Ventral Tegmental Area Dopamine Neurons

Glutamate plays an important role in stimulating catecholamine release at the somatic level. Disturbances at the level of the dopamine cell body may occur at a very early stage of development, giving rise to subsequent impaired dopamine neuron function in terminal areas such as the nucleus accumbens. The development of ADHD symptoms could be analogous to the process of drug addiction. Children who have been exposed prenatally to drugs of abuse exhibit ADHD-like behavior (66). Exposure to drugs of abuse increases the extracellular dopamine concentration, which activates D1- and D2-like receptors in the ventral tegmental area of the midbrain, which in turn increases glutamate-driven activity in dopamine-containing neurons (67). The mechanism is suggested to involve increased AMPA receptor-mediated excitatory transmission in ventral tegmental area dopamine neurons (67,68). Increased activation by glutamate initially causes sensitization of ventral tegmental dopamine neurons with subsequent adaptations in the nucleus accumbens (68). The increased glutamate drive is suggested ultimately to lead to pathophysiological conditions associated with high intracellular concentrations of Ca2+, which gives rise to impaired function of ventral tegmental dopamine neurons consistent with adaptation (68). Similarly, ADHD symptoms may result from adaptation to initially increased extracellular dopamine in the ventral tegmental area of the mid-brain at a very early stage of development, giving rise to increased glutamate drive and subsequent loss of function of dopamine neurons.

Inappropriate activation of ventral tegmental dopamine neurons by glutamate afferents from the prefrontal cortex or other excitatory inputs could have increased dopamine release from ventral tegmental dopamine neurons at an early stage of development, giving rise to sensitization and subsequent impairment of ventral tegmental dopamine neuron function.

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Summary of Major Differences Between SHR and WKY

Authors names

Date SHR age

Test used

Differences between SHR and WKY

Knardahl S, 1979 6 wk

Sagvolden T Myers MM, 1981 Whittemore SR, Hendley ED

Open-field exploration

6 and 10 wk Norepinephrine uptake and receptor binding studies

Linthorst ACE, 1990 4, 8, and Van Den 12 wk

Linthorst ACE, 1991 De Lang H, De Jong W, et al.

Sagvolden T, 1992 Hendley ED, Knardahl S

1990 adult

6-7 wk, adults

Wultz B, Sagvolden T

1992 adult

In vitro superfusion

In vitro superfusion

Trans-striatal brain dialysis

Free- and forced-exploration in open-field, plus multiple fixed-interval schedules of reinforcement/ extinction

Differentially reinforced immobility requiring the rat to remain immobile at a particular place in an operant chamber in order to obtain a reinforcer

SHRs gradually became more active than controls

SHRs have greater rates of norepinephrine uptake and decreased P-adrenergic receptor density in the frontal cortex

Decreased electrically stimulated release of [3H]dopamine from SHR caudate slices. Nomifensine did not influence the difference in release between SHR and WKY

Inhibitory effect of a2-adrenoceptor agonist on [3H]norepinephrine release from the medulla oblongata slices of SHR significantly less than WKY

Extracellular striatal dopamine concentration was lower in SHR. D2 receptor inhibition of dopamine release was greater in SHR

SHRs were more active than controls in the open field. SHRs emitted more lever presses during the extinction component of the schedule than controls. SHRs became more active toward the end of the session

SHRs received more reinforcers than controls as long as the schedule did not require long periods of immobility. The total number of movements on target of SHRs increased as the schedule requirements increased.

Authors names

Date SHR age

Test used

Differences between SHR and WKY

Sagvolden T, 1992 Metzger MA, Schi0rbeck HK, et al.


Mook DM, Jeffrey J, Neuringer A

1993 adult

Sagvolden T, 1993 Pettersen MB, Larsen MC


Kirouac G, 1993 5 and 15 Ganguly P wk

Linthorst AC, 1994 10 wk van

Giersbergen PL, Gras M, et al.

Versteeg HG

Multiple fixed-interval extinction schedules of reinforcement

Rewarded 12-arm radial maze

Free- and forced-exploration plus two-component multiple schedules of reinforcement with a fixed interval 2 min signaled by houselight on and a 5-min extinction signaled by houselight off.

D1 and D2 receptor autoradiography

High-performance liquid chromatography (HPLC)

In vitro and in vivo release of dopamine

Psychomotor stimulants weakened control by immediate reinforcers and strengthened control by delayed reinforcers

SHRs varied their choices more, making fewer repetition errors than WKYs. When rewards depended on variable sequences of responses on two levers in an operant chamber, SHRs' sequences were more variable than those of WKYs. WKYs learned to repeat more readily than the SHRs

SHRs were more active than WKYs in free exploration and forced exploration open field tests. SHRs were not overactive initially but activity increased toward the end of the extinction period

Increased D1 receptor density at 5 and 15 wk of age, increased D2 receptor density at 5 wk of age

Homovanillic acid (HVA) and the ratios DOPAC/dopamine and HVA/dopamine were lower in sham-treated SHR than in sham-treated WKY

No difference in blood pressure at 4 wk of age. Decreased release of [3H]dopamine from SHR caudate slices of 4-wk-old SHRs. Decreased extracellular concentration of dopamine in caudate of 8-wk-old SHRs

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Authors names

Date SHR age

Test used

Differences between SHR and WKY

Russell VA, de Villiers A, Sagvolden T, et al.

1995 12-14 wk

De Villiers A, 1995 12-14 wk Russell VA, Sagvolden T, et al.

Horn JL, 1995 adult

Janicki PK, Franks JJ

Papa M, 1996 6 wk

Sagvolden T, Sergeant JA, et al.,

Watanabe Y, 1997 2 and 15 Fujita M, Ito Y, wk et al.

Thibault C, 2 wk,

Anand Srivastava MB 4 wk, and 8 wk

Papa M, Sergeant JA, Sadile AG

Papa M, Sergeant JA, Sadile AG

1997 6 wk

1998 6 wk

In vitro superfusion

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