BRAIN RESEARCH ELSEVIER Brain Research 674 (1995) 63-74 Research report Chronic administration of ( +)-amphetamine alters the reactivity of midbrain dopaminergic neurons to prefrontal cortex stimulation in the rat Z.-Y. Tong, P.G. Overton *, D. Clark Department of Psychology and Centre for Substance Abuse Research, University of Wales Swansea, SA2 8PP UK Accepted 29 November 1994 Abstract Repeated intermittent administration of (+)-amphetamine produces sensitisation to many of the behavioural effects of the drug. Evidence suggests that excitatory amino acidergic projections from the prefrontal cortex (PFC) to dopaminergic (DA) neurons in the ventral midbrain may be partly involved in the maintenance of sensitisation once induced. The present study was designed to investigate whether chronic amphetamine administration produces any alteration to this input, by assessing the impact of single pulse electrical stimulation of the PFC (0.25 and 0.5 mA) on the extracellular activity of individual midbrain DA neurons in drug and vehicle treated rats. Animals were administered amphetamine according to a schedule known to produce sensitisation (2.5 mg/kg free base, once daily for 6 days; s.c.), and the effect of PFC stimulation was assessed on withdrawal days 2 and 10. In addition to single spike firing patterns, the ability of the stimulation to elicit stimulus bound (time-locked) burst events was also noted. In the majority of cases, the elicited responses could be broadly categorised into two types -- ones characterised by an initial excitation (E responses) and ones characterised by excitiation following an initial inhibition (IE responses). On withdrawal day 2, IE responses were affected such that, in those responses which contained time-locked bursts in their excitatory phases, the stimulus produced a time-locked burst on a greater percentage of trials. On withdrawal day 10, the principal change was that E responses were more likely to occur in amphetamine-treated animals than controls (0.25 mA; 57.1% vs. 41.2% of responses, respectively; 0.5 mA; 36.7% vs. 23.5% of responses, respectively). It is argued that an increase in the proportion of excitatory responses in drug animals indicates a potentiation of the excitatory drive to the DA neurons. Insofar as sensitisation in the longer term relies upon an enhancement of amphetamine-induced dopamine release in the forebrain, this may be one mechanism by which it is achieved. Keywords: Electrical stimulation; Prefrontal cortex; Dopaminergic neurons; Synaptic plasticity; Sensitisation 1. Introduction Repeated intermittent administration of (+)- amphetamine produces sensitisation to many of the behavioural effects of the drug. Sensitisation is mani- fest as a long lasting enhancement of certain be- havioural responses (e.g. locomotion) to the same dose of amphetamine, or lower, in drug-treated animals relative to controls, after various periods of withdrawal (see [29] for a review). The production of long-lasting changes in response implies that alterations have taken place at the neuronal level, although the substrate of the changes involved in sensitisation is still largely undetermined. However, pharmacological dissimilari- * Corresponding author. Fax: (44) (792) 29-5679. 0006-8993/95/$09.50 © 1995 Elsevier Science B.V. All rights reserved SSDI 0006-8993(94)01439-6 ties between the induction and maintenance of the enhanced response (see below) implies that different mechanisms may be involved at different points in the sensitisation process. Behavioural studies have implicated the ventral tegmental area (VTA) and the substantia nigra pars compacta (SNPc) as the sites of the changes in neu- ronal function which underlie the induction of sensiti- sation to amphetamine (although the VTA has been more extensively studied in this regard). Hence, micro- injection of amphetamine directly into the VTA pro- duces sensitisation to later systemic challenge with the drug, whereas sensitisation is not produced if am- phetamine is microinjected into the neostriatum or nucleus accumbens [16], which are projection targets of the A10 dopaminergic (DA) system, the principal out-