or little cortical input. Thus, the findings support models that assign dopamine the capacity to increase the gain of neuronal information processing. Basic research relevant to these models is reviewed and potential clinical implications are discussed