Charles D. Blaha

Sexual behavior enhances central dopamine transmission In the male rat

Central dopamine transmission was examined in the nucleus accumbens and striatum of sexually experienced male rats during mating behaviour using in vivo brain microdialysis. Dopamine release increased significantly in the nucleus accumbens when males were placed in a novel mating chamber and when a receptive female was introduced behind a screen partitioning this chamber. Subsequently, during copulation dopamine transmission increased sharply, this being followed by a gradual decrease after the female was removed. In contrast, striatal dopamine transmission increased significantly only during copulation. These data provide a neurochemical basis for the well-known interactions between dopaminergic drugs and male sexual behaviour and demonstrate the feasibility of using brain microdialysis to elucidate the neurochemical correlates of motivated behaviour.

Stimulation of the Ventral Subiculum of the Hippocampus Evokes Glutamate Receptor-mediated Changes in Dopamine Efflux in the Rat Nucleus Accumbens

The effects of electrical stimulation of the ventral subiculum/CA1 region of the hippocampus on changes in dopamine oxidation current (corresponding to dopamine efflux) in the nucleus accumbens were examined using in vivo chronoamperometry with stearate‐graphite paste electrodes in urethane‐anaesthetized rats. Burst‐patterned monophasic pulses (10–100 Hz/burst delivered at 0.84 Hz) evoked a three‐component change in dopamine efflux in the nucleus accumbens with an initial transient increase in the dopamine signal above baseline, followed by an immediate decrease below baseline, and thereafter by a prolonged increase in the dopamine signal above baseline. 6–Hydroxydopamine lesions of the mesoaccumbens dopamine pathway or transection of the fimbria‐fornix blocked all of the evoked changes in the dopamine signal. Both the first and third components of enhanced dopamine efflux were blocked by microinfusion into the nucleus accumbens of the ionotropic glutamate receptor antagonists (±)‐2‐amino‐5‐phosphonopentanoic acid, 6,7‐dinitroquinoxaline‐2,3‐dione and kynurenate. Burst stimulation‐evoked decreases in the dopamine signal were abolished following microinfusions into the nucleus accumbens of the metabotropic glutamate receptor antagonist (+)‐α‐methyl‐4‐carboxyphenylglycine. These results suggest that ventral subiculum/CA1 glutamatergic inputs to the nucleus accumbens may presynaptically modulate dopamine efflux by synaptic activation of both ionotropic and metabotropic glutamate receptors in the nucleus accumbens. These glutamate‐dopamine interactions may constitute part of the mechanisms by which hippocampal signals are integrated through selective modulation of dopamine release in the nucleus accumbens in both physiological and pathological conditions.

Pre-exposure of rats to amphetamine sensitizes self-administration of this drug under a progressive ratio schedule

Abstract Two groups of male rats were tested to determine whether pre-exposure to d-amphetamine would enhance the motivation to self-administer the drug under a progressive ratio schedule of reinforcement. In the first phase of the experiment, one group of rats received d-amphetamine (2 mg/kg IP), while a second group received saline on alternate days for a total of ten injections. Following a 21-day drug withdrawal period, behavioral sensitization was confirmed by a significant increase in amphetamine-induced stereotypy in the d-amphetamine-pretreated group, relative to the saline-pretreated group. In the second phase of the study, all rats were implanted with chronic jugular catheters and trained to self-administer d-amphetamine (0.2 mg/kg per infusion) under a fixed-ratio schedule of reinforcement. The progressive ratio paradigm was then imposed for 7 consecutive days; d-amphetamine-pretreated rats attained significantly higher break points than saline-pretreated animals. These data suggest that pre-exposure to d-amphetamine may enhance the motivation to self-administer this drug.

Basolateral amygdala stimulation evokes glutamate receptor-dependent dopamine efflux in the nucleus accumbens of the anaesthetized rat

Afferents from the basolateral amygdala and dopamine projections from the ventral tegmental area to the nucleus accumbens have both been implicated in reward‐related processes. The present study used in vivo chronoamperometry with stearate‐graphite paste electrodes in urethane‐anaesthetized rats to determine how basolateral amygdala efferents to the nucleus accumbens synaptically regulate dopamine efflux. Repetitive‐pulse (20 Hz for 10 s) electrical stimulation of the basolateral amygdala evoked a complex pattern of changes in monitored dopamine oxidation currents in the nucleus accumbens related to dopamine efflux. These changes were characterized by an initial increase that was time‐locked to stimulation, a secondary decrease below baseline, followed by a prolonged increase in the dopamine signal above baseline. The effects of burst‐patterned stimulation (100 Hz, 5 pulses/burst, 1‐s interburst interval, 40 s) of the basolateral amygdala on the basal accumbens dopamine signal were similar to those evoked by 20 Hz stimulation, with the lack of a secondary suppressive component. Infusions of the ionotropic glutamate receptor antagonists (±)‐2‐amino‐5‐phosphonopentanoic acid (APV) or 6,7‐dinitroquinoxaline‐2,3‐dione (DNQX) into the nucleus accumbens dose‐dependently blocked or attenuated the initial and prolonged increases in the dopamine signal following 20 Hz or burst‐patterned basolateral amygdala stimulation. Infusions of the metabotropic glutamate receptor antagonist (+)‐α‐methyl‐4‐carboxyphenylglycine selectively blocked the intermediate suppressive effect of 20 Hz basolateral amygdala stimulation on dopamine oxidation currents. Blockade of glutamate receptors or inhibition of dopamine neuronal activity via infusions of either APV + DNQX, lidocaine or γ‐hydroxybutyric acid, respectively, into the ventral tegmental area did not effect the pattern of changes in the accumbens dopamine signal evoked by basolateral amygdala stimulation. These data suggest that the glutamatergic basolateral amygdala inputs to nucleus accumbens dopamine terminals synaptically facilitate or depress dopamine efflux, and these effects are independent of dopamine neuronal firing activity. Moreover, these results imply that changes in nucleus accumbens dopamine levels following presentation of reward‐related stimuli may be mediated, in part, by the basolateral amygdala.

Neurochemical correlates of brain-stimulation reward measured by ex vivo and in vivo analyses

Evidence from ex vivo analyses of dopaminergic function following self-stimulation behavior is reviewed and compared to in vivo analyses of extracellular dopamine measured by chronoamperometry during self-stimulation. Both data bases provide strong support for a dopaminergic substrate for brain-stimulation reward obtained by electrical stimulation of the ventral tegmental area (VTA). Data obtained from in vivo measures of dopamine release are particularly compelling as a positive correlation was observed between the rate/intensity function for self-stimulation and increments in the oxidation current for dopamine. An examination of the effects of the dopamine uptake blockers, cocaine and GBR 12909 on self-stimulation and stimulated release of dopamine revealed a facilitation of both measures. In contrast, the noradrenaline uptake blocker desipramine had no effect on either self-stimulation or extracellular dopamine. These pharmacological experiments also are consistent with a dopaminergic substrate of brain-stimulation reward at electrode sites in the VTA.

CONDITIONED CHANGES IN DOPAMINE OXIDATION CURRENTS IN THE NUCLEUS ACCUMBENS OF RATS BY STIMULI PAIRED WITH SELF-ADMINISTRATION OR YOKED-ADMINISTRATION OF D-AMPHETAMINE

In vivo chronoamperometry was used to monitor changes in dopamine oxidation currents corresponding to dopamine efflux in the nucleus accumbens of rats after presentation of a conditioned light stimulus repeatedly paired with either yoked‐ or self‐administered intravenous injections of the psychostimulant d‐amphetamine. Daily conditioning trials began with a non‐contingent drug injection, paired with a conditioned stimulus consisting of a 5 s flashing light and 30 s lights out, after which a house light was illuminated during the 3 h session, signalling drug availability. Each subsequent injection of d‐amphetamine was paired with the conditioned stimulus. Electrochemical measures were taken on conditioning trials 4–7, and on each trial, intravenous

Increased striatal dopamine efflux follows scopolamine administered systemically or to the tegmental pedunculopontine nucleus

The cholinergic cells of the tegmental pedunculopontine nucleus monosynaptically excite dopaminergic neurons of the substantia nigra. In vivo electrochemical methods were used to monitor dorsal striatal dopamine efflux in awake rats following intraperitoneal scopolamine injections and following the direct application of scopolamine to the tegmental pedunculopontine nucleus. Systemic injections of scopolamine (1.0, 3.0 or 10.0 mg/kg) resulted in dose-related increases in peak striatal dopamine oxidation currents of between 1.1 and 2.0 nA. Increases began within 10-20 min after injection and peaked after 40-90 min. Unilateral microinjections of scopolamine into the tegmental pedunculopontine nucleus (10, 50 or 100 micrograms/0.5 microliter) resulted in dose-related increases in dopamine oxidation currents that peaked 60-90 min postinjection (2.9-5.0 nA). Carbachol (4.0 micrograms/0.5 microliter) injected unilaterally into the tegmental pedunculopontine nucleus 20 min before 100 micrograms tegmental pedunculopontine nucleus scopolamine, or injected bilaterally 20 min before 3.0 mg/kg systemic scopolamine, attenuated the increases produced by scopolamine alone. The carbachol preinjection tests suggest that the effects of both systemic and tegmental pedunculopontine nucleus scopolamine treatments are mediated largely by muscarinic receptors near the tegmental pedunculopontine nucleus. These findings are consistent with the proposal that enhanced activation of substantia nigra dopamine cells results from scopolamine-induced disinhibition of the tegemental pedunculopontine nucleus cholinergic cell group via blockade of their inhibitory autoreceptors.

Effects of neurotensin on dopamine release and metabolism in the rat striatum and nucleus accumbens: Cross-validation using in vivo voltammetry and microdialysis

The effects of the neuropeptide neurotensin on dopamine release and metabolism in the posteromedial nucleus accumbens and anterior dorsomedial striatum of the anesthetized rat were investigated using in vivo chronoamperometry and intracerebral microdialysis techniques. A dose-dependent augmentation of dopamine efflux as evidenced by increases in the chronoamperometric signal was observed in the nucleus accumbens following intracerebroventricular injections of neurotensin. However, neurotensin failed to alter extracellular concentrations of dopamine in the striatum. The selective effects of neurotensin on mesolimbic dopamine neurons were confirmed using in vivo microdialysis. These results demonstrate that neurotensin can selectively enhance the release and metabolism of dopamine in neurons projecting from the ventral tegmental area to the nucleus accumbens.

Pituitary-adrenal and dopaminergic modulation of Schedule-induced polydipsia: behavioral and neurochemical evidence

Five experiments investigated in rats the effects of increasing or decreasing plasma corticosterone levels on schedule-induced polydipsia and dopamine efflux in the nucleus accumbens. The results indicate that the acquisition of schedule-induced polydipsia could be decreased by adrenalectomy, blockade of corticosterone synthesis, or administration of corticosterone. Performance of established schedule-induced polydipsia was also decreased by adrenalectomy. The effects of corticosterone administration on established schedule-induced polydipsia depended on the level of performance. High levels of drinking were enhanced by a high dose of corticosterone, whereas low rates of drinking were increased by a low dose. Similar injections of corticosterone also significantly increased dopamine efflux. The relative involvement of pituitary-adrenal activity and dopamine neurotransmission in the nucleus accumbens in the acquisition and performance of SIP is discussed and related to contemporary hypotheses of schedule-induced behavior.

Application of in vivo electrochemistry to the measurement of changes in dopamine release during intracranial self-stimulation

Stearate-modified graphite paste recording electrodes were acutely or chronically implanted into the nucleus accumbens along with bipolar stimulating electrodes in the ipsilateral ventral tegmental area (VTA). Chronoamperometry was used to monitor changes in electrochemical signals that may correspond to the oxidation of dopamine (DA) during experimenter-administered stimulation (EAS) and intracranial self-stimulation (ICS). Application of EAS to stimulating electrodes in the VTA produced increases in the electrochemical signal in both the anesthetized and conscious preparation. The magnitude of both effects increased as a function of current intensity. Initiation of ICS was also accompanied by an immediate increase in the electrochemical signal. Rate-intensity experiments revealed a corresponding increase in both the ICS rates and the electrochemical signal with successive increases or decreases in current intensity. In subsequent experiments, intraperitoneal injections of DA uptake blockers nomifensine and GBR-12909 produced significant increases in the amplitude of the chronoamperometric signal which corresponded to drug-induced increases in bar press rates. The noradrenergic uptake blocker desipramine had no significant effect on either ICS rates or oxidation current. These data indicate that ICS of the VTA may produce concurrent increases in DA neurotransmission in the nucleus accumbens. The pharmacological studies are consistent with a dopaminergic substrate of brain stimulation reward at electrode sites in the VTA.